Alexion Pharmaceuticals, Inc. (ALXN) Positive Top-Line Results Showing Successful Phase 3 Clinical Study of ALXN1210

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Alexion Announces Positive Top-Line Results Showing Successful Phase 3 Clinical Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Endpoint Treatment effect [95% CI: LB,UB]

Treatment difference
ALXN1210 vs. Soliris®
[95% CI: LB,UB]

Non-inferiority

ALXN1210
n=125

Soliris®
n=121

Requirement

Achieved*

Primary
Transfusion avoidance 73.6% [65.9%,81.3%] 66.1% [57.7%,74.6%] 6.8% [-4.7%,18.1%]a LB > -20% Yes
LDH normalization 53.6% [45.9%,61.2%] 49.4% [41.7%,57.0%] 1.19 [0.80,1.77]b LB > 0.39 Yes
Secondary
Change in LDH levels -76.8% [-80.0%,-73.7%] -76.0% [-79.2%,-72.8%] -0.83% [-5.2%,3.6%]c,† UB < 20% Yes
Improvement in FACIT scale 7.1 [5.6,8.6] 6.4 [4.9,8.0] 0.67 [-1.2,2.6]c LB > -5.0 Yes
Breakthrough hemolysis 4.0% [0.6%,7.4%] 10.7% [5.2%,16.3%] -6.7% [-14.2%,0.18%]a,† UB < 20% Yes
Stabilization of Hb levels 68.0% [59.8%,76.2%] 64.5% [55.9%,73.0%] 2.9% [-8.8%,14.6%]a LB > -20% Yes

LDH: lactate dehydrogenase; FACIT: Functional Assessment of Chronic Illness Therapy; Hb: hemoglobin; CI: confidence interval; LB: lower bound; UB: upper bound

*

Non-inferiority is achieved if the LB or UB of the 95% CI of the treatment difference meets the pre-defined requirement. Since non-inferiority was achieved across both co-primary and all four key secondary endpoints, the protocol allowed for superiority testing. Testing for superiority followed a closed-testing procedure, using a 2-sided 0.05 test for each parameter, and followed the pre-specified order per protocol: breakthrough hemolysis, change in LDH levels vs. Baseline, LDH normalization, improvement in FACIT scale, stabilization of Hb levels, transfusion avoidance. As breakthrough hemolysis did not achieve statistical significance (p-value = 0.074), no other endpoints were tested.

a)

Difference in proportion of patients; b) Odds ratio; c) Difference in change vs. Baseline

Negative value meaning a difference in favor of ALXN1210

Since non-inferiority was achieved across both co-primary and all four key secondary endpoints, the protocol allowed for superiority testing. The hierarchical testing order pre-specified breakthrough hemolysis as the first endpoint tested for superiority. Although ALXN1210 did not achieve superiority, a numeric trend in favor of ALXN1210 was observed for breakthrough hemolysis (4.0% [0.6%,7.4%] vs. 10.7% [5.2%,16.3%] for Soliris®) with a p-value of 0.074. The study also confirmed that ALXN1210 provides immediate and complete (>99%) inhibition of the complement C5 protein that is sustained over the entire 8 week dosing interval. Additionally, treatment with ALXN1210 reduced mean LDH levels to approximately the upper limit of normal (1.0-1.1 times ULN) between months one and six.

“We are very pleased with these positive data for ALXN1210 in the first and only head-to-head study versus Soliris, and the results reinforce our ambition to establish ALXN1210 as the new standard of care for patients with PNH. The data are also consistent with our hypothesis that immediate, complete, and sustained C5 inhibition is critical for patients with this potentially life-threatening disease,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “Soliris has established a high bar for efficacy. Achieving non-inferiority on both co-primary and all key secondary endpoints, as well as seeing numeric results in favor of ALXN1210, in such a rigorous study met a very high hurdle. We look forward to regulatory submissions of ALXN1210 in PNH in the U.S., EU, and Japan in the second half of 2018.”

“Having a new treatment option that achieves transfusion avoidance, and provides rapid and sustained normalization of LDH levels when administered 6 times a year could be a meaningful improvement for patients with PNH who currently need 26 infusions per year,” said Jong Wook Lee, M.D., Professor of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea, and an investigator in the ALXN1210 study.

ALXN1210 was generally well tolerated with a safety profile that is consistent with that seen for Soliris®. The most frequently observed adverse event was headache. The most frequently observed serious adverse event was pyrexia. One patient in the Soliris® arm died from lung cancer (unrelated to Soliris® treatment) during the extension phase of the study. Two patients withdrew from the Soliris® arm for reasons unrelated to treatment. One anti-drug antibody was observed for ALXN1210 and one for Soliris®. No neutralizing antibodies and no apparent effects on efficacy, safety, pharmacokinetics, or pharmacodynamics were detected. There were no cases of meningococcal infection observed in either the ALXN1210 or Soliris® arms. Meningococcal infections are a known risk with terminal complement inhibition, and specific risk-mitigation plans have been in place for ten years for Soliris® to minimize the risk for patients.

Detailed results from this Phase 3 study will be presented at a future medical congress.

About the ALXN1210-PNH-301 Study

This Phase 3, randomized, open-label, active-controlled, multinational, and multicenter study evaluated the efficacy and safety of ALXN1210 compared to Soliris® administered by intravenous (IV) infusion to adult patients (≥ 18 years of age) with PNH who are naïve to complement inhibitor treatment. The study enrolled 246 adult patients with a confirmed diagnosis of PNH who had never been treated with a complement inhibitor and presented with LDH levels ≥ 1.5 times the upper limit of normal (ULN) at the time of screening, as well as with one or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g/dL), history of a major adverse vascular event (MAVE, including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell (pRBC) transfusion due to PNH. 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 Soliris® arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks. Both arms were treated for 26 weeks. The study was designed to evaluate the non-inferiority of ALXN1210 compared to Soliris®.

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