Will Pharmacovigilance Be Enough To Address Questions About Pfizer’s Tofacitinib?

Definitive data on structural damage measurement can be collected post-market, FDA’s Arthritis Advisory Committee said in voting to support approval. But the panel and FDA were both troubled by uncertainties over the safety profile, especially because the rheumatoid arthritis therapy would be for chronic use.

FDA’s challenge during the final phase of the review of Pfizer Inc.’s rheumatoid arthritis treatment tofacitinib will be to determine if risk-management steps proposed by the sponsor are sufficient to handle the unknowns about the first-in-class Janus kinase inhibitor’s safety profile – a chord repeatedly sounded by the Arthritis Advisory Committee during its May 9 meeting.

The committee voted 8-2 that the efficacy and safety data provide substantial evidence to support approval for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more disease-modifying anti-rheumatic drugs, although with reservations about the drug’s safety, especially at the higher of the two doses studied (10 mg vs. 5 mg), and concerns that the indicated population may be too broad (Also see "Panel Backs Pfizer’s Tofacitinib For RA, With Narrower Indication" - Pink Sheet, 9 May, 2012.).

Arthritis Advisory Committee Votes

• 8-2 that the data do not provide substantial evidence of the efficacy of tofacitinib for radiographic outcomes
• 10-0 that, overall, the data provide substantial evidence of the efficacy of tofacitinib for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more disease-modifying anti-rheumatic drugs
• 7-2, with one abstention, that the safety profile of tofacitinib is adequate to support its approval for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more DMARDs
• 8-2 that the efficacy and safety data provide substantial evidence to support approval of tofacitinib for the treatment of moderately to severely active rheumatoid arthritis in patients who have had inadequate response to one or more DMARDs

Committee chair Lenore Buckley, Virginia Commonwealth University School of Medicine, was one of two members voting that the safety profile of tofacitinib was not acceptable. “Sometimes, the best way to understand this is to think about sitting with a patient discussing risks and benefits. And I would struggle on this drug,” she said. “As we look at the list of things we worry about – malignancy, infection, hematologic parameters, lipid parameters, cardiovascular disease – these things are all things that patients with rheumatoid arthritis are at risk for already. They’re at risk for anemia, they usually have other abnormalities, they have cardiovascular risk. And there’s some indicators that this drug may increase those risks.”

Rheumatoid arthritis is a chronic disease, and patients may have to be on medication for it for 10 or 20 years, she pointed out. Therefore, “I’m a little concerned about the data showing increasing risks over time. It’s also a condition where patients are aging as they’re taking these drugs … increasing risks of infections and other problems as they age. We don’t have a lot of long-term data.”

However, there was a general consensus on the committee that the 5 mg dose was safer, at least in the short range, and no calls for banning the 10 mg dose outright, so a majority of seven members said the drug’s safety profile is acceptable.

“Even though there are concerns with some of the safety signals that were presented today, I think the sponsor made a good-faith effort to investigate all the potential safety concerns that might be associated with this new drug application, and I think they did as much as a sponsor can do at this stage of the process to assess the risks,” David Blumenthal, Case Western Reserve University, said in explaining his affirmative vote on safety.

“I really struggled with this,” Vernon Chinchilli, Penn State Hershey College of Medicine, added, but “it seemed to me that in the 5 mg dose, the safety did seem somewhat comparable to other drugs.”

First-In-Class Oral Therapy

Tofacitinib would be the first JAK inhibitor approved for RA, although another JAK inhibitor, Incyte Corp.’sJakafi (ruxolitinib), was approved to treat myelofibrosis in November (Also see "Incyte’s Jakafi Gets Broad Label, Early Approval For Myelofibrosis" - Pink Sheet, 16 Nov, 2011.).

“This is a drug working through a whole new pathway that’s ubiquitously present in cells of the body,” Buckley said, adding that there is some concern “about really significant immunosuppression that we haven’t seen [in other RA drugs].”

Most of the safety issues seen with tofacitinib were within the range expected with biologic immunosuppressants, like malignancies, including lymphoproliferative disorder, and serious infections, including opportunistic infections. FDA had noted some concern that the incidence was potentially high, however, and that there are significant unknowns.

As an oral therapy, unlike other RA treatments, tofacitinib is likely to be very popular. “People would rather be on an oral therapy,” Buckley said, “so there might be a widespread move to use this oral therapy. But given the limited data we have on safety over a long period of time in this drug, I would have trouble with the safety data in a broad indication, to move to this treatment.” Thus, given the safety concerns, “a decision may have to be made to limit its use,” Buckley said.

Many of the panelists suggested that the proposed indication be narrowed to only patients who had tried another biologic agent, including a tumor necrosis factor inhibitor; the proposed indication, while second-line, did not specify beyond previous experience with a disease-modifying anti-rheumatic drug (Also see "Panel Backs Pfizer’s Tofacitinib For RA, With Narrower Indication" - Pink Sheet, 9 May, 2012.).

