Edward V. Loftus Jr, MD, AGAF

 

I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week^® 2017.

In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).

After several years of discussing the advent of biosimilars, one has arrived in the United States, infliximab-dyyb (Inflectra^®, Pfizer). This molecule was approved on the basis of a phase 3 trial in rheumatoid arthritis and a pharmacokinetic trial in psoriasis, and approval was extrapolated to most approved indications including IBD. Concerns had been raised that, despite the rigorous approval process, there might be subtle differences in biosimilars leading to suboptimal efficacy or to less favorable safety. A phase 3 trial of infliximab-dyyb in moderate to severe CD showed practically identical efficacy and safety compared with originator infliximab (Gastroenterology. 2017;152[5 Suppl 1]:S65). Another study compared switching from originator to infliximab-dyyb to continuation of originator infliximab among patients with a variety of conditions including IBD, and overall, there were no significant differences in clinical worsening between the “switchers” and those continued on the originator compound (Gastroenterology 2017;152[5 Suppl 1]:S65-6).

Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.

Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).

Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).

In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
 

 

Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

 

I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week^® 2017.

In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).

After several years of discussing the advent of biosimilars, one has arrived in the United States, infliximab-dyyb (Inflectra^®, Pfizer). This molecule was approved on the basis of a phase 3 trial in rheumatoid arthritis and a pharmacokinetic trial in psoriasis, and approval was extrapolated to most approved indications including IBD. Concerns had been raised that, despite the rigorous approval process, there might be subtle differences in biosimilars leading to suboptimal efficacy or to less favorable safety. A phase 3 trial of infliximab-dyyb in moderate to severe CD showed practically identical efficacy and safety compared with originator infliximab (Gastroenterology. 2017;152[5 Suppl 1]:S65). Another study compared switching from originator to infliximab-dyyb to continuation of originator infliximab among patients with a variety of conditions including IBD, and overall, there were no significant differences in clinical worsening between the “switchers” and those continued on the originator compound (Gastroenterology 2017;152[5 Suppl 1]:S65-6).

Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.

Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).

Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).

In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
 

 

Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

 

I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week^® 2017.

In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).

After several years of discussing the advent of biosimilars, one has arrived in the United States, infliximab-dyyb (Inflectra^®, Pfizer). This molecule was approved on the basis of a phase 3 trial in rheumatoid arthritis and a pharmacokinetic trial in psoriasis, and approval was extrapolated to most approved indications including IBD. Concerns had been raised that, despite the rigorous approval process, there might be subtle differences in biosimilars leading to suboptimal efficacy or to less favorable safety. A phase 3 trial of infliximab-dyyb in moderate to severe CD showed practically identical efficacy and safety compared with originator infliximab (Gastroenterology. 2017;152[5 Suppl 1]:S65). Another study compared switching from originator to infliximab-dyyb to continuation of originator infliximab among patients with a variety of conditions including IBD, and overall, there were no significant differences in clinical worsening between the “switchers” and those continued on the originator compound (Gastroenterology 2017;152[5 Suppl 1]:S65-6).

Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.

Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).

Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).

In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
 

 

Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.