Pfizer Inc. on Sept. 8 released some data from three previously undisclosed pivotal trials for tofacitinib, its high-profile, first-in-class JAK3 inhibitor for rheumatoid arthritis, which it says shows that the drug is equal in efficacy to Abbott Laboratory Inc.’s bestselling TNF inhibitor Humira.

The data, particularly those comparing the drug to Humira (adalimumab), were long awaited. They were the last undisclosed findings from Pfizer’s massive ORAL Phase III trial program for tofacitinib. In addition, Pfizer is continuing two long-term trials of tofacitinib.

If approved, the drug will be the first oral immunomodulator for RA and will compete directly against Humira and a handful of other best-selling anti-TNFs, such as Simponi (J&J’s golimumab) and Remicade (J&J’s infliximab), all of which are administered via IV infusion or subcutaneous injection. The trial results were generally consistent with those from earlier studies, although a more complete picture of mortality has emerged, which will require further clarification.

The data were released in abstracts that the company plans to present in fuller form at the American College of Rheumatology in November. Safety and efficacy data were summarized from the 12-month ORAL Standard, the 24-month ORAL Scan, and six-month ORAL Step trials. The drug was tested in two doses in all three trials, a 5mg and a 10mg BID (twice a day) dose, in patients with moderate-to-severe active RA. Patients in all trials were on background methotrexate (MTX).

The ORAL Standard trial (717 patients) was the only one of the three trials to evaluate the safety and efficacy of tofacitinib in comparison to Humira. It did so through a trial design in which tofacitinib and Humira were each compared to placebo rather than directly to one another.

The ORAL Scan trial (797 patients) is an ongoing 24-month efficacy study of tofacitinib against placebo.

The ORAL Step trial (399 patients) evaluated tofacitinib against placebo in patients who had an inadequate response or lack of tolerance to TNF inhibiting therapy.

The size and geographic scale of the tofacitinib trials was unprecedented in RA trials, said Vibeke Strand, adjunct clinical professor, division of immunology and rheumatology at Stanford University, and clinical consultant to Pfizer for Phase II and III tofacitinib trials. The drug met all primary endpoints in the three trials at 3 and 6 months – timelines that FDA accepts for primary endpoints in RA trials.

In the ORAL Standard study, the 10mg dose reported slightly higher scores than Humira on the ACR20 response rates at 6 months (ACR, or American College of Rheumatology, is a system for measuring the efficacy of arthritis treatments, with ACR20 being 20% improvement, ACR50 showing 50%, and ACR70 demonstrating 70% improvement). In the ORAL Standard study, the 10mg dose of tofacitinib was shown to be more effective than 5mg, but it came with higher rates of adverse events.

The drug is equivalent in efficacy to Humira with respect to reduction of signs and symptoms of RA, improvement of physical function, and reduction of disease activity, in particular progression of structural joint damage, according to the trials. However, the efficacy of Humira in these particular trials, as measured by ACR scores, was lower than its performance in other trials, raising questions about whether Humira’s ACR scores in the ORAL trials were representative of the comparator’s data set, according to one analyst who spoke not for attribution.

Mortality

With the inclusion of the latest data, an overall picture emerged of the entire program’s mortality data. Twelve patients died in the Phase III program (a total of five pivotal trials involving 3,030 patients with RA) for all doses of tofacitinib. This includes five deaths in two earlier Phase III trials: one in ORAL Solo, and four in ORAL Sync. But the additional Phase III trials also included seven previously undisclosed deaths, including one in ORAL Step, five in the ongoing 24-month ORAL Scan, and one more in ORAL Standard. Pfizer stated that the death rate for tofacitinib was “consistent with the reported rates from individual clinical trials with biologic DMARDs [disease modifying anti-rheumatic drugs] RA patients.” (Also see "Death Scare For Pfizer's Pipeline Star Tofacitinib May Be Just A Storm In a Teacup" - Pink Sheet, 22 April, 2011.).

