New Anti-C5 Agents on the Way as Biosimilar Competition for Eculizumab Nears

Patents covering eculizumab (Soliris) are set to expire in the United States and Europe within the next 3 years, and with biosimilar competition looming for the innovator drug that binds to the C5 complement protein, Alexion Pharmaceuticals may have found a way to retain its share of the market for treatments targeting paroxysmal nocturnal hemoglobinuria (PNH). Yesterday, the drug maker announced pivotal phase 3 data from a study of a new longer-acting C5 complement inhibitor, ALXN1210.

PNH is an ultra-rare blood disorder that causes uncontrolled activation of the complement system and results in hemolysis, the destruction of red blood cells, which in turn can cause thrombosis.

The study, says Alexion, demonstrated the noninferiority of the longer-acting ALXN1210 to eculizumab in patients with PNH who had not been previously treated with a complement inhibitor. The study of ALXN1210 met its co-primary end points of transfusion avoidance and normalization of lactate dehydrogenase (LDH) levels.

The investigational drug also demonstrated noninferiority to eculizumab in all 4 key secondary end points: the percentage change from baseline in LDH levels, change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy Fatigue scale, proportion of patients with breakthrough hemolysis, and proportion of patients with stabilized hemoglobin levels. Although ALXN1210 did not achieve superiority to eculizumab, Alexion reports that numeric results for all 6 end points favored ALXN1210.

The company plans to submit applications for approval of the drug to regulators in Japan, the United States, and the European Union by the second half of 2018.

ALXN1210’s 8-week dosing schedule, compared with eculizumab’s 2-week dosing schedule, may present distinct benefits for patients. However, it is unclear at what cost those benefits may come; the brand name Soliris, also approved to treat generalized myasthenia gravis and atypical hemolytic uremic syndrome, costs more than $500,000 per patient per year and is among the costliest therapies in the world.

Biosimilars of eculizumab, which have the potential to reduce costs for both patients and the healthcare system, have been eagerly awaited, and Amgen is currently developing a biosimilar candidate. However, as reported in a recent paper¹ in the American Journal of Hematology, even more drug makers are developing novel anti-C5 drugs:

• Amgen is engaged in a large phase 3 trial comparing safety and efficacy of its ABP 959 with those of eculizumab.
• Roche is developing SKY59/RO711268, a C5 inhibitor with a long half-life, but enrollment was halted in the phase 1 and phase 2 COMPOSER trial recently after 2 patients who received the investigational drug developed symptoms of immune-mediated hypersensitivity. The trial was later restarted after the reactions were determined to be nonserious.
• Novartis is undertaking a proof-of-concept study to assess LFG316 in patients with PNH. This drug could eventually prove to be an option for patients who have C5 polymorphisms associated with resistance to eculizumab.
• Akari is investigating Coversin, which has the potential advantage of self-administration given its subcutaneous route of administration.

Reference

1. Ristano AM, Marotta S. Toward complement inhibition 2.0: next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2018;93(4):564-577. doi: 10.1002/ajh.25016.