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Why ustekinumab dosing differs in Crohn’s disease
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
AGA Resource
AGA offers an IBD Clinical Service Line that provides tools to help you become more efficient, understand quality standards, and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/ibd
Meta-analysis compares infliximab with tacrolimus in ulcerative colitis
ORLANDO – Infliximab and tacrolimus each demonstrate efficacy for treatment of moderate to severe active ulcerative colitis in published studies. However, it remains unknown if one agent offers greater efficacy than the other in this patient population, so researchers in Japan conducted a meta-analysis to find out more.
Lead investigator Shinichi Kawano, MD, at Kyushu University, Fukuoka, Japan, and his colleagues searched PubMed for relevant studies up until August 2016. They conducted a systematic review and identified 79 potential studies of tumor necrosis factor blocker infliximab (Remicade, Janssen) and the calcineurin inhibitor tacrolimus (various brands) in this patient population. They ruled out the vast majority, 75 studies, for not directly comparing therapeutic efficacy. They also excluded one additional study for insufficient data on their five outcomes of interest: rates of clinical remission, clinical response, freedom from colectomy, adverse events, and serious adverse events. They focused on three 2016 retrospective studies with a total of 244 patients, and added 13 of their own patients, 5 taking infliximab and 8 taking tacrolimus, to their dataset.
Similarly, the short-term clinical response rate favored infliximab (overall RR, 1.55), but again the difference was not statistically significant.
The investigators found the rate of colectomy was comparable between patients taking infliximab and tacrolimus (overall RR, 1.01). They reported their findings in a poster presentation at the Advances in Inflammatory Bowel Diseases meeting, sponsored by the Crohn’s & Colitis Foundation of America.
The adverse event rate favored tacrolimus over infliximab, but it was not significant (overall RR, 0.23). The serious adverse event rate slightly favored tacrolimus as well (overall RR, 0.88). The incidences of adverse events and serious adverse events were comparable between the two groups, the study authors wrote.
The trials included in the meta-analysis looked at either adults only or adults and pediatric patients with active ulcerative colitis. In one study, there were 40 patients taking infliximab and 50 taking tacrolimus (Aliment Pharmacol Ther. 2016;43:705-16); in another 48 patients took infliximab and 47 took tacrolimus (Gastroenterol Res Pract. 2016;2016:3162595); and in the third study 30 were treated with infliximab and 29 with tacrolimus (Scand J Gastroenterol. 2016;51:700-5).
“This meta-analysis demonstrates equivalent therapeutic efficacy and safety between infliximab and tacrolimus,” the authors continued. Dr. Kawano said he was not surprised by the findings. “Because there are only three retrospective studies, it is reasonable that there is no significant difference in efficacy between infliximab and tacrolimus.”
However, he added, “We think that further prospective, comparative trials are needed.”
Dr. Kawano had no relevant financial disclosures.
ORLANDO – Infliximab and tacrolimus each demonstrate efficacy for treatment of moderate to severe active ulcerative colitis in published studies. However, it remains unknown if one agent offers greater efficacy than the other in this patient population, so researchers in Japan conducted a meta-analysis to find out more.
Lead investigator Shinichi Kawano, MD, at Kyushu University, Fukuoka, Japan, and his colleagues searched PubMed for relevant studies up until August 2016. They conducted a systematic review and identified 79 potential studies of tumor necrosis factor blocker infliximab (Remicade, Janssen) and the calcineurin inhibitor tacrolimus (various brands) in this patient population. They ruled out the vast majority, 75 studies, for not directly comparing therapeutic efficacy. They also excluded one additional study for insufficient data on their five outcomes of interest: rates of clinical remission, clinical response, freedom from colectomy, adverse events, and serious adverse events. They focused on three 2016 retrospective studies with a total of 244 patients, and added 13 of their own patients, 5 taking infliximab and 8 taking tacrolimus, to their dataset.
Similarly, the short-term clinical response rate favored infliximab (overall RR, 1.55), but again the difference was not statistically significant.
The investigators found the rate of colectomy was comparable between patients taking infliximab and tacrolimus (overall RR, 1.01). They reported their findings in a poster presentation at the Advances in Inflammatory Bowel Diseases meeting, sponsored by the Crohn’s & Colitis Foundation of America.
