ASH – Ninlaro throws down the all-oral gauntlet to Kyprolis

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As lifecycle strategies go, Takeda looks to have a pretty good one in Ninlaro. The drug, a proteasome inhibitor that secured approval for multiple myeloma in November, offers an obvious advantage over the Japanese firm’s established and similarly acting agent Velcade – it is dosed orally.

That said, there is no direct comparability head-to-head with either Velcade or Amgen’s proteasome inhibitor, Kyprolis, the drug against which Takeda will want to maintain market share after Velcade’s patent expires in 2017. However, the boast of an all-oral regimen in this setting should be enough in itself.

Ninlaro, formerly ixazomib oral, was approved on the basis of Tourmaline-MM1, a phase III trial in which it was added on top of Revlimid and dexamethasone. This hit its primary endpoint at the first interim analysis, statistically extending progression-free survival, though until ASH the actual numbers had not been revealed.

At a presentation on December 6 Dr Philippe Moreau, of the University of Nantes, France, spelled out the median PFS benefit, which with Ninlaro was extended by 5.9 months versus Revlimid and dexamethasone alone in 722 relapsed/refractory multiple myeloma patients, reducing risk of progression by 25.8% (p=0.012).

Of course there is no other proteasome inhibitor in the protocol, and neither is there one in any of the other advanced Ninlaro studies, so direct comparison is impossible. Head-to-head studies risk giving unexpected answers, so pharma companies tend to avoid them unless absolutely necessary.

Exciting time

But the availability of an all-oral regimen is not to be sniffed at, and in addition the data came at an exciting time for multiple myeloma treatment: Ninlaro was one of three new drugs approved for the condition just before ASH began (Multiple multiple myeloma approvals come just in time for ASH, December 1, 2015).

Speaking at an ASH media briefing, Dr Andrew Zelenetz, a physician from Memorial Sloan Kettering Cancer Center, likened this to a flurry of chronic lymphocytic leukaemia approvals a year ago. He suggested that this array of new treatments was making it difficult for investigators designing studies in such diseases – a nice problem to have, some might think.

In his presentation Dr Moreau also highlighted the fact that Ninlaro improved the Revlimid/dexamethasone combo’s efficacy while “adding limited toxicity”. There was no substantial increase in overall toxicity, including cardiac toxicity and peripheral neuropathy, over the control arm.

Especially pleasing was the finding that rash – a concern in phase I – was much reduced, with five cases of grade 3 rash versus two in Revlimid/dexamethasone alone.

As for secondary endpoints, Ninlaro hit statistical significance for overall response and complete response versus the control arm. Dr Moreau also said patients with high-risk cytogenetics were enjoying the same PFS benefit as low-risk ones, suggesting that Ninlaro could have an impact on the adverse prognosis associated with genetic mutations in multiple myeloma.

Three other Tourmaline trials are testing Ninlaro in various first-line settings, but will not read out until 2018.

Third Millennium blockbuster

Ninlaro looks like it could become the third blockbuster, after Velcade and Entyvio, to emerge from Takeda’s 2008 acquisition of Millennium (Payback for Takeda’s Millennium move with a third blockbuster, July 17, 2015).

The sellside expects Ninlaro to breach the blockbuster revenue barrier in 2019, and post sales of $1.5bn the following year; at 100% probability of success the product’s NPV, based on EvaluatePharma consensus expectations, stands at $7.3bn.

Consensus forecasts see the drug carving out a handy slice of the market, accounting for 36% of the combined market for proteasome inhibitors in 2020. This will still be less than Kyprolis’s share, but when combined with remaining Velcade revenue it should maintain Takeda’s dominance over the proteasome inhibitor space.

Study Trial ID ASH abstract
Tourmaline-MM1 NCT01564537 727

To contact the writer of this story email Jacob Plieth in Orlando at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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