Vedolizumab rated first line for ulcerative colitis

VIENNA  – Vedolizumab, a second-line biologic for treating patients who have ulcerative colitis or Crohn’s disease and don’t respond to an anti-tumor necrosis factor drug, is gaining traction with experts who have used the drug investigationally for several years and consider vedolizumab to be their first-line biologic for ulcerative colitis. But they agree that for Crohn’s disease the available data support using vedolizumab as a second-line agent.

“I think vedolizumab [Entyvio] is a first-line biologic for ulcerative colitis. Full stop,” said Dr. Brian G. Feagan during a talk at the United European Gastroenterology Global Congress. He cited his 12-year experience using vedolizumab, which has compiled a strong record of efficacy as well as safety for ulcerative colitis.

“It’s the promise of a reduced risk of systemic adverse events, especially secondary infections,” by using vedolizumab instead of a drug that blocks tumor necrosis factor (TNF), said Dr. Feagan in an interview.

“For Crohn’s disease, vedolizumab seems to have a slower onset of action, so for sicker Crohn’s patients you may want to choose a TNF blocker,” said Dr. Feagan, a gastroenterologist and professor of medicine at the University of Western Ontario in London, Ont. “For Crohn’s disease you could use vedolizumab first in some patients and an anti-TNF first line in other patients.”

Another gastroenterologist experienced in using vedolizumab to treat inflammatory bowel diseases largely agreed. “Vedolizumab is a first-line biologic for ulcerative colitis, For Crohn’s disease, the anti-TNF drugs are still the way to go,” said Dr. Paul Rutgeerts, a gastroenterologist and professor of medicine at Catholic University in Leuven, Belgium.

Dr. Feagan and Dr. Rutgeerts as well as others cite a fundamental difference in the way vedolizumab mitigates autoimmunity compared with TNF blocking drugs as the likely explanation for why vedolizumab seems to work much better for ulcerative colitis than it does for Crohn’s disease.

As spelled out last year in an editorial by Dr. Fabio Cominelli (N. Engl. J. Med. 2013;369:775-6), vedolizumab specifically blocks the integrin that directs leukocytes to the gut musoca, and this limited, gut-specific action may explain why the drug has such a favorable adverse effect profile as well as why it is less effective at inducing remissions in Crohn’s disease, which can hit any site along the entire gastrointestinal tract and cause transmural fistulas and multi-organ involvement. In contrast, ulcerative colitis is limited to the superficial mucosa of the large bowel.

“With ulcerative colitis it is only the mucosa. Crohn’s disease is more of a transmural disorder that involves the entire wall of the gut so you have more need for systemic action, which is better delivered by anti-TNFs” than by vedolizumab, Dr. Rutgeerts said in an interview.

Perhaps vedolizumab’s only major drawback as first-line biologic treatment for ulcerative colitis and even for some Crohn’s disease patients is its high cost, especially at a time when the price for the anti-TNF drug infliximab has begun to fall following introduction of biosimilar infliximab in Europe and its expected appearance soon in the United States.

“The cost [of vedolizumab] is very high,” especially when administered every 4 weeks, which seems to be the dosage many patients need to maintain long-term responses and remissions, Dr. Rutgeerts said.

“Now we have biosimilar infliximab, which is cheaper than vedolizumab” and hence more attractive, at least for cost, noted Dr. C. Janneke van der Woude, head of the inflammatory bowel diseases unit at Erasmus University in Rotterdam, The Netherlands. She also noted that many patients prefer subcutaneous drug treatment with the anti-TNF agent adalimumab over intravenous treatments, which is the route for vedolizumab.

Two-year data show durable efficacy, safety

Vedolizumab demonstrated its ability to safely maintain remission in responsive patients with inflammatory bowel disease in results from long-term treatment and follow-up of patients enrolled in the pivotal phase III trials that supplied the data that led to vedolizumab’s marketing approval earlier this year in both the United States and in Europe.

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study. The same pattern of low event rates similar to the placebo patients also occurred for episodes of nasopharyngitis, upper respiratory tract infections, Clostridium difficile infections, and tuberculosis cases.

