May 4, 2012 7:15 pm

Pfizer’s arthritis drug tofacitinib to receive positive FDA AdCom recommendation in May, safety concerns to be discussed

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Pfizer’s (NYSE: PFE) investigational drug tofacitinib is expected to receive a positive recommendation in moderate-to-severely active rheumatoid arthritis (RA) at an FDA advisory panel on 9 May, according to rheumatologists interviewed by Biopharm Insight. However, experts noted that risk management strategies will likely be discussed to mitigate safety risks associated with this drug and the safety concerns could warrant a post-approval study.

The FDA accepted Pfizer’s application for NDA on 20 December 2011 with a PDUFA date set for August 2012.

According to the limited clinical data, tofacitinib, a JAK inhibitor, will have a similar efficacy profile to the existing TNF inhibitors, with “reasonably good safety,” said Dr Jonathan Kay, director of clinical research in rheumatology, University of Massachusetts Medical School.

The currently marketed TNF-inhibitors include Pfizer/Amgen’s (NASDAQ: AMGN) Enbrel, Abbott Laboratories’ (NYSE:ABT) Humira, Johnson & Johnson’s (NYSE:JNJ) Remicade and Simponi and UCB’s (EBR:UCB) Cimzia.

Formerly known as tasocitinib and CP-690550, tofacitinib has displayed comparability to TNF-inhibitors versus placebo.

In a 700-patient Phase III ORAL Standard trial, 51.5% and 52.6% of patients given tofacitinib 5mg and 10mg, respectively, achieved ACR20 scores at 6 months compared to 47.2% for adalimumab (Humira) which were all statistically significant compared to placebo.

The ORAL clinical trials program consists of five studies.

The usual measure in arthritis trials is based on an improvement in tender or swollen joint counts, as well as other parameters. The ACR criteria is indicated as ACR 20, ACR 50, and ACR 70.

An ACR20 response requires a patient to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three out of five other parameters.

Tofacitinib’s efficacy “speaks for itself,” said Dr Nathan Wei, a Maryland-based rheumatologist. But Wei and his colleagues remained cautious of safety concerns surrounding JAK inhibitors including neutropenia, liver toxicity, creatinine elevation and lipid elevation.

The panel will likely discuss the four deaths that occurred in the ORAL Sync Phase III study, said Wei. Though only one death related to the tofacitinib treatment, according to a Pfizer press release, deaths in clinical trials were never an issue for other TNF-inhibitor biologic medications, he explained.

The most discussed safety concern likely will be hyperlipidemia, said Dr Daniel Furst, chair of rheumatology, University of California, Los Angeles Medical Center for Health Sciences, since both HDL and HDL levels were elevated in trials.

While some rheumatologists expect concomitant lipid- lowering therapies to be required by the FDA, Dr David Sandoval, assistant professor of medicine in rheumatology, University of Washington, did not think this measure would be necessary. Sandoval said he and fellow physicians would maintain a low threshold for deciding when to add lipid-lowering therapies.

Expecting lipid and liver issues to be the primary points of discussion, Furst was concerned that neutropenia and creatinine data might ultimately be of greater concerns for the drug. Furst did not expect these issues to affect the approval process, but did think rheumatologists will need to be vigilant regarding these factors.

The rheumatologists interviewed by this news service expected Risk Evaluation and Mitigation Strategies (REMS) to be an important advisory committee topic, considering other RA drugs carry REMS such as Roche (VTX: ROG)/Genentech’s Actemra. For example, the FDA might require patient registration, Wei said, but noted that rheumatologists already have experience with the CORRONA, an independent registry maintained by academic and clinical rheumatologists.

Wei added that a black box is almost a “given” as with other RA drugs that carry serious side effects, such it would minimally affect how rheumatologists already approach patient treatment and monitoring, he noted. The rheumatologists agreed that given prior experience, the side effects will be manageable. Monitoring lipid and cardiac function, liver markers, creatinine and immune function are precautions that are in already in place for RA patients, they noted.

Post-marketing study likely

A post-marketing study could be as large as 5000-6000 patients lasting for three-to-four years, according to Furst.

Furst suggested that FDA reviewers might require an additional smaller study, possibly folded into the large study, to look at liver toxicity and interaction with methotrexate, a standard RA drug well-known for being liver toxic. But Furst did not think a contra-indication was likely. Wei estimated a smaller study of 500-1000 patients, over a minimum of two years. Any study that was larger would be too difficult to enroll patients, considering tofacitinib prescriptions will still have to follow other first- and second-line TNF-inhibitors.

Sandoval added there is a possibility that an additional study may require an arm to look the lipid effect specifically.

Drug likely to face niche market

Specialists agreed that tofacitinib will likely have a first-to-market advantage over other JAK inhibitors for RA which include Rigel’s (NASDAQ: RIGL) fostamatinib, Incyte’s (NASDAQ:INCY) INCB28050 and Vertex’s (NASDAQ:VRTX) VX-509, but it will still be selectively used.

Dr Robert Keenan, a rheumatologist at Duke University Medical Center, North Carolina, said he plans to begin treating patients who do not respond well to methotrexate and other traditional disease-modifying anti-rheumatic drugs (DMARDs). Furst agreed that tofacitinib, at least initially, will fill a niche as an option for patients who show incomplete response to TNF-inhibitors, approximately 20% of those who try one of these drugs. He said rheumatologists are generally “conservative,” so they likely will stick to the TNF-inhibitors before trying something new.

If tofacitinib’s price will be in the range of traditional TNF inhibitors, Dr Lou Bridges, director of Clinical Immunology and Rheumatology, University of Alabama in Birmingham, said he did not expect tofacitinib’s initial market impact to be significant.

A Pfizer spokesperson said the company could not speculate about the FDA committee’s application review. In RA clinical trials to date, tofacitinib has demonstrated efficacy across patient populations–prior DMARD use, including traditional DMARD and TNF inhibitor failures–and over time, with sustained improvements over three years, according to a response by Pfizer.

RA affects approximately 1.3 million Americans and one percent of the global population, according to the company website.

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