The adverse event rate favored tacrolimus over infliximab, but it was not significant (overall RR, 0.23). The serious adverse event rate slightly favored tacrolimus as well (overall RR, 0.88). The incidences of adverse events and serious adverse events were comparable between the two groups, the study authors wrote.
The trials included in the meta-analysis looked at either adults only or adults and pediatric patients with active ulcerative colitis. In one study, there were 40 patients taking infliximab and 50 taking tacrolimus (Aliment Pharmacol Ther. 2016;43:705-16); in another 48 patients took infliximab and 47 took tacrolimus (Gastroenterol Res Pract. 2016;2016:3162595); and in the third study 30 were treated with infliximab and 29 with tacrolimus (Scand J Gastroenterol. 2016;51:700-5).
“This meta-analysis demonstrates equivalent therapeutic efficacy and safety between infliximab and tacrolimus,” the authors continued. Dr. Kawano said he was not surprised by the findings. “Because there are only three retrospective studies, it is reasonable that there is no significant difference in efficacy between infliximab and tacrolimus.”
However, he added, “We think that further prospective, comparative trials are needed.”
Dr. Kawano had no relevant financial disclosures.
ORLANDO – Infliximab and tacrolimus each demonstrate efficacy for treatment of moderate to severe active ulcerative colitis in published studies. However, it remains unknown if one agent offers greater efficacy than the other in this patient population, so researchers in Japan conducted a meta-analysis to find out more.
Lead investigator Shinichi Kawano, MD, at Kyushu University, Fukuoka, Japan, and his colleagues searched PubMed for relevant studies up until August 2016. They conducted a systematic review and identified 79 potential studies of tumor necrosis factor blocker infliximab (Remicade, Janssen) and the calcineurin inhibitor tacrolimus (various brands) in this patient population. They ruled out the vast majority, 75 studies, for not directly comparing therapeutic efficacy. They also excluded one additional study for insufficient data on their five outcomes of interest: rates of clinical remission, clinical response, freedom from colectomy, adverse events, and serious adverse events. They focused on three 2016 retrospective studies with a total of 244 patients, and added 13 of their own patients, 5 taking infliximab and 8 taking tacrolimus, to their dataset.
Similarly, the short-term clinical response rate favored infliximab (overall RR, 1.55), but again the difference was not statistically significant.
The investigators found the rate of colectomy was comparable between patients taking infliximab and tacrolimus (overall RR, 1.01). They reported their findings in a poster presentation at the Advances in Inflammatory Bowel Diseases meeting, sponsored by the Crohn’s & Colitis Foundation of America.
The adverse event rate favored tacrolimus over infliximab, but it was not significant (overall RR, 0.23). The serious adverse event rate slightly favored tacrolimus as well (overall RR, 0.88). The incidences of adverse events and serious adverse events were comparable between the two groups, the study authors wrote.
The trials included in the meta-analysis looked at either adults only or adults and pediatric patients with active ulcerative colitis. In one study, there were 40 patients taking infliximab and 50 taking tacrolimus (Aliment Pharmacol Ther. 2016;43:705-16); in another 48 patients took infliximab and 47 took tacrolimus (Gastroenterol Res Pract. 2016;2016:3162595); and in the third study 30 were treated with infliximab and 29 with tacrolimus (Scand J Gastroenterol. 2016;51:700-5).
“This meta-analysis demonstrates equivalent therapeutic efficacy and safety between infliximab and tacrolimus,” the authors continued. Dr. Kawano said he was not surprised by the findings. “Because there are only three retrospective studies, it is reasonable that there is no significant difference in efficacy between infliximab and tacrolimus.”
However, he added, “We think that further prospective, comparative trials are needed.”
Dr. Kawano had no relevant financial disclosures.
AT AIBD 2016
Key clinical point: Infliximab and tacrolimus both demonstrate efficacy for active ulcerative colitis in published studies, but few direct comparisons exist.
Major finding: The reported rate of clinical remission with infliximab was higher than with tacrolimus (risk ratio, 1.17), but the difference was not statistically significant.
Data source: Meta-analysis of relevant articles identified in a PubMed search through August 2016.
Disclosures: Dr. Kawano had no relevant financial disclosures.
Systemic inflammation expands clinical challenge in IBD
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting. 
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.
To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.
“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”
A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.
Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.
Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”
Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?
“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”
The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”
It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”
A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”
“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”
Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”
Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”
The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
AT AIBD 2016
Key clinical point: Extra-intestinal manifestations of inflammatory bowel disease can leave gastroenterologists wondering about the best approach to treatment.
