Ocrelizumab posts first-ever positive outcome data for primary progressive MS

The selective B-cell–targeting monoclonal antibody ocrelizumab became the first drug to improve outcomes in primary progressive multiple sclerosis based on results from the randomized, placebo-controlled, phase III ORATORIO trial.

After 24 weeks of treatment, ocrelizumab reduced the risk of progression in clinical disability by 25%, compared with placebo. Over 2 years, the antibody also reduced the volume of hyperintense T2 lesions by 3.4%, whereas patients taking placebo experienced a 7% increase. The rate of whole brain volume loss was also significantly reduced.

The findings confer the first really good news in how to treat patients with this very difficult condition, said Dr. Xavier Montalbán, who presented the results at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis, held in Barcelona.

“We’ve been looking for something positive for these patients for years and have never found this,” said Dr. Montalbán, director of clinical neuroimmunology at Vall d’Hebron University Hospital, Barcelona. “We can discuss the magnitude of the effect, but I have to say I am very, very happy with this.”

The results are certainly encouraging, said Dr. Peter Calabresi, director of the Johns Hopkins Multiple Sclerosis Center and the division of neuroimmunology at The Johns Hopkins Hospital, Baltimore, although he tempered his enthusiasm a bit regarding patient selection and safety. In the entire cohort of 732 patients, 13 malignancies occurred over 3 years and occurred more than twice as often in the ocrelizumab arm than in the placebo arm (2.3% vs. 0.8%). These included four breast cancers in the active arm and none in the placebo arm.

“The data in general look very strong but with a possible safety signal related to cancers and deaths,” Dr. Calabresi said in an interview. “I’d need to see more detail in this regard, but overall I am very happy to see something work for primary progressive MS, where we have no approved drugs, so this is very important in that regard.

“As others have pointed out, though, the study was designed to target young people with inflammation (active MRIs) in which cases the drug works well. But many of our people with progressive MS are older and have no inflammation, so I’m guessing there is no effect in that group.”

Ocrelizumab, a humanized monoclonal antibody, selectively targets CD20-positive B cells. Since not all B cells are positive for the marker, ocrelizumab leaves intact the patient’s immune memory, as well as the ability to create more B cells. Its success bolsters the emerging idea that B cells may be even more important than T cells in the pathophysiology of MS.

ORATORIO was a 2:1 randomization of 732 patients with primary progressive MS to infusions of either 600 mg ocrelizumab or placebo every 24 weeks for 120 months.

Most patients finished the trial (80% active, 66% placebo). The withdrawals in the placebo arm were primarily due to lack of efficacy. Patients were a mean of 44 years old, with a mean 6.5 years since symptom onset. Most (88%) were treatment-naive. The Expanded Disability Status Score (EDSS) at baseline was 4.7 in both groups. At baseline, about a quarter of patients had gadolinium-enhancing lesions (mean number, 1) with a mean T2 lesion volume of 11 cm³, and their mean whole-brain volume was 1,467 cm³. All patients had either elevated immunoglobulin in cerebrospinal fluid or oligoclonal bands.

The primary endpoint of ORATORIO was 12-week confirmed disability progression (CDP). Secondary endpoints included 24-week CDP; timed 25-foot walk; and T2 lesion and whole brain volume.

By 120 weeks, patients taking the study drug experienced a mean 24% reduction in the risk of CDP (hazard ratio, 0.76; P = .0321). The treatment curves began to separate at week 24, and the differences in the risk of CDP were statistically significant at every evaluation. The benefit has been maintained in a safety evaluation that is extending treatment to 216 weeks in a subset of patients.

*Ocrelizumab significantly slowed the worsening of patients’ 25-foot walking time by 29% at 120 weeks when compared against placebo. Walking times increased by 39% from baseline on ocrelizumab, compared with a 55% rise for those on placebo (P = .0404).

On the imaging endpoints, the drug was associated with a highly significant difference in T2 lesion volume, decreasing the load by 3.4%, while the placebo arm experienced an increase of 7.4% from baseline (P = .0001).

Those taking the drug also experienced a small but significantly lower amount of whole-brain volume loss (–0.9% vs. –1.1%; P = .02).

Infusion reactions were most common with the first dose (27% active vs. 7% placebo). One patient taking the study drug withdrew at that time from a serious reaction, but the remainder were mild to moderate in severity. Reactions decreased over time, and all remained at the mild-moderate level.

Overall adverse events occurred at similar rates between those taking the drug and those taking placebo (95% vs. 90%). Infections were similar (70% vs. 68%) overall, although upper respiratory infections were more common among the active group (11% vs. 6%).

There were five deaths: one in the placebo arm (a motor vehicle accident) and four in the active arm (pulmonary embolism, pneumonia, pancreatic cancer, and pneumonia aspiration). These, as well as the malignancy findings, are still being evaluated, Dr. Montalbán said.

Based on the positive results, Genentech will be submitting the drug for approval in both the United States and Europe in the first quarter of 2016.

Dr. Montalbán disclosed ties with Genentech – the trial’s sponsor – and other pharmaceutical companies.