The statistical significance of the mortality numbers is not clear, nor is it certain whether the deaths were tied directly to the drug. The numbers are a concern, however, because tofacitinib has to meet a high safety hurdle since existing therapies are effective and safe. There is a considerable body of evidence supporting the safety of biologics. Physicians know these drugs and feel comfortable prescribing them. Some patients have been on Enbrel (Pfizer’s etanercept), the first-to-market TNF inhibitor, for 10 years, for example.

On the other hand, mortality could have been tied to geography. “Co-morbidities may not have been as aggressively treated in China, E. Europe, Russia, or South America,” Strand said. “We simply don’t have any prior experience for multi-national trials like this.”

Lee Simon (a rheumatologist, former FDA division head and NIH investigator and co-managing director of SDG LLC, a drug development consultancy) noted that Pfizer has not previously publicly acknowledged the 12-death total. Strand said that Pfizer has set up an independent committee to look into the deaths.

If the drug is approved, Lee expects FDA will require a restrictive Risk Evaluation and Mitigation Strategy.

Safety

Infections were the most common type of adverse event Pfizer reported, totaling “more than 5%” in the LTE (Long Term Extension) studies, and “less than 5%” in the Phase III trials. Common infections included nasopharyngitis, upper respiratory tract infection, urinary tract, and a few others. According to Pfizer, rates of serious infection in both the LTE studies and Phase III trials were “consistent with rates seen in observational databases for TNF inhibiting therapies.”

In the Phase III trials, rates of serious infection were similar at both doses; but in the LTE studies (3,227 patients), rates were higher at the 10mg dose than at the 5 mg dose. Patients’ cholesterol rates rose in these three trials, consistent with elevation trends in an earlier Phase II/III study, but the clinical community appears divided on concerns about that. Based on the earlier data, Tony Butler, an analyst at Barclays Capital, suggested in a November 2010 research note that the medical community is likely to be cautious about use of the drug in a high-CV risk population ([A#061011190006]).

Strand did not wholly agree. Most cases of elevated cholesterol could be managed with statins, and “some changes in high-density lipoprotein and low-density lipoprotein may represent a good effect, a reversal of inflammation,” she said. Many of tofacitinib’s side effects have been observed with other JAK and SYK inhibitors, such as those in development at Vertex and AstraZeneca/Rigel (“[A#0610201002]).

Also, tofacitinib inhibits JAK 1 and 3 pathways with functional activity over JAK 2, whereas Vertex’s VX-509 is selective for the JAK 3 pathway. The full safety implications of these mechanistic differences are as yet unknown.

In assessing safety, Pfizer extrapolated from comparisons of tofacitinib with Humira to general comparisons of tofacitinib with the TNF inhibitor class, a comparison that some clinicians contacted by “The Pink Sheet” questioned because of differences among anti-TNF products. Strand, however, noted that the TNF inhibitors “are a remarkably similar class of agents” exhibiting only small differences among them.”

NDA and Beyond

Pfizer plans to file for U.S. and EU approval in moderate-to-severe active RA later in 2011. In view of the drug’s basic equivalence in efficacy to Humira, its similar safety profile, and lingering questions about its mortality rate, Lee did not think that treating physicians would switch patients who had stabilized on anti-TNFs to tofacitinib, if it gets regulatory approval, nor would they likely start new patients on it. He noted, however, that approximately 40% of RA patients are resistant/refractory to, or intolerant of, the biologicals, and that population might be the opportunity for a novel acting drug.

He also said that in the current safety-conscious climate, the prudent filing would be for the 5 mg dose because it carries “less efficacy, but also less chance of harm.” Lee predicted that it would find its use in a third-line setting, after patients had failed methotrexate and an older anti-TNF. Strand agreed, though she felt that Pfizer’s NDA submission should include data on both doses. She also noted that RA is a variable disease and wondered whether patients on a BID dose would remember to take their second dose.

Meanwhile, analysts who cover Pfizer haven’t backed off their forecasts: Tim Anderson of Bernstein Research projects tofacitinib’s sales will be $1.4 billion in 2015, and Barclay’s Tony Butler puts it at $1.5 billion in 2016.

By Michael Goodman

Tofacitinib Data Is In: As Effective As Humira, But Safety Remains A Question

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