Red blood cells
The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.
With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.
The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.
PNH-301 trial
This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).
Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.
Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.
The study’s co-primary endpoints are:
- Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
- Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.
ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.
ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:
- Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
- Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
- Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
- Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).
Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.
One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.
Switch study
This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.
ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.
Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.
Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:
- The proportion of patients with breakthrough hemolysis
- The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
- The proportion of patients avoiding transfusion
- The proportion of patients with stabilized hemoglobin levels.
ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.
There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.