Gilead’s (NASDAQ:GILD) recent decision to terminate a number of clinical trials with Zydelig as a front-line therapy for chronic lymphocytic leukaemia because of serious adverse events raises the question of whether any of its competitors in the PI3K inhibitor space could receive a boost.
And, assuming that the Zydelig safety issues are not a class effect, the answer is that TG Therapeutics (NASDAQ:TGTX) might do (see table below). TG’s PI3K inhibitor TGR-1202 is in a phase III study for CLL and squarely targets the malignancy where both of the abandoned Gilead phase III studies were pitched.
Earlier this month, Gilead disclosed that six Zydelig trials – including two of four ongoing phase IIIs – had been stopped after serious adverse events including deaths had emerged. Both of the now closed phase III studies were in previously untreated CLL, one in which the drug was added to bendamustine/Rituxan, and another in which it was being tested against chlorambucil, on top of Roche's (OTCQX:RHHBY) Gazyva.
Four phase II studies have also been closed, and an investigator-sponsored trial in Waldenström's macroglobulinaemia is listed as suspended pending a safety review.
The closure of these studies leaves Zydelig in two ongoing phase III studies: Bridalveil and Yosemite, which are both in previously treated indolent non-Hodgkin lymphoma (iNHL).
At last year’s ASH meeting Gilead reported solid evidence of Zydelig's efficacy in previously treated CLL. The “115” phase III study showed a 67% reduction in the risk of disease progression or death, and a 45% reduction in the risk of death, at an interim analysis. At the time the group said it planned to file a supplemental NDA this year.
Zydelig is approved for relapsed CLL in combination with Rituxan, and for relapsed follicular and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. However, it was already looking sickly before even the latest events; it carries a black box for various serious adverse events, and this warning meant that it had been losing out to J&J/AbbVie’s BTK inhibitor Imbruvica, which has a much cleaner side-effect profile.
The approval earlier this month of Imbruvica for front-line CLL, based on the Resonate-2 study, could seal the fate of PI3K inhibitors in this indication. Data published at Asco last year showed that Imbruvica reduced risk of death or disease progression by 84% compared with chlorambucil, and the overall response rate of 86% was also significantly greater than chlorambucil's 35%.
EvaluatePharma data suggest consensus 2020 sale expectations for Zydelig of around $950m, a figure that although stable for some time fell by around 30% in mid-2014, when competition from Imbrivica first materialised. The number should now fall further.
Whether or not TG’s TGR-1202 gains an advantage in front-line CLL at the expense of Zydelig, Gilead’s drug faces potential competition in NHL from the two other PI3K inhibitors that are in development for haematological indications, AbbVie/Infinity’s duvelisib and Bayer’s copanlisib, EP Vantage’s review of the space suggests.
AbbVie and Infinity expect to report topline data from the Dynamo phase II study of duvelisib in refractory iNHL and to complete an interim analysis of the Duo study in relapsed/refractory CLL in the third quarter of 2016.
At one point Gilead had looked like it could build a therapy franchise in haematological cancer around Zydelig, but this strategy is no longer tenable. This must put more pressure on Gilead to make a bold acquisition to shore up its presence in oncology.