Arena Rises, But Raises Questions With Phase II Ralinepag Data In PAH

Arena reported statistically and "clinically" significant results from its Phase II study for ralinepag in pulmonary arterial hypertension (PAH), driving its share price up by more than 40%, but details expected later this year or in 2018 are needed to shed more light on the data.

Arena Pharmaceuticals Inc.'s pulmonary arterial hypertension (PAH) drug candidate ralinepag met the efficacy bar that the company set for its oral therapy in a Phase II placebo-controlled study, but baseline characteristics of patients in the two treatment arms raise questions about what drove the results.

Investors liked what they saw when Arena released the highly-anticipated top-line data – the first Phase II efficacy results for one of two lead drugs under the company's new strategy, which represented a shift in focus from approved obesity therapy Belviq (lorcaserin) to ralinepag (APD811) and other early clinical-stage programs. (Also see "Deal Watch: Taking Care Of Business Before J.P. Morgan" - Scrip, 6 Jan, 2017.) Arena shot up 41.3% in after-hours trading on July 10 to $26.50 per share after the company said PAH patients treated with its selective agonist of the prostacyclin receptor had a statistically significant reduction in pulmonary vascular resistance (PVR) compared with placebo.

PVR changes and six-minute walk distance (6MWD) results were co-primary endpoints in the 61-patient Phase II study, in which patients were randomized 2:1 to ralinepag and placebo. Arena CEO Amit Munshi told Scrip that the trial was not powered to show a statistically significant difference between ralinepag and placebo in terms of the 6MWD, but he said the improvement from baseline was "clinically significant" for the company's drug.

"We're very pleased with the data and the conduct of the study and we think we're headed down a positive path," Munshi said.

Arena reported that ralinepag reduced median PVR by 163.9 dyn.s.cm-5 from baseline compared to a 0.7 dyn.s.cm-5 increase from baseline in the placebo arm at the end of the 22-week treatment period (p=0.02). The 20.1% improvement for ralinepag-treated patients versus baseline came in at the high end of the 15% to 20% gain that the company was hoping to reach based on feedback from physicians about what would be a significant result.

PVR had farther to fall for the ralinepag-treated patients, however, as Chief Medical Officer Preston Klassen shared baseline patient population characteristics during the company's conference call that showed median PVR was much higher in the ralinepag treatment group versus the placebo group – 705 versus 480 dyn.s.cm-5. Even so, median PVR at 22 weeks improved by 29.8% when comparing ralinepag-treated patients with the placebo arm based on a least square means analysis (p=0.03).

"These Phase II data for oral ralinepag were supportive of further study, with a good improvement in PVR, though the data on 6MWD was confounded by a large increase in the placebo group," the Informa Pharma Intelligence service Biomedtracker noted in a July 10 report.

Small Difference Versus Placebo On 6MWD

The 6MWD results revealed during Arena's conference call showed that ralinepag-treated patients gained a mean of 36.2m versus their baseline performance while patients in the placebo group gained a mean of 29.4m from baseline for a difference of 6.8m. Mean total distances at baseline were 393m in the ralinepag group versus 351m in the placebo arm.

The ralinepag result versus baseline was statistically significant, but the placebo group's performance versus baseline and the 6MWD gains for ralinepag versus placebo were not significant. However, individuals in the placebo group may have benefited from recent changes in their background medicines. At baseline, 38% in the placebo group changed their background therapy within six months of initiating treatment in the Phase II study versus 12.5% in the ralinepag group.

It's also worth noting that ralinepag patients were more heavily medicated, since 48% of placebo patients were on a combination therapy regimen, while 65% in the ralinepag group took more than one background drug. In practice, most PAH patients are treated with a combination of drugs.

Side effects in the Phase II ralinepag study were described as "consistent with other prostacyclin treatments for the management of PAH, with headache, nausea, diarrhea, jaw pain and flushing being the most commonly reported adverse events." The events were more frequent in the nine-week dose titration period than during the 13-week stable treatment period.

Klassen noted during Arena's conference call that 12.5% of ralinepag-treated patients discontinued the study during the 25-week safety assessment period due to adverse events compared with 10% in the placebo group. However, only four patients (10%) in the ralinepag arm experienced a serious adverse event versus six (28.6%) placebo-treated patients. There were two deaths during the Phase II study, both of which occurred in the placebo arm.

