TG slips out a nasty surprise for investors

Yet another US clinical hold hits, and this time the unlucky recipient is TG Therapeutics.

TG Therapeutics has worked hard, sometimes against the odds, to convince investors and the FDA of the benefits of U2, its chronic lymphocytic leukaemia project. Yesterday the story took another twist as it emerged that the combo, under review by the agency for close to a year, was on partial clinical hold.

TG fell 41%, a harsh reaction even considering the abysmal performance of biotech markets so far this year. One reason why investors and analysts have come down hard on the company is that the hold bombshell did not fall in a formal announcement but was slipped out at an investor meeting and subsequently confirmed in a low-key regulatory filing.

If the company was hoping to create minimum fuss the strategy clearly failed. For whatever reason US clinical holds now appear to be a near-daily occurrence, with companies hit including Denali, Dyne, Yumanity, Viking, Cortexyme, Mustang Bio and Gilead. TG has not escaped the FDA’s attention.

U2 comprises Ukoniq, a PI3K delta inhibitor approved as monotherapy for indolent lymphomas, and the anti-CD20 MAb ublituximab, separately under US review for multiple sclerosis, an indication the sellside now sees as generating the vast majority of its blockbuster 2026 sales forecasts, according to Evaluate Pharma.

The combo has not had an easy ride, to say the least. Its registrational Unity-CLL trial suffered delays and a primary endpoint overhaul, but despite not showing a benefit on response rates it read out positively for progression-free survival against Roche’s Gazyva plus chlorambucil. A filing was accepted last May, with an action date of March 25, 2022.

However, the revelation that an advisory panel would be convened came as a nasty surprise, especially as the agency cited as a concern Unity-CLL’s lack of overall survival benefit, a key efficacy measure but one the study had not been powered to show. The adcom, due to occur in March or April, means that the approval action date will be missed.

Rollercoaster

Now there is even greater uncertainty given the company’s dribbling out news of the clinical hold on “select studies of U2 and its components”, something Evercore ISI’s Josh Schimmer said was presumably also due to concerns over overall survival. OS analysis, requested by the FDA last year, had revealed a 1.23 hazard ratio, or 1.04 when Covid-related deaths were excluded.

Obviously an HR over 1.00 implies that patients on U2 died more quickly than those on control, at least numerically, with the caveat that this was an immature analysis that included a lot of data censoring. Coming on top of the apparent divergence between ORR and PFS, however, it does not add confidence to U2’s chances of approval.

After the FDA request TG followed up missing patients to reduce data censoring, and apparently the HR has since improved further, though the group will not say whether it now stands below 1.00.

At least the PI3K part of the U2 combo, Ukoniq, looks untroubled by its class’s toxicity problems, which recently saw Gilead and Incyte pull certain uses of Zydelig and parsaclisib. Mr Schimmer wrote in a note to clients that TG still had a good case to make for U2’s approval, but cut his rating to reflect the uncertainty.

The sellside’s frustration at the opacity around TG’s data disclosure was summed up when he said he was looking forward to more data, “hopefully in press releases and earnings calls rather than competitor conferences and [SEC filings]”.

Annus horribilis: recent US setbacks
Date Company Project Status/detail Company timeline
28 Jan Lilly /Incyte Olumiant Filed for atopic dermatitis, but disagreement makes CRL possible; discontinued for lupus (ph3) Remains approved for rheumatoid arthritis
28 Jan Sanofi/ Regeneron Libtayo Filing withdrawn for cervical cancer after disagreement over post-marketing trials  Remains approved for other cancers
27 Jan TG Therapeutics U2 (Ukoniq + ublituximab) Filed; some combo & monoRx trials on hold, likely over adverse OS finding Update after Mar/Apr adcom
26 Jan Cortexyme Atuzaginstat Ph2/3 (IND application on hold for Alzheimer's disease) None, but immediate cost cutting to extend cash
25 Jan Gilead Magrolimab Ph3 (& other) haem-onc studies on hold; suspected unexpected serious adverse reactions None disclosed
25 Jan Incyte Parsaclisib Filings for FL, MZL & MCL withdrawn after confirmatory studies were deemed unrealistic Remains in ph3 for myelofibrosis
24 Jan Mustang Bio MB-207 Ph1/2 (IND application for ph2 XSCID trial on hold over CMC clearance Expects to start the ph2 in Q3 2022
24 Jan Viking VK0214 Ph1 (now ph2) X-linked adrenoleukodystrophy trial on hold; rodent genotoxicity trial needed Expects to fulfil request Q2 2022
29 Jan Yumanity YTX-7739 Preclinical (IND application on hold for multiple dosing in Parkinson's disease) None (no official hold letter yet)
18 Jan Dyne DYNE-251 Preclinical (IND application on hold for exon 51 skipper in Duchenne muscular dystrophy; more preclinical & clinical data requested) Expects to fulfil request Q2 2022
14 Jan Gilead Zydelig Approved; withdrawn for FL & SLL Remains approved for CLL
13 Jan Denali DNL919 Preclinical (IND application on hold for anti-Trem 2 MAb in Alzheimer's) None (no official hold letter yet)
Source: company announcements.

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