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Remicade to infliximab biosimilar switches fare well in real-life practice
GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.
A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.
CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.
In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.
In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.
“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.
Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).
There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.
Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).
There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).
Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.
A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.
Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”
Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.
GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.
A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.
CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.
In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.
In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.
“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.
Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).
There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.
Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).
There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).
Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.
A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.
Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”
Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.
GLASGOW – Switching patients on the anti–tumor necrosis factor drug Remicade to a biosimilar infliximab product resulted in good efficacy and tolerability with substantial cost savings in two real-world studies from the United Kingdom.
A total of 52 (88%) of 59 patients who had switched to the biosimilar infliximab CT-P13 (Inflectra) for the treatment of various indications for which Remicade is approved remained on the biosimilar after 10 months of follow-up and experienced comparable adverse events and similar levels of efficacy before and after switching, Dr. Lucy Parker of University Hospital Southampton NHS Foundation Trust reported at the British Society for Rheumatology annual conference. A second smaller study reported at the conference also showed similar results with the same infliximab biosimilar, which is also marketed as Remsima in Europe.
CT-P13 had efficacy, immunogenicity, and pharmacokinetic and pharmacodynamic parameters comparable to Remicade in 1-year follow-up data from the phase III randomized PLANETRAstudy (Arthritis Res Ther. 2016;18:82. doi: 10.1186/s13075-016-0981-6), but whether these study findings hold in a routine practice setting remains to be determined, Dr. Parker noted.
In Dr. Parker and colleagues’ study of data from the Southampton Biological Therapies Review Service, every patient was initially “seen in clinic and had the opportunity to speak to their consultant rheumatologist about the potential switchover from the originator drug to the new version,” she explained. Patients were then contacted directly by letter to explain the potential switch and given an information leaflet on Inflectra. They were also given access to a dedicated helpline number that could be used to re-explain the switch and discuss any concerns after switching had occurred.
In May 2015, all 59 patients being treated with Remicade were gradually switched over to the biosimilar version. Patients were reviewed after 3 months and then at 6-month intervals.
“Every single patient agreed to switch,” Dr. Parker observed. No patient used the helpline service or asked to talk with the consultant rheumatologist. One delegate noted during discussion that it was impressive that all patients agreed to switch, but Dr. Parker suggested that it was probably important that people were invited to switch rather being told that they would be switched. “If anyone had refused, then they would have been kept on Remicade,” she observed.
Dr. Parker noted that the patients were taking Remicade for various rheumatologic conditions, including 29 with rheumatoid arthritis (RA), 14 with ankylosing spondylitis (AS), 14 with psoriatic arthritis (PsA), and 2 with enteropathic arthritis. The mean age was 58.9 years, 51% of patients were female, mean disease duration was 18 years, and there was a mean of 5.7 years on Remicade before the switch. Patients had been diagnosed an average of 10 years before the first use of a biologic agent, 56% were also taking methotrexate, and 17% were on another disease-modifying antirheumatic drug (DMARD).
There was no significant difference in disease activity before or after switching, with respective mean 28-joint Disease Activity Scores of 3.4 and 3.3 and Bath Ankylosing Spondylitis Disease Activity Index scores of 3.7 and 3.6.
Dr. Parker noted that two 6-month periods before switching were compared to a 6-month period after switching and there were a similarly low number of cases reporting inefficacy, which was defined as any increase in symptoms or disease activity measure. Inefficacy was seen in one patient 12 months before the switch, two patients 6 months before the switch, and three patients after the switch. All three of the latter patients were switched back to Remicade, with one being then further switched to rituximab (Rituxan).
There were four adverse events in patients switched to the biosimilar versus three and four cases in the two 6-month periods before the switch. Adverse events after switching were widespread pain or myalgia and arthralgia after two infusions in two patients with PsA, multiple subjective symptoms such as dizziness and labile blood pressure and forgetfulness in another patient with PsA who also had these symptoms before the switch, and a case of chronic osteomyelitic foot infection in a patient with RA that also predated the switch. Biologic therapy was stopped in the RA patient, one of the PsA patients switched back to Remicade, and the other two were switched to ustekinumab (Stelara).
Dr. Parker reported that switching to the biosimilar has significantly cut the cost of treatment by £197,974 (about $291,000 USD) or 41.5% in their practice.
A team from St. George’s University Hospitals NHS Foundation Trust in London reported in a poster session similar findings after switching 31 patients to Remsima (Rheumatology [Oxford]. 2016;55[suppl 1]:i125-i126). Most switches occurred in RA patients (n = 18), followed by seven with AS and five with PsA. One patient did not switch following a consultant decision after the patient in question developed septic arthritis.
Dr. Ritu Malaiya and associates found equivalent efficacy responses in the vast majority of cases. Only one patient switched back to Remicade. Dr. Malaiya said that their experience of switching was, “on the whole, positive.” Effective planning and education of patients and staff around the switch was again considered vital and “instrumental to our early success,” the team reported. “Overall, patients were keen for others to benefit from more cost-effective drugs.”
Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.
Key clinical point: Both biosimilar versions of infliximab available in Europe appear to be as effective and tolerated as Remicade after switching from it.
Major finding: Of 59 patients who had switched to Inflectra, 88% remained on the biosimilar after 10 months of follow-up.
Data source: Two real-world studies of switching to biosimilar infliximab in the United Kingdom.
Disclosures: Dr. Parker and Dr. Malaiya reported having no financial disclosures. Coauthors of the studies disclosed acting as consultants or receiving research grants from manufacturers of anti-TNF therapies.
Effective psoriasis therapy may reduce coronary plaque burden
CHICAGO – Improvement in psoriasis was associated with a significant reduction in coronary plaque burden within 1 year in a pilot study conducted at the National Heart, Lung, and Blood Institute, Joseph B. Lerman reported at the annual meeting of the American College of Cardiology.
“If you look at psoriatic plaque on the skin, it’s spewing out cytokines such as tumor necrosis factor–alpha and interleukin-17 which are highly linked to atherosclerosis. What we’ve found is that if you treat those plaques and reduce the severity of psoriasis, we’ve noticed small but statistically significant regression in the early noncalcified plaque. It’s a very exciting observation,” said Mr. Lerman, a medical student at Mount Sinai School of Medicine, New York.
He presented an observational study involving 50 consecutive patients with mild to moderate psoriasis of roughly 20 years duration and a median baseline Framingham Risk Score of 4. They underwent measurement of coronary plaque burden by coronary CT angiography at baseline and 1 year later.
During the study year, 33 patients showed significant improvement in their psoriasis as reflected in a decline in their mean Psoriasis Area and Severity Index score from 5.6 to 3.1. Those patients also showed significant improvement in their total and noncalcified plaque burden, with total plaque burden adjusted for luminal attenuation declining from 126 mm2 to 117 mm2. The association remained significant even after adjustment for traditional cardiovascular risk factors, the use of statin therapy, body mass index, and the use of systemic psoriasis therapies, including biologic agents.
Importantly, the reduction in plaque burden appeared to be largely concentrated in the subgroup of 31 patients on methotrexate or a biologic. And while this was a naturalistic observational study, the investigators have followed up with a prospective study of psoriasis patients placed on tumor necrosis factor inhibitors and confirmed that they, too, experienced a reduction in coronary plaque as measured by coronary CT angiography.
