“As one door closes many more open for us,” said TG Therapeutics’ chief executive, Michael Weiss, announcing yesterday that the accelerated approval plan for ublituximab plus umbralisib was being scrapped. Certainly, the first part of the quote is known to be correct.
The message to investors is to sit tight and wait until sometime next year, when the all-important Unity-CLL trial could yield progression-free survival data, in which Mr Weiss has a “high level of conviction of a successful outcome”. In reality, of course, the likeliest scenario is that Unity-CLL has already failed.
The problem stems from Unity-CLL’s inability to show an improvement in overall response among chronic lymphocytic leukaemia (CLL) patients given TG’s combo at interim review. It was this readout that TG had instructed the markets to look for, saying a positive result might have served as the basis for immediate US accelerated approval filing.
But the ORR results had been delayed twice, and were only reviewed by Unity-CLL’s data safety monitoring board over the weekend. The verdict? “Interim analysis of overall response could not be conducted at this time as the data were not sufficiently mature,” said TG yesterday.
While strictly speaking this is not incorrect, the company is muddying the waters. The board would only have halted the trial had there been a safety issue, and there was none. It would have reported an ORR benefit had there been one, and the fact that it has been unable to do so indicates that this readout has drawn a blank.
After all, Unity-CLL completed enrolment last October, and the planned 12 cycles of therapy meant all patients should have responded (or not) within 11 months; remissions tend to occur shortly after treatment, in contrast to survival data, which develop over time. TG admitted on an analyst call yesterday that the data monitoring board “did not conduct a formal futility analysis” of the study.
So there’s still a chance?
Some investors had already seen the writing on the wall, and might have been expecting TG to kick the can down the road to a survival readout (Slowly, TG investors start to fear the worst, September 18, 2018). Remaining bulls must now ask themselves whether a CLL trial that has failed to show an ORR benefit can nevertheless read out positively for PFS.
Unity-CLL pits ublituximab and umbralisib against Roche’s Gazyva and the chemo chlorambucil. Yesterday Mr Weiss stated: “We’re looking for a relatively tight difference in overall response, which is not likely to be a key driver of the difference in PFS.” The implication is that no ORR benefit can still translate into a “very big difference in PFS”, he told analysts.
History does not back up such a bullish view, however, as survival and response tend to be closely correlated.
In front-line CLL Abbvie’s Imbruvica yielded an 82% ORR benefit, well above the 35% with control, translating into 18-month PFS of 90%, versus 52%. Gazyva’s label cites median PFS of 26.7 months versus 14.9 months, and ORR of 80% against 66%. Relapsed/refractory CLL offers little more promise: 18-month PFS of 79% and an 83% ORR for Imbruvica, against 24% and 68% respectively for control.
TG will not reveal how many PFS events will trigger Unity-CLL’s unblinding, but said the median numbers to beat were 27-28 months in first-line and 14-15 months in relapsed CLL; 60% of Unity-CLL subjects are front-line. Mr Weiss said the trial’s assumptions remained unchanged, with most statistical power assigned to PFS.
TG had earlier hoped to show a 15-point improvement in ORR, but yesterday played this down, saying it had always viewed ORR as an “upside option”. Now is the right time to focus on PFS to back full approval, said Mr Weiss.
Investors keeping the faith will have to wait another year – knowing that the odds of hitting a positive PFS readout have lengthened considerably. Meanwhile, even after yesterday’s 44% share price decline TG is worth $425m, well above its first-half cash balance of $126m. The risk of another fall is obvious.