Biotech’s important upcoming data

Evaluate Vantage has delved into upcoming data readouts due in the third quarter for companies with a market cap of $1bn plus, and here Apellis stands out. The group will be hoping its complement inhibitor pegcetacoplan can succeed where others have failed.

Meanwhile, Ionis and Biogen will release late-stage results in amyotrophic lateral sclerosis, an area littered with previous failures, and combination data are due from Mirati’s Kras inhibitor adagrasib in lung and colorectal cancers. 

Targeting complement

Apellis is expecting phase 3 data with its intravitreal formulation of pegcetacoplan in geographic atrophy, an advanced form of dry age-related macular degeneration. The group believes it can succeed where other complement-targeting agents, such as Roche’s lampalizumab and more recently Gemini's GEM103, have struggled to show a benefit.

Apellis's confidence comes from the project's mechanism of action: by inhibiting C3 pegcetacoplan knocks out all three pathways involved in the complement system. Other experimental agents have tended to inhibit only one pathway, so pegcetacoplan could have a stronger effect, Apellis reckons.

That theory will be put to the test with Derby and Oaks studies, whose primary endpoints are a reduction in the growth of the GA lesion at month 12 with pegcetacoplan versus sham injection. One potential stumbling block could be choroidal neovascularisations, or abnormal blood vessels, which were seen in intravitreal pegcetacoplan’s phase 2 trial, Filly. Another worry is patients missing doses due to Covid-19 disruption.

If intravitreal pegcetacoplan does succeed, it could have the GA market to itself for a while. Evaluate Pharma's consensus forecasts that the project will bring in $1.2bn in 2026.

Kras combinations

Amgen’s Kras G12C inhibitor Lumakras gained an early US approval in second-line lung cancer in May, and now Mirati is gearing up for data with its similarly acting adagrasib. The phase 1/2 Krystal-1 study is combining adagrasib plus Keytruda in NSCLC, and adagrasib plus Erbitux in colorectal cancer; updated monotherapy and initial combination results are expected next quarter.

So far, adagrasib monotherapy has bested Lumakras in terms of efficacy. At last year’s Triple meeting adagrasib showed an overall response rate of 45% in NSCLC, versus 37% in Lumakras's phase 2 Codebreak-100 study.

However, at present Amgen has the larger dataset and the edge when it comes to safety. 14% of adagrasib-treated patients suffered QT prolongation which carries a risk of sudden cardiac death, an issue that has not been seen with Lumakras.

Mirati plans to file for accelerated approval in second/third line NSCLC in the second half of the year. 

ALS hopeful

The next big readout in ALS will concern the phase 3 study of tofersen, which Biogen licensed from Ionis in 2018. The field desperately needs a win; recent failures include Brainstorm Cell Therapeutics' cell therapy NurOwn and Orphazyme's arimoclomol (Arimoclomol failure leaves Biogen/Ionis exposed, May 7, 2021)

Tofersen is an antisense medicine targeting superoxide dismutase 1 (SOD1). A mutation in the SOD1 gene is the genetic driver in approximately 2% of ALS cases – this is thought to cause misfolded proteins leading to degeneration of motor neurons.

The Valor study has three segments, and it is part C, testing a 100mg dose, that will yield data. The study includes 99 patients with a confirmed SOD1 mutation, and the primary efficacy endpoint is change from baseline in ALSFRS-R total score, a measure of disability, at week 28. 

Data from parts A and B, which tested ascending doses of tofersen, showed a knockdown of cerebrospinal SOD1 protein, which was highest with the 100mg dose. There were also benefits on the ALSFRS-R scale, with a 1.19-point decrease with the 100mg dose versus a 5.63-point fall with placebo. A lower score represents worsening function. 

A phase 3 in presymptomatic SOD1 ALS patients called Atlas is also under way.

The table below contains a fuller list of upcoming catalysts with consensus forecasts from Evaluate Pharma. A look at big pharma clinical catalysts can be found here.