Pfizer has proposed a risk-management plan that includes a Risk Evaluation and Mitigation Strategy and a range of post-market studies. Long-term extension studies are already ongoing, looking at mortality, malignancies, serious and opportunistic infections, and cardiovascular safety, including myocardial infarction, with external adjudication of events of interest, said Pfizer’s Yvonne Greenstreet, senior vice president for specialty care in the Medicine Development Group.

Planned post-marketing studies will include pneumococcal- and influenza-vaccination studies, a study measuring glomerular filtration rate in RA patients to evaluate the effect of tofacitinib on renal function, and a study of the kinetics of cholesterol flux through the HDL/reverse cholesterol transport pathway in RA patients. Proposed post-marketing surveillance studies would involve existing registries: CORRONA, a U.S. registry that contains more than 30,000 patients in 39 states; German, Swedish and U.K. registries containing about 41,000 patients; and OTIS, a U.S. pregnancy registry with RA patients. CORRONA and the European registries would be used to monitor malignancies, cardiovascular outcomes, serious infections, herpes zoster and pregnancy.

Apart from this, Pfizer’s proposed labeling would include a boxed warning about the risk of serious infections, and additional warnings and precautions about serious infections, tuberculosis, viral reactivation, malignancy and lymphoproliferative disorder, gastrointestinal perforations, and additional risks when tofacitinib is used in combination with biological DMARDs. The REMS would include educational materials for health care professionals, “Dear Health Care Professional” letters, information in journals and at scientific meetings, a Medication Guide and ongoing evaluation of the effectiveness of the communication plan.

Sherine Gabriel, Mayo Medical School, complained that this was not detailed enough, and that FDA also had not been forthcoming about the post-approval plans. “I would just suggest that if we do move forward with a decision to approve this, that there’s a much more comprehensive process put in place to really analyze these risks over time so that we can better advise our patients. I think it’s clear or at least suggestive that the 10 mg dose has some concerns that are worrisome to me – infection and malignancy being the greatest – but we just don’t have the data that we need to advise our patients at this time. If we move forward with approval, we need more of a post-marketing effort to get those data.”

“I really think there needs to be much more attention paid to ongoing pharmacovigilance,” she added. “We’ve heard from the sponsor a commitment, but really not much in terms of detail in terms of ongoing pharmacovigilance on this, and I just want to underscore what one of our commenters in the public comment period said … that really having a systematic, more patient-centered, much more thorough approach and plan for pharmacovigilance is what’s needed.”

“I think a very stringent post-marketing follow-up for safety signals is needed,” agreed Leslie Crofford, University of Kentucky College of Medicine.

Proof Of Symptomatic But Not Structural Benefit

The post-marketing studies might also gather data on radiographic outcomes, a measure of clinical benefit that the committee voted 8-2 had not been proven in the clinical trials. Radiographic assessments of structural damage are of increasing importance in the space, and tofacitinib failed on the one such endpoint in its clinical program.

“I don’t think it’s necessary to have certainty about radiographic outcomes today,” Blumenthal said. “I personally find it acceptable to analyze the data as it might come in, perhaps in a post-marketing phase of data collection. And I do feel comfortable about making decisions about the efficacy of this agent based on the other clinical parameters that were studied.”

Panelists also were sympathetic that Pfizer’s challenge in the sole radiographic study was tough.

“There was an agreement with the agency that there would only be a placebo treatment period of three months,” James Ware, Harvard School of Public Health, pointed out. “And then we saw that the progression was very modest in placebo patients in that time period. And so it was really a situation that was very difficult in terms of showing an effect on progression. So I think we have to recognize that failure to show progression is not a negative signal. There were problems with the data, and I’m concerned with extrapolation creating outliers, so you certainly couldn’t say it was a definitive trial – but I’m encouraged that both dose groups showed an effect. It’s not a definitive result, but an encouraging result in a difficult situation.”

“With the differences in the patient populations that are enrolled in clinical trials for rheumatoid arthritis, we’re always going to be faced with a placebo rate that will be low and we might in fact be setting ourselves up for difficulties, setting the bar a little too high,” Crofford said. Therefore, “there was favorable if perhaps thin support for the idea that there was indeed a structural effect of the drug.”

On symptomatic measures, there was unanimous consent that Pfizer had proven its case (Also see "Tofacitinib Data Is In: As Effective As Humira, But Safety Remains A Question" - Pink Sheet, 12 Sep, 2011.). “I think the data are compelling [that tofacitinib is] at least as good as other biologic agents,” Maria Suarez-Almazor, MD Anderson Cancer Center, said.

“We did have an active comparator arm with adalimumab [Abbott Laboratories Inc.’s Humira], and this biologic performed favorably compared to the active comparator on a number of clinical outcome measures,” Blumenthal pointed out.

Chinchilli said he had voted yes on the overall risk-benefit question “because of the strong efficacy results,” adding that the 5 mg dose had a better safety profile.

Tofacitinib’s user fee goal date is in August.