*Correction, 10/14/15: The timed 25-foot walk test results were previously misstated.

msullivan@frontlinemedcom.com

The selective B-cell–targeting monoclonal antibody ocrelizumab became the first drug to improve outcomes in primary progressive multiple sclerosis based on results from the randomized, placebo-controlled, phase III ORATORIO trial.

After 24 weeks of treatment, ocrelizumab reduced the risk of progression in clinical disability by 25%, compared with placebo. Over 2 years, the antibody also reduced the volume of hyperintense T2 lesions by 3.4%, whereas patients taking placebo experienced a 7% increase. The rate of whole brain volume loss was also significantly reduced.

The findings confer the first really good news in how to treat patients with this very difficult condition, said Dr. Xavier Montalbán, who presented the results at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis, held in Barcelona.

“We’ve been looking for something positive for these patients for years and have never found this,” said Dr. Montalbán, director of clinical neuroimmunology at Vall d’Hebron University Hospital, Barcelona. “We can discuss the magnitude of the effect, but I have to say I am very, very happy with this.”

The results are certainly encouraging, said Dr. Peter Calabresi, director of the Johns Hopkins Multiple Sclerosis Center and the division of neuroimmunology at The Johns Hopkins Hospital, Baltimore, although he tempered his enthusiasm a bit regarding patient selection and safety. In the entire cohort of 732 patients, 13 malignancies occurred over 3 years and occurred more than twice as often in the ocrelizumab arm than in the placebo arm (2.3% vs. 0.8%). These included four breast cancers in the active arm and none in the placebo arm.

“The data in general look very strong but with a possible safety signal related to cancers and deaths,” Dr. Calabresi said in an interview. “I’d need to see more detail in this regard, but overall I am very happy to see something work for primary progressive MS, where we have no approved drugs, so this is very important in that regard.

“As others have pointed out, though, the study was designed to target young people with inflammation (active MRIs) in which cases the drug works well. But many of our people with progressive MS are older and have no inflammation, so I’m guessing there is no effect in that group.”

Ocrelizumab, a humanized monoclonal antibody, selectively targets CD20-positive B cells. Since not all B cells are positive for the marker, ocrelizumab leaves intact the patient’s immune memory, as well as the ability to create more B cells. Its success bolsters the emerging idea that B cells may be even more important than T cells in the pathophysiology of MS.

ORATORIO was a 2:1 randomization of 732 patients with primary progressive MS to infusions of either 600 mg ocrelizumab or placebo every 24 weeks for 120 months.

Most patients finished the trial (80% active, 66% placebo). The withdrawals in the placebo arm were primarily due to lack of efficacy. Patients were a mean of 44 years old, with a mean 6.5 years since symptom onset. Most (88%) were treatment-naive. The Expanded Disability Status Score (EDSS) at baseline was 4.7 in both groups. At baseline, about a quarter of patients had gadolinium-enhancing lesions (mean number, 1) with a mean T2 lesion volume of 11 cm³, and their mean whole-brain volume was 1,467 cm³. All patients had either elevated immunoglobulin in cerebrospinal fluid or oligoclonal bands.

The primary endpoint of ORATORIO was 12-week confirmed disability progression (CDP). Secondary endpoints included 24-week CDP; timed 25-foot walk; and T2 lesion and whole brain volume.

By 120 weeks, patients taking the study drug experienced a mean 24% reduction in the risk of CDP (hazard ratio, 0.76; P = .0321). The treatment curves began to separate at week 24, and the differences in the risk of CDP were statistically significant at every evaluation. The benefit has been maintained in a safety evaluation that is extending treatment to 216 weeks in a subset of patients.

*Ocrelizumab significantly slowed the worsening of patients’ 25-foot walking time by 29% at 120 weeks when compared against placebo. Walking times increased by 39% from baseline on ocrelizumab, compared with a 55% rise for those on placebo (P = .0404).

On the imaging endpoints, the drug was associated with a highly significant difference in T2 lesion volume, decreasing the load by 3.4%, while the placebo arm experienced an increase of 7.4% from baseline (P = .0001).

Those taking the drug also experienced a small but significantly lower amount of whole-brain volume loss (–0.9% vs. –1.1%; P = .02).

Infusion reactions were most common with the first dose (27% active vs. 7% placebo). One patient taking the study drug withdrew at that time from a serious reaction, but the remainder were mild to moderate in severity. Reactions decreased over time, and all remained at the mild-moderate level.

Overall adverse events occurred at similar rates between those taking the drug and those taking placebo (95% vs. 90%). Infections were similar (70% vs. 68%) overall, although upper respiratory infections were more common among the active group (11% vs. 6%).

There were five deaths: one in the placebo arm (a motor vehicle accident) and four in the active arm (pulmonary embolism, pneumonia, pancreatic cancer, and pneumonia aspiration). These, as well as the malignancy findings, are still being evaluated, Dr. Montalbán said.

Based on the positive results, Genentech will be submitting the drug for approval in both the United States and Europe in the first quarter of 2016.

Dr. Montalbán disclosed ties with Genentech – the trial’s sponsor – and other pharmaceutical companies.

