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Winners And Losers in CLL at ASCO '13

The second stage of the study will ultimately determine whether obinutuzumab is better than Rituxan when used with chlorambucil in elderly patients. Roche obtained Breakthrough Therapy designation from the FDA for obinutuzumab earlier this year. The company submitted a new drug application to FDA for approval in newly diagnosed CLL.

Loser: Infinity's IPI-145

IPI-145 is an oral inhibitor of PI3K-delta and gamma that was licensed from Intellikine (since acquired by Millennium/Takeda.) Both Infinity and Gilead have PI3K inhibitors in development for CLL, but Gilead's compound is ahead (already in a phase III clinical trial.) The key question is whether IPI-145 will prove to be more effective than idelalisib and whether hitting gamma adds efficacy or more side effects? Based on preclinical data, IPI-145 is a more potent PI3K-delta inhibitor than idelalisib.

However, IPI-145's promising CLL efficacy was overshadowed by a higher rate of serious adverse events and deaths due to respiratory infections (pneumonia/pneumonitis.) Whether this is attributable to targeting PI3K-gamma and suppression of T cells -- something idelaslib does not do -- is not known yet. The IPI-145 data presented at ASCO do raise safety concerns about the drug which did not exist before.

Loser: Abbvie/Roche's ABT-199

AbbVie and Roche are going after a different CLL target with ABT-199, a small molecule inhibitor of Bcl-2, a key protein that regulates cell death. ABT-199, also known as GDC-199, a re-engineered version of navitoclax that was discontinued because it caused a significant reduction in the number of platelets in the blood (thrombocytopenia.)

At ASCO, ABT-199 showed promising early data in lymphoma and efficacy in over 80% of relapsed/refractory CLL patients, including those with del(17p) who have poorer outcomes.

The promising CLL efficacy data has been overshadowed by a suspension of clinical trials earlier this year following two patient deaths due to tumor lysis syndrome (TLS.) This is a double-edged sword: Tumour lysis is usually a sign of a highly efficacious drug, but too rapid a response can cause serious adverse events. One trial participant unfortunately dropped dead unexpectedly in his bathroom!

Experts at ASCO said a less aggressive dosing schedule and closer monitoring of CLL patients, especially those with bulky disease at higher risk for TLS, could potentially address the TLS issue, but we don't yet have the data to confirm this.

One challenge for AbbVie and Roche is patients most at risk of TLS are those with bulky lymphadenopathy who constitute the majority of elderly CLL patients. At an ASCO investor event, Roche said targeting Bcl-2 in blood-based cancers is a key priority and future combination trials with ABT-199 are already planned.

We will have to wait for more data later this year at the American Society of Hematology (ASH) annual meeting to know whether the safety concerns have been addressed. I expect ABT-199 will advance faster in lymphoma where the early efficacy data is promising.

Droppert has no positions in any of the companies mentioned.
Pieter Droppert writes the Biotech Strategy Blog and is a marketing strategy consultant with a focus on oncology/hematology new product development. Pieter is a Sloan Fellow from London Business School and was formerly a project manager for a major phase III drug development program at a global CRO.
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