Major finding: Less gut-specific drug action may actually be better for these patients.
Data source: Panel discussion of challenging cases at AIBD 2016.
Disclosures: Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.
Intensifying vedolizumab could counter loss of response in IBD
ORLANDO – In a study of 644 people with moderate to severe inflammatory bowel disease treated with vedolizumab (Entyvio, Takeda Pharmaceuticals), 346 achieved remission or a significant response. This 54% response rate includes 192 people with Crohn’s disease and 154 others with ulcerative colitis.
However, after a median of 143 days, some of the initial responders experienced a loss of response to vedolizumab therapy.
“In our real-world study of vedolizumab use in patients with IBD predominantly refractory to anti-TNF [tumor necrosis factor] therapy, loss of response was observed in about 40% of patients at 12 months,” said Eugenia Shmidt, MD, a gastroenterology fellow at the Icahn School of Medicine at Mount Sinai hospital in New York City.
To counter the loss of response, Dr. Shmidt and her colleagues shortened the dosing interval of vedolizumab to either 4 or 6 weeks in a subgroup of 36 patients who lost response. They also shortened the dosing interval to try to attempt an initial response in a subgroup of 47 people who did not respond to initial induction therapy in the first place. “Dose intensification led to a successful recapture of response in 32% of patients who had initial response and in 19% of patients who did not have an initial response,” Dr. Shmidt said at the Advances in Inflammatory Bowel Diseases meeting.
“We find it interesting that there was greater success in recapturing significant response in patients who responded to vedolizumab initially compared to those who did not initially respond,” she said when asked if she found any of her findings surprising. “This emphasizes a likely need for different management strategies for initial vedolizumab responders and nonresponders, as well as early recognition of the need for dose optimization,” she added.
The study included adults with mild to moderate inflammatory bowel disease, based on clinical factors or confirmed through endoscopy. There were no significant differences in severity of disease between patients who were able to recapture response versus those were not. The mean age among the 374 participants with Crohn’s disease was 39 years; similarly, the mean age in the group of 270 with ulcerative colitis was 41 years. Mean duration of disease was 15 years and 9 years in the two groups, respectively.
To identify risk factors associated with loss of response to vedolizumab, Dr. Shmidt and her colleagues performed univariable and multivariable Cox proportional hazard analyses. They found concomitant use of an immunomodulator for Crohn’s disease was protective against loss of response (hazard ratio, 0.44). In the ulcerative colitis group, a baseline serum albumin level below a normal value achieved lower vedolizumab response rates; a value below 3.2 g/dL was an independent predictor of cumulative loss of response over time (HR, 2.39).
Inflammatory bowel disease patients treated at higher volume centers, which were defined as enrolling at least 100 patients in the study, had higher rates of loss of response to vedolizumab (HR, 1.92 on multivariable analysis).
The multicenter VICTORY consortium coinvestigators in this study are affiliated with Mayo Clinic in Rochester, Minn.; Cleveland Clinic Foundation in Ohio; University of California, San Diego; New York University in New York City; Montefiore Medical Center/Albert Einstein College of Medicine in the Bronx, N.Y.; and Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
Future studies are warranted to evaluate the pharmacodynamics and pharmacokinetics of vedolizumab, the authors noted, as well as to determine an optimal dosing strategy among people with high drug clearance.
The study was funded in part by Takeda Pharmaceuticals. Dr. Eugenia Shmidt did not have any relevant disclosures. The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
ORLANDO – In a study of 644 people with moderate to severe inflammatory bowel disease treated with vedolizumab (Entyvio, Takeda Pharmaceuticals), 346 achieved remission or a significant response. This 54% response rate includes 192 people with Crohn’s disease and 154 others with ulcerative colitis.
However, after a median of 143 days, some of the initial responders experienced a loss of response to vedolizumab therapy.
“In our real-world study of vedolizumab use in patients with IBD predominantly refractory to anti-TNF [tumor necrosis factor] therapy, loss of response was observed in about 40% of patients at 12 months,” said Eugenia Shmidt, MD, a gastroenterology fellow at the Icahn School of Medicine at Mount Sinai hospital in New York City.