The investigators plan to expand the size of the study in order to confirm the findings. Mr. Lerman said the next question they would like to address is, how early does a measurable reduction in coronary plaque burden occur in response to clinical improvement in psoriasis? In order to explore this, the investigators will have to obtain institutional approval of a new investigative protocol which permits more frequent use of coronary CT angiography. At present the imaging study can be conducted only once per year due to the radiation exposure.
Mr. Lerman was involved in the psoriasis study while participating in the National Institutes of Health Medical Research Scholars Program. Senior investigator in the pilot study was Dr. Nehal Mehta, chief of the Section of Inflammation and Metabolic Disease at NHLBI in Bethesda, Md.
Mr. Lerman reported having no financial conflicts of interest.
CHICAGO – Improvement in psoriasis was associated with a significant reduction in coronary plaque burden within 1 year in a pilot study conducted at the National Heart, Lung, and Blood Institute, Joseph B. Lerman reported at the annual meeting of the American College of Cardiology.
“If you look at psoriatic plaque on the skin, it’s spewing out cytokines such as tumor necrosis factor–alpha and interleukin-17 which are highly linked to atherosclerosis. What we’ve found is that if you treat those plaques and reduce the severity of psoriasis, we’ve noticed small but statistically significant regression in the early noncalcified plaque. It’s a very exciting observation,” said Mr. Lerman, a medical student at Mount Sinai School of Medicine, New York.
He presented an observational study involving 50 consecutive patients with mild to moderate psoriasis of roughly 20 years duration and a median baseline Framingham Risk Score of 4. They underwent measurement of coronary plaque burden by coronary CT angiography at baseline and 1 year later.
During the study year, 33 patients showed significant improvement in their psoriasis as reflected in a decline in their mean Psoriasis Area and Severity Index score from 5.6 to 3.1. Those patients also showed significant improvement in their total and noncalcified plaque burden, with total plaque burden adjusted for luminal attenuation declining from 126 mm2 to 117 mm2. The association remained significant even after adjustment for traditional cardiovascular risk factors, the use of statin therapy, body mass index, and the use of systemic psoriasis therapies, including biologic agents.
Importantly, the reduction in plaque burden appeared to be largely concentrated in the subgroup of 31 patients on methotrexate or a biologic. And while this was a naturalistic observational study, the investigators have followed up with a prospective study of psoriasis patients placed on tumor necrosis factor inhibitors and confirmed that they, too, experienced a reduction in coronary plaque as measured by coronary CT angiography.
The investigators plan to expand the size of the study in order to confirm the findings. Mr. Lerman said the next question they would like to address is, how early does a measurable reduction in coronary plaque burden occur in response to clinical improvement in psoriasis? In order to explore this, the investigators will have to obtain institutional approval of a new investigative protocol which permits more frequent use of coronary CT angiography. At present the imaging study can be conducted only once per year due to the radiation exposure.
Mr. Lerman was involved in the psoriasis study while participating in the National Institutes of Health Medical Research Scholars Program. Senior investigator in the pilot study was Dr. Nehal Mehta, chief of the Section of Inflammation and Metabolic Disease at NHLBI in Bethesda, Md.
Mr. Lerman reported having no financial conflicts of interest.
CHICAGO – Improvement in psoriasis was associated with a significant reduction in coronary plaque burden within 1 year in a pilot study conducted at the National Heart, Lung, and Blood Institute, Joseph B. Lerman reported at the annual meeting of the American College of Cardiology.
“If you look at psoriatic plaque on the skin, it’s spewing out cytokines such as tumor necrosis factor–alpha and interleukin-17 which are highly linked to atherosclerosis. What we’ve found is that if you treat those plaques and reduce the severity of psoriasis, we’ve noticed small but statistically significant regression in the early noncalcified plaque. It’s a very exciting observation,” said Mr. Lerman, a medical student at Mount Sinai School of Medicine, New York.
He presented an observational study involving 50 consecutive patients with mild to moderate psoriasis of roughly 20 years duration and a median baseline Framingham Risk Score of 4. They underwent measurement of coronary plaque burden by coronary CT angiography at baseline and 1 year later.
During the study year, 33 patients showed significant improvement in their psoriasis as reflected in a decline in their mean Psoriasis Area and Severity Index score from 5.6 to 3.1. Those patients also showed significant improvement in their total and noncalcified plaque burden, with total plaque burden adjusted for luminal attenuation declining from 126 mm2 to 117 mm2. The association remained significant even after adjustment for traditional cardiovascular risk factors, the use of statin therapy, body mass index, and the use of systemic psoriasis therapies, including biologic agents.
Importantly, the reduction in plaque burden appeared to be largely concentrated in the subgroup of 31 patients on methotrexate or a biologic. And while this was a naturalistic observational study, the investigators have followed up with a prospective study of psoriasis patients placed on tumor necrosis factor inhibitors and confirmed that they, too, experienced a reduction in coronary plaque as measured by coronary CT angiography.
The investigators plan to expand the size of the study in order to confirm the findings. Mr. Lerman said the next question they would like to address is, how early does a measurable reduction in coronary plaque burden occur in response to clinical improvement in psoriasis? In order to explore this, the investigators will have to obtain institutional approval of a new investigative protocol which permits more frequent use of coronary CT angiography. At present the imaging study can be conducted only once per year due to the radiation exposure.
Mr. Lerman was involved in the psoriasis study while participating in the National Institutes of Health Medical Research Scholars Program. Senior investigator in the pilot study was Dr. Nehal Mehta, chief of the Section of Inflammation and Metabolic Disease at NHLBI in Bethesda, Md.
Mr. Lerman reported having no financial conflicts of interest.
AT ACC 16
Key clinical point: Improved PASI scores were linked to regression of early noncalcified coronary plaque.
Major finding: Reduction in skin inflammation in psoriasis patients may cause regression of coronary plaque.
Data source: This prospective study of 50 patients with mild to moderate psoriasis featured precise measurements of coronary plaque burden at baseline and 1 year later.
Disclosures: The study was sponsored by the National Heart, Lung, and Blood Institute. The presenter reported having no financial conflicts of interest.
Secukinumab improves patient-reported outcomes in ankylosing spondylitis
GLASGOW, SCOTLAND – Treatment with the anti–interleukin-17A monoclonal antibody secukinumab improved a range of patient-reported outcome measures in a phase III trial of patients with ankylosing spondylitis.
Physical function, quality of life, fatigue, and work productivity were all significantly improved from baseline after 16 weeks of treatment with secukinumab (Cosentyx) versus placebo, and the effects were sustained for up to 1 year.
“PROMs [patient-reported outcome measures] are increasingly seen as the most important outcome measures [in trials] because of their importance to patients,” and they are very closely related to long-term retention and patients’ overall quality of life, Dr. Paul Emery said at the British Society for Rheumatology annual conference.
The new findings come from the MEASURE 2 study, a randomized, double-blind trial of 219 patients treated with one of two doses of secukinumab (150 mg or 75 mg) or placebo. Around 60% of the patient population was male, 95% were white, with a mean age around 42-44 years.