The results also showed better rates of long-term remission and response in the patients who had not previously failed treatment with an anti-TNF drug compared with those who had. Asked what might explain this, Dr. Feagan replied “we know that patients who fail prior drugs are always harder to treat.”

A very similar pattern occurred among the patients with Crohn’s disease who remained on vedolizumab for an additional 52 weeks following completion of a first year of treatment in the GEMINI 2 trial [the Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Crohn’s Disease], the pivotal, phase III study that led to the Crohn’s disease indication for vedolizumab (N. Engl. J. Med. 2013;369:711-21). Among 295 GEMINI 2 completer patients who remained on vedolizumab the rate of complete remissions was 57% at entry into the long-term study after 52 weeks on treatment, 64% after 80 weeks on treatment, and 61% after 104 weeks.The overall response rate was 81% at 52 weeks, 78% after 80 weeks, and 74% at 104 week, Dr. Rutgeerts reported. However, he noted that the study design allowed patients who experienced a flare to receive conventional rescue medications and still be counted a responder or in remission, which increased the number of patients in both of these two groups. “Patients did not need to be a responder or in remission at every time point,” he noted.

Once again, the rates of adverse events, serious adverse events, adverse events resulting in drug discontinuation, infections, serious infections, nasopharyngitis, and upper respiratory infection were all similar among patients on long-term vedolizumab compared with control patients with Crohn’s disease, Dr. Rutgeerts said.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish,” said Dr. Danese, head of the inflammatory bowel disease unit at the Humanitas Clinic and Research Center in Milan.

Dr. Danese also said that vedolizumab has a safety advantage over anti-TNF drugs when treating ulcerative colitis, although vedolizumab’s efficacy for treating steroid-refractory, fulminant ulcertative colitis remains untested. And he agreed that vedolizumab’s role as a go-to agent for inducing remission in active Crohn’s disease seems questionable.

Two other reports at the meeting further fleshed out vedolizumab’s performance in the GEMINI trials.

One analysis focused on 34 ulcerative colitis patients and 57 Crohn’s disease patients who responded to vedolizumab induction treatment but then lost their response when they subsequently received vedolizumab once every 8 weeks. These patients then switched to a regimen in which they received the drug every 4 weeks, and this resulted in significant reductions in disease activity among some of the ulcerative colitis and Crohn’s disease patients, reported Dr. Séverine Vermeire, a gastroenterologist and professor of medicine at Catholic University in Leuven.

She estimated that roughly a third of patients in both disease categories who lost response when put on the drug once every 8 weeks regained their complete response when their dosing frequency increased to once every 4 weeks.

The findings “suggest that dosing every 4 weeks may be beneficial for certain patients, with no apparent change in safety. These data provide insight into the potential value of dosing every 4 weeks, and in routine practice we will have patients who will lose response when they receive the drug every 8 weeks,” Dr. Vermeire said. “We should try to identify these patients early,” she said, and “we need to investigate why some patients lose their vedolizumab response.” The labeling for vedolizumab calls for treatment once every 8 weeks for maintenance.

Another analysis focused on the total of 1,443 inflammatory bowel disease patients who received vedolizumab for both induction and maintenance in the two GEMINI studies. This safety analysis examined the incidence of total infections and serious infections among patients who started on vedolizumab while on treatment with a corticosteroid, an immunomodulating drug, both of these agents, or neither of these agents.

The analysis showed similar rates of both total infections and serious infections in all four subgroups, suggesting no interaction between vedsolizumab and other immuno-active drugs in terms of vulnerability to infection, said Dr. Jean-Frédréic Colombel, professor of medicine and director of the inflammatory bowel disease center at Mount Sinai Medical Center in New York.

The low rate of serious infections, which occurred at 0.04-0.06 infections/person-year of follow-up was “reassuring,” said Dr. Colombel, but these infections were also so rare that it limited interpretation of the findings. He also noted that the analysis only focused on concomitant drugs at the time patients began vedolizumab treatment and did not take into account subsequent medication changes.

