The addition of more than a quarter of a billion dollars of valuation to TG Therapeutics on the back of positive phase III data for ublituximab looks a bit overdone. In combination with Imbruvica, the CD20-blocking antibody returned positive phase III data from its modified Genuine trial in chronic lymphocytic leukaemia (CLL), prompting bullish analysts and investors to predict approval on this single study.
Yesterday’s 90% boost to share price returned TG to levels only slightly above where it was before it removed a survival endpoint from Genuine, a decision that accelerated the study’s conclusion but negated an agreement with the US FDA. Given the regulator’s receptive stance on new cancer drugs, approval remains a distinct possibility, although differentiating ublituximab from Rituxan and its coming biosimilar rivals will remain a big problem.
The New York-based company said the ublituximab (TG-1101) and Imbruvica combination achieved an overall response rate of 80% versus 47% in the 117 patients on Imbruvica alone – the Imbruvica monotherapy result was similar to that achieved by Abbvie's BTK inhibitor in its clinical development. Patients enrolled in the trial had relapsed or refractory disease and expressed mutations that classified them as high risk.
In October, TG dropped progression-free survival as a study endpoint (Falling behind, TG tears up clinical plan and talks up combo, October 14, 2016). This decision allowed the group to cut enrolment from 330 to 117 and still be able to report a primary endpoint. It could have taken another two years to enrol 330 patients.
TG is planning to present its data at a medical meeting this summer and then discuss a filing for accelerated approval with the FDA after that, said its chief executive, Michael Weiss. If the agency is receptive a BLA could be filed by mid-2018.
Therein lies TG’s first issue: the PFS endpoint was part of a special protocol assessment with the US agency, and its absence could provide justification for the regulator to ask for more data. There is precedent for the FDA to accept the BLA for review, however – Imbruvica and Venclexta, for example, were initially approved in CLL on the basis of single-arm studies, though these late-line patients had few options at the time.
Comparing the combination against Imbruvica alone would certainly represent more robust data than those two agents’ single-arm studies. However, combination use raises a second issue – namely, that Rituxan got there first as a CD20 monoclonal antibody in combination with Imbruvica.
Indeed, the Rituxan-Imbruvica combination has already recorded similar response data and also has PFS data to back it up. And of course TG has not run a trial comparing ublituximab directly against Rituxan.
What’s more, Rituxan is reaching the end of its patent life, and Amgen’s biosimilar ABP 798 and Pfizer’s PF-05280586 could represent alternatives in 2018 and 2019; TG might need to consider this in pricing its newer offering.
In any case, TG has been focusing on ublituximab in combination with the PI3K inhibitor TGR-1202, which is the subject of the phase IIb/III Unity programme, with the IIb trial in second-line diffuse large B-cell lymphoma due to report data in 2019 and a phase III study in first and second-line CLL due next year.
Achieving approval with Imbruvica next year might unlock a small revenue stream for TG, but with this latest share boost it would be foolish not to raise money. It had $61m in cash at September 30 and had spent $55m in the first nine months of 2016. In the current environment cash call opportunities like this do not happen every day.
|Genuine||Ublituximab plus Imbruvica in CLL||NCT02301156|
|Unity-CLL||Ublituximab plus TGR-1202 in CLL||NCT02612311|
|Unity-DLBCL||Ublituximab plus TGR-1202 in DLBCL||NCT02793583|