The primary endpoint data from the trial, which was the proportion of patients with at least as 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) response criteria at 16 weeks, were published recently (N Engl J Med. 2015;373:2534-48) with the results of the MEASURE 1 study. These showed that a significantly higher percentage of patients treated with the recommended dose of 150 mg, given as a subcutaneous injection every week for the first 3 weeks, then every 4 weeks from week 4, achieved ASAS 20 versus placebo (61% vs. 28%, P less than .001). Effects were sustained, with 62.5%-73.8% of patients still at ASAS 20 at 1 year depending on the type of data analysis performed, and 75% of those who switched from placebo at 16 weeks. The highest response rates were seen in patients who had not received prior anti-TNF therapy (82% vs. 60% for prior therapy at 1 year).
Changes in patients’ general and disease-specific quality of life from baseline to week 16 were predefined secondary endpoints assessed in the MEASURE 2 trial and were determined by the Short-Form (SF) 36 Physical Component Score (PCS) and the AS Quality of Life (ASQoL) questionnaire. Other exploratory endpoints included assessment of these measures at 1 year and the effect of treatment on the SF-36 Mental Component Score (MCS), Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue questionnaire, and the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire.
“One of the things about secukinumab is that you do get very fast responses in the things that matter,” said Dr. Emery of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds.
Improvement in SF-36 PCS showed improvement as early as week 4, with a mean increase of 6 points from baseline with secukinumab 150 mg versus only 1.9 points for placebo at week 16, and a sustained improvement of 8 points by 1 year. The minimal clinically important difference (MCID) for change in SF-36 is 2.5 points or more. There was not such a clear-cut difference for the SF-36 MCS, but there was a clinically significant improvement of about 4 points at 16 weeks and 6.5 by 1 year.
There was a significant improvement in quality of life versus placebo measured using the ASQoL instrument, with a mean reduction of 4 points for the recommended dose of secukinumab at 16 weeks versus a 1.4 reduction for placebo, and a 5.23 reduction for secukinumab at 1 year. Here the MCID is a change of 1.8 points, Dr. Emery reported.
The MCID for changes in the FACIT-Fatigue score is 4 points or more and this was passed by secukinumab 150 mg at both 16 weeks, with a change of 8 points versus 3.3 points for placebo, and at 1 year, with an increase of 11.5 points for secukinumab.
Work productivity impairment was also improved with active treatment, with mean changes in the WPAI-GH from baseline to week 16 of –16.36 versus –10.22 for placebo, and a sustained reduction of 21.33 at 1 year. Higher scores on this outcome measure mean that work productivity is more severely affected.
Secukinumab was approved for use in ankylosing spondylitis by the European Medicines Agency in October 2015 and more recently by the Food and Drug Administration in January this year. Its availability could be a potential “game changer” for these patients, Dr. Emery suggested, because its mode of action is different from other available therapies, notably the tumor necrosis factor inhibitors. It could become the treatment of choice for AS patients, partially those with enthesitis and psoriasis, at least before drugs that target interleukin (IL)-23 become available that may be better for addressing the spinal component of the disease, he noted during the Q&A that followed his presentation.
Data on radiographic progression will be presented separately, Dr. Emery noted during discussion. He added that secukinumab “certainly works” to reduce radiographic progression, but whether or not it is better than anti-TNF therapy remains to be seen. Because of the mechanism of action on IL-17A, secukinumab could potentially offer an advantage, he said.
“I think it is a game changer because we’ve had such restricted access to therapy previously,” Dr. Emery said. Now having drugs with two different modes of action is a bonus. Deciding which to use first, and in which patients, is the next issue to address.
Novartis supported the study. Dr. Emery has been a paid consultant to AbbVie, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, UCB, Lilly, Samsung, and Sandoz.
GLASGOW, SCOTLAND – Treatment with the anti–interleukin-17A monoclonal antibody secukinumab improved a range of patient-reported outcome measures in a phase III trial of patients with ankylosing spondylitis.
Physical function, quality of life, fatigue, and work productivity were all significantly improved from baseline after 16 weeks of treatment with secukinumab (Cosentyx) versus placebo, and the effects were sustained for up to 1 year.
“PROMs [patient-reported outcome measures] are increasingly seen as the most important outcome measures [in trials] because of their importance to patients,” and they are very closely related to long-term retention and patients’ overall quality of life, Dr. Paul Emery said at the British Society for Rheumatology annual conference.
The new findings come from the MEASURE 2 study, a randomized, double-blind trial of 219 patients treated with one of two doses of secukinumab (150 mg or 75 mg) or placebo. Around 60% of the patient population was male, 95% were white, with a mean age around 42-44 years.
The primary endpoint data from the trial, which was the proportion of patients with at least as 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) response criteria at 16 weeks, were published recently (N Engl J Med. 2015;373:2534-48) with the results of the MEASURE 1 study. These showed that a significantly higher percentage of patients treated with the recommended dose of 150 mg, given as a subcutaneous injection every week for the first 3 weeks, then every 4 weeks from week 4, achieved ASAS 20 versus placebo (61% vs. 28%, P less than .001). Effects were sustained, with 62.5%-73.8% of patients still at ASAS 20 at 1 year depending on the type of data analysis performed, and 75% of those who switched from placebo at 16 weeks. The highest response rates were seen in patients who had not received prior anti-TNF therapy (82% vs. 60% for prior therapy at 1 year).
Changes in patients’ general and disease-specific quality of life from baseline to week 16 were predefined secondary endpoints assessed in the MEASURE 2 trial and were determined by the Short-Form (SF) 36 Physical Component Score (PCS) and the AS Quality of Life (ASQoL) questionnaire. Other exploratory endpoints included assessment of these measures at 1 year and the effect of treatment on the SF-36 Mental Component Score (MCS), Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue questionnaire, and the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire.
“One of the things about secukinumab is that you do get very fast responses in the things that matter,” said Dr. Emery of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds.
Improvement in SF-36 PCS showed improvement as early as week 4, with a mean increase of 6 points from baseline with secukinumab 150 mg versus only 1.9 points for placebo at week 16, and a sustained improvement of 8 points by 1 year. The minimal clinically important difference (MCID) for change in SF-36 is 2.5 points or more. There was not such a clear-cut difference for the SF-36 MCS, but there was a clinically significant improvement of about 4 points at 16 weeks and 6.5 by 1 year.
There was a significant improvement in quality of life versus placebo measured using the ASQoL instrument, with a mean reduction of 4 points for the recommended dose of secukinumab at 16 weeks versus a 1.4 reduction for placebo, and a 5.23 reduction for secukinumab at 1 year. Here the MCID is a change of 1.8 points, Dr. Emery reported.
The MCID for changes in the FACIT-Fatigue score is 4 points or more and this was passed by secukinumab 150 mg at both 16 weeks, with a change of 8 points versus 3.3 points for placebo, and at 1 year, with an increase of 11.5 points for secukinumab.
