Welcome to your weekly digest of approaching regulatory and clinical readouts. Further phase III results are expected shortly for AstraZeneca’s gout project lesinurad, whose first monotherapy trial met its primary endpoint but showed an increase in serious adverse events. These latest combination data must be positive if the agent is to succeed.
Meanwhile, readout from a trial of Takeda’s oral protease inhibitor MLN9708 in multiple myeloma is due this summer. With the Velcade patent expiring in the next couple of years MLN9708 is touted as its potential successor, and with a more convenient dosing regimen it could play a crucial part in maintaining Takeda's myeloma franchise.
At the end of last year topline results from the 214-patient Light study, testing lesinurad monotherapy in gout patients intolerant of allopurinol or Takeda’s Uloric, showed lesinurad to have met the sole efficacy endpoint, allowing significantly more patients to reach a target level of serum uric acid at six months compared with placebo.
However, safety data were worrying, with patients more likely to experience serum creatinine elevations and renal adverse events, including serious events, compared with those on placebo. Other commonly reported adverse events in treated patients were diarrhoea, nausea and constipation.
Astra will hope that this was just an aberration. The remaining phase III results should give a clearer picture of lesinurad's potential as an add-on treatment and are expected shortly. Lesinurad is being tested in combination with allopurinol, in the Clear1 and Clear2 trials, and febuxostat (Uloric) in the Crystal trial.
Even if lesinurad does avoid safety issues and secures approval it will enter a market dominated by generics, led by allopurinol. Although allopurinol’s effectiveness has been questioned, with just 40% of patients responding, it is cheap and therefore doctors are likely to start new patients on it (AstraZeneca hopes to take off heat with gout acquisition, April 23, 2012).
Astra's product would compete with Takeda’s Colcrys and Uloric and Novartis’s Ilaris in the second-line space. Consensus forecasts from EvaluatePharma assign $531m in sales to lesinurad by 2020, which if met would make it the market leader.
Astra bought Ardea BioSciences for $1.26bn back in 2012 solely for lesinurad, and these data could finally prove whether this was worthwhile.
MLN9708, known generically as ixazomib citrate, is the first oral proteasome inhibitor to enter phase III trials in multiple myeloma. The Tourmaline-MM1 study is testing MLN9708 with oral lenalidomide and dexamethasone against placebo and len-dex, and has recruited 703 adult patients with relapsed or refractory multiple myeloma.
MLN9708 is being given once weekly, with progression-free survival as the primary endpoint.
Phase I/II data presented at last year’s Ash meeting showed the effect of giving MLN9708 in combination with len-dex twice weekly to 64 patients with newly diagnosed multiple myeloma. The study reported a rate of combined complete response and very good partial response of 76%, with an overall response rate of 94%.
Drug-related serious adverse events were reported in 28% of patients, and drug-related grade 3 adverse events in 58%. Rates of rash, peripheral neuropathies and dose reductions were higher than in a parallel study using weekly MLN9708, with similar response rates, and therefore weekly dosing is being used in phase III.
Takeda’s multiple myeloma treatment Velcade is an intravenous protease inhibitor, and last year had total sales of $2.6bn, including $950m for Takeda. The Japanese group sells Velcade in the US and Japan, and co-promotes it with Johnson & Johnson in Europe.
The US patent is set to expire in 2017, and sales will fall to $1bn by 2020, just $103m of which will go to Takeda, according to consensus forecasts from EvaluatePharma. The European patent will lapse two years later.
MLN9708's 2020 sales are forecast to reach $929m, and the asset has an NPV of $2.5bn, 7% of Takeda's market cap, according to EvaluatePharma. It could become Takeda's third-biggest growth driver, and is also in phase III for untreated multiple myeloma patients and relapsed or refractory amyloidosis.
Barclays analysts note that Takeda could market the drug without a partner. The phase III results will have to live up to expectations if MLN9708 is to ultimately succeed Velcade.
NCT01383928 (phase I/II)