Gilead’s myelofibrosis stumble leaves way clear for Jakafi

Incyte’s Jakafi is far from the perfect drug, but it looks to have the myelofibrosis market to itself for a while longer after a disappointing phase III showing from Gilead’s fellow Jak inhibitor momelotinib.

The late-stage myelofibrosis pipeline looks decidedly sparse – with Shire handing CTI Biopharma back rights to pacritinib in September and momelotinib’s stumble, only Celgene’s Revlimid seems likely to mount a near-term challenge to Jakafi. Longer term, one of the 17 agents currently in phase II might provide competition (see table below).

However, much of this list is made up of products that are being trialled in a range of related or similar conditions, or that are already approved for other diseases, where myelofibrosis might not be the top priority. Incyte seems well positioned in the disorder – particularly with two more contenders in phase II of its own.

Perhaps the company is looking to improve on Jakafi, which in 2011 became the first FDA-approved drug for myelofibrosis in spite of only proving a benefit on a surrogate endpoint, reduction in spleen size.

While an increase in survival has not been shown, Jakafi has demonstrated an improvement in symptoms, something that momelotinib has now failed to do in phase III. Gilead had hoped to file for approval early next year on the back of the two pivotal studies, but this now looks very unlikely.

Simplify not good enough

Gilead's first phase III trial, Simplify-1, which compared momelotinib against Jakafi, found that Gilead’s project was non-inferior on its primary endpoint, the proportion of patients experiencing a 35% or greater reduction in spleen volume.

However, it failed to reach non-inferiority on a secondary endpoint, reduction in total symptom score. Momelotinib patients also had twice the rate of peripheral neuropathy than those receiving Jakafi.

The second study, Simplify-2, which tested momelotinib versus best available therapy in patients previously treated with Jakafi, missed its primary endpoint – Gilead had hoped to show superiority with its drug on the same spleen size reduction measure.

Gilead says it plans to discuss the next steps with the regulatory authorities, but it seems likely that momelotinib is destined for the scrapheap – where it would join the company's other recent R&D failures like simtuzumab, GS-5745 and eleclazine.

The company’s misfortune outside its core antiviral expertise continues, and will only strengthen calls for it to make an acquisition. Gilead, among others, has previously been linked with Incyte. But at nearly $19bn Incyte’s market cap seems overblown in light of a net present value of $11.6bn. This represents the combined value of Jakafi and its R&D projects, as calculated by EvaluatePharma.

Nevertheless Jakafi, which accounts for just over $8bn of this NPV, now has nothing on the immediate horizon to challenge its dominance.

Mid to late-stage myelofibrosis projects
Project Company Mechanism
Pacritinib CTI Biopharma Jak-2, FLT3 inhibitor, CSF1R inhibitor & Irak1 inhibitor
Phase III
Revlimid Celgene Immunomodulator
Momelotinib Gilead Jak-1/2 inhibitor
Phase II
Glasdegib Pfizer Hedgehog pathway/smoothened inhibitor
Pomalyst Celgene Immunomodulator
Sotatercept Celgene/Acceleron Pharma ACT2RB fusion protein
Imetelstat Geron/J&J Telomerase inhibitor
PRM-151 Bristol-Myers Squibb/ Promedior MREG differentiation inducer
BMS-911543 Bristol-Myers Squibb Jak-2 inhibitor
Farydak Novartis HDAC inhibitor
LCL161 Novartis Inhibitor of apoptosis protein antagonist
Odomzo Novartis Hedgehog pathway/smoothened inhibitor
INCB039110 Incyte Jak-1/2 inhibitor
INCB050465 Incyte PI3K-delta inhibitor
Pracinostat Helsinn Group/MEI Pharma HDAC inhibitor
NS-018 Nippon Shinyaku Jak-2 inhibitor
SL-401 Stemline Therapeutics IL-3/CD123 modulator
Ropeginterferon Alfa 2b AOP Orphan Pharmaceuticals/ PharmaEssentia Interferon alpha
Estybon (oral) Onconova Therapeutics RAS mimetic & multi-kinase inhibitor
LDE225 & INC424 Novartis Hedgehog pathway/smoothened inhibitor & Jak-1/2 inhibitor

Its closest rival, CTI’s pacritinib, is still on clinical hold following safety concerns. Shire pulled out of development of the asset, which it inherited through its acquisition of Baxalta, after mixed topline phase III data.

Results from a phase III trial of Revlimid are not due until 2021, according to And even then, this is in the broader indication of myelodysplastic syndrome, which can lead to fibrosis. Pfizer’s glasdegib looks like a strong contender for the future; it is in a sizeable phase II study exclusively in myelofibrosis.

However Jakafi looks like it will be sitting pretty for some time yet.

Project Study Trial ID
Momelotinib Simplify-1 NCT01969838
Momelotinib Simplify-2 NCT02101268
Pacritinib Persist-2 NCT02055781
Revlimid Sintra-Rev NCT01243476
Glasdegib  Phase II study NCT02226172

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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