Sierra’s not-so-nimble Jak scores at last

Momelotinib, a Jak inhibitor that has been through four companies, yields a positive result in its pivotal Momentum trial.

If Nick Glover were still chief executive of Sierra Oncology he would today be living the biotech dream. Having sold his previous company, YM Biosciences, to Gilead for $510m he then paid just $3m to buy back its lead asset, momelotinib, for his new company, Sierra; today, in Sierra’s hands, that lead asset scored in a pivotal myelofibrosis study.

Mr Glover has not headed Sierra since 2020. But this does not detract from the peculiar nature of momelotinib’s eleventh-hour success; the project has a long and convoluted history, and one of Sierra’s problems now might be its relatively short US patent life, not to mention a milestone and royalty payaway owed to Gilead.

One sign that not all is as rosy as it might seem is that Sierra today secured a $125m debt facility with Oxford Finance to support momelotinib’s commercialisation. It is more typical for a biotech to raise equity in light of a positive clinical readout, though in fairness the poor current state of the markets might have precluded this.

SEC filings cite momelotinib’s composition patents as expiring in 2028-30, though a salt form is apparently covered until 2035. An indication of how long this project has been around is that back in 2012, when known under the lab code CYT387, it was expected to be launched in 2014, just three years after Incyte’s Jak1/2 inhibitor rival, Jakafi.

Gaining Momentum

While the current timeframe will prove such expectations to have been at least nine years premature Jakafi, the first US-approved myelofibrosis drug, is still the target against which momelotinib is squaring up.

The Momentum trial suggests that Sierra might have found an addressable niche for momelotinib, namely myelofibrosis patients in whom anaemia is the main co-morbidity. The clever thing the company did was to have seized on this possible differentiation, and to have designed a pivotal study that demonstrated it.

Momentum took post-Jakafi patients and compared giving them momelotinib versus the steroid Danazol. Momelotinib beat danazol on its primary measure, 24-week total symptom score, with 25% versus 9% of patients scoring 50% or more (p=0.0095).

Even more important was that the secondary measure of transfusion independence at week 24 also appeared positive. 31% of momelotinib patients achieved this versus 20% of those on danazol, a finding that cleared the boundary for non-inferiority (one-sided p=0.0064) albeit not for superiority (two-sided p=0.0861).

And there is some mechanistic rationale to back momelotinib’s effect on anaemia and transfusion independence. While at the time of the Cytopia and YM transactions the project was described as a Jak1/2 inhibitor, by the time Sierra was buying it from Gilead it was said to hit Jak1/2 as well as ACVR1, a TGFβ receptor that regulates iron metabolism.

But if momelotinib held such promise why did Gilead give up on it? The big biotech group conducted two phase 3 studies, Simplify-1 and 2, but both failed.

Selected myelofibrosis trials featuring momelotinib (CYT387)
Sponsor Trial Design Result
Cytopia/YM Core Single-cohort ph1/2 study 31% spleen response; ≥12wk transfusion independence achieved by 54% of dependent patients
Gilead Simplify-1 Jak-naive, head-to-head vs Jakafi 24wk ≥35% spleen response (primary) failed to show superiority (27% vs 29%, p=0.011 for non-inferiority)
Gilead Simplify-2 Post Jakafi (no washout), vs best available therapy 24wk ≥35% spleen response (primary) failed (7% vs 6%, p=0.90)
Sierra Momentum Post Jakafi (with washout), vs danazol 24wk TSS ≥50% response (primary) superior (p=0.0095); 24wk transfusion independence (secondary) non-inferior (p=0.0064)
Source: company statements.

However, the mistake there might have been in setting momelotinib expectations too high – Simplify-1 pitted it head to head against Jakafi – and in not seizing on the anaemia advantage. Sierra today cited an analysis of Simplify-2, showing a not dissimilar outcome on total symptom score and transfusion independence to that seen in Momentum.

Back in 2012 Gilead had pulled the acquisition trigger for YM largely on the strength of a phase 1/2 study that Cytopia had initiated and YM completed. That had shown momelotinib to yield a 31% spleen response, with 54% of transfusion-dependent patients becoming independent for at least 12 weeks, and it made YM one of the stars of the 2011 Ash conference.

Of course, this was in the pre-Jakafi era, and it might be that the Incyte drug complicated things too much for Gilead. Today the persistence of Mr Glover and Sierra has been vindicated; the company is up 48% this morning, so some investors might hope that momelotinib might yet find a fifth home.

Momelotinib's ownership history
Date Deal Terms
Oct 2009 YM buys Cytopia (momelotinib is the lead asset) Not disclosed
Dec 2012 Gilead buys YM (momelotinib is the lead asset) $510m (note that YM had C$126m in cash)
Aug 2018 Sierra buys momelotinib from Gilead $3m up front, up to $195m in milestones, plus tiered royalties (mid teens to high 20s)

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