To counter the loss of response, Dr. Shmidt and her colleagues shortened the dosing interval of vedolizumab to either 4 or 6 weeks in a subgroup of 36 patients who lost response. They also shortened the dosing interval to try to attempt an initial response in a subgroup of 47 people who did not respond to initial induction therapy in the first place. “Dose intensification led to a successful recapture of response in 32% of patients who had initial response and in 19% of patients who did not have an initial response,” Dr. Shmidt said at the Advances in Inflammatory Bowel Diseases meeting.
“We find it interesting that there was greater success in recapturing significant response in patients who responded to vedolizumab initially compared to those who did not initially respond,” she said when asked if she found any of her findings surprising. “This emphasizes a likely need for different management strategies for initial vedolizumab responders and nonresponders, as well as early recognition of the need for dose optimization,” she added.
The study included adults with mild to moderate inflammatory bowel disease, based on clinical factors or confirmed through endoscopy. There were no significant differences in severity of disease between patients who were able to recapture response versus those were not. The mean age among the 374 participants with Crohn’s disease was 39 years; similarly, the mean age in the group of 270 with ulcerative colitis was 41 years. Mean duration of disease was 15 years and 9 years in the two groups, respectively.
To identify risk factors associated with loss of response to vedolizumab, Dr. Shmidt and her colleagues performed univariable and multivariable Cox proportional hazard analyses. They found concomitant use of an immunomodulator for Crohn’s disease was protective against loss of response (hazard ratio, 0.44). In the ulcerative colitis group, a baseline serum albumin level below a normal value achieved lower vedolizumab response rates; a value below 3.2 g/dL was an independent predictor of cumulative loss of response over time (HR, 2.39).
Inflammatory bowel disease patients treated at higher volume centers, which were defined as enrolling at least 100 patients in the study, had higher rates of loss of response to vedolizumab (HR, 1.92 on multivariable analysis).
The multicenter VICTORY consortium coinvestigators in this study are affiliated with Mayo Clinic in Rochester, Minn.; Cleveland Clinic Foundation in Ohio; University of California, San Diego; New York University in New York City; Montefiore Medical Center/Albert Einstein College of Medicine in the Bronx, N.Y.; and Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
Future studies are warranted to evaluate the pharmacodynamics and pharmacokinetics of vedolizumab, the authors noted, as well as to determine an optimal dosing strategy among people with high drug clearance.
The study was funded in part by Takeda Pharmaceuticals. Dr. Eugenia Shmidt did not have any relevant disclosures. The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
ORLANDO – In a study of 644 people with moderate to severe inflammatory bowel disease treated with vedolizumab (Entyvio, Takeda Pharmaceuticals), 346 achieved remission or a significant response. This 54% response rate includes 192 people with Crohn’s disease and 154 others with ulcerative colitis.
However, after a median of 143 days, some of the initial responders experienced a loss of response to vedolizumab therapy.
“In our real-world study of vedolizumab use in patients with IBD predominantly refractory to anti-TNF [tumor necrosis factor] therapy, loss of response was observed in about 40% of patients at 12 months,” said Eugenia Shmidt, MD, a gastroenterology fellow at the Icahn School of Medicine at Mount Sinai hospital in New York City.
To counter the loss of response, Dr. Shmidt and her colleagues shortened the dosing interval of vedolizumab to either 4 or 6 weeks in a subgroup of 36 patients who lost response. They also shortened the dosing interval to try to attempt an initial response in a subgroup of 47 people who did not respond to initial induction therapy in the first place. “Dose intensification led to a successful recapture of response in 32% of patients who had initial response and in 19% of patients who did not have an initial response,” Dr. Shmidt said at the Advances in Inflammatory Bowel Diseases meeting.
“We find it interesting that there was greater success in recapturing significant response in patients who responded to vedolizumab initially compared to those who did not initially respond,” she said when asked if she found any of her findings surprising. “This emphasizes a likely need for different management strategies for initial vedolizumab responders and nonresponders, as well as early recognition of the need for dose optimization,” she added.
The study included adults with mild to moderate inflammatory bowel disease, based on clinical factors or confirmed through endoscopy. There were no significant differences in severity of disease between patients who were able to recapture response versus those were not. The mean age among the 374 participants with Crohn’s disease was 39 years; similarly, the mean age in the group of 270 with ulcerative colitis was 41 years. Mean duration of disease was 15 years and 9 years in the two groups, respectively.
