Welcome to your weekly digest of approaching regulatory and clinical readouts. Phase II data are due next month on Arena’s prostacyclin receptor agonist ralinepag, which faces a crowded pulmonary arterial hypertension market, and tolerability issues with this class of compound (see table below).
Also, the pivotal trial of Astrazeneca’s severe asthma candidate tralokinumab is due to read out later in the year. After a previous phase III failure, Astra has highlighted a subpopulation in a second study in an attempt to turn the antibody’s fortunes around.
Pulmonary arterial hypertension (PAH) is characterised by increased pressure in the arteries that carry blood from the heart to the lungs, which if left untreated can lead to heart failure. Arena’s ralinepag is an oral agonist of prostacyclin, a potent vasodilator.
The phase II trial is in 60 PAH patients, with data due in July. During the first nine weeks of the trial patients were titrated to individual tolerance levels, and then sustained at this level for up to 22 weeks, versus placebo, on top of stable therapy with an endothelin receptor antagonist and/or a PDE-5 inhibitor.
The primary measures are change from baseline in pulmonary vascular resistance (PVR) and change in six-minute walk distance at 22 weeks. An open-label extension study is ongoing.
The PAH market is crowded, with Johnson & Johnson’s Uptravi set to take the crown in terms of sales by 2022, according to EvaluatePharma sellside consensus. This is also an oral prostacyclin receptor agonist, and in its phase II trial it achieved a statistically significant treatment difference of -30.3% on the PVR endpoint. Strangely, Leerink analysts claim that a 15-20% improvement would be clinically meaningful for ralinepag.
Uptravi, approved in 2015, is associated with significant adverse events including headache, diarrhoea, nausea, myalgia, jaw pain and vomiting. In its phase III trial 14% of patients on the drug discontinued owing to adverse events versus 7% on placebo (Selexipag hit puts Actelion back on the buyout radar, June 16, 2014).
Similar adverse events have been seen with other drugs targeting prostacyclin, so this will be something to watch out for with ralinepag.
|Top 5 PAH products by sales|
|Global sales ($m)|
|Product||Company||Pharma class||Patent expiry||2016||2022e||Route of admin|
|Uptravi||Johnson & Johnson||Prostacyclin agonist||Apr 2023||249||2,119||Oral|
|Opsumit||Johnson & Johnson||Endothelin A & B receptor antagonist||Oct 2022||843||1,782||Oral|
|Adempas||Bayer||Guanylate cyclase agonist||Dec 2026||281||475||Oral|
|Remodulin||United Therapeutics||Prostacyclin analogue||Jun 2018||602||360||Injection|
|Orenitram||United Therapeutics||Prostacyclin analogue||Feb 2030||157||294||Oral|
The pivotal study that Astra's tralokinumab already flunked was Stratos 1, failing to show a significant reduction in annual asthma exacerbation rate (AAER) in severe, uncontrolled asthma patients favouring the anti-IL13 antibody versus placebo.
But the company claimed that a clinically relevant reduction in AAER was observed in subjects with an elevated biomarker associated with increased IL-13 activity, and this subgroup is the focus for the analysis of the second trial, Stratos 2, results of which are due in the second half.
Stratos 2 enrolled 856 patients with asthma inadequately controlled by inhaled corticosteroid plus a LABA agonist. The design matches that of the first trial with 300mg tralokinumab administered subcutaneously every two weeks and compared with placebo.
The value of IL-13 inhibition in this indication was already clouded by Roche’s similarly acting lebrikizumab, which succeeded in one pivotal trial but failed a second. Roche has since abandoned efforts in asthma, but has ongoing trials in idiopathic pulmonary fibrosis and atopic dermatitis (Roche’s asthma stumble gives Glaxo the upper hand, February 29, 2016).
EvaluatePharma’s archive of consensus forecasts reveals that lebrikizumab sales were once expected to hit $591m by 2022, with $150m for tralokinumab in the same year. These days analysts have all but written off tralokinumab, though sentiment might change if the project hits in the subpopulation.
If tralokinumab fails completely Astra has some solace in the form of benralizumab in severe asthma. This anti-IL-5 MAb has a PDUFA date due in the second half of the year. Sellside forecast sales sit at $872m by 2022, placing benralizumab behind Glaxosmithkline’s Nucala, which was approved in 2015, and Sanofi’s Dupixent, due to report data towards the end of the year.
|Late-stage asthma antibody landscape|
|Annual indication sales ($m)|
|Cinqair||Teva Pharmaceutical Industries/Merck & Co||IL-5||5||69|
|Filed||Benralizumab||Astrazeneca/Kyowa Hakko Kirin||IL-5||-||872|
|Phase III||Dupixent||Sanofi/Regeneron||IL-4 & IL-13||-||1,310|