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Gilead Muscles Way into CLL; Halts Trial Early for Efficacy

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By Marie Powers
Staff Writer

Based on the recommendation of an independent data monitoring committee (DMC), Gilead Sciences Inc. put an early stop to its Phase III study (Study 116) evaluating idelalisib in previously treated chronic lymphocytic leukemia (CLL) patients who are not candidates for chemotherapy, after a predefined interim analysis showed “highly statistically significant efficacy” for the primary endpoint of progression-free survival (PFS) in patients receiving idelalisib plus Rituxan (rituximab, Biogen Idec Inc. and Roche AG) compared to a control arm of placebo plus rituximab.

Gilead, of Foster City, Calif., seemed unperturbed about the potential prospect of providing a smaller dataset from a shortened trial to an FDA advisory committee. The company said in a statement that idelalisib’s safety profile was acceptable and “consistent with prior experience in combination with rituximab in previously treated CLL.” Gilead said it informed the FDA of its decision to end the study early and planned to talk with the agency about a regulatory filing in CLL.

Gilead’s disclosure was short on details, which the company said it will submit for presentation at an upcoming scientific conference. ISI Group analyst Mark Schoenebaum speculated the data will be presented as a late-breaker at the American Society of Hematology (ASH) meeting in December.

The decision to design Study 116 using PFS, rather than the FDA’s gold standard of overall survival, as the primary endpoint for idelalisib also poses some regulatory risk. According to Cortellis Clinical Trials Intelligence, secondary endpoints included disease-related biomarkers, overall response rate, patient well-being, pharmacokinetics, incidence of adverse events and health resource utilization.

The randomized, double-blind, placebo-controlled study enrolled 220 adult patients with previously treated recurrent CLL who had measureable lymphadenopathy with disease progression of less than 24 months following completion of prior therapy, and who required treatment but were not fit to receive cytotoxic therapy. Patients were randomized to eight infusions of rituximab over 24 weeks plus either idelalisib (150 mg) or placebo taken orally twice daily. Patients who progressed were eligible to receive active idelalisib therapy in a double-blind extension study (Study 117).

Patients from Study 116 randomized to idelalisib will continue to receive the drug, and patients in the control arm will be eligible to receive open-label idelalisib therapy in an extension study. Gilead also plans an expanded access program for patients with recurrent CLL.

According to Gilead, Study 116 was the first Phase III to report positive results in the class of targeted therapies that inhibit B-cell receptor signaling as a major component of their mechanism of action – a focus of companies seeking to develop chemotherapy-free regimens in CLL and other B-cell malignancies.

Company officials did not respond to interview requests.

Gilead picked up idelalisib in its 2011 acquisition of Calistoga Pharmaceuticals Inc., for $375 million cash and $225 million in potential milestones. The compound, then known as CAL-101 and later as GS-1101 , targets the phosphoinositide-3 kinase (PI3K) delta isoform. At the time of the deal, idelalisib was already in Phase II studies at Calistoga as a single agent in refractory indolent non-Hodgkin’s lymphoma (iNHL) and in combination with rituximab in treatment-naïve elderly patients with CLL. (See BioWorld Today, Feb. 23, 2011 .)

Earlier this year, it became clear that idelalisib would pave the way for Gilead’s foray into oncology when Phase I findings on the compound as a single agent in CLL were singled out among early abstracts at the American Society of Clinical Oncology (ASCO) meeting. At the time, Leerink Swann LLC analyst Howard Liang wrote that, “Idelalisib is among the most important new agents in the industry’s pipeline for cancer, as indicated by the ASCO selection.” (See BioWorld Today, May 20, 2013.)

Last month, the company submitted a new drug application (NDA) for idelalisib in refractory iNHL and disclosed plans to submit a marketing authorization application in Europe in the fourth quarter. According to Cortellis, Gilead has completed or is running 18 trials involving idelalisib, including six Phase III studies in NHL or CLL.

Combination therapy with idelalisib and GS-9973, Gilead’s spleen tyrosine kinase inhibitor, also is being evaluated in a Phase II trial in relapsed or refractory CLL, iNHL and other lymphoid malignancies.

‘How Robust Are the PFS Results?’

Investors were enthusiastic about the Study 116 findings, sending Gilead’s shares (NASDAQ:GILD) up $3.84 on Thursday to close at $62.74.

Analysts were more mixed.

“We believe it’s possible that GILD could file by year-end with a potential approval in 2H14,” Schoenebaum wrote. “This was a modest upside surprise to us,” positioning idelalisib to compete directly in CLL against ibrutinib (Pharmacyclics Inc./Janssen Research & Development LLC) in as little as six months following ibrutinib’s anticipated approval in the indication, he added.

The FDA accepted the NDA for oral Bruton’s tyrosine kinase inhibitor ibrutinib in August, granting priority review in previously treated mantle cell lymphoma and previously treated CLL/small lymphocytic lymphoma. The move also triggered a $75 million milestone payment to Pharmacyclics by partner Janssen. (See BioWorld Today, Aug. 30, 2013.)

But Deutsche Bank analyst Robyn Karnauskas concluded the trial halt, though potentially beneficial to Gilead, would have little impact on ibrutinib. Relapsed/refractory CLL patients likely would get a PI3K and a BTK in sequence, she reasoned. “Based on data available so far, we continue to believe that Ibrutinib is a better drug than Idelalisib in terms of efficacy and safety and would potentially be used ahead of Idelalisib,” she wrote.

J.P. Morgan analyst Cory Kasimov also saw a positive read-through for Infinity Pharmaceuticals Inc., writing that “positive clinical updates for idelalisib are positive predictors of future success for IPI-145. Given that both drugs inhibit PI3K, and that ‘145’s data has looked the same/better than idelalisib’s at this point (at least in our view), we suspect GILD’s positive PI3K combo data could bode well for INFI’s ongoing combination trial (Phase Ib ongoing with bendamustine and rituximab).” (See BioWorld Today, Dec. 14, 2012.)

And Wells Fargo analyst Brian Abrahams raised the data bugaboo, asking, “How robust are the PFS results?” The question, he agreed, should be answered at ASH.

Abrahams also questioned whether the CLL filing will classify as an NDA or supplemental NDA, based on Gilead’s earlier iNHL filing. “We believe how FDA classifies the CLL filing will have an impact on the idelalisib approval timeline,” he wrote.