Welcome to your weekly roundup of approaching clinical readouts. In the coming weeks TG Therapeutics will unveil survival data from the Unity-CLL trial, a readout that became harder to handicap after the company controversially rowed back on conducting an overall response analysis last year.
At the time, TG executives claimed that the data were not sufficiently mature to take a look at ORR, though concerns were raised that the trial had actually drawn a blank (A dose of reality as TG Therapeutics kicks the can down the road, September 26, 2018).
The Unity-CLL study pits ublituximab and umbralisib – TG’s two experimental projects, respectively an anti-CD20 antibody and a PI3K delta inhibitor – against Roche’s Gazyva and the chemo chlorambucil. Patients with both treated and untreated chronic lymphocytic leukaemia have been recruited, with progression-free survival as the primary endpoint. TG has said results will appear in late 2019 or early 2020.
If TG really had failed to see a difference in ORR last year, disappointment could be on the horizon, as survival tends to be closely correlated with response. Gazyva’s label cites median PFS of 26.7 months versus 14.9 months for control, and ORR of 80% against 66%, in front-line patients. Around 60% of Unity-CLL subjects are thought to be front line; TG has previously suggested that the median numbers to beat are 27-28 months in first-line and 14-15 months in relapsed CLL.
Other concerns include the unique strategy of testing two unproven agents together in a pivotal trial. TG has received the FDA’s blessing for the design but this does not rule out the possibility of regulatory hold-ups down the road, should the results not provide clear evidence of efficacy. Toxicity will be closely watched.
With both front line and refractory patients enrolled, there would seem to be potential for TG to seek relevance in subgroups, should significance not be hit in the total trial population. But after waiting for so long, investors will be hoping that the waters are not muddied once again.
The phase II Willow trial of Insmed’s INS1007 in non-cystic fibrosis bronchiectasis, data from which are expected in the coming quarter, is a high-risk, high-reward play. The project is a reversible inhibitor of dipeptidyl peptidase I, and the fate of the only other such agent to reach the clinic does not make for comforting reading.
Glaxosmithkline was forced to abandon development of GSK2793660 after its first-in-human study revealed the unexpected toxicity of epidermal desquamation – skin peeling – on patients’ hands and feet. INS1007 avoided this in earlier trials, its phase I showing good tolerability, but must still prove its worth in a larger patient population.
Bronchiectasis is characterised by pathological dilation of the airways. This is diagnosed radiographically, since the condition’s clinical presentations vary widely; this heterogeneity is the main reason for difficulty in achieving endpoints in clinical trials. DPP1 catalyses the activation of neutrophil serine proteases, which drive chronic inflammatory lung diseases. Insmed licensed INS1007 from Astrazeneca in 2016 for $30m upfront and a host of milestone and royalty payments.
Willow is testing the small molecule as a once-daily pill of either 10 or 25mg, taken for six months, versus placebo. The primary endpoint is time to first pulmonary exacerbation, with the company believed to be seeking a 40% delta between treatment and placebo arms. Insmed’s management has acknowledged that a clear effectiveness signal may prove elusive owing to the differing signs and symptoms seen in bronchiectasis.
If data are mixed, there will be little point in the company pursuing INS1007 given that 40% of non-CF bronchiectasis already overlaps with nontuberculous mycobacterial lung infections. Insmed could still capture a sizeable proportion of these patients through its marketed inhaled antibiotic Arikayce.
Possibly because of the trickiness of showing a benefit in this disease, forecasts for INS1007 are modest at just $18m in 2024, according to EvaluatePharma’s consensus data. If the trial hits, expect these to increase sharply – as indeed will Insmed’s stock.