The GEMINI 1 and 2 trials were sponsored by Takeda, the company that markets vedolizumab (Entyvio). Dr. Feagan has been a consultant to Takeda, AbbVie, Merck, and UCB. Dr. Rutgeerts has been a consultant to Takeda, AbbVie, Janssen, Merch, and UCB. Dr. van der Woude has been an advisor to Dr. Falk, Abbvie, Janssen, Johnson&Johnson, and Cosmo. Dr. Danese has been a consultant to Takeda and to several other companies. Dr. Vermeire has been a consultant to Takeda and to several other companies. Dr. Colombel has been a consultant to Takeda and to several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

AGA Resources

• IBD Clinical Service  Line: www.gastro.org/practice/clinical-service-line/ibd-
clinical-service-line
• Clinical Decision Support Tool: Use of Biologic Drugs for Inflammatory Crohn’s Disease: http://campaigns.gastro.org/algorithms/crohns

VIENNA  – Vedolizumab, a second-line biologic for treating patients who have ulcerative colitis or Crohn’s disease and don’t respond to an anti-tumor necrosis factor drug, is gaining traction with experts who have used the drug investigationally for several years and consider vedolizumab to be their first-line biologic for ulcerative colitis. But they agree that for Crohn’s disease the available data support using vedolizumab as a second-line agent.

“I think vedolizumab [Entyvio] is a first-line biologic for ulcerative colitis. Full stop,” said Dr. Brian G. Feagan during a talk at the United European Gastroenterology Global Congress. He cited his 12-year experience using vedolizumab, which has compiled a strong record of efficacy as well as safety for ulcerative colitis.

“It’s the promise of a reduced risk of systemic adverse events, especially secondary infections,” by using vedolizumab instead of a drug that blocks tumor necrosis factor (TNF), said Dr. Feagan in an interview.

“For Crohn’s disease, vedolizumab seems to have a slower onset of action, so for sicker Crohn’s patients you may want to choose a TNF blocker,” said Dr. Feagan, a gastroenterologist and professor of medicine at the University of Western Ontario in London, Ont. “For Crohn’s disease you could use vedolizumab first in some patients and an anti-TNF first line in other patients.”

Another gastroenterologist experienced in using vedolizumab to treat inflammatory bowel diseases largely agreed. “Vedolizumab is a first-line biologic for ulcerative colitis, For Crohn’s disease, the anti-TNF drugs are still the way to go,” said Dr. Paul Rutgeerts, a gastroenterologist and professor of medicine at Catholic University in Leuven, Belgium.

Dr. Feagan and Dr. Rutgeerts as well as others cite a fundamental difference in the way vedolizumab mitigates autoimmunity compared with TNF blocking drugs as the likely explanation for why vedolizumab seems to work much better for ulcerative colitis than it does for Crohn’s disease.

As spelled out last year in an editorial by Dr. Fabio Cominelli (N. Engl. J. Med. 2013;369:775-6), vedolizumab specifically blocks the integrin that directs leukocytes to the gut musoca, and this limited, gut-specific action may explain why the drug has such a favorable adverse effect profile as well as why it is less effective at inducing remissions in Crohn’s disease, which can hit any site along the entire gastrointestinal tract and cause transmural fistulas and multi-organ involvement. In contrast, ulcerative colitis is limited to the superficial mucosa of the large bowel.

“With ulcerative colitis it is only the mucosa. Crohn’s disease is more of a transmural disorder that involves the entire wall of the gut so you have more need for systemic action, which is better delivered by anti-TNFs” than by vedolizumab, Dr. Rutgeerts said in an interview.

Perhaps vedolizumab’s only major drawback as first-line biologic treatment for ulcerative colitis and even for some Crohn’s disease patients is its high cost, especially at a time when the price for the anti-TNF drug infliximab has begun to fall following introduction of biosimilar infliximab in Europe and its expected appearance soon in the United States.

“The cost [of vedolizumab] is very high,” especially when administered every 4 weeks, which seems to be the dosage many patients need to maintain long-term responses and remissions, Dr. Rutgeerts said.