Work productivity impairment was also improved with active treatment, with mean changes in the WPAI-GH from baseline to week 16 of –16.36 versus –10.22 for placebo, and a sustained reduction of 21.33 at 1 year. Higher scores on this outcome measure mean that work productivity is more severely affected.
Secukinumab was approved for use in ankylosing spondylitis by the European Medicines Agency in October 2015 and more recently by the Food and Drug Administration in January this year. Its availability could be a potential “game changer” for these patients, Dr. Emery suggested, because its mode of action is different from other available therapies, notably the tumor necrosis factor inhibitors. It could become the treatment of choice for AS patients, partially those with enthesitis and psoriasis, at least before drugs that target interleukin (IL)-23 become available that may be better for addressing the spinal component of the disease, he noted during the Q&A that followed his presentation.
Data on radiographic progression will be presented separately, Dr. Emery noted during discussion. He added that secukinumab “certainly works” to reduce radiographic progression, but whether or not it is better than anti-TNF therapy remains to be seen. Because of the mechanism of action on IL-17A, secukinumab could potentially offer an advantage, he said.
“I think it is a game changer because we’ve had such restricted access to therapy previously,” Dr. Emery said. Now having drugs with two different modes of action is a bonus. Deciding which to use first, and in which patients, is the next issue to address.
Novartis supported the study. Dr. Emery has been a paid consultant to AbbVie, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, UCB, Lilly, Samsung, and Sandoz.
GLASGOW, SCOTLAND – Treatment with the anti–interleukin-17A monoclonal antibody secukinumab improved a range of patient-reported outcome measures in a phase III trial of patients with ankylosing spondylitis.
Physical function, quality of life, fatigue, and work productivity were all significantly improved from baseline after 16 weeks of treatment with secukinumab (Cosentyx) versus placebo, and the effects were sustained for up to 1 year.
“PROMs [patient-reported outcome measures] are increasingly seen as the most important outcome measures [in trials] because of their importance to patients,” and they are very closely related to long-term retention and patients’ overall quality of life, Dr. Paul Emery said at the British Society for Rheumatology annual conference.
The new findings come from the MEASURE 2 study, a randomized, double-blind trial of 219 patients treated with one of two doses of secukinumab (150 mg or 75 mg) or placebo. Around 60% of the patient population was male, 95% were white, with a mean age around 42-44 years.
The primary endpoint data from the trial, which was the proportion of patients with at least as 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) response criteria at 16 weeks, were published recently (N Engl J Med. 2015;373:2534-48) with the results of the MEASURE 1 study. These showed that a significantly higher percentage of patients treated with the recommended dose of 150 mg, given as a subcutaneous injection every week for the first 3 weeks, then every 4 weeks from week 4, achieved ASAS 20 versus placebo (61% vs. 28%, P less than .001). Effects were sustained, with 62.5%-73.8% of patients still at ASAS 20 at 1 year depending on the type of data analysis performed, and 75% of those who switched from placebo at 16 weeks. The highest response rates were seen in patients who had not received prior anti-TNF therapy (82% vs. 60% for prior therapy at 1 year).
Changes in patients’ general and disease-specific quality of life from baseline to week 16 were predefined secondary endpoints assessed in the MEASURE 2 trial and were determined by the Short-Form (SF) 36 Physical Component Score (PCS) and the AS Quality of Life (ASQoL) questionnaire. Other exploratory endpoints included assessment of these measures at 1 year and the effect of treatment on the SF-36 Mental Component Score (MCS), Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue questionnaire, and the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire.
“One of the things about secukinumab is that you do get very fast responses in the things that matter,” said Dr. Emery of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds.
Improvement in SF-36 PCS showed improvement as early as week 4, with a mean increase of 6 points from baseline with secukinumab 150 mg versus only 1.9 points for placebo at week 16, and a sustained improvement of 8 points by 1 year. The minimal clinically important difference (MCID) for change in SF-36 is 2.5 points or more. There was not such a clear-cut difference for the SF-36 MCS, but there was a clinically significant improvement of about 4 points at 16 weeks and 6.5 by 1 year.
There was a significant improvement in quality of life versus placebo measured using the ASQoL instrument, with a mean reduction of 4 points for the recommended dose of secukinumab at 16 weeks versus a 1.4 reduction for placebo, and a 5.23 reduction for secukinumab at 1 year. Here the MCID is a change of 1.8 points, Dr. Emery reported.
The MCID for changes in the FACIT-Fatigue score is 4 points or more and this was passed by secukinumab 150 mg at both 16 weeks, with a change of 8 points versus 3.3 points for placebo, and at 1 year, with an increase of 11.5 points for secukinumab.
Work productivity impairment was also improved with active treatment, with mean changes in the WPAI-GH from baseline to week 16 of –16.36 versus –10.22 for placebo, and a sustained reduction of 21.33 at 1 year. Higher scores on this outcome measure mean that work productivity is more severely affected.
Secukinumab was approved for use in ankylosing spondylitis by the European Medicines Agency in October 2015 and more recently by the Food and Drug Administration in January this year. Its availability could be a potential “game changer” for these patients, Dr. Emery suggested, because its mode of action is different from other available therapies, notably the tumor necrosis factor inhibitors. It could become the treatment of choice for AS patients, partially those with enthesitis and psoriasis, at least before drugs that target interleukin (IL)-23 become available that may be better for addressing the spinal component of the disease, he noted during the Q&A that followed his presentation.
Data on radiographic progression will be presented separately, Dr. Emery noted during discussion. He added that secukinumab “certainly works” to reduce radiographic progression, but whether or not it is better than anti-TNF therapy remains to be seen. Because of the mechanism of action on IL-17A, secukinumab could potentially offer an advantage, he said.
“I think it is a game changer because we’ve had such restricted access to therapy previously,” Dr. Emery said. Now having drugs with two different modes of action is a bonus. Deciding which to use first, and in which patients, is the next issue to address.
Novartis supported the study. Dr. Emery has been a paid consultant to AbbVie, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, UCB, Lilly, Samsung, and Sandoz.
AT RHEUMATOLOGY 2016
Key clinical point: Patient-reported outcome measures were improved by secukinumab and sustained at 1 year.
Major finding: Minimal clinically important differences in multiple PROMs were passed, including the SF-36 PCS and ASQoL.
Data source: The MEASURE 2 phase III, randomized, double-blind, placebo-controlled trial of 219 patients with ankylosing spondylitis treated with secukinumab or placebo.
Disclosures: Novartis supported the study. Dr. Emery has been a paid consultant to AbbVie, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, UCB, Lilly, Samsung, and Sandoz.
After Inflectra’s approval, challenges remain for biosimilars
Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.
Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.
It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.
Labeling questions
It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).
While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.
“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.
Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.
In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”
Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.
Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”
Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.
“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”
“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”
Substitution concerns
Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”
A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.
The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.
Patient costs uncertain
Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.
“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”
The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.
“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.
Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.
“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.
It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”
Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”
Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.
It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”
Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.
Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.
Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.
It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.
Labeling questions
It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).
While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.
“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.
Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.
In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”
Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.
Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”
Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.
“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”
“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”
Substitution concerns
Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”
A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.
The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.
Patient costs uncertain
Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.
“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”
The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.
“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.
Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.
