-- Data Demonstrate Rapid and Sustained Reduction of Plasma Lactate Dehydrogenase (LDH) --
"It is encouraging to see rapid and sustained reduction in plasma LDH levels in these dose optimization studies," said Alexander Röth, M.D. from the
"The strength of these data and exposure-response analyses, along with the totality of data for ALXN1210 and discussions with global regulators, allowed us to determine an eight-week, weight-based dosing regimen that targets complete C5 inhibition and rapid and sustained suppression of LDH," said
Optimization of Dose Regimen for ALXN1210, a Novel Complement C5 Inhibitor, in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results of Two Phase 1b/2 Studies3
The researchers presented results from two open-label Phase 1b/2 studies designed to provide dose ranging data to optimize the dosing regimen for the Phase 3 development of ALXN1210 as a treatment for patients with PNH based on exposure-response assessments. The studies included a total of 39 adult patients with PNH (Study 103, n=13; Study 201, n=26) who were naïve to complement inhibition. The primary efficacy endpoint was the change from BL in mean plasma LDH levels to day 169 in Study 103 and day 253 in Study 201. The secondary efficacy endpoints were changes from BL in free hemoglobin, haptoglobin, and reticulocytes. Post hoc efficacy analyses evaluated the proportion of patients achieving LDH levels within the normal range and the incidence of breakthrough hemolysis (days 29-253). LDH BL was defined as the average of values at screening, prior to the first ALXN1210 infusion. For other parameters, BL was defined as the most recent value prior to the first infusion. Study 103 evaluated two escalating intravenous (IV) dosing regimens of ALXN1210, and Study 201 evaluated four IV regimens with different doses and intervals. The results demonstrated exposure-response relationships, and further substantiate and extend previously presented results.4,5,6,7
|Study 201||Study 103|
|LDH at Protocol-Specified Endpointa||Cohort 1
1000 mg q4w
1600 mg q6w
2400 mg q8w
5400 mg q12w
900 mg q4w
1800 mg q4w
|% LDH reduction from BL, mean (SD)b||72.9 (12.1)||77.8 (6.5)||85.0 (4.4)||87.6 (6.9)||86.0 (3.2)||84.7 (3.8)|
|LDH levels, U/L, mean (SD)||230.0 (44.0)||266.0 (54.3)||306.1 (130.7)||276.4 (196.9)||232.0 (82.3)||227.9 (50.6)|
|LDH normalization (D29-D253)c|
|LDH normalized, n/N (%)||5/6 (83)||3/6 (50)||4/7 (57)||5/7 (71)||4/6 (67)||6/7 (86)|
|LDH > 1.5 x ULN, n/N (%)||4/6 (67)||3/6 (50)||2/7 (29)||3/7(43)||2/6 (33)||1/7 (14)|
|LDH > 2 x ULN, n/N (%)||2/6 (33)||1/6 (17)||2/7 (29)||1/7 (14)||1/6 (17)||0/7 (0)|
|Breakthrough hemolysis (D29-253)d|
|Incidence of breakthrough hemolysis through day 253, n/N (%)||2/6 (33.3)||1/6 (16.7)||2/7 (28.6)||1/7 (14.3)||1/6 (16.7)||0/7 (0)|
BL: baseline; SD: standard deviation; D: day; LDH: lactate dehydrogenase; ULN: upper limit of normal
q4w: every 4 weeks; q6w: every 6 weeks; q8w: every 8 weeks; q12w: every 12 weeks
a LDH parameters at protocol-specified endpoint: Study 103, day 169/24 weeks; Study 201, day 253/36 weeks.
b Primary efficacy endpoint.
c Patients meeting each parameter at least once after day 29 through day 253.
d Defined as at least 1 symptom or sign of intravascular hemolysis (fatigue, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g/dL and hemoglobin < baseline hemoglobin], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) within ±7 days of an elevated LDH ≥2 x ULN after prior LDH reduction to < 1.5 x ULN on therapy.
The most frequent related treatment-emergent adverse event (TEAE) was headache. No patient stopped treatment or withdrew from the studies, and there were no deaths. Two patients in Study 201 experienced meningococcal infections but recovered completely and continued receiving ALXN1210. Meningococcal infections are a known risk with terminal complement inhibition, and specific risk-management plans have been in place for ten years for Soliris® (eculizumab) to minimize the risk for patients.
About Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and potentially life-threatening ultra-rare blood disorder that can strike men and women of all races, backgrounds, and ages without warning, with an average age of onset in the early 30s.1,2,8 PNH often goes unrecognized, with delays in diagnosis ranging from one to more than 10 years.2 In patients with PNH, chronic, uncontrolled activation of the complement system, a component of the body's immune system, results in hemolysis (the destruction of red blood cells)9, which in turn can result in progressive anemia, fatigue, dark urine and shortness of breath.10,11,12 The most devastating consequence of chronic hemolysis is thrombosis (the formation of blood clots), which can damage vital organs and cause premature death.13 Historically, it had been estimated that one in three patients with PNH did not survive more than five years from the time of diagnosis.2 PNH is more common among patients with disorders of the bone marrow, including aplastic anemia (AA) and myelodysplastic syndromes (MDS).14,15,16 In certain patients with thrombosis of unknown origin, PNH may be an underlying cause.9
ALXN1210 is an innovative, long-acting C5 inhibitor discovered and developed by
ALXN1210 has received Orphan Drug Designation (ODD) for the intravenous treatment of patients with PNH in the
About Soliris® (eculizumab)
Soliris® is a first-in-class complement inhibitor that works by inhibiting the C5 protein in the terminal part of the complement cascade, a part of the immune system that, when activated in an uncontrolled manner, plays a role in severe rare and ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). Soliris is approved in the
Soliris has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the
For more information on Soliris, please see full prescribing information for Soliris, including BOXED WARNING regarding risk of serious meningococcal infection, available at www.soliris.net
Important Soliris Safety Information
Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenza type b (Hib). Soliris treatment of patients with PNH should not alter anticoagulant management because the effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established.
In patients with PNH, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, nasopharyngitis, back pain and nausea. In patients with aHUS, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, and pyrexia. In patients with gMG who are anti-AchR antibody-positive, the most frequently reported adverse reaction observed with Soliris treatment in the placebo-controlled clinical study (≥10%) was musculoskeletal pain.
This press release contains forward-looking statements, including statements related to the potential medical benefits of ALXN1210 for the treatment of PNH. Forward-looking statements are subject to factors that may cause
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