*Correction, 10/14/15: The timed 25-foot walk test results were previously misstated.

msullivan@frontlinemedcom.com

The selective B-cell–targeting monoclonal antibody ocrelizumab became the first drug to improve outcomes in primary progressive multiple sclerosis based on results from the randomized, placebo-controlled, phase III ORATORIO trial.

After 24 weeks of treatment, ocrelizumab reduced the risk of progression in clinical disability by 25%, compared with placebo. Over 2 years, the antibody also reduced the volume of hyperintense T2 lesions by 3.4%, whereas patients taking placebo experienced a 7% increase. The rate of whole brain volume loss was also significantly reduced.

The findings confer the first really good news in how to treat patients with this very difficult condition, said Dr. Xavier Montalbán, who presented the results at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis, held in Barcelona.

“We’ve been looking for something positive for these patients for years and have never found this,” said Dr. Montalbán, director of clinical neuroimmunology at Vall d’Hebron University Hospital, Barcelona. “We can discuss the magnitude of the effect, but I have to say I am very, very happy with this.”

The results are certainly encouraging, said Dr. Peter Calabresi, director of the Johns Hopkins Multiple Sclerosis Center and the division of neuroimmunology at The Johns Hopkins Hospital, Baltimore, although he tempered his enthusiasm a bit regarding patient selection and safety. In the entire cohort of 732 patients, 13 malignancies occurred over 3 years and occurred more than twice as often in the ocrelizumab arm than in the placebo arm (2.3% vs. 0.8%). These included four breast cancers in the active arm and none in the placebo arm.

“The data in general look very strong but with a possible safety signal related to cancers and deaths,” Dr. Calabresi said in an interview. “I’d need to see more detail in this regard, but overall I am very happy to see something work for primary progressive MS, where we have no approved drugs, so this is very important in that regard.

“As others have pointed out, though, the study was designed to target young people with inflammation (active MRIs) in which cases the drug works well. But many of our people with progressive MS are older and have no inflammation, so I’m guessing there is no effect in that group.”

Ocrelizumab, a humanized monoclonal antibody, selectively targets CD20-positive B cells. Since not all B cells are positive for the marker, ocrelizumab leaves intact the patient’s immune memory, as well as the ability to create more B cells. Its success bolsters the emerging idea that B cells may be even more important than T cells in the pathophysiology of MS.

ORATORIO was a 2:1 randomization of 732 patients with primary progressive MS to infusions of either 600 mg ocrelizumab or placebo every 24 weeks for 120 months.

Most patients finished the trial (80% active, 66% placebo). The withdrawals in the placebo arm were primarily due to lack of efficacy. Patients were a mean of 44 years old, with a mean 6.5 years since symptom onset. Most (88%) were treatment-naive. The Expanded Disability Status Score (EDSS) at baseline was 4.7 in both groups. At baseline, about a quarter of patients had gadolinium-enhancing lesions (mean number, 1) with a mean T2 lesion volume of 11 cm³, and their mean whole-brain volume was 1,467 cm³. All patients had either elevated immunoglobulin in cerebrospinal fluid or oligoclonal bands.

The primary endpoint of ORATORIO was 12-week confirmed disability progression (CDP). Secondary endpoints included 24-week CDP; timed 25-foot walk; and T2 lesion and whole brain volume.

By 120 weeks, patients taking the study drug experienced a mean 24% reduction in the risk of CDP (hazard ratio, 0.76; P = .0321). The treatment curves began to separate at week 24, and the differences in the risk of CDP were statistically significant at every evaluation. The benefit has been maintained in a safety evaluation that is extending treatment to 216 weeks in a subset of patients.

*Ocrelizumab significantly slowed the worsening of patients’ 25-foot walking time by 29% at 120 weeks when compared against placebo. Walking times increased by 39% from baseline on ocrelizumab, compared with a 55% rise for those on placebo (P = .0404).

On the imaging endpoints, the drug was associated with a highly significant difference in T2 lesion volume, decreasing the load by 3.4%, while the placebo arm experienced an increase of 7.4% from baseline (P = .0001).

Those taking the drug also experienced a small but significantly lower amount of whole-brain volume loss (–0.9% vs. –1.1%; P = .02).

Infusion reactions were most common with the first dose (27% active vs. 7% placebo). One patient taking the study drug withdrew at that time from a serious reaction, but the remainder were mild to moderate in severity. Reactions decreased over time, and all remained at the mild-moderate level.

Overall adverse events occurred at similar rates between those taking the drug and those taking placebo (95% vs. 90%). Infections were similar (70% vs. 68%) overall, although upper respiratory infections were more common among the active group (11% vs. 6%).

There were five deaths: one in the placebo arm (a motor vehicle accident) and four in the active arm (pulmonary embolism, pneumonia, pancreatic cancer, and pneumonia aspiration). These, as well as the malignancy findings, are still being evaluated, Dr. Montalbán said.

Based on the positive results, Genentech will be submitting the drug for approval in both the United States and Europe in the first quarter of 2016.

Dr. Montalbán disclosed ties with Genentech – the trial’s sponsor – and other pharmaceutical companies.

*Correction, 10/14/15: The timed 25-foot walk test results were previously misstated.

msullivan@frontlinemedcom.com