Data on Complement Inhibitors and Proposed Biosimilars Feature at ASH

Eculizumab, a C5 complement inhibitor, has changed the treatment landscape for several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, and atypical hemolytic uremic syndrome. However, the drug, sold by developer Alexion as Soliris, is among the most expensive biologic therapies in the world—carrying a cost of approximately $500,000 per patient per year—and that cost has an impact on patient access.

Multiple biosimilar developers are taking aim at eculizumab, however, and at the same time, Alexion is continuing to invest in longer-acting successor to eculizumab as biosimilars draw closer. During this week’s 61st meeting of the American Society of Hematology (ASH), researchers reported on eculizumab, a prospective biosimilar, and the long-acting ravulizumab.

Researchers report on PK and ADAs for proposed biosimilar eculizumab, ABP 959

Amgen is developing ABP 959, a proposed biosimilar eculizumab, and the product has previously been reported to have pharmacokinetic (PK) and pharmacodynamic equivalence with the reference Soliris.

During ASH, researchers reported on an assessment of the relationship between PK parameters and antidrug antibodies (ADA) for the proposed biosimilar and the reference.¹ Their data derive from a randomized, double-blind, single-dose, 3-arm, parallel-group study in healthy male volunteers.

In the study, the 219 participants were randomized to receive 300 mg of either the biosimilar (n = 71), its US-licensed reference (n = 74), or its EU-licensed reference (n = 74), and serum samples for PK evaluation were collected over 57 days.

No neutralizing antibodies were detected during the study. At any time, the incidence of binding ADAs was 9.9% in the biosimilar group, 6.9% in the US reference group, and 9.5% in the EU reference group. At the end of the study, 1.9% of participants had binding ADAs, with 1.4% in the biosimilar group, 2.9% in the US reference group, and 1.4% in the EU reference group testing positive for these ADAs.

In those who had binding ADAs, PK was within the same range as it was in those without any ADAs detected, write the authors. Furthermore, the incidence of ADAs was similar between products, and did not impact the overall PK similarity assessment.

Relatively few US patients with PNH start treatment with eculizumab

Complement inhibition is becoming the standard of care in treating PNH, but given the fact that PNH is a rare disease, little is known about how patients are managed after diagnosis in real-world practice.

Using Truven US MarketScan commercial and Medicare data from 2015 to 2018, researchers sought to estimate the incidence and prevalence of PNH and to describe real-world treatment in patients who are newly diagnosed with the blood disease.²

They found that the incidence rate over the study period was 5.7 per 1,000,000 person-years, or 257 new diagnoses. Over a mean follow-up time of 385.6 days (SD, 253.2), just 10.3% of patients started eculizumab (95% CI, 6.3%-14.1%), initiating the drug 60.5 days (SD, 55.9 days) after diagnosis.

At 1 years, approximately one-third of patients had discontinued eculizumab or taken a break in treatment.

Future studies should explore factors related to initiating eculizumab, say the researchers, as well as those related to treatment persistence.

Successor to eculizumab proves effective, safe at week 52

Meanwhile, ravulizumab, Alexion’s longer-acting C5 complement inhibitor that offers less frequent administration than eculizumab, was also the subject of a presentation of new data; researchers presented 1-year efficacy and safety data from a phase 3 study in patients with PNH who had received eculizumab and transitioned to ravulizumab.³

Previously, treatment every 8 weeks with ravulizumab was shown to be noninferior to treatment every 2 weeks with eculizumab at 26 weeks.

The new data, up to 52 weeks, derive from an extension of the open-label trial; in the extension, patients who had received ravulizumab continued maintenance therapy, and those who had received eculizumab switched to ravulizumab. In total, 191 of 192 patients in the study entered the extension, and 96 of them were in the ravulizumab-only group while the other 95 were in the switch group.

Patients in both groups showed a durable response for percent change in lactate dehydrogenase (LDH) at 52 weeks; patients in the ravulizumab-only group had an 8.8% increase in LDH from baseline (SD, 29%), while pts in the switch group had 5.8% (SD, 27%) change.

During weeks 0 to 26, 88% of patients in the ravulizumab-only group avoided transfusion, versus 87% of patients in weeks 27 to 52. In the switch group, 83% avoided transfusion during both periods.

During the extension period, 79% of patients in the ravulizumab-only group and 75% in the switch group had a treatment-emergent adverse event (AE). Eight patients (8%) in the ravulizumab-only group and 5 (5%) in the switch group experienced serious AEs, none of which led to discontinuation or death.

According to the researchers, ravulizumab continues to be well tolerated at week 52, with no new safety concerns arising in the extension, and the drug appears to have durable efficacy.

References

1. Hanes V, Pan J, Mytych DT, Chien D, Chow V. Relationship between pharmacokinetics and antidrug antibody status of ABP 959, a biosimilar candidate to eculizumab: results from a pharmacokinetic similarity study. Presented at: The 61th Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 3520.

2. Jalbert JJ, Chaudhari U, Zhang H, Weyne J, Shammo JM. Epidemiology of PNH and real-world treatment patterns following an incident PNH diagnosis in the US. Presented at: The 61th Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 3407.

3. Kulasekararaj A, Hill A, Langemeijer S, et al. One-year efficacy and safety from a phase 3 trial of ravulizumab in adult patients with paroxysmal nocturnal hemoglobinuria receiving prior eculizumab treatment. Presented at: The 61th Annual Meeting and Exposition of the American Society of Hematology; December 7-10, 2019; Orlando, FL. Abstract 2231.