Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Digestive Disease Week (DDW 2014)

Chicago, Illinois / May 3-6, 2014

Chicago - New biologic treatments for ulcerative colitis (UC) are being developed to offer advantages to patients with respect to administration route, dosing regimen and side effect profile; in addition, agents with different mechanisms of action are being developed for patients who fail or become intolerant to first-line treatment. At DDW 2014, new clinical data were presented on new monoclonal antibodies that have been either recently approved or are under regulatory review in North America and Europe.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

“Although medical therapy has come a long way since IBD was first recognized, significant numbers of patients do not benefit from current medications, and although surgical rates have declined, up to 20% of patients still go on to surgery,” said Dr. Gary. R. Lichtenstein, University of Pennsylvania School of Medicine, Philadelphia, addressing a congress plenary session. “The biologics are the most effective therapies we have for ulcerative colitis (UC), but studies have shown that less than 40% of patients achieve remission, hence there remains an unmet need for novel agents,” he stated.

Novel agents featured among the studies presented in Chicago, including the most recently approved tumor necrosis factor alpha (TNF) inhibitor, golimumab, and the second in a class of antiadhesion molecules, vedolizumab. Golimumab, the newest biologic to become available for the treatment of moderate to severe UC in adults with a previous inadequate response to, or medical contraindications for conventional therapy, is a human IgG1 monoclonal antibody administered by subcutaneous injection. It has also been approved to treat rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in Canada. Vedolizumab, a humanized, anti-a4b7 integrin monoclonal antibody administered intravenously, has recently been approved in Europe and the United States for treatment of UC and Crohn’s disease (CD).

Long-term Safety and Efficacy

Approval for golimumab in UC treatment was supported by data from the PURSUIT Phase 3 clinical trials. In the 54-week PURSUIT-Maintenance study, significantly higher clinical response rates to 50- and 100-mg doses of golimumab (47% and 51%) were seen in patients compared with placebo (31%; P=0.010 and P<0.001, respectively) (Sandborn WJ et al. Gastroenterology 2014;146:96-109). Adverse events observed and their incidence appeared similar to those described for other anti-TNF biologics, including serious infections, tuberculosis and malignancies. According to the PURSUIT-Maintenance study extension, this TNF inhibitor has continued to show a positive benefit/risk profile over 2 years, with clinical benefit including a reduction in corticosteroid use, reported lead investigator, Prof. Peter Gibson, Monash University, Melbourne, Australia (Abstract 1214). “No new safety signals were observed with continued treatment,” Prof. Gibson said. “Rates of infections, including tuberculosis and opportunistic infections, remained low and steady throughout the study. Malignancy rate and the incidence of deaths through 2 years of treatment were comparable to those observed through week 54.”

The study extension involved 203 patients who completed 52 weeks of maintenance treatment in the PURSUIT-Maintenance study. At week 104 of maintenance therapy, 62% had an Inflammatory Bowel Disease Questionnaire (IBDQ) remission (score ≥170) and among patients not on corticosteroids at week 54, 89% remained corticosteroid-free through week 104. “We know from this that golimumab has long-term efficacy, it has long-term safety, and these are all the key issues,” Prof. Gibson said. “Basically we see this agent being used in people who have particularly chronically active disease, who have limited options,” he said. “We now have a choice between infliximab, adalimumab, and golimumab.” Golimumab is the only TNF inhibitor administered subcutaneously with a 4-week dosing schedule for maintenance treatment, he noted.

Non-responders

In a Phase 3 induction and maintenance trial in UC patients, vedolizumab treatment was associated with a significantly greater clinical response rate at week 6 compared with placebo (47% vs 26%, P<0.001; GEMINI 1; Feagan BG et al. N Engl J Med 2013;369:699-710). In CD patients, vedolizumab did not induce a clinical response at week 6 (31% vs 26% with placebo, P=0.23) but showed benefit in maintaining remission in responders (36-39% at week 52 vs 22% with placebo, P<0.005; GEMINI 2; Sandborn WJ et al. N Engl J Med 2013;369:711-21). Analyses presented in Chicago showed that in both trials, although this did not reach statistically significance, the number of non-responders to vedolizumab induction therapy at week 6 who went on to clinical response or remission at weeks 10, 14 and 52 were numerically greater with continued vedolizumab (every 4 weeks) therapy compared with placebo. In GEMINI-2, the proportion of week 6 non-responders to vedolizumab in clinical remission or with a CDAI-100 response were numerically greater at week 10 to week 52 compared to placebo, reported lead investigator Dr. William J. Sandborn (University of California-San Diego, La Jolla), (Abstract Mo1217).

