Summary
Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based ...on long‐term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient‐years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy‐six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit‐risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
Involvement of lower gastrointestinal tract (LGI) occurs in 60% of patients with graft-versus-host-disease (GVHD). Complement components C3 and C5 are involved in GVHD pathogenesis. In this phase 2a ...study, we evaluated the safety and efficacy of ALXN1007, a monoclonal antibody against C5a, in patients with newly diagnosed LGI acute GVHD receiving concomitant corticosteroid. Twenty-five patients were enrolled; one was excluded from the efficacy analysis based upon negative biopsy. Most patients (16/25, 64%) had acute leukemia; 52% (13/25) had an HLA-matched unrelated donor; and 68% (17/25) received myeloablative conditioning. Half the patients (12/24) had a high biomarker profile, Ann Arbor score 3; 42% (10/24) had high-risk GVHD per Minnesota classification. Day-28 overall response was 58% (13/24 complete response, 1/24 partial response), and 63% by Day-56 (all complete responses). Day-28 overall response was 50% (5/10) in Minnesota high-risk and 42% (5/12) in high-risk Ann Arbor patients, increasing to 58% (7/12) by Day-56. Non-relapse mortality at 6-months was 24% (95% CI 11-53). The most common treatment-related adverse event was infection (6/25, 24%). Neither baseline complement levels (except for C5), activity, nor inhibition of C5a with ALXN1007 correlated with GVHD severity or responses. Further studies are needed to evaluate the role of complement inhibition in GVHD treatment.
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Introduction: ALXN1210 is a humanized monoclonal antibody (mAb), with a sequence closely related to eculizumab (Soliris®). ALXN1210 binds specifically to human complement protein C5 and was ...engineered to eliminate the formation of C5a and the terminal complement complex with extended duration of complete complement inhibition. The mechanism of action of ALXN1210 provides strong clinical rationale for potential therapeutic use in patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and other complement-mediated diseases. Clinical experience with eculizumab supports the reduction of free C5 to undetectable levels for complete inhibition of hemolysis.
Methods: In this Phase 1, randomized, blinded, placebo-controlled, single-ascending dose study, healthy subjects received a single intravenous (IV) dose of 200 mg (cohort 1) or 400 mg (cohort 2) ALXN1210 or placebo (PBO), and were then followed for 150 days. Subjects were vaccinated with a tetravalent conjugate N. meningitidis vaccine and received prophylactic penicillin V. The primary objective was to evaluate the safety and tolerability of a single dose of ALXN1210. Secondary objectives were to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALXN1210. PD effects of ALXN1210 were assessed as the change in serum free C5 and ex vivo (cell-based) hemolytic activity.
Results: Fourteen subjects enrolled in the study: 4 received 200 mg ALXN1210, 6 received 400 mg ALXN1210, and 4 received PBO. Serum ALXN1210 concentrations were measureable for the entire 150-day follow-up period. Mean Cmax and AUC∞ increased in a dose-proportional manner, with a mean terminal half-life of approximately 32 days and low (<20%) intersubject variability in PK parameters.
Levels of free C5 were reduced by >99% from baseline in all subjects who received ALXN1210. Additionally, all subjects who received a single dose of 400 mg ALXN1210 reached or exceeded the ALXN1210 threshold level of 100 µg/ml and had >99% elimination of free C5. For subjects with ALXN1210 levels >100 µg/ml, average elimination of C5 was >99%. No reductions in free C5 concentrations were observed in subjects who received PBO. Mean chicken red blood cell (cRBC) hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210. The duration of suppression of mean cRBC hemolysis was dose dependent. No anti-drug antibody (ADA) response was observed during the 150-day follow-up period.
Seven subjects (70%) receiving ALXN1210 reported 21 treatment-emergent adverse events (TEAEs); 3 in cohort 1 (200 mg) reported 6 TEAEs, and 4 in cohort 2 (400 mg) reported 15 TEAEs. The most frequently reported event was headache in subjects receiving ALXN1210 (3 subjects 50%, 3 events) or PBO (3 subjects 75%; 7 events). Most (17/21; 81%) TEAEs were reported as mild, and all resolved during the trial. No drug-related serious AEs or treatment discontinuations due to TEAEs were reported.
Conclusions:•Single IV doses of 200 mg or 400 mg ALXN1210 were well tolerated in healthy subjects.•Serum ALXN1210 concentration data exhibited a terminal half-life of 32 days-longer than eculizumab (9 days).•Mean ALXN1210 Cmax and AUC∞ increased in a dose-proportional manner.•100% of subjects who received ALXN1210 had samples with >99% elimination of free C5.•In subjects who received a single IV 400-mg dose of ALXN1210: •100% reached or exceeded the ALXN1210 threshold level of 100 µg/mL;•100% obtained >99% elimination of free C5;•Mean elimination of free C5 was >99%.•For ALXN1210 levels >100 µg/ml, average elimination of free C5 was >99%.•Mean cRBC hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210, and duration of suppression of mean cRBC hemolysis was dose dependent.•No ADA response was observed after a single dose of ALXN1210 during the 150-day follow-up period.•Data modeling supports that >99% elimination of free C5 will be achieved with doses of ALXN1210 administered at 4-week or longer dosing intervals.
A multiple ascending dose study is ongoing, and 2 studies examining the safety, tolerability, efficacy, PK, and PD of ALXN1210 administered at ≥4-week dosing intervals will be initiated in PNH patients before the end of 2015.
Sahelijo:Alexion Pharmaceuticals: Employment, Equity Ownership. Mujeebuddin:Alexion Pharmaceuticals: Employment, Equity Ownership. Mitchell:Alexion Pharmaceuticals: Consultancy. Larouche:Inventiv Health: Employment, Other: Inventiv Health Conducted the Study; Alexion Pharmaceuticals: Other: Principal Investigator Of Trial Related to Abstract, Research Funding. Yu:Alexion Pharmaceuticals: Employment, Equity Ownership. Zhang:Alexion Pharmaceuticals: Employment, Equity Ownership. Patel:Alexion Pharmaceuticals: Employment, Equity Ownership. Lasaro:Alexion Pharmaceuticals: Employment. Bouchard:Alexion Pharmaceuticals: Employment. Andrien:Alexion Pharmaceuticals: Employment. Wang:Alexion Pharmaceuticals: Employment. Tamburini:Alexion Pharmaceuticals: Employment, Equity Ownership. Macdonald:Alexion Pharmaceuticals: Employment, Equity Ownership. Sheridan:Alexion Pharmaceuticals: Employment, Equity Ownership. Soni:Alexion Pharmaceuticals: Employment, Equity Ownership.
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