12 years on, Jakafi faces serious JAK competition

Approval of GSK’s momelotinib brings to a close one of the most unlikely biopharma rollercoaster rides of recent years. Not only is the US greenlight, under the trade name Ojjaara, unexpectedly broad, it concerns an asset that had been passed around numerous owners, at one point being divested for just $3m, and at another for $1.9bn.

Its approval marks the fourth for a JAK inhibitor in myelofibrosis. While the market leader, Incyte/Novartis’s blockbuster Jakafi, has been on the market for 12 years now, there is reason to believe that it could face the sort of pressure from Ojjaara that the other two incumbents, Bristol Myers Squibb’s Inrebic and Sobi’s Vonjo, have failed to deliver.

That’s largely because Inrebic’s 2019 US nod came with a boxed warning for encephalopathy, and that drug’s 2022 sales came in at just $85m, versus Jakafi’s $2.4bn (including two other indications). Interestingly, though the risks were known at the time, the Bristol legacy company Celgene had bought Inrebic’s owner, Impact Biomedicines, for $1.1bn in 2018.

Meanwhile, Vonjo got accelerated approved last year on the back of a surrogate endpoint, a fact likely to hold back use. However, despite the lack of controlled data on a hard endpoint, and though the approval is conditional on the phase 3 Pacifica study that won’t read out until 2026, Vonjo’s maker, CTI Biopharma, was in May bought by Sobi for $1.7bn.

JAK inhibitors in myelofibrosis

Source: prescribing information.

So how does Ojjaara fit in? This drug too came via acquisition – GSK paid $1.9bn for Sierra Oncology last year – but here prospects look far better. The US approval has come with no highlighted toxicity warnings, and is surprisingly broad, including primary as well as secondary myelofibrosis in adults with anaemia.

It was a focus on anaemia – a known co-morbidity in myelofibrosis – that proved to be the stroke of genius for Sierra, successfully differentiating Ojjaara from Jakafi.

But Ojjaara’s key trial, Momentum, concerned post-Jakafi patients, and compared versus the steroid Danazol, so the approval in primary myelofibrosis is an unexpected boon. That has been backed by the first-line Simplify-1 trial against Jakafi, which had underwhelmed, but which Sierra had argued was meaningful since it showed non-inferiority plus an anaemia advantage.

This is where the story has another twist. Simplify-1 was run by Gilead, which had bought momelotinib’s owner, YM Biosciences, for $519m, but which gave up on it after the failures of Simplify-1 and 2 (the latter was a post-Jakafi trial). That prompted Gilead to sell the asset for just $3m to Sierra, a company run by Nick Glover – the same Nick Glover who as chief exec of YM had sold YM to Gilead.

Ojjaara’s convoluted ownership history

Source: company announcements.

With the benefit of hindsight, it seems that Gilead had set momelotinib expectations too high, trying to show superiority over Jakafi, and not seizing on the anaemia advantage. It’s also notable that at the time of the YM takeout momelotinib was described as a JAK1/2 inhibitor, but 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.

Either way, Truist Securities analysts wrote that Ojjaara’s approval would likely put pressure on Jakafi sales, because some 40% of myelofibrosis patients exhibit anaemia symptoms at diagnosis. They also see use in Jakafi-ineligibles, and say many second-line patients are anaemic.

Intellectual property protection could be an issue, however. SEC filings cite momelotinib’s composition patents as expiring in 2028-30, though a salt form is apparently covered until 2035. Similarly, Vonjo’s patent exclusivity is set to end just three years after expected readout of its confirmatory Pacifica trial.

All this testifies to how long these JAK inhibitors have been in development. Back in 2012 momelotinib was expected to be launched in 2014. The threat to Jakafi has come, albeit nine years late.