“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.
It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”
Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”
Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.
It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”
Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.
Now that the Food and Drug Administration has approved Inflectra as the first biosimilar version of the anti–tumor necrosis factor-alpha agent Remicade, rheumatologists and patient advocacy groups are taking stock of how it may be used in practice, and what the future holds for biosimilar drugs, with so many questions still unanswered regarding price, substitution, and safety.
Inflectra, approved in early April and given the generic name of infliximab-dyyb under the FDA’s nomenclature for biosimilar products, will have the same indications as Remicade. The agency extrapolated the clinical trial data that Inflectra’s South Korea–based manufacturer, Celltrion, submitted for rheumatoid arthritis and ankylosing spondylitis to all other indications for which Remicade is approved.
It’s currently unclear how the FDA will note which clinical data in Inflectra’s labeling come from Inflectra and which from Remicade, and the same concerns lie with future biosimilar approvals if their results are extrapolated to indications not tested to show biosimilarity in clinical trials.
Labeling questions
It’s concerning to rheumatologists and the patients who will be using them that biosimilars such as Inflectra are not subject to the same pivotal trial experience as the reference biologics on which they are based, according to Dr. Jonathan Krant, section chief of rheumatology for Adirondack Health Systems in Saranac Lake, N.Y., and medical director for CreakyJoints, a community of patients with arthritis and caregivers, and its larger parent nonprofit advocacy organization, the Global Healthy Living Foundation (GHLF).
While the unique regulatory requirements in the biosimilar approval pathway reduce development costs and could potentially make Inflectra’s average wholesale price 30% less than Remicade – as was the case when Inflectra was first on the market in Europe – it’s not known how reduced costs may affect the safety of biosimilars.
“It worries all of us that manufacturers may cut corners to manage the cost constraints imposed by managed care,” Dr. Krant said in an interview.
Given that U.S. rheumatologists don’t have experience with biosimilars, Dr. Krant is anticipating some push back. “I think some physicians are going to fight back and won’t want to prescribe them, even if mandated, because of concerns regarding patient safety,” he said.
In a written statement, Dr. Joan Von Feldt, president of the American College of Rheumatology, welcomed the potential benefits on access to care that cost-saving biosimilars may bring to the U.S. health care system, but also said that “the safety of our patients remains our highest priority. As such, we encourage the FDA to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and the origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.”
Inflectra met the FDA’s “very similar” criteria to be approved as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade, the agency said. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
However, it may not hold true that Inflectra will have the same efficacy and safety for all indications that Remicade had due to potential differences in the mechanism of action through which Remicade exerts its effect across indications, which in this case may apply to the indications for Crohn’s disease and ulcerative colitis.
Health Canada chose not to extrapolate the indications for Inflectra (known as Remsima in Canada) to Crohn’s disease and ulcerative colitis because of “observed differences in the level of afucosylation, Fc-gammaRIIIa receptor binding, and some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays” that could not rule out the possibility that Inflectra and Remicade differ in their ability to induce ADCC. Unlike the other indications for Remicade, Health Canada said “ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases. This position is supported by the observation that certolizumab pegol, another anti-TNF [anti–tumor necrosis factor] that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn’s patients, compared with other anti-TNFs, namely infliximab.”
Other organizations suggest that extrapolation of indications is only appropriate when it is benefiting the patient to the greatest extent possible.
“GHLF is okay with extrapolation of indication unless the mechanism of action for the therapy is either scientifically or therapeutically outdated,” Stephen Marmaras, state and national advocacy manager for the GHLF, said in an interview. “Patients are okay with extrapolating data in order to expedite the approval process as long as you are extrapolating to best in class therapy for a particular indication. What [the GHLF is] saying is we want biosimilars to be an improvement on what we have, not the lowest common denominator. We shouldn’t be extrapolating indications data from products that aren’t considered to be the best product for that indication.”
“If we’re just judging on expediting the approval process for indications that are not considered to be really treated well by this particular drug, you have to always assume that the insurance company is going to go with the lowest common denominator,” he added. “What that could lead to, from a slippery-slope perspective, is the chipping away of the use of cutting-edge therapies.”
Substitution concerns
Inflectra was not approved as interchangeable with Remicade or other infliximab biosimilars. The FDA has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”
A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
One of the biggest concerns that physicians have is that biosimilars will be substituted for the reference products without notification, Dr. Krant said. “State by state we’re looking at potential substitution rules which allow pharmacists to switch out these cheaper molecules for the reference product,” he said, and without timely notification, patients and rheumatologists won’t know whether it was the reference product or a biosimilar that was associated with an adverse event or loss of efficacy.
The ACR and patient advocacy organizations such as the GHLF are against forced switching of patients for nonmedical reasons. Patients’ and rheumatologists’ confidence in biosimilar safety will be key to their uptake and the overall expansion of access to biologics to more patients, Mr. Marmaras said.
Patient costs uncertain
Although rheumatologists hope that with biosimilars’ lower costs, access will expand, there is no guarantee it will do so by saving patients money.
“It’s a common misperception that a 30% decrease in the cost of a several thousand dollar-a-month drug is going to automatically open all the doors to access,” said Dr. Sean Fahey, a rheumatologist in Mooresville, N.C., and chair of the insurance subcommittee of the ACR’s Committee on Rheumatologic Care. “Most of my patients who use biologics do so either through copay cards from the pharmaceutical industry or through Medicare and a secondary [payer] covering their out-of-pocket costs for the infusible biologics. This is clearly saving the system money, which is important no doubt, but unless it’s significantly less expensive, it actually might not change the patient’s out-of pocket [cost] all that much.”
The patient assistance programs from biologics manufacturers that offer copay assistance, access hotlines, and administration benefits could be in jeopardy with the rise of biosimilars. Since the programs are bundled into the average wholesale price of the drug, the savings offered by the reduced wholesale price of biosimilars may squeeze them out, Dr. Krant said.
“There’s going to be a lot of hue and cry from the patients who cannot self-administer or have problems with compliance because of copays in the first place,” he predicted.
Another factor that could affect how much biosimilars such as Inflectra will be used is the amount of rebates or discounts that payers receive directly from the pharmaceutical manufacturers.
“We know for the Medicaid population what the average sales prices are, but for private payers, we don’t know if they’re giving 2%, 5%, 18%; we have no idea what the data are. This could affect how much market share Inflectra gets,” said Dr. Fahey, who is also president of the North Carolina Rheumatology Association.
It may be awhile before Inflectra is available on the U.S. market. In a statement following the approval of Inflectra, Remicade-maker Janssen said the “patents for Remicade remain valid and enforceable until September 2018. A commercial launch of Celltrion’s infliximab-dyyb in advance of this date would be an infringement of our patents, and we intend to defend our intellectual property rights.”
Janssen notes that its patient support program for Remicade “continues to offer a copay card for patients with commercial insurance that reduces the patient out-of-pocket cost to no more than $5 per infusion. Eligible uninsured and underinsured patients may be able to access Remicade through the Johnson & Johnson Patient Assistance Foundation.”
