Tofacitinib: Sacrificing Safety for Novelty?

Tofacitinib (tasocitinib, CP-690550), Pfizer’s novel Janus Kinase 3 (JAK) inhibitor for the treatment of rheumatoid arthritis (RA), had an anticipated FDA PDUFA (Prescription Drug User Fee Act) date for, August 21, 2012.

The FDA has just announced it has extended the review period of tofacitinib by three months. Interestingly, earlier in August, more data from The ORAL Start Phase III clinical trials were submitted by Pfizer for review, thus pushing the anticipated PDUFA date potentially into Q4.

The safety profile more than the efficacy profile of tofacitinib was brought into question, even during the May 2012 FDA advisory panel meeting.

The oral JAK3 therapy is also in Phase III for other indications, such as psoriasis (oral) and ulcerative colitis (UC), and Phase II for psoriatic arthritis, ankylosing spondylitis, psoriasis (topical), and Crohn’s disease.

Tofacitinib targets the JAK pathway, thus disrupting the intracellular signal pathway which is used by cytokines to regulate immune responses.

Tofacitinib is selective for JAK3, as it is most associated with inflammation, but it overlaps JAK1 and JAK2. This therapy has been shown to prevent inflammation caused by proliferation and cytokine overexpression.

Subsequently, it was shown to prevent further radiographic progression of joint erosion as well. Tofacitinib has been compared to Abbott’s Humira and in a 12-month trial tofacitinib was found to be statistically superior to placebo and similarly effective to Humira.

However, the abundance of safety data accumulated does not mean that tofacitinib comes without baggage. Clinical trial designs, dosage of tofacitinib, and patient populations have differed, not to mention 12 deaths that occurred during trials.

With this said, a definitive conclusion about its treatment effect has come into question, which may have spurred the submission of extra data.

On August 15, 2012, Pfizer released promising tofacitinib results for the treatment of UC. In a randomized trial, 194 patients with moderate to severe UC were given treatment or placebo in a dose-ranging Phase II trial.

Within eight weeks, almost 80% of the treatment arm achieved a clinical response compared with 42% from the placebo group. Clinical remission was achieved in close to 48% and 10% of the treatment arm and placebo group, respectively.

While patients achieved some disease remission, the safety profile was curiously similar, but oddly different to what was recorded from previous RA studies. These statistical changes from the studies were recognized and compared.

In the RA and UC clinical studies, the higher doses of 10mg and 15mg, respectively, had more adverse effects (AEs) than the lower doses and those given placebo.

The AEs reported from the UC clinical trials were similar to those from the RA clinical trials in that cholesterol levels increased, as did infections, while neutrophil counts decreased.

However, hematological laboratory values for liver enzymes, serum creatinine, and hemoglobin were unchanged during the UC trials. This was not the case during the RA studies; these same laboratory values actually decreased, thus becoming flagged warnings, and may have contributed to one or more of the deaths. With values compared, it appears that doses of 10mg and higher of tofacitinib produce undesired AEs. Of particular interest is the type of background medications given to the patients during the RA and UC studies.

Background therapy of methotrexate (MTX) was given to RA patients during one 12-month Phase III study involving 717 RA patients.

During the UC Phase II study, background medication included mesalamine or prednisone, but not azathioprine or MTX, due to their immunosuppressant effect. It is likely the background medications may play a role in increased AEs; however, even with tofacitinib as a monotherapy, laboratory values were seen as undesirable.

The mechanism of action or the formulation of tofacitinib may come into question, thus leaving us to wonder whether novelty is trumping safety of the drug.

As requested by the FDA, Pfizer submitted more supporting Phase III data several weeks before the anticipated FDA PDUFA date for tofacitinib.

GlobalData believes it is possible that Pfizer has felt the scrutiny over the safety of tofacitinib and submitted more data in hopes to cement an approval.

Also, GlobalData feels that the recent release of tofacitinib data from the UC study was timely in that it may inadvertently support tofacitinib as being safe and effective thus promoting the drug to gain approval.

Without the approval of tofacitinib, Pfizer stands to miss out of grossing up to $3 billion in annual sales.