Welcome to your weekly roundup of approaching clinical readouts. Axsome is sitting on a 1,646% share price gain this year, making the company now worth an impressive $1.6bn. Two catalysts due shortly for the company’s lead project, AXS-05, could shake things up further.
First to the Gemini study. This tests daily AXS-05, a combination of bupropion and dextromethorphan, versus placebo. It has recruited 300 MDD patients, and its primary endpoints are safety and MADRS, a clinician-rated scale designed to measure depression severity, at six weeks. Hopes are high given positive results in an earlier trial called Ascend, where AXS-05 beat the active control bupropion; this data sent Axsome shares up 161%.
Stride-1 meanwhile pits AXS-05 against bupropion with a primary endpoint of MADRS at six weeks. Some aspects of the trial design raise questions: patients are required to have an inadequate response to bupropion during a lead-in period. Since this is the very agent being used as the active control the trial's design is a near-certain way of achieving zero response in the control group. Since bupropion is also an ingredient in AXS-05, being non-responsive to bupropion could also be seen as detrimental for the treatment arm.
Meanwhile the company’s definition of treatment-resistant depression seems to differ from the FDA’s own guidance, which could cause issues further down the line (Round two for Axsome, January 17, 2019).
Initially Stride-1 was due to readout at a similar time to Gemini but was delayed to allow for enough patients to enter the safety database required for filing. The FDA designated the earlier Ascend study as pivotal so alongside a second positive trial, either Gemini or Stride-1, a submission could go ahead. The company has said that an MDD filing could come in the second half of 2020; if Stride-1 hits TRD, a potentially more lucrative indication, would also be on the cards.
AXS-05 sales are forecast to reach $488m by 2024 according to consensus from EvaluatePharma.
|AXS-05 studies in depression|
|Ascend||Major depressive disorder, experiencing an acute episode||NCT03595579|
|Gemini||Major depressive disorder||NCT04019704|
|Stride-1||Treatment resistant depression, historical inadequate response to 1 or 2 antidepressant treatments and a prospective inadequate response to treatment with bupropion||NCT02741791|
|Open-label safety study||MDD and TRD||NCT04039022|
Pegilodecakin’s failure in pancreatic cancer in October set the tone for Lilly to dial down expectations in lung cancer, where data are due early next year.
Two trials are pending, both of which were started before the asset was acquired from Armo Biosciences for $1.6bn. Cypress 1 is the more interesting; this is examining whether pegilodecakin can add anything to Keytruda in first-line patients with high PD-L1 expression, defined as at least 50%. The second study, Cypress 2, combines pegilodecakin with Opdivo in second-line PD-L1-naive patients with low PD-L1 expression, a setting that is now largely irrelevant.
The primary measure for both studies is objective response rate. Overall survival and progression free survival are secondary endpoints. In Keytruda's Keynote-024 study in patients with PD-L1 >50% the ORR was 45% versus 28% for chemotherapy. This is the bar Cypress 1 must clear.
In the failed Sequoia pancreatic trial pegilodecakin missed the overall survival endpoint, and while few details were given at the time it is presumed that the drug added nothing to Folfox chemotherapy. Lilly noted that neutropenia, thrombocytopenia, fatigue and anaemia occurred at higher rates on the pegilodecakin arm, something to watch out for in the upcoming lung cancer studies.
Eli Lilly sat out the first round of immuno-oncology development and was hoping to play catch up with cytokines, however the data that has emerged on pegilodecakin so far shows that a lot still needs to be understood about this asset. The Cypress trials seem likely to confirm that opinion.
|Pegilodecakin clinical programme|
|Cypress 1 (phase II)||1st-line NSCLC, PD-L1 high (>50%), Keytruda +/- pegilodecakin||NCT03382899|
|Cypress 2 (phase II)||2nd-line PD-(L)1-naïve NSCLC, PD-L1 low (<49%), Opdivo +/- pegilodecakin||NCT03382912|
|Sequoia (phase III)||Second-line pancreatic, Folfox +/- pegilodecakin||NCT02923921|