“Now we have biosimilar infliximab, which is cheaper than vedolizumab” and hence more attractive, at least for cost, noted Dr. C. Janneke van der Woude, head of the inflammatory bowel diseases unit at Erasmus University in Rotterdam, The Netherlands. She also noted that many patients prefer subcutaneous drug treatment with the anti-TNF agent adalimumab over intravenous treatments, which is the route for vedolizumab.

Two-year data show durable efficacy, safety

Vedolizumab demonstrated its ability to safely maintain remission in responsive patients with inflammatory bowel disease in results from long-term treatment and follow-up of patients enrolled in the pivotal phase III trials that supplied the data that led to vedolizumab’s marketing approval earlier this year in both the United States and in Europe.

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study. The same pattern of low event rates similar to the placebo patients also occurred for episodes of nasopharyngitis, upper respiratory tract infections, Clostridium difficile infections, and tuberculosis cases.

The results also showed better rates of long-term remission and response in the patients who had not previously failed treatment with an anti-TNF drug compared with those who had. Asked what might explain this, Dr. Feagan replied “we know that patients who fail prior drugs are always harder to treat.”

A very similar pattern occurred among the patients with Crohn’s disease who remained on vedolizumab for an additional 52 weeks following completion of a first year of treatment in the GEMINI 2 trial [the Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Crohn’s Disease], the pivotal, phase III study that led to the Crohn’s disease indication for vedolizumab (N. Engl. J. Med. 2013;369:711-21). Among 295 GEMINI 2 completer patients who remained on vedolizumab the rate of complete remissions was 57% at entry into the long-term study after 52 weeks on treatment, 64% after 80 weeks on treatment, and 61% after 104 weeks.The overall response rate was 81% at 52 weeks, 78% after 80 weeks, and 74% at 104 week, Dr. Rutgeerts reported. However, he noted that the study design allowed patients who experienced a flare to receive conventional rescue medications and still be counted a responder or in remission, which increased the number of patients in both of these two groups. “Patients did not need to be a responder or in remission at every time point,” he noted.

Once again, the rates of adverse events, serious adverse events, adverse events resulting in drug discontinuation, infections, serious infections, nasopharyngitis, and upper respiratory infection were all similar among patients on long-term vedolizumab compared with control patients with Crohn’s disease, Dr. Rutgeerts said.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish,” said Dr. Danese, head of the inflammatory bowel disease unit at the Humanitas Clinic and Research Center in Milan.

Dr. Danese also said that vedolizumab has a safety advantage over anti-TNF drugs when treating ulcerative colitis, although vedolizumab’s efficacy for treating steroid-refractory, fulminant ulcertative colitis remains untested. And he agreed that vedolizumab’s role as a go-to agent for inducing remission in active Crohn’s disease seems questionable.

Two other reports at the meeting further fleshed out vedolizumab’s performance in the GEMINI trials.

One analysis focused on 34 ulcerative colitis patients and 57 Crohn’s disease patients who responded to vedolizumab induction treatment but then lost their response when they subsequently received vedolizumab once every 8 weeks. These patients then switched to a regimen in which they received the drug every 4 weeks, and this resulted in significant reductions in disease activity among some of the ulcerative colitis and Crohn’s disease patients, reported Dr. Séverine Vermeire, a gastroenterologist and professor of medicine at Catholic University in Leuven.

She estimated that roughly a third of patients in both disease categories who lost response when put on the drug once every 8 weeks regained their complete response when their dosing frequency increased to once every 4 weeks.

The findings “suggest that dosing every 4 weeks may be beneficial for certain patients, with no apparent change in safety. These data provide insight into the potential value of dosing every 4 weeks, and in routine practice we will have patients who will lose response when they receive the drug every 8 weeks,” Dr. Vermeire said. “We should try to identify these patients early,” she said, and “we need to investigate why some patients lose their vedolizumab response.” The labeling for vedolizumab calls for treatment once every 8 weeks for maintenance.

