Therapeutic focus – Jaks still need to prove worth in rheumatoid arthritis

Analysis

The commercial flop that is Pfizer’s Xeljanz proves that being first to market does not guarantee success. This has not deterred other developers of Jak inhibitors, and several companies with follow-on molecules are poised to attempt to grab a bigger slice of the $23bn rheumatoid arthritis market.

Lilly fired the starting gun on data from the extensive pivotal programme of Incyte-partnered baricitinib this week; few details were released and it is too soon to determine how the project will differentiate itself. However, Johnson & Johnson’s decision to walk away from another advanced Jak earlier this month no doubt reflects the view that this space is going to get even more competitive, with no place for “me-too” molecules (see table).

Lilly said earlier this week that the RA-Beacon study met its primary endpoint of improved ACR20 compared with placebo at 12 weeks, and that the incidence of serious adverse events, including serious infections, was similar to placebo. The most common adverse events associated with baricitinib were headache, upper respiratory tract infection and nasopharyngitis, and discontinuation rates were similar between treatment groups.

Few conclusions can be drawn from this level of detail – further data will be released at a medical meeting next year, along with topline results from three other phase III studies, Build, Beam and Begin. Beam, in methotrexate-refractory patients yet to receive a biologic, is considered the most important commercially as it contains a Humira comparator arm and could form the basis of a label claim to inhibit the progression of structural damage to the joints. Humira has this claim on its label while Xeljanz does not.

Ultimately, Lilly needs to differentiate itself from Xeljanz by establishing greater potency with at least equivalent safety, and at the same time provide a match for the anti-TNFs like Humira. The AbbVie blockbuster has been on the market since 2003 so naturally has a major advantage in terms of clinical experience, but Lilly will be hoping – just as Pfizer did – that baricitinib’s oral administration will aid its appeal.

History lesson

Baricitinib is pegged for launch in 2016 and EvaluatePharma has sales of $551m by 2020; consensus has largely remained stable over the last 12 months.

This is perhaps surprising considering the downgrades seen for Xeljanz. Consensus for 2018 stands at $1.3bn; this figure has come down by almost a third over the past 12 months, and was as high as $2.6bn in the months after the drug’s launch.

As it turned out, regulators and then physicians were much more cautious about Xeljanz's safety, particularly over the long term, than expected. The drug carries black box warnings over infections and cancer risks – as do the anti-TNFs – and these concerns prompted the FDA to refuse approval for the higher dose that Pfizer was seeking. At the lower dose now available it struggles to stand up to the anti-TNFs on many efficacy measures.

In Europe, regulators refused to grant approval at all, also blaming the drug’s risk-benefit profile (Xeljanz train derails in Europe, April 26, 2013).

This poor commercial start for the class has not deterred other developers of small molecules that target Jak – J&J notwithstanding. The RA market is worth more than $20bn a year and is expected to be pushing $30bn by 2020, according to EvaluatePharma, and with injected therapies set to remain dominant an effective oral competitor should be in demand.

Jaks to watch in RA     
Status Project (generic name) Pharma class Company Originator 2020 sales ($m)
Marketed Xeljanz JAK-3 inhibitor Pfizer Pfizer 1,690
Phase III baricitinib JAK-1/2 inhibitor Eli Lilly Incyte 551
Phase III ASP015K (peficitinib) JA-1/3  inhibitor Astellas Pharma Astellas Pharma 41
Phase II VX-509 (decernotinib) JAK-3 inhibitor Vertex Vertex -
Phase II GLPG0634 (filgotinib) JAK-1 inhibitor AbbVie Galapagos 363
Phase II INCB47986 JAK-1 inhibitor Incyte Incyte -
Phase II PF-04965842 JAK-1 inhibitor Pfizer Pfizer

Baricitinib is the most advanced new contender, although Astellas’s perficitinib is in phase III in Japan. This is the project that J&J walked away from, citing a “strategic portfolio decision”. A number of Astellas-run mid-stage studies have completed and could have informed J&J’s decision. However the US pharma giant is testing several other novel mechanisms in RA, so it could also have been a call on a crowded class.

This means that Galapagos’ filgotinib is probably closest behind baricitinib. The selective Jak-1 inhibitor is an extensive phase IIb programme, and has been licensed by AbbVie. Under the deal, which involved $150m up front, the European biotech is funding the current studies and the US company is essentially delaying its full commitment to the project, pending the data. Top-line results are due to emerge around March 2015.

AbbVie is clearly keen to protect its dominance in RA and has work going on with a variety of other pharmacological mechanisms in RA, including another organically discovered Jak inhibitor, ABT-494. So it seems likely that filgotinib will be measured not only against other Jaks, but other projects on which the biotech is focusing.

Also in phase II is Vertex’s VX-509 or decernotinib, though the company has not started any new trials on the compound since early 2013. The company is expected to partner the project; unfortunately, after the release of the phase II data last year analysts commented that it does not appear to be notably differentiated from Xeljanz. Lack of news on the deal front perhaps speaks to this point.

Earlier in clinical development is Incyte with INCB47986, which is recruiting patients in a phase II trial, while Pfizer is preparing to move another Jak into patients – here the initial indication appears to be psoriasis.

Wide open

With multiple other novel mechanisms being tested, it is clear that the next-generation Jak inhibitors will not just be held up against each other.

Xeljanz has demonstrated that Jak is an effective target in RA. The main problem to date has been teasing out potency without the side effects. Safety is therefore likely to be a key battleground for those in development which target different kinases of the Jak family with various levels of specificity.

However few other orally delivered mechanisms are in development. And as Biogen Idec has shown with Tecfidera in MS, a potent and relatively safe oral option can generate huge demand in chronic conditions.

This opportunity is still wide open in RA.

Key ongoing trials
Project Trial ID Acronym
Baricitinib  NCT01721044 RA-Beacon
NCT01721057 RA-Build
NCT01711359 RA-Begin
NCT01710358 RA-Beam
ASP015K  NCT01638013
NCT02308163
GLPG0634  NCT02065700 Darwin3
NCT01888874 Darwin1
NCT01894516 Darwin2
INCB47986 NCT02151474
PF-04965842 NCT02201524

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @AmyEPVantage on Twitter

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