Pfizer, which owns the rights to marketing Inflectra in the United States, did not respond directly to a question about whether it would have a payment assistance program for Inflectra. “While we cannot comment on specific commercialization strategies at this time, we are working to bring these important therapies to market in the U.S. as quickly as possible,” said Rachel Hooper, Director of Public Affairs, West, for Pfizer.
It seems likely that once Inflectra does come to the market, new starts will account for many patients who will use the drug because of the lack of information available about whether there is, or is not, significant risk of immunogenicity with switching or loss of efficacy, Dr. Fahey said. “What is less certain is whether the payers will try to force us to move people from the Remicade brand to the infliximab biosimilar, and what the potential consequences of that is going to be.”
Dr. Krant, Dr. Fahey, and Mr. Marmaras had no relevant disclosures.
Psoriasis tied to abdominal aortic aneurysm in nationwide study
Patients with severe psoriasis were nearly 70% more likely to develop abdominal aortic aneurysms compared with the general population, according to a Danish population-based cohort study.
The findings augment existing evidence linking psoriasis and cardiovascular diseases, wrote Dr. Usman Khalid of Copenhagen University Herlev and Gentofte Hospital, Denmark. The report was published online April 14 in Arteriosclerosis, Thrombosis, and Vascular Biology.
While the mechanisms for the link are unclear, “emerging evidence suggests that AAA is a focal representation of a systemic disease with a distinct inflammatory component, rather than a mere consequence of atherosclerosis,” wrote Dr. Khalid and his associates.
Several case series have linked AAA with other autoimmune disorders, including systemic lupus erythematosus and rheumatoid arthritis, they noted. Their study comprised nearly 5.5 million adults in Denmark between 1997 and 2011. The researchers identified 59,423 patients with mild psoriasis and 11,566 patients with severe psoriasis (Arterioscler Thromb Vasc Biol. 2016 April 14. doi: 10.1161/ATVBAHA.116.307449).
The incidence of AAA in the reference population was 3.72 cases per 10,000 person-years, with an average follow-up period of 14.4 years. In contrast, the incidence of AAA in patients with mild psoriasis was 7.30 cases per 10,000 person-years, and the rate in patients with severe psoriasis was 9.87 cases of per 10,000 person-years, with average follow-up periods of 5.7 years. Both mild and severe psoriasis were significantly associated with AAA after the researchers accounted for age, sex, comorbidities, medications, socioeconomic status, and smoking, with adjusted incidence rate ratios of 1.20 (95% confidence interval, 1.03-1.39) and 1.67 (95% CI, 1.21-2.32), respectively.
The historical view that AAA is caused mainly by atherosclerosis has largely been upended, the researchers noted. Instead, AAA appears to be a multifactorial process involving inflammation, matrix degradation, thrombosis, and aortic wall stress. Furthermore, inflammation in both AAA and psoriasis is centrally mediated by T-helper-17 cells and interleukin-17. Together, the data suggest that shared inflammatory mechanisms link psoriasis and AAA, especially because the association correlates with psoriatic disease activity, they said. “This finding clearly requires independent replication, and the clinical consequences are unclear at present.”
The LEO Foundation and the Novo Nordisk Foundation funded the study. Dr. Khalid had no disclosures. Four coinvestigators reported financial ties with Abbott, Pfizer, AstraZeneca, Bayer, and several other pharmaceutical companies.
Patients with severe psoriasis were nearly 70% more likely to develop abdominal aortic aneurysms compared with the general population, according to a Danish population-based cohort study.
The findings augment existing evidence linking psoriasis and cardiovascular diseases, wrote Dr. Usman Khalid of Copenhagen University Herlev and Gentofte Hospital, Denmark. The report was published online April 14 in Arteriosclerosis, Thrombosis, and Vascular Biology.
While the mechanisms for the link are unclear, “emerging evidence suggests that AAA is a focal representation of a systemic disease with a distinct inflammatory component, rather than a mere consequence of atherosclerosis,” wrote Dr. Khalid and his associates.
Several case series have linked AAA with other autoimmune disorders, including systemic lupus erythematosus and rheumatoid arthritis, they noted. Their study comprised nearly 5.5 million adults in Denmark between 1997 and 2011. The researchers identified 59,423 patients with mild psoriasis and 11,566 patients with severe psoriasis (Arterioscler Thromb Vasc Biol. 2016 April 14. doi: 10.1161/ATVBAHA.116.307449).
The incidence of AAA in the reference population was 3.72 cases per 10,000 person-years, with an average follow-up period of 14.4 years. In contrast, the incidence of AAA in patients with mild psoriasis was 7.30 cases per 10,000 person-years, and the rate in patients with severe psoriasis was 9.87 cases of per 10,000 person-years, with average follow-up periods of 5.7 years. Both mild and severe psoriasis were significantly associated with AAA after the researchers accounted for age, sex, comorbidities, medications, socioeconomic status, and smoking, with adjusted incidence rate ratios of 1.20 (95% confidence interval, 1.03-1.39) and 1.67 (95% CI, 1.21-2.32), respectively.
The historical view that AAA is caused mainly by atherosclerosis has largely been upended, the researchers noted. Instead, AAA appears to be a multifactorial process involving inflammation, matrix degradation, thrombosis, and aortic wall stress. Furthermore, inflammation in both AAA and psoriasis is centrally mediated by T-helper-17 cells and interleukin-17. Together, the data suggest that shared inflammatory mechanisms link psoriasis and AAA, especially because the association correlates with psoriatic disease activity, they said. “This finding clearly requires independent replication, and the clinical consequences are unclear at present.”
The LEO Foundation and the Novo Nordisk Foundation funded the study. Dr. Khalid had no disclosures. Four coinvestigators reported financial ties with Abbott, Pfizer, AstraZeneca, Bayer, and several other pharmaceutical companies.
Patients with severe psoriasis were nearly 70% more likely to develop abdominal aortic aneurysms compared with the general population, according to a Danish population-based cohort study.
The findings augment existing evidence linking psoriasis and cardiovascular diseases, wrote Dr. Usman Khalid of Copenhagen University Herlev and Gentofte Hospital, Denmark. The report was published online April 14 in Arteriosclerosis, Thrombosis, and Vascular Biology.
While the mechanisms for the link are unclear, “emerging evidence suggests that AAA is a focal representation of a systemic disease with a distinct inflammatory component, rather than a mere consequence of atherosclerosis,” wrote Dr. Khalid and his associates.
Several case series have linked AAA with other autoimmune disorders, including systemic lupus erythematosus and rheumatoid arthritis, they noted. Their study comprised nearly 5.5 million adults in Denmark between 1997 and 2011. The researchers identified 59,423 patients with mild psoriasis and 11,566 patients with severe psoriasis (Arterioscler Thromb Vasc Biol. 2016 April 14. doi: 10.1161/ATVBAHA.116.307449).
The incidence of AAA in the reference population was 3.72 cases per 10,000 person-years, with an average follow-up period of 14.4 years. In contrast, the incidence of AAA in patients with mild psoriasis was 7.30 cases per 10,000 person-years, and the rate in patients with severe psoriasis was 9.87 cases of per 10,000 person-years, with average follow-up periods of 5.7 years. Both mild and severe psoriasis were significantly associated with AAA after the researchers accounted for age, sex, comorbidities, medications, socioeconomic status, and smoking, with adjusted incidence rate ratios of 1.20 (95% confidence interval, 1.03-1.39) and 1.67 (95% CI, 1.21-2.32), respectively.