Another analysis focused on the total of 1,443 inflammatory bowel disease patients who received vedolizumab for both induction and maintenance in the two GEMINI studies. This safety analysis examined the incidence of total infections and serious infections among patients who started on vedolizumab while on treatment with a corticosteroid, an immunomodulating drug, both of these agents, or neither of these agents.

The analysis showed similar rates of both total infections and serious infections in all four subgroups, suggesting no interaction between vedsolizumab and other immuno-active drugs in terms of vulnerability to infection, said Dr. Jean-Frédréic Colombel, professor of medicine and director of the inflammatory bowel disease center at Mount Sinai Medical Center in New York.

The low rate of serious infections, which occurred at 0.04-0.06 infections/person-year of follow-up was “reassuring,” said Dr. Colombel, but these infections were also so rare that it limited interpretation of the findings. He also noted that the analysis only focused on concomitant drugs at the time patients began vedolizumab treatment and did not take into account subsequent medication changes.

The GEMINI 1 and 2 trials were sponsored by Takeda, the company that markets vedolizumab (Entyvio). Dr. Feagan has been a consultant to Takeda, AbbVie, Merck, and UCB. Dr. Rutgeerts has been a consultant to Takeda, AbbVie, Janssen, Merch, and UCB. Dr. van der Woude has been an advisor to Dr. Falk, Abbvie, Janssen, Johnson&Johnson, and Cosmo. Dr. Danese has been a consultant to Takeda and to several other companies. Dr. Vermeire has been a consultant to Takeda and to several other companies. Dr. Colombel has been a consultant to Takeda and to several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

AGA Resources

• IBD Clinical Service  Line: www.gastro.org/practice/clinical-service-line/ibd-
clinical-service-line
• Clinical Decision Support Tool: Use of Biologic Drugs for Inflammatory Crohn’s Disease: http://campaigns.gastro.org/algorithms/crohns

VIENNA  – Vedolizumab, a second-line biologic for treating patients who have ulcerative colitis or Crohn’s disease and don’t respond to an anti-tumor necrosis factor drug, is gaining traction with experts who have used the drug investigationally for several years and consider vedolizumab to be their first-line biologic for ulcerative colitis. But they agree that for Crohn’s disease the available data support using vedolizumab as a second-line agent.

“I think vedolizumab [Entyvio] is a first-line biologic for ulcerative colitis. Full stop,” said Dr. Brian G. Feagan during a talk at the United European Gastroenterology Global Congress. He cited his 12-year experience using vedolizumab, which has compiled a strong record of efficacy as well as safety for ulcerative colitis.

“It’s the promise of a reduced risk of systemic adverse events, especially secondary infections,” by using vedolizumab instead of a drug that blocks tumor necrosis factor (TNF), said Dr. Feagan in an interview.

“For Crohn’s disease, vedolizumab seems to have a slower onset of action, so for sicker Crohn’s patients you may want to choose a TNF blocker,” said Dr. Feagan, a gastroenterologist and professor of medicine at the University of Western Ontario in London, Ont. “For Crohn’s disease you could use vedolizumab first in some patients and an anti-TNF first line in other patients.”

Another gastroenterologist experienced in using vedolizumab to treat inflammatory bowel diseases largely agreed. “Vedolizumab is a first-line biologic for ulcerative colitis, For Crohn’s disease, the anti-TNF drugs are still the way to go,” said Dr. Paul Rutgeerts, a gastroenterologist and professor of medicine at Catholic University in Leuven, Belgium.

Dr. Feagan and Dr. Rutgeerts as well as others cite a fundamental difference in the way vedolizumab mitigates autoimmunity compared with TNF blocking drugs as the likely explanation for why vedolizumab seems to work much better for ulcerative colitis than it does for Crohn’s disease.

As spelled out last year in an editorial by Dr. Fabio Cominelli (N. Engl. J. Med. 2013;369:775-6), vedolizumab specifically blocks the integrin that directs leukocytes to the gut musoca, and this limited, gut-specific action may explain why the drug has such a favorable adverse effect profile as well as why it is less effective at inducing remissions in Crohn’s disease, which can hit any site along the entire gastrointestinal tract and cause transmural fistulas and multi-organ involvement. In contrast, ulcerative colitis is limited to the superficial mucosa of the large bowel.

