by Ayisha Sharma in London.

Subcutaneous (SC) formulations of Apellis Pharmaceuticals’ pegcetacoplan and Alexion Pharmaceuticals’ Ultomiris (ravulizumab-cwvz) are unlikely to have widespread uptake in first-line paroxysmal nocturnal haemoglobinuria (PNH) despite both drugs’ anticipated FDA approvals. PNH is a rare blood disease that causes red blood cells to break apart.

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Although both companies are looking to market their respective drugs as an alternative to standard-of-care intravenous (IV) Ultomiris, many PNH patients may still prefer the IV drug as it only requires one outpatient visit every eight weeks. While the SC formulations allow for at-home administration, pegcetacoplan is administered twice per week and Ultomiris is administered once per week.

In the small number of patients who may consider switching, pegcetacoplan may have an edge over SC Ultomiris. Pegcetacoplan would be attractive to patients who do not fully experience efficacy with IV drugs such as Ultomiris’ predecessor, Alexion’s Soliris (eculizumab), which is also approved in first-line PNH. Additionally, pegcetacoplan may be more likely to ease extravascular hemolysis (EVH) in a number of PNH patients due to its mechanism. This is a limitation of Ultomiris and Soliris. The Covid-19 pandemic may positively affect the uptake potential for both injectables, as onsite visits are currently being discouraged.

Nonetheless, the FDA approval prospects for both SC drugs are likely to be positive. In the Phase III PEGASUS trial (NCT03500549), pegcetacoplan was better able to wean patients from regular blood transfusions versus Soliris, noted investigators who are all involved in the PEGASUS trial. SC Ultomiris’ approval is also likely, as topline Phase III data shows it is noninferior to its IV counterpart at day 71. However, a potential approval spoiler for SC Ultomiris is its applicator, which may have different approval bars as a medical device.

Apellis plans to file a New Drug Application to the FDA for pegcetacoplan in 2H20, with an analyst report noting it could attain peak sales of $400m. Alexion aims to file for FDA approval of SC Ultomiris in 3Q21 upon completion of another 12-month Phase III study, with a second analyst report stating both Ultomiris formulations have the potential of $1.2bn peak sales in PNH in 2025. Apellis has a market cap of $2.24bn, and Alexion’s market cap is $23.71bn.

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Neither Apellis nor Alexion responded to a comment request.

Majority of patients will prefer to stay with IV, but chance to switch some patients

Frequency of treatment is a notable deciding factor for patients in choosing their preferred route of administration in first-line PNH, giving IV Ultomiris an advantage, said Dr Jeff Szer, professor, Hematology & BMT, Peter MacCullum Cancer Centre, Victoria, Australia. Patients may prefer to stick with outpatient treatment as they want to have a clear delineation between where they are treated and where they live, added Dr Regis Peffault de Latour, professor, Hematology and Bone Marrow Transplant Department, Hôpital Saint-Louis, Paris, France. At-home administration may seem like an obvious reason for patients to switch, but at least 50% of his patients would still prefer IV administration, he added.

Between the SC drugs pegcetacoplan and Ultomiris, the former may be more successful in finding patients. Specifically, pegcetacoplan would see interest from patients with inadequate responses to IV Ultomiris and Soliris, said Dr Ilene Weitz, associate professor, Keck School of Medicine, University of Southern California, Los Angeles. Pegcetacoplan, a C3 inhibitor, could be better at addressing the cause of EVH better than Ultomiris and Soliris, which are both C5 inhibitors, she explained. Inhibiting C5 expression actually leads to an increase of C3, which contributes to EVH, Szer explained. IV Ultomiris received FDA approval for PNH in December 2018, while Soliris was approved in 2007.

There is room for improvement in patients taking Soliris, which could be achieved by switching to pegcetacoplan, Weitz said. PEGASUS met its primary endpoint, with pegcetacoplan patients experiencing a higher haemoglobin level with a mean of 3.8g/dL versus Soliris at week 16 (p<0.0001). Around 20% of Soliris patients who remain transfusion-dependent during treatment could switch to pegcetacoplan, she added. However, it may still be too late for pegcetacoplan to capture these patients, as they may already to have been switched it IV Ultomiris, she noted.

Due to the Covid-19 pandemic, fewer onsite visits may be an incentive for clinicians to advocate for the SC-administered drugs, Weitz said. However, PNH patients are still happy to come into the hospital during the pandemic due to the IV administration’s advantages, Szer said. Alexion reported Ultomiris IV sales of USD 223m in 1Q20, which was 87% higher than anticipated despite Covid-19 restrictions, according to a third analyst report.

Positive approval prospects for both subcutaneous drugs

Investigators expect both SC drugs’ FDA approval prospects to be positive. In the 80-patient PEGASUS trial efficacy endpoint, 85% of pegcetacoplan patients were transfusion-free at week 16, versus 15% in the Soliris arm. For SC Ultomiris, the 136-patient Phase III reported both the IV and SC formulations are noninferior at day 71.

Pegcetacoplan also has a positive side-effect profile, including the lack of serious meningococcal infection, which is a concern with Soliris, Szer added. The common treatment-related adverse events in PEGASUS were infection (29.3%), injection site reactions (36.6%) and diarrhoea (22%). The most common adverse events associated with IV Ultomiris (>10%) are upper respiratory infection and headache, according to its FDA label.

However, since SC Ultomiris is administered via a medical device, its approval chances are also impacted by whether the device meets FDA expectations for its own approval, Szer said. If approved, SC Ultomiris would be the only PNH treatment with a specialised applicator. The prefilled, single-use SmartDose device was developed with Exton, Pennsylvania-based designer and manufacturer West Pharmaceutical Services.

The FDA has already reviewed this device in the past, and so would not have to conduct its full review for the Ultomiris approval, said Alan Schwartz, executive vice president for pharma and device consulting agency mdi Consultants, Great Neck, New York. The SmartDose platform was first approved to deliver single, monthly doses of Amgen’s Repatha (evolocumab) for high cholesterol in 2016. The FDA’s primary concern with different routes of administration is noninferiority data, so as long as this is demonstrated, there are no foreseeable roadblocks to approval, said Schwartz.

Ayisha Sharma is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.