Upcoming events – Phase II readouts loom for Concert and Reata

Welcome to your weekly digest of approaching regulatory and clinical readouts. Impressive data with Pfizer’s PF-06651600 earlier this week raised hopes that Jak inhibitors could be effective in alopecia. Now Concert Pharmaceuticals hopes to follow in its bigger rival’s footsteps.

Phase II data with Concert’s Jak blocker CTP-543 are due in the fourth quarter. Even if the company eventually gets its project to market it might struggle against a competitor the size of Pfizer. But, with the best Jak-targeting strategy still unknown, there is still much to play for, especially in the underserved alopecia indication.  

The 90-patient study of CTP-543 is evaluating 4mg or 8mg twice daily, and the primary endpoint is hair loss, measured by the severity of alopecia tool (SALT), at 24 weeks. Concert also hopes to incorporate a 12mg arm, pending a safety review with the 8mg dose, a cautious dosing approach that allowed a 2017 clinical hold on the project to be lifted.

Pfizer has already set the bar with a placebo-adjusted 33.6-point improvement in SALT with PF-06651600. The result led to Pfizer taking that project forward in alopecia instead of its Tyk2/Jak1 inhibitor PF-06700841 (Tyk2 reaches tipping point, September 17, 2018).

The decision raised eyebrows because PF-06700841 appeared to be more effective, but safety might have been the deal breaker: there were no serious adverse events with PF-06651600, whereas the PF-06700841 group had two cases of rhabdomyolysis that led to discontinuations.

Investors will also be watching for any signs of differences in safety and/or efficacy between PF-06651600 and CTP-543. Pfizer’s project is selective for Jak3, while Concert’s is a Jak1 & 2 inhibitor – in fact it is a deuterated version of ruxolitinib, the active ingredient in Incyte and Novartis’s myelofibrosis drug Jakafi. Ruxolitinib has previously shown promising results in investigator-sponsored studies in alopecia.

It is thought that the thrombosis side effects seen with Lilly’s rheumatoid arthritis drug Olumiant could be down to its activity against Jak2, and Concert will want to avoid such problems.

Meanwhile, Reata Pharmaceuticals will hope to continue the roll it has been on since the start of the year with more positive data from its lead compound, bardoxolone methyl, in the phase II Phoenix trial.

The open-label study examining the safety, tolerability and efficacy of bardoxolone in patients with a range of rare chronic kidney diseases is due to report results in IgA nephropathy (IgAN) and type 1 diabetes chronic kidney disease (T1D-CKD) by the end of this quarter.

If readout from this cohort is successful it will be the second positive outcome from the Phoenix trial; earlier this year Reata reported initial data from the IgAN cohort, as well as full results in patients with autosomal dominant polycystic kidney disease.

A final cohort, in focal segmental glomerular sclerosis patients, is set to report in the first half of 2019.

Phoenix's primary endpoint is improvement in kidney function, as measured by estimated glomerular filtration rate, against baseline after 12 weeks of therapy. This endpoint is the same across all four cohorts, but each group will be assessed separately.

So far investors appear hopeful of victory in IgAN and T1D-CKD, largely because of bardoxolone’s previous success. The data from the polycystic kidney cohort of the Phoenix trial, along with a win in the phase II Cardinal trial in CKD caused by Alport syndrome, sent the group’s shares up 65% in July.

Still, it has not all been plain sailing for bardoxolone. A phase III trial in the broader indication of diabetes-related chronic kidney disease was terminated in in 2012 after a heart failure signal. A programme to identify patients at risk of heart failure and the decision to restrict the drug’s use to orphan indications have so far kept the safety profile clean, and continued funding from Reata’s partner Abbvie has also helped.

Reata’s persistence and narrowing of focus to rare/orphan forms of CKD, where bardoxolone has the chance to become the only approved product, has paid off, and shares in the group have more than tripled since the start of the year. The 2024 consensus sales forecast for bardoxolone stands at $862m, according to EvaluatePharma. This could rise if the remainder of Phoenix also reads out positively.