China has become the first nation to approve Roche’s crovalimab, a paroxysmal nocturnal hemoglobinuria (PNH) treatment. Unlike AstraZeneca’s infused treatments Soliris and Ultomiris, crovalimab is administered subcutaneously. Developed by Roche’s subsidiary Chugai Pharmaceutical, crovalimab is a humanized complement inhibitor C5 monoclonal antibody. The approval from China’s National Medical Products Administration (NMPA) allows its use in patients aged 12 and above who haven’t undergone complement inhibitor therapy before.
Crovalimab, a genetically engineered anti-C5 antibody developed using Chugai’s Recycling Antibody technology, is designed to bind to its target antigen repeatedly due to its pH-dependent binding properties. This unique feature allows for prolonged efficacy compared to traditional antibodies. By specifically targeting C5, a crucial component of the complement system, crovalimab aims to regulate complement activity, offering potential benefits for patients and caregivers through its subcutaneous administration route, thus reducing treatment burden.
Given its distinct binding site on complement C5 compared to existing antibody treatments, crovalimab presents a promising option for patients with specific C5 gene mutations, particularly prevalent in Asian populations. These mutations, found in around 3.2% of Japanese patients with paroxysmal nocturnal hemoglobinuria, render existing antibody drugs ineffective against C5.
Crovalimab has undergone regulatory filing for approval as a novel PNH treatment in Japan, the US, and the EU. Additionally, ongoing clinical trials are exploring its efficacy in treating atypical hemolytic uremic syndrome (aHUS), while Roche is conducting trials for sickle cell disease (SCD) and lupus nephritis internationally.
The approval in China arrives a year after Roche revealed findings from a phase II investigation demonstrating crovalimab’s comparable performance to Soliris, a highly successful drug developed by Alexion, a subsidiary of AstraZeneca, which has maintained its dominance in the PNH treatment market for over ten years. Roche has completed three effective phase III trials, including COMMODORE 3 conducted in China, which facilitated the NMPA’s authorization.
Crovalimab marks the second drug to receive approval, utilizing Chugai’s innovative recycling antibody approach. The first was Enspryng, sanctioned by the FDA in 2020 for addressing neuromyelitis spectrum disorder (NMOSD). Unlike conventional antibodies that bind to antigens once, crovalimab is engineered to repeatedly bind to the antigen, facilitating prolonged complement inhibition at a minimal dosage. This feature enables the therapy to be administered every four weeks, as elucidated by the company. One more benefit of crovalimab is its suitability for self-administration. This offers a different option compared to Soliris and Utomiris, which require infusion every two and eight weeks, respectively.
The market for PNH is significant. AstraZeneca reported sales of Soliris in 2023, which was approved by the FDA in 2007, totaling $3.2 billion. Ultomiris, a longer-acting alternative approved in 2021, generated $3 billion in sales last year. Both drugs are also approved to treat generalized myasthenia gravis (gMG) and aHUS. In 2021, Apellis entered the competition with Empaveli receiving FDA approval. Recently, Novartis gained FDA approval for Fabhalta, an oral alternative that might have an advantage over AstraZeneca’s products as it targets an earlier stage in the C5 terminal pathway.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and severe blood condition where red blood cells break down within blood vessels, a process known as intravascular hemolysis (IVH). This disorder also involves the activation of white blood cells and platelets, potentially leading to blood clot formation and organ damage, which can be fatal. Effective management of PNH involves timely and consistent inhibition of the terminal complement pathway by targeting the C5 protein. This approach helps alleviate symptoms and reduce complications, thereby improving survival rates for PNH patients. However, it’s important to note that despite treatment with a C5 inhibitor, around 10-20% of PNH patients may still experience significant extravascular hemolysis (EVH), resulting in ongoing anemia symptoms and the need for blood transfusions.
According to DelveInsight’s estimates, in 2023, the total diagnosed prevalent cases of PNH in the US were 6.1K cases which is anticipated to increase by 2034 at a moderate CAGR during the study period 2024-2034. Among the 7MM countries, the US comprised ~49% of the total diagnosed prevalent cases of PNH in 2023. The gender-specific prevalence of PNH, in 2023 females accounted for 3.1K cases as compared to 2.9K cases in males in the United States.
While in the US, Genentech, a subsidiary of Roche, is progressing in the treatment of PNH, AstraZeneca remains the predominant force in this domain. In addition to Soliris, AstraZeneca also possesses Ultomiris, another C5 inhibitor used for PNH treatment. AstraZeneca further solidified its leading position in PNH treatment by achieving a significant milestone in September 2022. In the Phase III ALPHA study, danicopan, an investigational oral inhibitor of factor D, successfully met its primary endpoint. Danicopan is intended to complement Ultomiris or Soliris as an additional therapy.
Danicopan, Ultomiris, and Soliris were developed by Alexion, a company specializing in rare diseases, which AstraZeneca acquired in 2020. Novartis, another player in the rare disease field, joined AstraZeneca and Genentech. In October 2022, Novartis announced that iptacopan had performed better than Ultomiris and Soliris in the Phase III APPLY-PNH trial. Unlike AstraZeneca and Genentech, Novartis is focusing on factor B of the alternative complement pathway. In December 2022, iptacopan achieved another success in Phase III trials for PNH treatment.
With so much happening in the PNH treatment space, it is clear that the long run of AstraZeneca is at stake. AstraZeneca will face fierce competition from the emerging leaders such as Roche and Novartis. It will be interesting to see how AstraZeneca save itself from Roche’s crovalimab in the PNH treatment segment.
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