To identify risk factors associated with loss of response to vedolizumab, Dr. Shmidt and her colleagues performed univariable and multivariable Cox proportional hazard analyses. They found concomitant use of an immunomodulator for Crohn’s disease was protective against loss of response (hazard ratio, 0.44). In the ulcerative colitis group, a baseline serum albumin level below a normal value achieved lower vedolizumab response rates; a value below 3.2 g/dL was an independent predictor of cumulative loss of response over time (HR, 2.39).
Inflammatory bowel disease patients treated at higher volume centers, which were defined as enrolling at least 100 patients in the study, had higher rates of loss of response to vedolizumab (HR, 1.92 on multivariable analysis).
The multicenter VICTORY consortium coinvestigators in this study are affiliated with Mayo Clinic in Rochester, Minn.; Cleveland Clinic Foundation in Ohio; University of California, San Diego; New York University in New York City; Montefiore Medical Center/Albert Einstein College of Medicine in the Bronx, N.Y.; and Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
Future studies are warranted to evaluate the pharmacodynamics and pharmacokinetics of vedolizumab, the authors noted, as well as to determine an optimal dosing strategy among people with high drug clearance.
The study was funded in part by Takeda Pharmaceuticals. Dr. Eugenia Shmidt did not have any relevant disclosures. The meeting was sponsored by the Crohn’s & Colitis Foundation of America.
Key clinical point: Some patients with moderate to severe inflammatory bowel disease experience loss of response to vedolizumab over time.
Major finding: At a median 143 days, 41% of patients with Crohn’s disease and 42% of those with ulcerative colitis who initially had a strong response or experienced remission with vedolizumab experienced subsequent loss of response.
Data source: Study of 644 patients with moderate to severe Crohn’s disease or ulcerative colitis followed for 12 months.
Disclosures: The study was funded in part by Takeda Pharmaceuticals. Dr. Eugenia Shmidt did not have any relevant disclosures.
Why ustekinumab dosing differs in Crohn’s disease
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
ORLANDO – Preclinical studies and years of clinical experience using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech) in psoriasis and psoriatic arthritis offer important clues to any gastroenterologist perplexed by the official Food and Drug Administration indication, dosing frequency, and intensity for Crohn’s disease. Phase II and phase III findings also reveal where the monoclonal antibody may offer particular advantages, compared with other agents.
“Ustekinumab landed in your lap in September. You’re probably all trying to figure out how to get the ID formulation paid for with insurance,” William J. Sanborn, MD, professor and chief of the division of gastroenterology at the University of California, San Diego, said at the Advances in Inflammatory Bowel Diseases meeting. “But this is now the reality that you have this in your Crohn’s practice.”
The FDA approved ustekinumab to treat adults with moderately to severely active Crohn’s disease who 1) failed or were intolerant to immune modulators or corticosteroids but did not fail tumor necrosis factor (TNF) blockers or 2) failed or were intolerant to one or more TNF blockers. Dr. Sanborn and colleagues observed a significant induction of clinical response in a subgroup of patients who previously failed a TNF blocker in an early efficacy study (Gastroenterology. 2008;135:1130-41). “This is where the idea of initially focusing on TNF failures came from,” he added at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
Induction dosing in Crohn’s disease is intravenous versus subcutaneous in psoriasis and psoriatic arthritis, in part because of the same study. “It looked like relatively better bioavailability and relatively better effect with intravenous dosing,” Dr. Sanborn said. “In Crohn’s disease, it’s a completely different animal.”
Official induction dosing is approximately 6 mg/kg in three fixed doses according to patient weight in Crohn’s disease. The 6-mg/kg dose yielded the most consistent response, compared with 1-mg/kg or 3-mg/kg doses in a subsequent phase IIb study (N Engl J Med. 2012;367:1519-28).
The most consistent induction results at weeks 6 and 8 were observed with 6 mg/kg ustekinumab versus 1 mg/kg or 3 mg/kg.
Dr. Sanborn and coinvestigators also saw “numeric differences in drug versus placebo for remission at 6 and 8 weeks “but it was not that clear from the phase II trial what the remission efficacy was, so that needed more exploration to really understand.”
Another distinction for ustekinumab in Crohn’s disease is the approved maintenance dosing of 90 mg subcutaneously every 8 weeks versus a 12-week interval recommended for psoriasis. “Why so much more in Crohn’s disease, and is that necessary?” Dr. Sanborn asked.
