PS Targeting vs PI3K....and Gileads phase III was stopped due to a safety risk increase.
Gilead Pushes Cancer Pipeline; Enters Phase III with PI3K Drug
Gilead Sciences Inc. began a Phase III trial of its PI3K inhibitor, GS-1101, in chronic lymphocytic leukemia (CLL). If successful, the company could add a cancer candidate to its powerhouse lineup of products currently led by its HIV and hepatitis C virus franchises.
In the trial, called Study 116, 160 patients at about 70 sites in the U.S. and Europe will be randomized to receive eight infusions of Rituxan (rituximab, Biogen Idec Inc. and Roche AG) over 24 weeks plus GS-1101 or placebo taken orally twice daily.
The primary efficacy endpoint is progression-free survival. An extension trial, Study 117, will follow patients who tolerated primary study therapy.
Gilead described the PI3K inhibitor as a first-in-class drug. "There are other companies pursuing PI3K as a target, but we are interested in the specificity of GS-1101 for the PI3K delta isoform," explained Nathan Kaiser, senior manager of public affairs for Foster City, Calif.-based Gilead.
PI3K is one of the hottest pathways in biotech, and compounds that inhibit it have been the objects of some major deals. Roche AG acquired Piramed Ltd. for $175 million on the strength of its PI3K assets in 2008. More recently, Intellikine Inc. licensed its PI3K delta and gamma inhibitors to Infinity Pharmaceuticals Inc. for $488.5 million, and then later was acquired by Takeda Pharmaceutical Co. for $190 million up front, and $120 million in milestones. (See BioWorld Today, April 16, 2008, July 9, 2010, and Dec. 22, 2011.)
And, in fact, Gilead's PI3K compound, GS-1101, came from its acquisition of Calistoga Pharmaceuticals Inc. for $375 million. (See BioWorld Today, Feb. 23, 2011.)
While early efforts to target PI3K focused on pan-inhibition, newer-generation products, including GS-1101, are designed to selectively target the alpha, beta, delta or gamma isoforms rather than the whole family. That narrow focus on exactly the right target is believed to decrease side effects associated with off-target activity. It also decreases risks associated with drug combinations and allows for a higher dose. (See BioWorld Insight, Feb. 27, 2012.)
The alpha isoform is one of the most frequently mutated kinases in cancer, and alpha inhibition is thought to offer better efficacy and safety in solid tumors than pan-inhibitors. However, the evidence is stronger for delta and gamma inhibitors in hematological cancers and in asthma, allergy and autoimmune disease.
In CLL, the bone marrow makes too many lymphocytes, and those lymphocytes are abnormal. It is the second most common type of leukemia in adults.
The delta isoform of PI3K (PI3K[delta]) supports the growth and functioning of immune cells. Constitutive activation of the PI3K[delta] pathway leads to proliferation, survival and trafficking of those abnormal cells in CLL.
In preclinical models, GS-1101 shut down the PI3K[delta]-dependent signals, reduced proliferation and enhanced apoptosis of the cancer cells, providing validation for the delta isoform mechanism.
In spite of the crowded field for PI3K inhibitors, GS-1101 may face its toughest competition in Btk inhibitor ibrutinib (PCI-32765) from Pharmacyclics Inc. and Johnson & Johnson.
Pharmacyclics made a splash when it presented data from its Phase Ib/II trial in relapsed or refractory chronic lymphocytic leukemia at the American Society of Hematology meeting in December, showing a response rate of 70 percent. (See BioWorld Today, Dec. 13, 2011.)
Rodman and Renshaw analyst Michael King noted that GS-1101 and ibrutinib eventually may be complementary. "In the near- to mid-term, however, these agents will compete for patient enrollment and investigator share-of-mind. Today's release clearly positions GS-1101 slightly ahead of ibrutinib in terms of timing."
The two agents could compete outside of CLL, as well. Gilead plans to pursue trials of GS-1101 in multiple myeloma, while Pharmacyclics has recently begun a trial in that indication.
In addition to Study 116 and its extension trial, Study 117, Gilead is planning Study 115, a Phase III trial scheduled to begin in the second half of 2012, evaluating GS-1101 with Treanda (bendamustine, Teva) and Rituxan for 24 weeks of therapy.
A third Phase III trial, also beginning in the second half of 2012, will look at GS-1101 with Arzerra (ofatumumab, GlaxoSmithKline plc).
Gilead used an ongoing Phase I study of GS-1101 to inform its design of its Phase III studies. That trial, a dose-ranging study with endpoints of recommended dosing regimen, safety and antitumor activity, gave data on 55 CLL patients on GS-1101 monotherapy and 54 patients on GS-1101-based combination therapies.
All patients had received more than one prior treatment regimen and some had received as many as 15.
The trial showed no GS-1101-related dose-limiting toxicities, and adverse event profiles were consistent with the known safety profiles of each agent.
"GS-1101 monotherapy and combination therapy is highly active in these hard-to-treat patients; the majority of patients experience reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy and durable clinical benefit," Gilead concluded.
Shares of Gilead (NASDAQ:GILD) closed Wednesday at $51.88, up 44 cents.
"Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that is the cornerstone of a broad clinical pipeline." -- Big Pharmas nightmare... unless they are fortunate enough to have The Bavi Edge!
