On October 14th, 2015, Pfizer announced receipt of a Complete Response Letter (CRL) from the FDA regarding its recent supplemental New Drug Application (sNDA) for Xeljanz (tofacitinib) in moderate to severe plaque psoriasis.
The FDA accepted Pfizer’s filing in February 2015 based on data from the Phase III Oral treatment Psoriasis Trials (OPT) Program. A global, multi-study, clinical development program, OPT was designed to evaluate Xeljanz 5 mg and 10 mg twice daily in patients with the skin disorder.
Results from the trials suggest tofacitinib 10 mg and 5 mg tablets twice daily are statistically superior to placebo at 16 and 52 weeks for the co-primary efficacy endpoints Physician’s Global Assessment (PGA) response and Psoriasis Area and Severity Index (PASI75), two commonly used measures of efficacy. Both the tofacitinib doses also show statistically significant superiority over placebo for key secondary efficacy endpoints.
Efficacy may not be not enough
However, although the efficacy data presented are impressive, Xeljanz’s safety profile seems to be its "Achilles’ heel". The safety profile of tofacitinib in the OPT trials is similar to what has been previously observed: increased rates of gastrointestinal disorders, including pain and diarrhea, nausea, headaches, upper-respiratory and urinary tract infections, and increases in blood cholesterol and low-density lipoprotein compared to placebo.
Indeed, Xeljanz’s safety profile has been an issue of discussion since its initial 2012 FDA approval for adult patients with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to methotrexate. In the U.S., only the 5 mg dose was approved, and Xeljanz carries a black-box warning for the risk of serious infections and malignancies, as well as a Risk Evaluation and Mitigation Strategy (REMS). In Europe, due to a questionable risk-to-benefit ratio, the drug received a negative opinion from the Committee for Medicinal Products for Human Use (CHMP).
An already crowded marketplace
In its latest statement (October 14, 2015), Pfizer said they will work with the FDA to determine the appropriate path forward, including providing additional safety analysis. Assuming additional safety data will be sufficient for approval (which until we see the data we can only speculate), the question remains whether based on its efficacy, and history in RA, Xeljanz can compete in the psoriasis market.
- Six biologics are currently available for moderate to severe psoriasis, of which the TNF-alpha inhibitors (Janssen’s Remicade; Amgen’s Enbrel; AbbVie’s Humira) are often considered first-line therapy, primarily due to physicians’ long-term experience with the drugs. Biosimilars to the TNF-alpha inhibitors are due to enter the market, and assuming a discounted price, are likely to gain preference by physicians and payers.
- Approved in 2009, in clinical trials Janssen’s Stelara (IL-12/23 inhibitor) demonstrated superior efficacy over Enbrel. It is often the preferred second, and sometime first-line therapy, primarily due to its favorable safety profile and superior dosing convenience.
- In 2014, Celgene’s Otezla (PDE4 inhibitor) was the first oral therapy to gain FDA approval for psoriasis. Although the drug demonstrates only modest efficacy in moderate to severe psoriasis compared to the biologics, it has a favorable safety profile and a convenient oral formulation. Also approved for psoriatic arthritis in 2015, Otezla’s uptake and market share gains have been strong.
- Novartis’s Cosentyx (IL-17 inhibitor) is the most recent biologic approved in 2015. Pivotal clinical trials suggest superior efficacy over the other biologics and a favorable safety profile. With its promising mechanism of action, so far physicians have a positive view of the drug; it demonstrates strong uptake and market share.
- Several additional drugs are expected to enter the market starting in 2016, with promising efficacy and safety profiles.
Assuming Xeljanz meets the FDA’s approval for moderate to severe plaque psoriasis, the drug will face a very competitive market, where it must demonstrate significant superiority (preferably in head-to-head trials with a leading psoriasis therapy such as Humira, Stelara, or even Cosentyx) and a very favorable safety profile in order to gain uptake and market share.