Based on changes in C-reactive protein levels and a “rapid drop” in Crohn’s Disease Activity Index scores by 4 weeks, “clearly efficacy was there for induction,” he said. Ustekinumab has a “quick onset – analogous to the TNF blockers.”
“These were quite encouraging data, and paved the way to move on to phase III [studies],” Dr. Sanborn said. The preclinical studies up to this point focused on patients with Crohn’s disease who previously failed TNF blockers. However, “in clinical practice, we would be interested to know if it would work in anti-TNF naive or nonfailures as well.”
So two subsequent studies assessed safety and efficacy in a TNF blocker–failure population (UNITI-1 trial. Inflamm. Bowel Dis. 2016 Mar;22 Suppl 1:S1) and a non-TNF failure population of patients who did fail previous conventional therapy such as steroids or immunomodulators (UNITI-2 trial).
Clinical response and remission steadily rose following induction up to a significant difference versus placebo at 8 weeks in the non–TNF failure population. “Remember, in the phase IIa study, the remission rates were not as clear-cut, so this really nails down this as a good drug in both patient populations,” Dr. Sanborn said.
To evaluate long-term maintenance, investigators rerandomized all participants in the UNITI-1 and UNITI-2 studies. They saw a 15% gain in clinical remission out to week 44, compared with placebo. Dr. Sanborn noted that ustekinumab has a relatively long half-life, so the difference in patients switched to placebo may not have been as striking. “In practice it’s important to know the on-time and off-time of this agent, and I think the clinical trials make that clear.”
The trials also show that 12-week dosing works, Dr. Sanborn said. “You see about 20% gain for every 8-week dosing. You get extra 5% or 10% extra on all outcome measures at 8 weeks, compared to 12 weeks dosing, with no difference in safety signals.” He added, “So more intensive dosing of 90 mg every 8 weeks is what ended up getting approved in the United States.”
Safety profile
So what does all the preclinical evidence suggest about safety of ustekinumab? The UNITI trials combined included more than 1,000 patients, and there were no deaths, Dr. Sanborn said. “Usually with TNF blockers in 1,000 patients you would see a few deaths.”
Patient withdrawals from the preclinical studies were also relatively low, Dr. Sanborn reported. “With ustekinumab monotherapy, drug withdrawal is only 3% or 4%, so it seems to be different from TNF blockers in that sense [too].”
In addition, the rates of adverse events were similar between placebo (83.5%) and ustekinumab’s combined every 8 week and every 12 week dosing groups through 44 weeks (81.0%), Dr. Sanborn said. The rates of serious adverse events were likewise similar, 15.0% and 11.0%, respectively. Reported malignancy included two cases of basal cell skin cancers, one in the placebo group and one in the every-8-week dosing group, he added.
“So all those black box warnings you’re used to worrying about with TNF blockers – serious infections, about opportunistic infections, malignancy – there is no black box warning with this agent around that.”
Dr. Sanborn noted that the FDA labeling reports infections. “We know Crohn’s disease patients are [also] getting azathioprine, steroids, methotrexate, so you will see some infections, but there wasn’t a consistent opportunistic infection signal.”
One case of reversible posterior leukoencephalopathy syndrome is included on the labeling. Dr. Sanborn also put this in perspective: “With all the experience in psoriasis and psoriatic arthritis, and the clinical trials [in IBD], there is just one case. So the relationship is not very clear.”
“The safety signals with ustekinumab are really very good. It seems to be an extremely safe agent – we really don’t see much in terms of infections,” Brian Feagan, MD, an internist and gastroenterologist at the University of Western Ontario in London, said in a separate presentation at the conference. “We don’t have a lot of long-term experience with ustekinumab in Crohn’s disease, but we have a lot of experience in psoriasis, and it’s a safe drug.”
“Ustekinumab may be our first really valid monotherapy, with less immunogenicity,” Dr. Feagan said.
EXPERT ANALYSIS FROM AIBD 2016
Initial data on biosimilars in IBD are encouraging, but more needed
ORLANDO – The rapidly evolving field of biologic and biosimilar agents can leave gastroenterologists reeling in terms of what role biosimilars will play in practice and how best to utilize them for a patient with ulcerative colitis or Crohn’s disease. Limited data so far – primarily case series and limited postmarketing findings – suggest that a biosimilar can be as safe and effective as the innovator biologic. However, more rigorous research and more research overall are needed to confirm this comparative efficacy and to address unanswered questions around switching and cost effectiveness.