Munshi declined to say in an interview whether the single incidence of transient atrial fibrillation seen in a Phase Ia study was repeated in the Phase II trial, but noted that "we're not seeing anything that makes us concerned at all." More detailed safety and efficacy data will be presented at a medical meeting either later this year or in 2018. (Also see "Arena moves PAH drug forward despite Phase Ib adverse event" - Scrip, 29 Aug, 2013.)

Efficacy Similar To Other Prostacyclin Drugs?

Klassen praised the Phase II study in a statement from Arena for showing that ralinepag could be the first oral prostacyclin therapy to show efficacy similar to what is seen with intravenous prostacyclin receptor agonists. "These data give us confidence to move expeditiously toward a Phase III clinical program," the CMO noted.

The company will not provide details about its Phase III trial design until it speaks with the US FDA and the European Medicines Agency (EMA) about the Phase II results and the potential Phase III program, Munshi told Scrip. However, he noted that the regulators probably will only require one Phase III study, since that is what was required for other PAH drugs, including the only approved oral prostacyclin agonist Uptravi (selexipag) from Actelion Pharmaceuticals Ltd., which Johnson & Johnson recently acquired for $30bn. (Also see "J&J’s $30bn For Actelion Buys Immediate And Longer-Term Value" - Scrip, 26 Jan, 2017.)

While Munshi said "PVR is a strong proxy for being able to show you're affecting the underlying disease," he explained that Phase III PAH trials generally use 6MWD and clinical outcomes as primary and secondary endpoints. Testing for PVR requires the insertion of a catheter into the right side of the heart – a procedure that's difficult to do in a large clinical trial. However, the Phase II PVR and 6MWD results give Arena "a very good sense of how to design Phase III," Munshi said.

PAH is a rare and progressive disorder characterized by increased pressure in the arteries that carry blood from the heart to the lungs, which strains the heart, eventually leading to heart failure and reduced life expectancy. The disease primarily is treated with four types of drugs: endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, prostacyclin analogues and soluble guanylate cyclase (SGc) stimulators.

If Arena's Phase II results are repeated in Phase III, the company's oral drug will compete against well-established blockbuster PAH drug portfolios from United Therapeutics Corp. and Johnson & Johnson, including Actelion's oral Uptravi, which was approved at the end of 2015. (Also see "United Therapeutics Expects Actelion To Add To PAH Market" - Scrip, 14 Jan, 2016.)

While Uptravi is a twice-daily pill and Arena tested twice-daily ralinepag in its Phase II study, the company hopes to move forward with an extended-release formulation in Phase III that will allow for once-daily dosing. (Also see "Actelion's Uptravi Approval To Shake Up Market" - Scrip, 23 Dec, 2015.) However, Leerink analyst Joseph Schwartz noted in a June 6 report that GlaxoSmithKline PLC's long-generic intravenous drug Flolan (epoprostenol sodium) "is still considered the gold standard for efficacy in PAH."

Biomedtracker noted in a July 10 analysis that "Ralinepag had a reduction in PVR versus placebo of 25.8% using a geometric mean ratio (used as the data was not normally distributed) and 29.8% using a least square means method. For comparison, oral Uptravi had a geometric mean reduction of 33% in its Phase II study (per an FDA review and publication) and IV Flolan had a mean improvement of 30% [in Phase II]. The results could be quite variable given the small size of these studies, so it is difficult to make much of the differences. For example, patients in the Flolan and Uptravi studies started with higher PVR levels than those in the ralinepag trial."

Biomedtracker concluded that, "All in all, the PVR data suggest ralinepag could have at least similar efficacy to other agents in the class, though differences in the baseline characteristics of the treatment groups and lack of a benefit versus placebo on the 6MWD cloud the picture somewhat."

Phase III efficacy establishing ralinepag as a best-in-class oral prostacyclin agonist with similar efficacy to IV prostacyclin-targeting therapies could make Arena's drug a blockbuster product, JMP Securities analyst Jason Butler said in a July 7 report to help investors evaluate the Phase II results that were expected this month.

"In our view, addressing selexipag's suboptimal efficacy, and being better positioned to demonstrate a mortality benefit in Phase III development, while still providing the convenience of an oral therapy, would support a multibillion-dollar product opportunity," Butler wrote, pointing to ralinepag's superior preclinical pharmacology results compared with Uptravi.