“With ulcerative colitis it is only the mucosa. Crohn’s disease is more of a transmural disorder that involves the entire wall of the gut so you have more need for systemic action, which is better delivered by anti-TNFs” than by vedolizumab, Dr. Rutgeerts said in an interview.

Perhaps vedolizumab’s only major drawback as first-line biologic treatment for ulcerative colitis and even for some Crohn’s disease patients is its high cost, especially at a time when the price for the anti-TNF drug infliximab has begun to fall following introduction of biosimilar infliximab in Europe and its expected appearance soon in the United States.

“The cost [of vedolizumab] is very high,” especially when administered every 4 weeks, which seems to be the dosage many patients need to maintain long-term responses and remissions, Dr. Rutgeerts said.

“Now we have biosimilar infliximab, which is cheaper than vedolizumab” and hence more attractive, at least for cost, noted Dr. C. Janneke van der Woude, head of the inflammatory bowel diseases unit at Erasmus University in Rotterdam, The Netherlands. She also noted that many patients prefer subcutaneous drug treatment with the anti-TNF agent adalimumab over intravenous treatments, which is the route for vedolizumab.

Two-year data show durable efficacy, safety

Vedolizumab demonstrated its ability to safely maintain remission in responsive patients with inflammatory bowel disease in results from long-term treatment and follow-up of patients enrolled in the pivotal phase III trials that supplied the data that led to vedolizumab’s marketing approval earlier this year in both the United States and in Europe.

Dr. Feagan presented outcome results after 80 and 104 weeks of vedolizumab treatment of 278 patients with ulcerative colitis who had completed a full year of treatment during the GEMINI 1 trial [Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Ulcerative Colitis] (N. Engl. J. Med. 2013;369:699-710). He reported that the percentage of patients in clinical remission grew from 66% after 52 weeks on treatment (the time of entry into the long-term phase of the study), to 77% after 80 weeks, which then dropped to 73% after 104 weeks. Patients with a clinical response increased from 78% after 52 weeks to 88% after 80 weeks, and then dropped to 83% after 104 weeks.

During weeks 53-104 on treatment the rates of adverse events, serious adverse events, serious infections, adverse events resulting in treatment discontinuation, enteric infections, and malignancies were all low and similar to the event rates seen among the patients randomized to placebo in the GEMINI 1 study. The same pattern of low event rates similar to the placebo patients also occurred for episodes of nasopharyngitis, upper respiratory tract infections, Clostridium difficile infections, and tuberculosis cases.

The results also showed better rates of long-term remission and response in the patients who had not previously failed treatment with an anti-TNF drug compared with those who had. Asked what might explain this, Dr. Feagan replied “we know that patients who fail prior drugs are always harder to treat.”

A very similar pattern occurred among the patients with Crohn’s disease who remained on vedolizumab for an additional 52 weeks following completion of a first year of treatment in the GEMINI 2 trial [the Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab in Patients with Moderate to Severe Crohn’s Disease], the pivotal, phase III study that led to the Crohn’s disease indication for vedolizumab (N. Engl. J. Med. 2013;369:711-21). Among 295 GEMINI 2 completer patients who remained on vedolizumab the rate of complete remissions was 57% at entry into the long-term study after 52 weeks on treatment, 64% after 80 weeks on treatment, and 61% after 104 weeks.The overall response rate was 81% at 52 weeks, 78% after 80 weeks, and 74% at 104 week, Dr. Rutgeerts reported. However, he noted that the study design allowed patients who experienced a flare to receive conventional rescue medications and still be counted a responder or in remission, which increased the number of patients in both of these two groups. “Patients did not need to be a responder or in remission at every time point,” he noted.

Once again, the rates of adverse events, serious adverse events, adverse events resulting in drug discontinuation, infections, serious infections, nasopharyngitis, and upper respiratory infection were all similar among patients on long-term vedolizumab compared with control patients with Crohn’s disease, Dr. Rutgeerts said.

