Therapeutic focus - PI3Ks in the spotlight in 2012

By the end of 2012, oncologists will know much more about the potential of PI3K inhibitors in treating a variety of haematological cancers and solid tumours. With one big phase III trial about to report and as many as eight phase II trials nearing completion this year, the sector will know if its hopes of phosphatidylinositol 3-kinase as a useful target in restraining tumour cell growth and proliferation are well placed.

First up will be Keryx Biopharmaceuticals with pivotal data on its PI3K/Akt kinase inhibitor perifosine, or KRX-0401, in advanced refractory colorectal cancer. Whilst an extremely important event for the New York company, the trial’s outcome will be a sign of the drug class’s clinical promise and whether the investment of big pharma players such as Novartis, Pfizer, Roche and Sanofi will pay off, not to mention Merck’s $251m deal in December to lock up a preclinical candidate from Exelixis and Takeda's $190m takeover of Intellikine (see tables).

Product Pharmacological Class Company Originator Trial IDs
Phase III KRX-0401 Akt kinase/PI3K inhibitor Keryx Biopharmaceuticals/Æterna Zentaris Asta Medica NCT01002248
Phase II TORKi/CC-223 PI3K & mTOR inhibitor Celgene Celgene NCT01177397
GS 1101/CAL101 PI3K inhibitor Gilead Sciences ICOS NCT01393106
BEZ235 PI3K & mTOR inhibitor Novartis Novartis NCT01471847
BGT226 PI3K inhibitor Novartis Novartis NCT00600275
BKM120 PI3K inhibitor Novartis Novartis NCT01289041
RG7321 PI3K inhibitor Roche Piramed NCT01493843
RG7422 PI3K inhibitor Roche Roche NCT01455493
SAR245408 PI3K inhibitor Sanofi Exelixis NCT01013324
SAR245409 PI3K & mTOR inhibitor Sanofi Exelixis NCT01403636
PF-05212384 PI3K & mTOR inhibitor Pfizer Wyeth NCT01420081
PF-04691502 PI3K & mTOR inhibitor Pfizer Pfizer NCT01430585
PX-866 PI3K inhibitor Oncothyreon Burnham Institute/U. of Arizona/U. of Pittsburgh NCT01259869

Key moment

PI3K lies upstream of such well-known targets as mTOR, which has produced a cancer treatment in Afinitor, and Akt, which has proven less successful so far but in which many drug developers remain interested. In the body, the kinase is linked to a number of cell growth, proliferation, differentiation, motility, survival and intracellular trafficking functions; as such, genetic mutations that trigger aberrant signalling are believed to be involved in tumour development and drug-resistant cancers.

The number of clinical stage candidates and trials underway are evidence of the importance placed on PI3K in disease origin, as well as its relative novelty as a target. According to EvaluatePharma data, more than 60 trials are underway on 29 molecules, some of which are pure PI3K inhibitors and others that have additional action on mTOR and Akt.

For those with an interest in the space, the pivotal study of perifosine will be a key moment. The trial in colorectal cancer is expected to report sometime in the first quarter; being conducted under a special protocol assessment with the FDA, it tests perifosine plus capecitabine against the chemotherapy alone in 430 patients with overall survival as a primary endpoint and progression free survival as a secondary. Patients in the trial must have failed chemotherapy and targeted therapies, so it is a very sick population in need of another option.

Trial success would be an important catalyst for Keryx, which has partnered the drug with Aeterna Zentaris in Europe; it has a net present value of $308m for the group, well above its market capitalisation. However, there is some scepticism about its chance of success – shares have fallen by one-third in the last six months and more than 10% of its shares are held in short positions. Thus, a successful trial result would likely see a significant ramping up of the share price.

A second phase III, in multiple myeloma, could wrap up by the end of the year.

Following in the footsteps

Several phase II trials are expected to report this year. Gilead Sciences' GS 1101, which it brought on board with its purchase of Calistoga Pharmaceuticals in a push into the oncological space, is expected to wrap up a single agent trial sometime around the middle of the year in relapsed or refractory Hodgkin lymphoma. Around the same time, Novartis’ BKM120 is expected to wrap up mid-stage trials in three different cancers: a 70-patient phase I/II trial in combination with Herceptin in breast cancer patients with relapsing HER2-overexpressing disease who have become resistant to Herceptin; a trial of 65 glioblastoma patients both eligible and ineligible for surgery; and a 93-patient trial in glioblastoma multiforme in combination with Avastin.

By the end of the year, BKM120 also may have completed a 140 patient trial in advanced endometrial cancer. It may be joined by Celgene’s TORKi, being tested in 120 non-Hodgkins lymphoma patients, which could report in the third quarter; and Oncothyreon’s PX-866 in non-small cell lung cancer and glioblastoma multiforme.

Another 15 mid- and late-stage trials are likely to report in 2013, including candidates from Sanofi, Pfizer and Roche. Thus, the next 24 months will be a defining moment for the drug class.

Product Pharmacological Class Company Originator Trial IDs
Phase I AMG 319 PI3K delta inhibitor Amgen Amgen NCT01300026
BAY80-6946 PI3K inhibitor Bayer Bayer NCT01392521
MSC1936369B + SAR245408 MEK & PI3K inhibitor Merck KGaA/Sanofi Exelixis/Santhera Pharmaceuticals NCT01357330
MSC1936369B + SAR245409 MEK, PI3K/mTOR inhibitor Merck KGaA/Sanofi Exelixis/Santhera Pharmaceuticals NCT01390818
BYL719 PI3K inhibitor Novartis Novartis NCT01387321
RG7604 PI3K inhibitor Roche Genentech NCT01296555 
IPI-145 PI3K inhibitor Purdue Pharma/Infinity Pharmaceuticals/Intellikine Intellikine NCT01476657
INK1117 PI3K inhibitor Intellikine Intellikine NCT01449370
ZSTK474 PI3K inhibitor Zenyaku Kogyo Zenyaku Kogyo NCT01280487
PWT33597 PI3K alpha/mTOR inhibitor Pathway Therapeutics Pathway Therapeutics NCT01407380
P529 intravitreal PI3K/Akt/mTOR antagonist Paloma Pharmaceuticals Paloma Pharmaceuticals NCT01033721
GSK2126458 PI3K inhibitor GlaxoSmithKline GlaxoSmithKline NCT00972686
INK128 TOR kinase inhibitor Intellikine Intellikine NCT01351350
DS-7423 mTOR/PI3Kinhibitor Daiichi Sankyo Daiichi Sankyo NCT01364844 
Carboxyamidotriazole Orotate VEGF-1 & PI3K inhibitor Tactical Therapeutics Tactical Therapeutics NCT01107522 
RG7603 PI3K inhibitor Roche Roche NCT01356173 

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