Probably the best thing about Infinity’s Dynamo trial of duvelisib is that it was one of the few studies in the group’s 15-year history to have rendered a positive result.
There the good news ends, however, and the group has made no secret of Dynamo’s lack of clinical benefit; its market cap crashing yesterday to a level 70% below its first-quarter cash balance shows that investors already assume that both duvelisib and Infinity’s deal with Abbvie are dead in the water. The next question is whether this verdict should also apply to all other PI3K inhibitors.
After all, the precedent is poor, and duvelisib’s failure to excite adds to the disappointment of Gilead’s Zydelig, the first PI3K inhibitor to reach the market. A poor toxicity profile turned Zydelig into a damp squib against the onslaught of AbbVie/Johnson & Johnson’s Imbruvica, and Gilead recently axed several trials.
No positive spin
While Infinity is not yet admitting defeat, in yesterday’s announcement it did not try to put any gloss on the disappointment of the Dynamo data in non-Hodgkin’s lymphoma.
The study met its goal of showing remissions in 46% of 129 NHL patients, but the actual response rate – and the fact that all the remissions were partial and not complete – was underwhelming. Infinity said it had hoped for a larger clinical benefit, but would not elaborate or provide further details about the study.
There are three immediate effects: the group is closing its discovery operation with the loss of 21% of its workforce, pausing a separate trial combining duvelisib with AbbVie’s Venclexta, and reviewing its collaboration with Abbvie.
That deal, struck in 2014, breathed new life into duvelisib, which back then was already seen as a struggling asset, though the $275m up-front fee was negated by the fact Infinity was on the hook for R&D costs. It can probably be assumed that Abbvie, now with Venclexta and Imbruvica in its possession, will have no need for duvelisib and will walk away.
Infinity had $193m in the bank at the end of March, and its market cap slumping yesterday to just $62m shows the market’s lack of confidence and assumption that much of the cash is tied to ongoing studies. A $200m AbbVie milestone, due on acceptance of US and EU duvelisib filings, is now also a pipe dream.
A further data readout, from duvelisib’s Duo trial in chronic lymphoblastic leukaemia, remains on track for early in the second half. However, even if this is positive, Imbruvica’s approval in first-line CLL means that there is little space in the market for another player unless knockout efficacy can be shown.
The TG question
The flops of Zydelig and duvelisib put into serious doubt the PI3K inhibition mechanism as a whole (Therapy focus – TG could benefit from Zydelig setback, March 29, 2016).
Thus the spotlight falls on two late-stage PI3K agents: Bayer’s copanlisib and TG Therapeutics’ TGR-1202. TG is especially vulnerable since it offers near-complete exposure to this mechanistic approach, though its stock was virtually unmoved yesterday, suggesting that investors saw no readacross from the duvelisib setback.
At the recent EHA meeting TGR-1202 at its phase III dose yielded a 53% overall remission rate in NHL patients, with a third of the responses being complete. Ladenburg Thalmann analysts said TGR-1202’s tolerability profile was best in class, and highlighted greater efficacy at higher doses and in combination with TG’s own anti-CD20 MAb, ublituximab.
Infinity also stressed its continued faith in duvelisib “especially in combination”, though this seems optimistic. It is perhaps telling that TG has not managed to secure partners for its lead assets, but at least for the time being its dream remains alive.
|Selected duvelisib studies|
|Dynamo||Single-arm, 129 iNHL pts||46% ORR, all PRs||NCT01882803|
|Duo||Vs Arzerra in 300 r/rCLL pts||Data due early H2||NCT02004522|
|–||Venclexta combo in 174 CLL/NHL pts||Study paused||NCT02640833|