The results suggest that with vedolizumab treatment of inflammatory bowel disease “once you achieve an effect it is long-lasting,” Dr. Rutgeerts said in an interview. But he cautioned that the long-lasting efficacy was achieved with treatment every 4 weeks. While this approach was safe, it would also be expensive in routine practice, he noted. “The safety looks good, but the cost would be very high.”

“A key concept of vedolizumab is that it builds efficacy over time,” commented Dr. Silvio Danese during a talk at the meeting. “Vedolizumab is not the fastest runner, but [treating inflammatory bowel disease] is a marathon, and the important thing is getting to the finish,” said Dr. Danese, head of the inflammatory bowel disease unit at the Humanitas Clinic and Research Center in Milan.

Dr. Danese also said that vedolizumab has a safety advantage over anti-TNF drugs when treating ulcerative colitis, although vedolizumab’s efficacy for treating steroid-refractory, fulminant ulcertative colitis remains untested. And he agreed that vedolizumab’s role as a go-to agent for inducing remission in active Crohn’s disease seems questionable.

Two other reports at the meeting further fleshed out vedolizumab’s performance in the GEMINI trials.

One analysis focused on 34 ulcerative colitis patients and 57 Crohn’s disease patients who responded to vedolizumab induction treatment but then lost their response when they subsequently received vedolizumab once every 8 weeks. These patients then switched to a regimen in which they received the drug every 4 weeks, and this resulted in significant reductions in disease activity among some of the ulcerative colitis and Crohn’s disease patients, reported Dr. Séverine Vermeire, a gastroenterologist and professor of medicine at Catholic University in Leuven.

She estimated that roughly a third of patients in both disease categories who lost response when put on the drug once every 8 weeks regained their complete response when their dosing frequency increased to once every 4 weeks.

The findings “suggest that dosing every 4 weeks may be beneficial for certain patients, with no apparent change in safety. These data provide insight into the potential value of dosing every 4 weeks, and in routine practice we will have patients who will lose response when they receive the drug every 8 weeks,” Dr. Vermeire said. “We should try to identify these patients early,” she said, and “we need to investigate why some patients lose their vedolizumab response.” The labeling for vedolizumab calls for treatment once every 8 weeks for maintenance.

Another analysis focused on the total of 1,443 inflammatory bowel disease patients who received vedolizumab for both induction and maintenance in the two GEMINI studies. This safety analysis examined the incidence of total infections and serious infections among patients who started on vedolizumab while on treatment with a corticosteroid, an immunomodulating drug, both of these agents, or neither of these agents.

The analysis showed similar rates of both total infections and serious infections in all four subgroups, suggesting no interaction between vedsolizumab and other immuno-active drugs in terms of vulnerability to infection, said Dr. Jean-Frédréic Colombel, professor of medicine and director of the inflammatory bowel disease center at Mount Sinai Medical Center in New York.

The low rate of serious infections, which occurred at 0.04-0.06 infections/person-year of follow-up was “reassuring,” said Dr. Colombel, but these infections were also so rare that it limited interpretation of the findings. He also noted that the analysis only focused on concomitant drugs at the time patients began vedolizumab treatment and did not take into account subsequent medication changes.

The GEMINI 1 and 2 trials were sponsored by Takeda, the company that markets vedolizumab (Entyvio). Dr. Feagan has been a consultant to Takeda, AbbVie, Merck, and UCB. Dr. Rutgeerts has been a consultant to Takeda, AbbVie, Janssen, Merch, and UCB. Dr. van der Woude has been an advisor to Dr. Falk, Abbvie, Janssen, Johnson&Johnson, and Cosmo. Dr. Danese has been a consultant to Takeda and to several other companies. Dr. Vermeire has been a consultant to Takeda and to several other companies. Dr. Colombel has been a consultant to Takeda and to several other companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

AGA Resources

• IBD Clinical Service  Line: www.gastro.org/practice/clinical-service-line/ibd-
clinical-service-line
• Clinical Decision Support Tool: Use of Biologic Drugs for Inflammatory Crohn’s Disease: http://campaigns.gastro.org/algorithms/crohns