Arena Pharmaceuticals has been given a new lease of life with phase II results of its pulmonary arterial hypertension (PAH) candidate ralinepag. But the company, formerly focused on obesity, still has to clear phase III and, even if it does succeed, it will be entering a crowded market dominated by Johnson & Johnson.
Arena executives are already trying to set ralinepag apart from the competition, claiming on a conference call that its phase II data are better than those seen with J&J’s rival oral prostacyclin agonist Uptravi. The latter is forecast to be the biggest PAH product by 2022, according to EvaluatePharma consensus (see tables below).
However, the company’s assertion is based on an across-trial comparison, and one with several caveats at that. The bottom line is that in phase III ralinepag will likely need to replicate the morbidity/mortality benefit that Uptravi showed in the pivotal Griphon study (Selexipag hit puts Actelion back on the buyout radar, June 16, 2014). Arena has not yet revealed its phase III plans.
Still, its shares opened up 38% this morning on the back of the phase II results, which showed a significant reduction in pulmonary vascular resistance (PVR), the primary endpoint.
However, the results did not all go Arena’s way: ralinepag did not improve six-minute walk distance versus placebo, although there was a significant benefit over baseline. Arena blamed a high response in the placebo group, which was “a bit different from historic controls”, according to its chief medical officer, Preston Klassen.
On safety, which has been a problem with Uptravi, Arena said ralinepag’s profile was consistent with other prostacyclin agonists, with the most common adverse events being headache, nausea, diarrhoea, jaw pain and flushing.
|Ralinepag phase II trial results|
|Absolute change in PVR vs baseline*||-163.9dyn.s.cm
|% change in PVR vs baseline||-20.1%||9.6%||0.03|
|Absolute change in 6MWD vs baseline||36.2m||29.4m||Not significant vs placebo|
|*Primary endpoint. PVR: pulmonary vascular resistance. 6MWD: six-minute walk distance. Source: Company presentation.|
The 20% PVR improvement over baseline with ralinepag is at the high end of the 15-20% range that Leerink analysts previously said would be clinically meaningful (Upcoming events – Arena’s PAH play and Astra tries again with tralokinumab, June 30, 2017).
And it puts ralinepag’s efficacy on a par with one of the gold-standard PAH therapies, Flolan, which has been approved since 1983 and is given via continuous infusion versus ralinepag’s more convenient oral delivery. Of course, the usual caution about across-trial comparisons applies.
Perhaps the more relevant comparison is against Uptravi, and here the Arena execs are already claiming victory. Although J&J’s drug showed a 30% improvement on PVR versus placebo in phase II, Arena believes that a 16% change from baseline is a more accurate reflection of its efficacy.
A couple of factors confounded Uptravi's phase II study, Arena's chief executive, Amit Munshi, told EP Vantage. First, patients in the placebo arm were sicker at baseline than those in the Uptravi arm – this led to a large deterioration in the placebo group that drove the drug's relative benefit, he believes.
In addition, the standard of care has changed since the Uptravi phase II trial, and more patients are now treated with dual background therapy with endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. This could have led to Arena having “healthier” patients at baseline and given ralinepag a higher hurdle to clear, the Leerink analysts pointed out.
65% of patients in the ralinepag arm of the phase II trial were receiving dual background therapy at baseline, compared with around 33% of patients in Uptravi’s phase II study.
Unravelling Arena’s claims without a head-to-head trial is tricky and, in any case, they will be irrelevant if ralinepag does not succeed in phase III. The latest data will give investors hope that Arena can compete in the PAH market, but the pressure is still on. Arena will need to show that ralinepag outshines Uptravi on clinical endpoints – and to succeed against the marketing muscle of J&J it might also need a partner.
|Top five PAH products by 2022|
|Global sales ($m)|
|Product||Company||Pharma class||Route of admin||2016||2022e|
|Uptravi||Johnson & Johnson||Prostacyclin agonist||Oral||249||2,119|
|Opsumit||Johnson & Johnson||Endothelin A & B receptor antagonist||Oral||843||1,782|
|Adempas||Bayer||Guanylate cyclase agonist||Oral||281||475|
|Remodulin||United Therapeutics||Prostacyclin analogue||Injection||602||360|
|Orenitram||United Therapeutics||Prostacyclin analogue||Oral||157||294|