The historical view that AAA is caused mainly by atherosclerosis has largely been upended, the researchers noted. Instead, AAA appears to be a multifactorial process involving inflammation, matrix degradation, thrombosis, and aortic wall stress. Furthermore, inflammation in both AAA and psoriasis is centrally mediated by T-helper-17 cells and interleukin-17. Together, the data suggest that shared inflammatory mechanisms link psoriasis and AAA, especially because the association correlates with psoriatic disease activity, they said. “This finding clearly requires independent replication, and the clinical consequences are unclear at present.”
The LEO Foundation and the Novo Nordisk Foundation funded the study. Dr. Khalid had no disclosures. Four coinvestigators reported financial ties with Abbott, Pfizer, AstraZeneca, Bayer, and several other pharmaceutical companies.
FROM ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY
Key clinical point: Psoriasis predicted abdominal aortic aneurysm in a large, population-based study.
Major finding: The adjusted risk of abdominal aortic aneurysm was 1.67 times greater among patients with severe psoriasis than in the reference population.
Data source: A retrospective cohort study of 5.5 million Danish adults, including 59,423 patients with mild psoriasis and 11,566 patients with severe psoriasis.
Disclosures: The LEO Foundation and the Novo Nordisk Foundation funded the study. Dr. Khalid had no disclosures. Four coinvestigators reported financial ties with Abbott, Pfizer, AstraZeneca, Bayer, and several other pharmaceutical companies.
Clazakizumab safe, effective for PsA treatment
Treatment with clazakizumab was well tolerated and effective at treating musculoskeletal stress in patients with psoriatic arthritis (PsA), Dr. Philip Mease and his associates reported in a phase IIB study published in Arthritis & Rheumatology.
After 16 weeks, American College of Rheumatology (ACR) 20 response rates were highest in the group that received 100-mg doses of clazakizumab at 52.4%, compared with 46.3% for the 25-mg group, 39% for the 200-mg group, and 29.3% for the placebo group. ACR 50/ACR 70 response rates were higher for clazakizumab than for placebo after 16 weeks and 24 weeks, without clear evidence of a dose response.
Adverse events were more common for patients taking clazakizumab and occurred most frequently in the 200-mg group. However, serious adverse events were no more common in the 25-mg and 100-mg groups, compared with the placebo group. Discontinuations due to adverse events were highest in the 200-mg group, and were similar in all other groups.
“Clazakizumab may be particularly suited for patients with PsA in whom skin disease is well controlled with topical agents, ultraviolet therapy, and/or oral systemic therapy such as MTX [methotrexate], but whose musculoskeletal manifestations, such as joint signs and symptoms, enthesitis, and dactylitis, require more potent systemic therapy. Furthermore, some PsA patients do not present with skin lesions at diagnosis; those patients may also benefit from clazakizumab treatment,” the investigators noted.
Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39700).
Treatment with clazakizumab was well tolerated and effective at treating musculoskeletal stress in patients with psoriatic arthritis (PsA), Dr. Philip Mease and his associates reported in a phase IIB study published in Arthritis & Rheumatology.
After 16 weeks, American College of Rheumatology (ACR) 20 response rates were highest in the group that received 100-mg doses of clazakizumab at 52.4%, compared with 46.3% for the 25-mg group, 39% for the 200-mg group, and 29.3% for the placebo group. ACR 50/ACR 70 response rates were higher for clazakizumab than for placebo after 16 weeks and 24 weeks, without clear evidence of a dose response.
Adverse events were more common for patients taking clazakizumab and occurred most frequently in the 200-mg group. However, serious adverse events were no more common in the 25-mg and 100-mg groups, compared with the placebo group. Discontinuations due to adverse events were highest in the 200-mg group, and were similar in all other groups.
“Clazakizumab may be particularly suited for patients with PsA in whom skin disease is well controlled with topical agents, ultraviolet therapy, and/or oral systemic therapy such as MTX [methotrexate], but whose musculoskeletal manifestations, such as joint signs and symptoms, enthesitis, and dactylitis, require more potent systemic therapy. Furthermore, some PsA patients do not present with skin lesions at diagnosis; those patients may also benefit from clazakizumab treatment,” the investigators noted.
Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39700).
Treatment with clazakizumab was well tolerated and effective at treating musculoskeletal stress in patients with psoriatic arthritis (PsA), Dr. Philip Mease and his associates reported in a phase IIB study published in Arthritis & Rheumatology.
After 16 weeks, American College of Rheumatology (ACR) 20 response rates were highest in the group that received 100-mg doses of clazakizumab at 52.4%, compared with 46.3% for the 25-mg group, 39% for the 200-mg group, and 29.3% for the placebo group. ACR 50/ACR 70 response rates were higher for clazakizumab than for placebo after 16 weeks and 24 weeks, without clear evidence of a dose response.
Adverse events were more common for patients taking clazakizumab and occurred most frequently in the 200-mg group. However, serious adverse events were no more common in the 25-mg and 100-mg groups, compared with the placebo group. Discontinuations due to adverse events were highest in the 200-mg group, and were similar in all other groups.
“Clazakizumab may be particularly suited for patients with PsA in whom skin disease is well controlled with topical agents, ultraviolet therapy, and/or oral systemic therapy such as MTX [methotrexate], but whose musculoskeletal manifestations, such as joint signs and symptoms, enthesitis, and dactylitis, require more potent systemic therapy. Furthermore, some PsA patients do not present with skin lesions at diagnosis; those patients may also benefit from clazakizumab treatment,” the investigators noted.
Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39700).
FROM ARTHRITIS & RHEUMATOLOGY
Inflectra becomes first FDA-approved biosimilar for inflammatory diseases
A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.
The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.
The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.
A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.
The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.
The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.
A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.
The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.
The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.
Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”
Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.
Severe psoriasis, kidney disease linked
WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.
The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.
“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”
The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).
A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).
Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.
In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.
Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).
But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”
Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.
Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.
WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.
The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.
“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”
The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).
A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).
Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.
In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.
Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).
But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”
Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.
Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.
WASHINGTON – Another population-based study has found a link between severe psoriasis and kidney disease – this one discovering almost a fivefold increase in the risk of immunoglobulin A nephropathy (IgAN) and a doubling in the risk of glomerular disease.
The findings suggest yet again that psoriasis is a systemic illness, and not something that affects only the skin, Sungat Grewal said at the annual meeting of the American Academy of Dermatology.
“Numerous case reports have generated a hypothesis that psoriasis may be associated,” with an increased risk of IgAN, said Ms. Grewal, of the department of dermatology at the University of Pennsylvania, Philadelphia. “Our study is the first to test this, and it supports the notion that this is no coincidence. Now we need further research to determine if this association is due to causality or to a shared pathophysiology.”
