TG Therapeutics (NASDAQ:TGTX) has learned the perils of coming late to a quickly evolving hemato-oncology market. Blaming slow enrollment in the Genuine trial of TG-1101 in combination with Imbruvica in chronic lymphocytic leukaemia, the New York-based group will no longer measure survival data, annulling a special protocol assessment with the FDA.
Exclusion of patients who have already taken Imbruvica is an obvious barrier to enrollment given the quick launch of Imbruvica in this space, although executives blamed slow recruitment on their insistence on enrolling only high-risk patients into Genuine. The 17% decline in share prices yesterday shows that investors have doubts about a regulatory strategy that relies solely on response data.
Not big enough
The phase III Genuine trial had sought to show that TG-1101 (ublituximab) in combination with Imbruvica could show an improvement in response rate and progression-free survival (PFS) in 330 previously treated patients with 17p, 11q or p53 mutations – these alter tumor suppression pathways and are markers of poor prognosis.
In a call with analysts, TG’s interim chief executive, Michael Weiss, said the company had set late 2016 or early 2017 as its target for getting full enrollment, but because of the slow pace the group believed it might take another two years to reach 330 patients, the number needed to have sufficient powering to show a PFS benefit.
PFS was one of two primary endpoints to the trial, along with overall response rate. The 120 patients now proposed will represent a large enough pool to measure response, and the company expects to complete enrollment by the end of 2016 and report topline data in early 2017.
However, in dropping the survival endpoint the special protocol assessment (SPA) – an agreement with the FDA about trial design that will answer scientific and regulatory questions – has been invalidated. Mr Weiss was quick to point out that Imbruvica, Zydelig and Venclexta were all approved on response data from single-arm studies and no SPA, so he argued that a positive benefit in Genuine ought to achieve the same result.
In any case, he said TG’s emphasis has shifted somewhat from single-agent TG-1101 to its combination with TG-2202 in the Unity-CLL trial – indeed, he claimed that expanding the eligibility criteria for Genuine to all relapsed CLL patients might have disrupted enrollment in the Unity program.
TG might be wise to make that shift to the combination strategy. As an antibody targeting CD-20, TG-1101 targets the same pathway as Roche’s (OTCQX:RHHBY) Rituxan – due to face biosimilar competition in 2018 – and Novartis’ (NYSE:NVS) Arzerra.
Use in combination with Imbruvica would be a differentiating factor in this crowded market, of course, but, given that many patients would already have first been treated with either an anti-CD20 or Imbruvica, oncologists might turn to a different mechanism after progression.
Of course, the combination strategy is not without its own risks. TG-2202 is a PI3K inhibitor, a class that has so far disappointed, and Gilead Sciences has already got there first with Zydelig – which must be used in combination with Rituxan.
Zydelig’s forecasts have shrunk massively because of its restrictive label and safety profile, while the rest of the PI3K pipeline has yet to live up to expectations. In other words, TG’s combination will need to outperform Zydelig and Rituxan when Unity-CLL reads out in 2018 for TG’s shift in focus to have been smart.
Thus, the Genuine trial now matters more as a prelude to Unity than as a key readout. The risk is that poor results could undermine confidence in the TG-1101/2202 combination. There seems to be more to lose than to gain.