The uncertainty stems in part from a lack of prospective, randomized comparison studies to guide evidence-based clinical practice, Miguel D. Regueiro, MD, gastroenterologist and IBD clinical medical director at the University of Pittsburgh Medical Center.
As clinicians await more definitive evidence, a number of limited studies have been published in the past year assessing biosimilars in inflammatory bowel disease (IBD). “The clinical response ranges were high, in most studies more than two-thirds [of patients] had a response, but again there are no head-to-head studies,” Dr. Regueiro said at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
“We don’t have the data yet in IBD.”
A review of the literature on anti-tumor necrosis factor antibody biosimilar Inflectra (infliximab-dyyb, Celltrion) supports its bioequivalence to infliximab (Remicade, Janssen) in ankylosing spondylitis (Aliment Pharmacol Ther. 2015;42:1158-69). However, dosing regimens and use of concomitant medications differ in the IBD population, the investigators noted, so the case series and short-duration postmarketing results published in the literature leave unanswered questions for gastroenterologists.
Just because biosimilars appear bioequivalent so far in IBD, it does not mean this new class of agents is free of controversy. When the U.S. Food and Drug Administration approved Inflectra in April 2016 based on evidence in ankylosing spondylitis and rheumatoid arthritis, it extrapolated the approval to all conditions for which infliximab is approved, including ulcerative colitis and Crohn’s disease. However, this “highly controversial approach has been criticized by various rheumatology and gastroenterology professional societies around the world,” according to authors of a critical review on biosimilars in IBD (Inflamm Bowel Dis. 2016;22:2513-26).
Clinicians can safely switch patients from infliximab to Inflectra, according to the noninferiority phase IV NOR-SWITCH study conducted in Norway. Researchers assessed almost 500 patients on stable infliximab treatment for a minimum of 6 months prior to switching. However, this was a multi-indication study that included inflammatory bowel disease patients and many others, Dr. Regueiro said. “When you read the fine print in these studies, especially with Crohn’s disease, you start to see differences,” he added.
Although the evidence is encouraging so far, “we do not have prospective, comparative studies yet.”
During a Q&A panel session, a meeting attendee asked if clinicians will be able to use the same laboratory assay used to check a biologic’s drug and antibody levels for its biosimilar. “Our understanding is you will not be able to use the same assay as you do for infliximab. There are companies developing assays specifically for the biosimilars, and I think they will be available in addition to the ones for the innovator agents.”
ORLANDO – The rapidly evolving field of biologic and biosimilar agents can leave gastroenterologists reeling in terms of what role biosimilars will play in practice and how best to utilize them for a patient with ulcerative colitis or Crohn’s disease. Limited data so far – primarily case series and limited postmarketing findings – suggest that a biosimilar can be as safe and effective as the innovator biologic. However, more rigorous research and more research overall are needed to confirm this comparative efficacy and to address unanswered questions around switching and cost effectiveness.
The uncertainty stems in part from a lack of prospective, randomized comparison studies to guide evidence-based clinical practice, Miguel D. Regueiro, MD, gastroenterologist and IBD clinical medical director at the University of Pittsburgh Medical Center.
As clinicians await more definitive evidence, a number of limited studies have been published in the past year assessing biosimilars in inflammatory bowel disease (IBD). “The clinical response ranges were high, in most studies more than two-thirds [of patients] had a response, but again there are no head-to-head studies,” Dr. Regueiro said at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
“We don’t have the data yet in IBD.”
A review of the literature on anti-tumor necrosis factor antibody biosimilar Inflectra (infliximab-dyyb, Celltrion) supports its bioequivalence to infliximab (Remicade, Janssen) in ankylosing spondylitis (Aliment Pharmacol Ther. 2015;42:1158-69). However, dosing regimens and use of concomitant medications differ in the IBD population, the investigators noted, so the case series and short-duration postmarketing results published in the literature leave unanswered questions for gastroenterologists.
Just because biosimilars appear bioequivalent so far in IBD, it does not mean this new class of agents is free of controversy. When the U.S. Food and Drug Administration approved Inflectra in April 2016 based on evidence in ankylosing spondylitis and rheumatoid arthritis, it extrapolated the approval to all conditions for which infliximab is approved, including ulcerative colitis and Crohn’s disease. However, this “highly controversial approach has been criticized by various rheumatology and gastroenterology professional societies around the world,” according to authors of a critical review on biosimilars in IBD (Inflamm Bowel Dis. 2016;22:2513-26).