Exposure Response Relationships

No apparent correlation was detected between serum golimumab exposure and the occurrence of infections, serious infections, or serious adverse events (SAEs) in UC patients treated with 50 mg or 100 mg every 4 weeks over 1 year, according to a study of PURSUIT-Maintenance data (Abstract Mo1215). An exploratory analysis of data of pharmacokinetic exposure metrics and safety events, including infections, serious infections, and SAEs through week 54 of maintenance was carried out in 1227 patients who received anti-TNF or placebo in the PURSUIT-Maintenance study. Increased serum exposure, measured by cumulative AUC and expressed per quartile, showed no apparent increase in the rates of infections, serious infections, or SAEs. The AUC distribution in patients who experienced ≥1 safety event was comparable to that in patients with no safety events. These results were consistent when other pharmacokinetic exposure metrics (C_max, C_average, and C_trough) were assessed. The findings are similar to those observed in rheumatology patients treated with the subcutaneous TNF inhibitor, the investigators noted (Leu JH et al. Arthr Rheum 2013;65(S10):S123 
Abstract 292).

An apparent exposure-response relationship (ERR) after induction therapy observed with vedolizumab 300 mg in patients in the GEMINI 1 and 2 studies was confirmed in further analyses. Results for GEMINI 1 suggested that increasing vedolizumab Caverage increased the probability of clinical response and remission at week 6. Estimated ERRs were positive for both clinical response (P<0.01) and remission (P<0.01) (Abstract Mo1229). In GEMINI 2, a higher C_average increased the probability of clinical response and remission at week 6, with a lesser effect observed for clinical remission (Abstract Mo1231). In both analyses the ERR appeared to plateau at high Caverage values for both endpoints. No dependency was found for any covariates tested, such as prior TNF inhibitor use, albumin, C-reactive protein CRP), or fecal calprotectin levels.

Comparative Safety of Biologics

Golimumab and vedolizumab data were included in a study comparing the relative benefit versus harm for long-term monotherapy with biologic agents compared with thiopurines in UC, using a new metric developed by Dr. Eric D. Shah, Cedars-Sinai Medical Center,
Los Angeles, (Abstract 5). Data were extracted from 14 Phase 3 randomized, placebo-controlled trials of single-agent therapy in active UC, including 10 trials of biologics infliximab, adalimumab, golimumab, and vedolizumab and 4 trials of immunomodulators tacrolimus and 6-mercaptopurine/azathioprine. For each agent, Dr. Shah and his colleagues calculated the ratio of the number needed to harm (NNH), based on study withdrawals due to adverse events, divided by the number needed to treat (NNT) based on efficacy endpoints in clinical trials. For induction immunosuppressive therapy, there was no evidence for excess harm with tacrolimus, although an NNH of 14 (RR=2.8, 95% CI 0.7-10.5) was reported with immunosuppressive maintenance therapy. For biologics, the ratio was favourable for induction, maintenance, and combined induction/maintenance therapy. “On the other hand, our data suggest that azathioprine as monotherapy causes harm,” Dr. Shah added.

Summary

“The anti-TNFs are clearly the most effective and the least toxic medications approved for moderate to severe UC,” said Dr. Stephen B. Hanauer, Northwestern Feinberg School of Medicine, Chicago, Illinois. We now have another anti-TNF agent approved for the treatment of UC in Canada and an antiadhesion molecule under review. With new therapies becoming available, there is continued hope that more patients will achieve remission and even fewer will go on to surgery.