Big pharma’s key fourth-quarter data 

Alzheimer’s readouts are the dominant events on the horizon as biopharma heads into the final months of the year, with Roche and the smaller developers Biogen and Eisai all set set to report phase 3 data with beta-amyloid MAbs. Gantenerumab and lecanemab are both highly risky given the numerous clinical setbacks here. 

Other notable catalysts include registrational data from Merck & Co on sotatercept, gained through the $11.5bn acquisition of Acceleron. And Novartis aims to move its radioligand Pluvicto into earlier lines in prostate cancer, though safety worries could scupper these plans. 

Battle of the Alzheimer MAbs 

A first look at Biogen/Eisai’s lecanemab could come as early as this week, but the initial release is likely to be short on detail, with full data saved for the CTAD conference, where Biogen/Eisai and Roche are slated to present on November 29 and 30 respectively.

The lecanemab data will come from the Clarity AD study. The primary measure is change from baseline in CDR-SB score at 18 months, versus placebo. The company has previously stressed the importance of the “totality of the data”, meaning that several secondary endpoints will likely be prioritised should the primary fail (Biogen primes investors for a lecanemab data dredge, July 20, 2022). 

The project already has a Pdufa set for January; Eisai used a rolling submission under the accelerated approval pathway based on phase 2b data from Study 201 Core and blinded safety data from Clarity AD. 

201 Core failed to meet its primary endpoint, the change from baseline in Alzheimer's disease composite score. However a Bayesian analysis concluded that lecanemab, dosed 10mg/kg biweekly, was associated with 26% lower decline on CDR-SB than placebo. It is generally agreed by clinicians that a 20% reduction in cognitive decline is clinically meaningful for patients. 

For the Clarity AD readout to be considered a win, Mizuho analysts want to see a benefit of around 25% over placebo on the primary endpoint, with a p value of less than 0.01.

Roche, meanwhile, will follow later in the quarter with readouts from two studies, Graduate I and II. Both tested a gantenerumab dose of 1.02g, given subcutaneously, and have CDR-SB as the primary measure at 27 months. An up-titration schedule was used to try to reduce the rate of Aria-E, a brain swelling condition that is a common side effect of beta-amyloid MAbs. 

Earlier studies with gantenerumab failed to show a treatment effect until a 1.2g dose was used in open-label extension studies. The higher dosing led to reductions in amyloid plaque levels.  

Lilly will be watching with interest. Its own MAb, donanemab, has phase 3 data coming next year. 

Money well spent? 

Sotatercept was the main driver of Merck & Co's acquisition of Acceleron 12 months ago, and the first set of registrational data in pulmonary arterial hypertension (PAH) could emerge before the end of the year. 

PAH is a progressive disease that leads to hypertrophy of the right ventricle and right heart failure, and premature death. The PAH market is crowded, mainly with vasodilators that target symptoms. Sotatercept, which blocks the TGF-beta superfamily pathway, aims to treat the underlying cause. 

Data are due from the Stellar study in class II/III PAH. Six-minute walk distance (6MWD) at week 24 is the primary endpoint. An important secondary measure is a multicomponent endpoint consisting of an improvement in 6MWD, right ventricular function and disease severity. 

The phase 2 Pulsar trial found a statistically significant reduction in pulmonary vascular resistance at week 24, its primary endpoint. Sotatercept also produced greater improvements than placebo on several secondary efficacy measures, including 6MWD, which showed a 25m placebo-adjusted improvement.  

Safety was said to be acceptable in Pulsar, with thrombocytopaenia and increased haemoglobin the most notable toxicities.  

Earlier 

Meanwhile, Novartis aims to move Pluvicto into earlier lines of therapy. The PSMA-targeted radioligand is already approved in metastatic castrate-resistant prostate cancer after taxane-based chemotherapy, and pivotal data are due in chemo-naive patients. The results could come before the end of the year, or early in 2023. 

Novartis estimates that moving into pre-chemo and even earlier hormone-sensitive settings could expand Pluvicto’s accessible patient population three or fourfold. A pivotal trial in hormone-sensitive disease should report in 2024.   

The chemo-naive PSMAfore study is an open-label trial and tests Pluvicto against androgen receptor-directed therapy; both arms also include best supportive care. The primary measure is radiographic PFS, with overall survival as a secondary. 

Key to determining Pluvicto’s use in earlier therapy will be tolerability; the drug's current label comes with warnings over myelosuppression such as anaemia and thrombocytopaenia, and renal toxicity. 

One of the most advanced PSMA-targeted radioligand competitors is Point Biopharma’s PNT2002. Phase 3 data from the Splash study in pre-chemo patients are due by the middle of next year. At Esmo the company reported a median rPFS of 11.5 months in the 27-patient safety and dosimetry lead-in cohort for Splash. The most common adverse events were dry mouth, fatigue, nausea and anaemia. 

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