The link between psoriasis and kidney disease has long been noted, but the first study formally investigating this association was published in 2013 (BMJ. 2013 Oct;347:f5961). The study, also conducted by University of Pennsylvania investigators, used a large patient database in the United Kingdom, matched about 143,000 patients with psoriasis with up to five controls without psoriasis each, and found the risk of chronic kidney disease was nearly doubled for those with severe psoriasis (hazard ratio, 1.93).
A similar finding emerged from Taiwan in 2015. Using the national healthcare database, researchers matched about 4,600 patients with psoriasis with about 923,000 controls. They found that having severe psoriasis was associated with almost a doubling in the risk of chronic kidney disease (HR, 1.90) and almost a tripling in the risk of end stage renal disease (HR, 2.97), after adjusting for age, gender, comorbidities, and use of nonsteroidal anti-inflammatory drugs (J Dermatol Sci. 2015 Jun;78[3]:232-8).
Ms. Grewal and her coinvestigators used data from The Health Improvement Network in the United Kingdom – the same database used in the 2013 study. The study group comprised 206,000 patients with psoriasis and about 1 million controls.
In the overall group of patients, the risk of IgAN was not significantly increased. Nor was there a significant overall association with glomerular disease. And when the group was divided by disease severity, there were no significant associations with either IgAN or glomerular disease in the group with mild psoriasis.
Among those with severe psoriasis, however, the risk of IgAN was almost five times higher (HR, 4.75) and the risk of glomerular disease was doubled (HR, 2.05).
But although the hazard ratios look impressive, the clinical reality shouldn’t spark too much concern, Ms. Grewal said. “To keep things in context, it’s very important to remember that the excess risk of nephropathy attributed to severe psoriasis was still quite small – similar to the chance of a spontaneous pregnancy resulting in triplets.”
Still, she said, the link is intriguing, and something clinicians should keep in mind when managing patients with severe psoriasis.
Ms. Grewal had no financial disclosures. She is a medical student at the Commonwealth Medical College (Scranton, Pa.), and is currently spending a year at the Gelfand Clinical Research Lab at the University of Pennsylvania, Philadelphia.
AT AAD 16
Key clinical point: Severe psoriasis appears to increase the risk of both immunoglobulin A glomerulonephritis and glomerular disease.
Major finding: The risk of glomerulonephritis was five-fold higher and the risk of glomerular disease doubled in those with severe psoriasis.
Data source: A population based cohort study comprised about 1.2 million subjects.
Disclosures: Ms. Sungat Grewal had no financial disclosures.
How to beat apremilast-induced diarrhea
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
EXPERT ANALYSIS FROM RWCS 2016
How to beat apremilast-induced diarrhea
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
MAUI, HAWAII – If you’re going to prescribe apremilast for psoriasis or psoriatic arthritis – and more and more physicians are doing so because of the drug’s exceptional safety profile – you’d better get familiar with the oral phosphodiesterase-4 inhibitor’s gastrointestinal side effects, Dr. George M. Martin advised at the 2016 Rheumatology Winter Clinical Symposium.
“One of the biggest hurdles we have to deal with when we prescribe apremilast is the fact that there are these GI side effects,” said Dr. Martin, a dermatologist practicing in Maui and codirector of the rheumatology symposium.
Celgene, which markets apremilast (Otezla), sponsored an analysis of the pattern of diarrhea that emerged in the pooled results of the phase III ESTEEM 1 and 2 trials of apremilast at 30 mg twice daily for psoriasis and the PALACE 1-3 phase III psoriatic arthritis trials.
Diarrhea occurred in 16%-18% of patients on apremilast, a rate roughly threefold greater than in placebo-treated controls. Diarrhea onset was usually within the first 14 days of therapy. When it occurred, the duration was typically about 2 weeks.
“This you can relay to your patients so they’re not surprised if it happens,” the dermatologist said.
It’s a secretory diarrhea, and it is believed to be a classwide effect for the phosphodiesterase-4 (PDE-4) inhibitors. For example, roflumilast (Daliresp), an oral PDE-4 inhibitor used in the treatment of chronic obstructive pulmonary disease, has the same diarrhea issues. The mechanism has been worked out: The drug increases intracellular cyclic adenosine monophosphate, with resultant activation of chloride channels in crypts in the small bowel, which in turn leads to secretion of chloride ions. It takes the large bowel a couple of weeks to adapt. Caffeine causes diarrhea in some individuals through a similar mechanism.
Apremilast-related diarrhea often responds to the time-tested OTC remedies, including bismuth salicylate or fiber supplements. Alternatively, Dr. Martin said he is a fan of the oral prescription agent crofelemer (Fulyzaq) because of its exceptional safety, tolerability, and effectiveness. Plus, many residents of the garden islands of Hawaii like the idea of using a botanical derived from the latexlike sap – known as ‘dragon’s blood – of a South American tree. Crofelemer’s approved indication is the treatment of diarrhea associated with anti-HIV agents.
Diphenoxylate/atropine (Lomotil) is another effective prescription option.
Nausea and/or vomiting occurred in 15%-17% of apremilast-treated patients in the phase III trials. As with diarrhea, if nausea and/or vomiting is going to happen, it occurs early, within the first week or two. Dr. Martin said he finds in his own practice that the nausea/vomiting is less bothersome for patients than the diarrhea. Drug discontinuation due to any GI side effects is rarely necessary.
The nausea/vomiting is usually readily managed by encouraging affected patients to make sure that they’re well hydrated, take their apremilast with food, and eat smaller, more frequent meals. OTC diphenhydramine (Benadryl) is often effective, as are the usual prescription antiemetic agents.
Pharmaceutical industry data indicate apremilast has quickly captured a 17% share of the market for systemic psoriasis therapies. There is a good reason for that, according to Dr. Martin: “Dermatologists have historically been risk averse. And apremilast is arguably the safest systemic agent we have to treat psoriasis. The beauty of apremilast is it requires no laboratory monitoring. That makes it attractive to dermatologists who are concerned about systemic therapy. It’s why there has been a huge jump in adoption of apremilast.”
Apremilast is comparable to methotrexate in terms of efficacy as reflected in week 16 PASI-75 response rates of about 35%, meaning 35% of treated patients obtain at least a 75% improvement in Psoriasis Area and Severity Index scores, he continued. Apremilast is particularly effective for scalp and nail psoriasis, making it a good option for patients who have psoriasis at those sites but not extensive involvement elsewhere, which might call for the use of a more potent biologic agent.
Surveys indicate that 20% of dermatologists write 80% of all prescriptions for biologic agents used to treat psoriasis. The thinking was that apremilast would appeal to the 80% of dermatologists who have steered clear of the biologics, and that after becoming comfortable with apremilast, they might become more receptive to using biologics for their patients with an inadequate response to the oral PDE-4 inhibitor. That hasn’t happened yet.
“We’re not seeing apremilast function as the gateway drug we thought it would be. It’s just going to take some time for those prescribers either to refer their patients who aren’t getting a good response to the next doctor who’s more adept at treating with biologic agents, or perhaps they themselves will get more involved,” Dr. Martin predicted.
He reported serving on scientific advisory boards for, and/or as a consultant to, nine pharmaceutical companies.
EXPERT ANALYSIS FROM RWCS 2016
