Recently, Galapagos NV and Gilead entered a partnership, potentially worth more than $2 billion, to develop Galapagos’s oral JAK1 inhibitor, filgotinib, for inflammatory diseases.
Earlier in December 2015, Galapagos announced positive interim Phase II Crohn’s disease results for filgotinib. Based on the data presented, 48% of moderate to severe CD patient treated with filgotinib achieved clinical remission at 10 weeks compared to 23% placebo (p=0.0067); clinical response (CDAI decrease of 100 points or more) as well improvement in patients’ quality of life were also met in the study. According to the company’s CEO, results from the Phase II trial merit moving the drug into a Phase III Crohn's program “as soon as possible”.
Filgotinib is not the only JAK inhibitor to be tested in Crohn’s disease. AbbVie which in September 2015 ended its licensing agreement with Galapagos in order to develop its own JAK1 inhibitor, ABT-494, is currently recruiting patients for a Phase II trial in Crohn’s disease patients who failed TNF-alpha inhibitors.
Pfizer, too, has been testing its JAK inhibitor tofacitinib (Xeljanz) in inflammatory bowel disease patients for quite a while now. Although in ulcerative colitis, tofacitinib has been very promising in clinical trials, in Crohn’s disease, Phase II data were less promising, with no statistically significant differences in clinical response and clinical remission between the drug and placebo; although reductions in C-reactive protein and fecal calprotectin levels among patients given the higher dose of tofacitinib indicate its biologic activity. During Pfizer’s recent Q3 earning call (October, 2015), the company announced its decision to deprioritize tofacitnib’s development in Crohn’s disease and focus its development on rheumatoid arthritis, psoriatic arthritis and ulcerative colitis.
A Different JAK inhibitor?
So the question remains, what makes Galapagos’s JAK inhibitor different? Why the excitement based on the successful Phase II trial?
Since we are yet to see results from the ABT-494 trial in CD patients, let’s for now focus on filgotinib and tofacitinib. While tofacitinib blocks JAK 1, 2 and 3; filgotinib is a selective inhibitors of JAK1, which could result in better efficacy and safety. Considering the patient population in each of the trials, both trials looked at moderate to severe CD patients with a CDAI score between 220 and 450; however, while in the tofacitinib trial, clinical response and remission were evaluated at 4 weeks, in the filgotinib trial, clinical response and remission were evaluated at 10 weeks.
Perhaps, as seen with other therapies for IBD, the tofacitinib response is not immediate, and may require a longer time period for response. Indeed, an 8-week trial of tofacitinib in patients with moderate-to-severe ulcerative colitis was more effective in the induction of clinical response, clinical remission, and mucosal healing, as well as the reduction of CRP and fecal calprotectin concentrations, vs. placebo. Whether this relates to the difference between UC and CD, or the duration of treatment needs further studies. In any case, thus far, both drugs have looked only at induction of remission; further analysis is required to elucidate the drugs’ maintenance of clinical remission over a longer time duration.
With regards to safety, the tofacitinib trial in CD was too short and too small of a sample size to come to any concrete conclusion regarding tofacitinib’s safety profile in CD.
However, in rheumatoid arthritis, where the drug is FDA approved, the drug carries a black-box warning for the risk of serious infections, and for malignancies, as well as a Risk Evaluation and Mitigation Strategy (REMS); and has demonstrated increase rates of gastrointestinal disorders, including pain and diarrhea, nausea, headaches, upper-respiratory and urinary tract infections, and increase in blood cholesterol and low-density lipoprotein compared to placebo. Results from the trial in UC showed similar adverse events.
Based on the presented results however, filgotinib was well tolerated, with adverse events not significantly different from placebo with regards to infections, gastrointestinal disorders, and nervous system disorders. However, this too was a short study of 10 weeks, and longer safety studies are required in order to assess the drug’s safety profile.
A Market with an Unmet Need
Infliximab (Remicade) was the first biologic to be approved for the treatment of moderate to severe CD patients back in 1998.
Since then, several more TNF-alpha inhibitors have been approved for the indication, some administered as subcutaneous formulation, which has much advantage to patients with a chronic condition requiring once or twice-monthly dosing. Yet, all are relatively similar with regards to efficacy (although no head-to-head studies have been reported to date), and all carry a black-box warning with regards to safety.
More recently, a gut-specific intravenous cell-adhesion molecule inhibitor (vedolizumab; Takeda’s Entyvio) was approved for the treatment of moderate to severe CD patients; but although it has a better safety profile, it too, is not a home-run, with better efficacy results seen in UC than in CD. Other therapies are currently in development, and results from the Phase III induction and maintenance trials will decide on their significance in the treatment algorithm.
Of significant interest is Celgene's oral SMAD7 inhibitor, mongersen, which demonstrated a statistically significant improvement over placebo in the induction of remission at 2 weeks (65% vs. 10% placebo), a considerable difference compared to filgotinib at the same time point. Although worth noting that based on the patient baseline demographics at the start of the trial, the mongersen trial had patients with a lower initial CDAI score compared to the tofacitinib and filgotinib trial (meaning, the patients may have been slightly less severe).
As the race for the next generation moderate to severe CD therapy continues, the oral therapies are likely to have a great advantage, especially if significant improvement in efficacy and quality of life is demonstrated in the TNF-naive patient population. However, it is much too early to jump to conclusions as these are still data based on short-term Phase II studies only; more studies, in particular long-term maintenance studies are required.