Welcome to your weekly digest of approaching regulatory and clinical readouts. Ardelyx is awaiting pharmacodynamics data on its potassium binder RDX022, a crucial step on its streamlined track to approval.
Both Sanofi/Regeneron and AstraZeneca have their eyes on the poorly served atopic dermatitis market, and in the first quarter data will emerge on their rival antibodies, dupilumab and tralokinumab.
Fast work for Ardelyx
RDX022 was the rabbit Ardelyx pulled from the hat to soften investors' reaction to the loss of AstraZeneca as partner for its lead project, tenapanor (Ardelyx deserted but far from depressed, June 4, 2015).
In January the California-based group expects to report pharmacodynamics data on RDX022, a brief stopover on the accelerated development of this candidate into a pivotal study in hyperkalaemia next year.
Ardelyx has yet to say much about RDX022 other than it being a potassium binder. But because it is on the 505(b)2 development pathway this is almost certainly a known agent.
The pharmacodynamics study is short, testing one 15g twice-daily dose and three thrice-daily doses of 5g, 10g and 15g, and measuring potassium excretion over four days as well as safety parameters. Ardelyx has not filed the study with clinicaltrials.gov but has described it in a corporate presentation.
Signs of biological activity and a clean safety report could support advancing ’022 into phase III without having to pass proof-of-concept studies, again because it is on the 505(b)2 pathway.
Hyperkalaemia is a condition attracting a great deal of interest as it is a complication of kidney and heart disease. In the case of the latter, hyperkalaemia often means taking patients off heart failure medications such as angiotensin inhibitors.
Relypsa’s Veltassa, launched earlier this week, shows that there is a need for better treatments; its drug-drug interactions leave obvious room for improvement, and a potential competitor in ZS-9 has already disappointed (Forehead slaps in order for Astra as data dwarf $2.7bn deal, November 9, 2015).
RDX022 now figures nearly as large in Ardelyx’s future as tenapanor, according to Leerink analysts. Tenapanor is being tested in constipation-predominant irritable bowel syndrome and hyperphosphataemia in kidney dialysis patients; the former indication is reckoned to account for $87m in royalties in 2023 and the latter $119m in in-line sales. For RDX022, meanwhile, Leerink forecasts 2023 sales of $103m.
Atopic dermatitis is a chronic form of eczema, and few on-patent therapies exist. Corticosteroids such as clobetasone butyrate and mometasone are typical treatments.
Both Regeneron/Sanofi and AstraZeneca are aiming for a slice of the market. The former’s candidate, dupilumab, is the more advanced, with three phase III trials in nearly 2,000 patients set to read out in the first months of 2016. A phase IIb study of Astra’s tralokinumab in 184 patients will report in the same timeframe.
Mechanistically, both target inflammatory cytokines that mediate the autoimmune response that characterises atopic dermatitis. Dupilumab blocks both interleukin-4 and IL-13, whereas tralokinumab blocks IL-13 alone.
The first of the dupilumab trials, Chronos, has enrolled more than 700 adults with moderate to severe AD that is not adequately controlled with topical medications. The double-blind, placebo-controlled study is testing the antibody concomitantly with topical corticosteroids. Two more trials, Solo-1 and 2, have each enrolled 600 patients who will receive dupilumab monotherapy. All three studies are part of a planned phase III clinical programme called Liberty AD, to consist of at least five trials.
The project was a big hit in phase II. Its highest dose, 300mg weekly, resulted in a 74% reduction in the Eczema Area and Severity Index (EASI) from baseline to week 16, compared with 18% for placebo. Its safety was not perfect, but was acceptable (Sanofi and Regeneron itching to move dupilumab into phase III, July 10, 2014).
Thus expectations are high, with some on the sellside forecasting huge numbers: Leerink puts 2026 sales of dupilumab in this indication at $3.5bn. EvaluatePharma’s consensus forecasts put its dermatitis sales in 2020 at $915m.
Astra’s tralokinumab trails dupilumab in that it is still in phase II, and as such analysts have not yet forecast any sales specifically for dermatitis. The current trial is assessing three dose levels, and has co-primary endpoints of change from baseline versus placebo on the EASI and percentage of patients achieving Investigator's Global Assessment response of 0 (clear) or 1 (almost clear) and at least a 2-grade reduction from baseline at 12 weeks.
Far less is known about tralokinumab than dupilumab, so it is not surprising that much of the attention is on the latter. Bearing in mind that Astra’s asset will have a longer path to market, it will have not noly to equal but to beat dupilumab’s achievements in phase II if it is to compete. The shorter time period in tralokinumab’s trial compared with dupilumab’s phase II study could make this tricky to accomplish.
|Dupilumab||Chronos||Phase III efficacy and long-term safety trial in 739 adult patients with moderate to severe atopic dermatitis||NCT02260986|
|Dupilumab||Solo 1||Phase III monotherapy trial in 600 adult patients with moderate to severe atopic dermatitis||NCT02277743|
|Dupilumab||Solo 2||Phase III monotherapy trial in 600 adult patients with moderate to severe atopic dermatitis||NCT02277769|
|Tralokinumab||D2213C00001||Phase II efficacy and safety trial of tralokinumab in 184 adults with atopic dermatitis||NCT02347176|