Therapeutic focus – AbbVie endorses the bull case for PI3K inhibition

If the deal AbbVie struck last week to get its hands on Infinity’s IPI-145 signals renewed interest in using PI3K inhibitors for haematological cancers then several small developers of similarly acting projects should start marketing themselves sharpish.

It is perhaps surprising that the only significant share price gainer of this group on September 3 was TG Therapeutics, up 9% on a bullish note from Roth Capital that saw a direct read across from the Infinity deal. While for most it is very early days, an analysis of EvaluatePharma data reveals other interesting biotech targets (see table below).

Much has changed in this space recently, perhaps largely as a result of intense competition in the haematological cancer space. Many of the projects highlighted two years ago, when EP Vantage last performed this analysis, have fallen by the wayside (Therapeutic focus – PI3Ks in the spotlight in 2012, January 27, 2012).

If there is still mileage in PI3K inhibition then it is thanks to the disappointment of Gilead’s Zydelig, the first PI3K inhibitor to reach the market, but one that did so hobbled by toxicity warnings. AbbVie’s endorsement tells us as much, though buying in a similar compound at this stage would have to make sense as a basis for a combination therapy.

Indeed, this is one reason why excitement has built around TG, whose TGR-1202 recently began a phase I study in combination with Pharmacyclics’ marketed BTK inhibitor, Imbruvica. The bull case says that, were this to be successful, Pharmacyclics will buy out TG, having no other agent in house with which to combine Imbruvica.

Still, TGR-1202 is not an unencumbered asset, having been licensed by TG from the private Swiss group Rhizen Pharmaceuticals. Buying out Rhizen’s interest would cost $250m plus a royalty obligation, though it is not clear for instance whether Pharmacyclics could just try to buy Rhizen instead.

Three other private biotechs are active in this space: SignalRx Pharmaceuticals, Acerta Pharma and Piqur Therapeutics, though the last seems only to be targeting solid cancers.

Acerta is running a phase I study combining ACP-319 with its own BTK inhibitor ACP-196 – mirroring the Pharmacyclics/TG approach; ACP-196 is a Merck & Co cast-off. SignalRx claims to have a pipeline of PI3K inhibitors, but little information about it is publicly available.

The table below also shows the numerous takes on the specificity of inhibition, some molecules inhibiting PI3K broadly, and others targeting the delta or other isotypes.

PI3K inhibitors in development for haematological cancers
Status Project Company Pharmacology Selected studies
Marketed Zydelig (idelalisib) Gilead Sciences PI3K inhibitor NCT01732926
Phase III IPI-145 (duvelisib) Infinity/AbbVie PI3K-delta/gamma inhibitor NCT02004522
Phase II Copanlisib Bayer PI3K-alpha/delta inhibitor NCT01660451
CC-223 Celgene PI3K & mTOR inhibitor NCT01177397
SAR245409 Sanofi/Exelixis PI3K & mTOR inhibitor NCT01403636
SF1126 SignalRx Pharmaceuticals PI3K & mTOR inhibitor NCT00907205
Phase I GS-9820 Gilead Sciences PI3K-delta inhibitor NCT01705847
CUDC-907 Curis PI3K & HDAC inhibitor NCT01742988
AMG 319 Amgen PI3K-delta inhibitor NCT01300026
LY3023414 Lilly PI3K & mTOR inhibitor NCT01655225
INCB040093 Incyte PI3K-delta inhibitor NCT01905813
ACP-319 Acerta Pharma PI3K inhibitor NCT02157324
TGR-1202 TG Therapeutics/ Rhizen Pharmaceuticals PI3K-delta inhibitor NCT02006485
VS-5584 Verastem PI3K & mTOR 1/2 inhibitor NCT01991938
Source: EvaluatePharma

Among recent failures, perhaps the most prominent has been Keryx/Aeterna Zentaris’s perifosine, which flunked phase III in colorectal cancer in 2012 and in multiple myeloma a year later. Numerous other PI3K inhibitors are only being targeted at solid tumours, meanwhile; Novartis and Roche have three each, for instance, focused on breast and other cancers.

Novartis’s BEZ235 and Roche’s pictilisib inhibit PI3K as well as mTOR, a target further down the signalling pathway, which is a strategy that in haematology is being pursued by Sanofi, SignalRx, Lilly and Verastem. However, Verastem’s VS-5584 is not this company’s key focus.

Sanofi’s SAR245409, meanwhile, has been associated with adverse events, casting some doubt on this dual inhibition approach. Toxicity has also been a problem for Bayer’s copanlisib, though efficacy in a small phase II study in B-cell lymphomas impressed at last year’s ASH meeting.

Among smaller developers, Acerta’s phase I combo trial should generate data imminently, while phase I studies of Verastem’s VS-5584 and Curis’s CUDC-907 are due to read out next year.

Of course, as far as investment triggers go, further moves on the business development front would provide more immediate evidence that PI3K inhibition has been given a new lease of life. The ASH meeting in December should provide a good indicator of shifts in this space.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter

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