Whether Pfizer Inc. cleared the efficacy bar with tofacitinib, its first-in-class JAK inhibitor for rheumatoid arthritis (RA), will be open for debate at Wednesday's meeting of the FDA's Arthritis Advisory Committee (AAC).

Citing the small apparent treatment effect size and inconsistent dose data from Pfizer's trials, the FDA said it's not possible to draw definitive conclusions about tofacitinib's effect in slowing the progression of structural damage in RA.

To support its new drug application for tofacitinib, New York-based Pfizer conducted five Phase III trials. While all of the studies demonstrated tofacitinib's efficacy in treating the signs and symptoms of RA, only one provided radiographic outcomes of structural damage progression. And those results varied depending on the analysis.

The inability to draw efficacy conclusions, based on radiographic outcomes, calls into question the benefit-risk profile for tofacitinib, given the safety concerns associated with the drug, the agency said in briefing documents released ahead of the meeting.

The documents noted a number of safety concerns, including a possible increased risk of lymphoma. While patients with rheumatoid arthritis have an underlying risk of lymphomas, the agency said the incidence of atypical central nervous system and breast lymphomas, findings of lymphoma in the nonclinical program and the likelihood of increased risk in the post-renal transplant setting suggested a consistent safety signal of increased risk with tofacitinib.

Also concerning was that the risk of malignancies seemed to increase over time, the agency said.

In addition to the malignancy risk, the AAC will be asked to discuss other safety issues, including serious infections, abnormal hematologic parameters, changes in lipid parameters and the drug's cardiovascular safety profile.

Since tofacitinib is the first of the oral JAK inhibitors to come before the FDA for an RA indication, the AAC debate over its risk-benefit profile will be a learning experience for the agency, as well as the other companies with similar products in late-stage development.

JAK inhibitors have been touted as potential treatments for patients who have failed on, or become resistant to, anti-TNF antibodies. In light of their oral availability and modest side-effect profiles in clinical trials, JAK inhibitors – given time and appropriate efficacy – could replace injected antibodies such as Humira (adalimumab), Abbott's blockbuster arthritis drug.

With growing interest in the compounds, Galapagos NV recently landed a deal with Abbott worth $1.35 billion, plus royalties, for its JAK1 inhibitor, GLPG0634, which is in Phase II development for RA. Like Humira, GLPG0634 also could have potential in other autoimmune diseases. (See BioWorld Today, March 1, 2012.)

Other JAK inhibitors in development for RA include Vertex Inc.'s VX509 and Incyte Corp.'s INCB28050, which is licensed to Eli Lilly and Co. Both compounds are in Phase II.

Another compound that could benefit from this week's debate is Rigel Pharmaceuticals Inc.'s fostamatinib, a Phase III syk inhibitor partnered with Astra Zeneca plc.

The fact that the FDA didn't seem too concerned about lipid elevations and other laboratory abnormalities with tofacitinib is a positive for others in the class, Piper Jaffray analyst M. Ian Somaiya said, given the class effect of JAK inhibitors on cholesterol.

He didn't see the malignancy issues as a setback for other JAK inhibitors, saying they may be specific to tofactinib. Malignancies weren't a problem with Incyte's Jakafi (ruxolitinib), a JAK inhibitor approved late last year for myelofibrosis, he pointed out. (See BioWorld Today, Nov. 17, 2011.)

As for Pfizer's chances with tofacitinib, several analysts expect the AAC to recommend approval. But Jefferies analyst Tom Holford said the FDA could hold off on allowing data about structural damage progression on the label until more structural data are available and fully analyzed.

Such data will be available from the ORAL Start study later this year, along with two-year data from the ORAL Scan study, he noted.