Biotech catalysts on the horizon

An earlier analysis by Evaluate Vantage concentrated on upcoming big pharma data reveals; here, we look at the clinical results due for biotech companies with a market cap of $1bn and above. 

Pivotal data are expected on Karuna’s schizophrenia project KarXT, and the hope is that it can maintain the effect size seen in an earlier study. Alnylam, meanwhile, is keen to expand Onpattro into cardiomyopathy in amyloidosis. Ionis might be lagging behind with its amyloidosis project eplontersen, with polyneuropathy results due soon, but it has at least secured a big pharma partner. 

Karuna Emerges

KarXT is Karuna’s lead programme. It is a fixed-dose combination of xanomeline, a muscarinic M1/M4 agonist, and trospium chloride, a muscarinic antagonist, an approach designed to reduce peripheral side effects. The therapy performed well in an earlier study, but a phase 3 study will show whether the effect size narrows – a common issue for CNS studies. 

In the phase 3 Emergent-2 trial, 246 patients were given KarXT twice daily versus placebo. The primary endpoint, the change from baseline in positive and negative syndrome scale (PANSS) total score at week 5, is the same as in the phase 2 Emergent-1 trial.

Emergent-1, which enrolled 182 patients, showed a statistically significant placebo-adjusted 11.6-point mean reduction in total PANSS score at week 5. Between treatment and placebo there were also similar rates of weight gain and somnolence, issues that have plagued older schizophrenia drugs. 

For filing the FDA says Emergent-1 plus a successful phase 3 and additional safety data are needed. A second pivotal study, Emergent-3, is ongoing and data were due in the second half of this year; however, more than half of the trial sites are in Ukraine, leading Karuna to withdraw its previous timing guidance. 

Despite the setback Karuna should have enough data for a filling as Emergent-5, an ongoing open-label study, is to be upsized and should provide long-term safety and tolerability data.

Amyloidosis

Apollo-B data will see whether Alnylam can move Onpattro, its intravenous RNAi therapy, into cardiomyopathy of transthyretin-mediated amyloidosis. Onpattro is already approved for polyneuropathy, a disorder where amyloid is deposited in the peripheral nerves, but getting a win in cardiomyopathy would open a bigger market. 

The primary endpoint of Apollo-B is the change from baseline in six-minute walk test at 12 months. Sentiment over the endpoint took a hit at the end of last year when Bridgebio’s acoramidis failed on the same measure, with placebo patients performing better than expected.

There are several theories regarding Bridgebio’s failure, including a possible training effect on six-minute walk, and that the study recruited patients with mild disease. Alnylam has said it has minimised the number of screening and baseline assessments to try and combat a potential training effect. 

Results from Apollo-B will read through to Alnylam’s subcutaneous Onpattro follow-on, vutrisiran. This project has a Pdufa date in April for polyneuropathy, and an ongoing cardiomyopathy study, Helios-B, is expected to yield data in 2024.

Another company hoping to make its mark in a crowded amyloidosis space is Ionis. Data on its subcutaneous antisense project eplontersen are due in polyneuropathy. The group struck a partnership in December with Astrazeneca worth $200m up front.

Eplontersen’s own cardiomyopathy data are still a long way off as its Cardio-TTRansform study has a primary completion date in 2024. Here the primary measure is a composite outcome of cardiovascular mortality and CV events, with the six-minute walk test as a secondary. 

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