Fourth-quarter data for the little guys

Evaluate Vantage has already delved into the key upcoming fourth-quarter data for big pharma and large biotech groups. Now it is the turn of companies with a market cap under $1bn. 

Relmada will reveal the first late-stage results with its depression project REL-1017, although concerns over abuse potential could hinder its commercial prospects. Elsewhere, Albireo and Mirum are jostling for space in the rare paediatric biliary disorder market.

One catalyst came today as Intercept revealed that Ocaliva failed in the Reverse study in advanced Nash patients. The company still plans to file in patients with stage 2 or 3 liver fibrosis due to Nash, but recent reanalysis of data from the Regenerate trial provided little solace. Intercept, which got a complete response letter two years ago, will have to watch out for Madrigal stealing its Nash crown as pivotal data with resmetirom are expected soon.

Crowded

Onto upcoming fourth quarter readouts, Relmada’s major depressive disorder asset REL-1017 is set to yield data from three phase 3 studies, two as an adjunctive treatment and one as monotherapy.

There is a lack of previous monotherapy data, though REL-1017 did show a strong phase 2 result in an adjunctive setting. Here there was an 8.7 and 7.2-point placebo-adjusted MADRS depression score reduction from baseline at day 7, respectively in the 25mg and 50mg cohorts. 25mg is the phase 3 dose, and 28-day change in MADRS is the primary measure for all three upcoming studies. 

Mizuho analysts assume a 3.8-point placebo-adjusted reduction on MADRS for the upcoming adjunctive trials, above the two-point reduction for which the studies are powered. 

REL-1017 is an isomer of methadone, so safety will be key. Relmada’s therapy has already shown significantly different abuse potential than Ketamine or Oxycodone, but there are still concerns over how the FDA and DEA may restrict use.  

Safety issues aside, Relmada is also playing in a crowded space; Axsome’s Auvelity recently gained FDA approval, and Biogen/Sage’s zuranolone is undergoing a rolling submission. Stifel cites a key opinion leader predicting fifth or sixth-line use, at best, for REL-1017. 

Rare conditions 

Mirum and Albireo are vying for a space in Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), running higher-dose studies of their drugs targeting each other’s approved indications. 

Albireo’s Bylvay is approved in PFIC and Mirum’s Livmarli in Alagille syndrome, which is a slightly bigger use. Both therapies are bile acid transporter inhibitors used to reduce pruritus or itching, a troublesome symptom. It has not been determined whether either therapy can delay disease progression or the need for a liver transplant. 

Now Albireo wants to add Alagille to its label, with a phase 3 study testing a daily 120ug/kg dose. Bylvay's approved dose in PFIC is 40ug/kg per day with an increase to 120ug/kg daily if there are no improvements in pruritus after 3 months. The primary endpoint of the Assert study in Alagille is change in 24-week scratching score versus placebo, with a change in bile acid levels and safety as secondaries. 

Meanwhile Mirum hopes to score in PFIC with 570ug/kg twice daily; Livmarli's approved dose in Alagille is once-daily 380ug/kg. The primary measure of the phase 3 March-PFIC study is mean change in average morning itching score up to 26 weeks. Primary cohort patients include those with PFIC type 2, with a supplemental cohort including PFIC 1, 3 and 4. Albireo’s Bylvay is approved in types 1 and 2 patients. 

A dose-response analysis by Evercore suggests that Mirum could win in both PFIC and Alagille, with the potential for Livmarli's higher dose yielding differentiated results in PFIC, a scenario that seems less likely for Albireo’s Bylvay in Alagille.

The table below contains a fuller list of upcoming catalysts with consensus forecasts from Evaluate Pharma.