Clinicians can safely switch patients from infliximab to Inflectra, according to the noninferiority phase IV NOR-SWITCH study conducted in Norway. Researchers assessed almost 500 patients on stable infliximab treatment for a minimum of 6 months prior to switching. However, this was a multi-indication study that included inflammatory bowel disease patients and many others, Dr. Regueiro said. “When you read the fine print in these studies, especially with Crohn’s disease, you start to see differences,” he added.
Although the evidence is encouraging so far, “we do not have prospective, comparative studies yet.”
During a Q&A panel session, a meeting attendee asked if clinicians will be able to use the same laboratory assay used to check a biologic’s drug and antibody levels for its biosimilar. “Our understanding is you will not be able to use the same assay as you do for infliximab. There are companies developing assays specifically for the biosimilars, and I think they will be available in addition to the ones for the innovator agents.”
ORLANDO – The rapidly evolving field of biologic and biosimilar agents can leave gastroenterologists reeling in terms of what role biosimilars will play in practice and how best to utilize them for a patient with ulcerative colitis or Crohn’s disease. Limited data so far – primarily case series and limited postmarketing findings – suggest that a biosimilar can be as safe and effective as the innovator biologic. However, more rigorous research and more research overall are needed to confirm this comparative efficacy and to address unanswered questions around switching and cost effectiveness.
The uncertainty stems in part from a lack of prospective, randomized comparison studies to guide evidence-based clinical practice, Miguel D. Regueiro, MD, gastroenterologist and IBD clinical medical director at the University of Pittsburgh Medical Center.
As clinicians await more definitive evidence, a number of limited studies have been published in the past year assessing biosimilars in inflammatory bowel disease (IBD). “The clinical response ranges were high, in most studies more than two-thirds [of patients] had a response, but again there are no head-to-head studies,” Dr. Regueiro said at the meeting sponsored by the Crohn’s & Colitis Foundation of America.
“We don’t have the data yet in IBD.”
A review of the literature on anti-tumor necrosis factor antibody biosimilar Inflectra (infliximab-dyyb, Celltrion) supports its bioequivalence to infliximab (Remicade, Janssen) in ankylosing spondylitis (Aliment Pharmacol Ther. 2015;42:1158-69). However, dosing regimens and use of concomitant medications differ in the IBD population, the investigators noted, so the case series and short-duration postmarketing results published in the literature leave unanswered questions for gastroenterologists.
Just because biosimilars appear bioequivalent so far in IBD, it does not mean this new class of agents is free of controversy. When the U.S. Food and Drug Administration approved Inflectra in April 2016 based on evidence in ankylosing spondylitis and rheumatoid arthritis, it extrapolated the approval to all conditions for which infliximab is approved, including ulcerative colitis and Crohn’s disease. However, this “highly controversial approach has been criticized by various rheumatology and gastroenterology professional societies around the world,” according to authors of a critical review on biosimilars in IBD (Inflamm Bowel Dis. 2016;22:2513-26).
Clinicians can safely switch patients from infliximab to Inflectra, according to the noninferiority phase IV NOR-SWITCH study conducted in Norway. Researchers assessed almost 500 patients on stable infliximab treatment for a minimum of 6 months prior to switching. However, this was a multi-indication study that included inflammatory bowel disease patients and many others, Dr. Regueiro said. “When you read the fine print in these studies, especially with Crohn’s disease, you start to see differences,” he added.
Although the evidence is encouraging so far, “we do not have prospective, comparative studies yet.”
During a Q&A panel session, a meeting attendee asked if clinicians will be able to use the same laboratory assay used to check a biologic’s drug and antibody levels for its biosimilar. “Our understanding is you will not be able to use the same assay as you do for infliximab. There are companies developing assays specifically for the biosimilars, and I think they will be available in addition to the ones for the innovator agents.”
AT AIBD 2016
Key clinical point: Initial research on biosimilars in ulcerative colitis and Crohn’s disease suggests similar efficacy and safety to originator biologic agents, which researchers hope to confirm in larger, prospective studies underway.
Major finding: The clinical response ranges were high – in most studies more than two-thirds of patients had a response to a biosimilar agent.
Data source: Literature review, expert opinion.
Disclosures: Dr. Regueiro reported he is a consultant for AbbVie, Janssen, Pfizer, Takeda, and UCB.