Upcoming events – Pivotal data readouts for Ardelyx and Rhythm will set the tone for next year

Both Ardelyx and Rhythm Pharmaceuticals are looking for phase III clinical wins to kick off filing discussions for pipeline leads.

Welcome to your weekly digest of approaching regulatory and clinical readouts.The next six months are going to be very busy for Ardelyx, which expects a raft of data with its lead project, tenapanor, in a number of indications.

First up is the phase III Amplify trial, looking at tenapanor as an adjunctive therapy to phosphate binders for patients with end-stage renal disease. The multipurpose asset is also looking to land its first approval, with a PDUFA decision in irritable bowel syndrome with constipation (IBS-C) due by September 12.

Tenapanor, a small molecule, targets the NHE3 transporter in the gut, resulting in the excretion of excess phosphate. While not in itself a treatment for renal disease it could reduce the pill burden of patients using phosphate binders, and therefore increase compliance.

The primary endpoint of the 214-patient Amplify study is change in serum phosphate levels after four weeks with tenapanor versus placebo. The project is also being tested as monotherapy in the phase III Phreedom study, which is due to read out in the fourth quarter. If it is successful in both trials it could become the only phosphate-lowering drug approved as a mono and adjunctive therapy.

In terms of IBS-C, tenapanor is designed to act directly in the gut to reduce absorption of sodium; this increases fluid in the gut, loosening stool and alleviating constipation. However, the project has had several setbacks in this setting, leaving it significantly behind the industry leader, Allergan’s Linzess.

Top IBS-C products by 2024
    Annual indication sales ($m) 
Product Company 2018 2024e
Tenapanor Ardelyx  - 443
Linzess Allergan 372 434
Movicol Norgine 188 179

Analysts now forecast a launch in IBS-C in 2021. Given Linzess’s headstart, and the fact tenapanor has so far lagged on efficacy and adverse events, the latter will face a tough time achieving the $443m of IBS-C revenues expected in 2024. A partner could help Ardelyx drive sales, and the company has previously said it was in discussions; these could accelerate if tenapanor is approved.

If all of these catalysts turn out to be positive it could make for a year-end turnaround for Ardelyx, which has recently seen its shares fall by 15%.

Hungry for success

Meanwhile, Rhythm Pharmaceuticals is expected to announce topline data from two pivotal trials of its lead project, setmelanotide, in two ultra-rare genetic obesity disorders in the third quarter.

Patients with the diseases, homozygous pro-opiomelanocortin (POMC) deficiency and leptin receptor (LepR) deficiency, have insatiable hunger and suffer from obesity at an early age. 

Setmelanotide is designed to activate the melanocortin-4 pathway, which should lead to increased energy expenditure and reduced appetite. 

The primary endpoint of both studies is the number of setmelanotide-treated patients who achieve 10% reduction in weight from baseline after 52 weeks versus placebo. The studies also include a double-blind, placebo-controlled, eight-week withdrawal period to measure weight and hunger scores when the therapy is stopped.

If the results are positive a US filing could be on the cards for the end of 2019 or early 2020. So far, if phase II studies are anything to go by, the omens look good for approval. In phase II patients reported body weight reductions of 10-30% after 52 weeks, and setmelanotide has not demonstrated the cardiovascular side effects that have plagued previous MC4 receptor agonists.

However, even if setmelanotide succeeds in the clinic, its commercial chances look less clear, with questions remaining over the size of the market. Indeed, consensus sellside forecasts from EvaluatePharma put 2024 sales at just $47m.

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