Phase III Survival Benefit Boosts Imbruvica’s Profile Ahead Of FDA’s CLL Decision

RESONATE study is halted after Pharmacyclics/Janssen’s Imbruvica shows a survival benefit as a monotherapy compared to GlaxoSmithKline’s Arzerra. Analysts expect results will pave way for off-label use ahead of FDA’s approval in CLL, though a delay for official clearance is possible.

Having shown a significant overall survival advantage in the Phase III RESONATE study, Janssen Biotech Inc./Pharmacyclics Inc.’s oral Bruton’s kinase inhibitor Imbruvica (ibrutinib) could reach the market without some of the limitations of accelerated approval.

The Phase III RESONATE study in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia was halted by the independent data monitoring committee at an interim analysis based on Imbruvica’s efficacy, the companies announced Jan. 7. In the study, which is the first Phase III trial of the drug to report, Imbruvica as a single agent demonstrated statistically significant progression-free survival and overall survival – the primary and secondary endpoints respectively – over GlaxoSmithKline PLC’s anti-CD20 antibody Arzerra (ofatumumab). Safety results were acceptable and consistent with prior experience, the companies said.

The drug is already under review at FDA for the indication, and is already on the market for relapsed/refractory mantle cell lymphoma (Also see "Ibrutinib’s Clean Label For Mantle Cell Leukemia Bodes Well For CLL Claim" - Pink Sheet, 13 Nov, 2013.). Janssen had submitted an NDA for accelerated approval for MCL and chronic lymphocytic leukemia in June 2013, supported by two Phase II, single-arm studies (Also see "Ibrutinib, Obinutuzumab Are Early Tests Of How Fast Breakthrough Reviews Will Be" - Pink Sheet, 23 Jul, 2013.).

Single-arm studies are not the regulatory ideal, but Office of Hematology and Oncology Products Director Richard Pazdur has acknowledged that they are increasingly a necessity (Also see "The Next Phase In Oncology: FDA’s Pazdur Has New Vision For Drug Development" - Pink Sheet, 11 Nov, 2013.). Ibrutinib has “breakthrough therapy” status in these indications, which has meant FDA has consulted on the development plans.

FDA wound up splitting the submission in two, both with the user fee date of Feb. 28. Analysts speculated that the agency might be holding off on approving Imbruvica for the CLL indication until the RESONATE results were in. Imbruvica was approved early for relapsed MCL in November 2013. As an accelerated approval, labeling notes that clearance was based on response rate and a survival benefit had not been demonstrated.

But with the significant survival benefit from the interim analysis, the labeling for CLL could be much stronger. FDA has hustled to incorporate late-breaking results for other cancer drugs. The agency waited for the initial results of an ongoing Phase III study of Bristol-Myers Squibb Co.’s metastatic melanoma immunotherapy Yervoy (ipilimumab) as a first-line agent – which came out just prior to approval – to shore up the second-line pivotal study; the agency then granted an indication without restrictions for lines of therapy (Also see "Yervoy Survival Data From First-Line Study Sealed The Deal For FDA Approval" - Pink Sheet, 28 Nov, 2011.).

U.S. and European regulators have been informed about the recommendation to terminate the study and provided with the interim results. Pharmacyclics and Janssen are engaging in a dialogue with the health authorities to define the next regulatory steps and anticipate “providing a comprehensive RESONATE study report to them within the coming months,” the companies said.

As JP Morgan analyst Cory Kasimov observed in a Jan. 6 note, the termination of the study was expected and is in line with early completion due to efficacy of other new CLL drugs, like Gilead Sciences Inc.’s idelalisib and Roche’s Gazyva (obinutuzumab), both of which demonstrated an overall survival benefit as add-on therapies in Phase III CLL trials. But RESONATE marks the first time that a single agent has demonstrated an OS benefit and Kasimov expects that the results could fuel off-label use.

There is potential for a slight delay to an official CLL launch, Kasimov said, as submission of a full report could constitute a major amendment to the filing, triggering a three-month extension for the review. But anecdotal commentary at the 2013 American Society of Hematology meeting in December suggest the drug is already being used off label in CLL, which could offset the impact of a delay, the analyst said.

Similarly, in a Jan. 7 note, Deutsche Bank analyst Robin Karnauskas said that she doesn’t expect a three-month extension, but added that in any case, a delay would not matter much because off-label use would compensate for the delay. Based on IMS figures, Karnauskas noted that the drug had about $6 million in sales for the fourth quarter of 2013 and estimates that about 40% of use has been off label in CLL.

JMP Securities analyst Michael King, however, expects the companies will amend the current NDA to include the confirmatory data sometime after a formal approval for relapsed/refractory CLL. The RESONATE results represent the “best of all worlds,” supporting full approval, likely driving off-label use in earlier lines of CLL and solidifying Imbruvica’s best-in-class status, King said in a Jan. 7 note.

Imbruvica will face an increasingly competitive market and availability of randomized data showing a survival benefit is expected to be an important consideration for prescribing clinicians. A range of new oral therapies were on display at the recent ASH meeting, including Gilead’s idelalisib (Also see "Novel CLL Drugs Jockey For Position In Tomorrow’s Revolutionized Market" - Pink Sheet, 16 Dec, 2013.). In a Phase III study of heavily pretreated relapsed CLL, idelalisib in combination with Roche’s Rituxan (rituximab) demonstrated a significantly improved overall response rate compared to Rituxan/placebo. And, importantly, there was a 85% reduced risk for PFS and a 72% reduced risk for death in the idelalisib arm.

Idelalisib is now under FDA review for indolent non-Hodgkin lymphoma and has breakthrough status in CLL. At the time of the ASH meeting in early December 2013, Gilead said it was talking to FDA regarding a potential filing in in CLL.

Ibrutinib is being tested on top of a backbone including Rituxan and Teva Pharmaceutical Industries Ltd.’s Treanda (bendamustine) in the Phase III HELIOS relapsed/refractory study, which started enrolling in September 2012.