Potential Paroxysmal Nocturnal Hemoglobinuria Treatment, APL-2, Shows Positive Trial Update

Results from the open-label, dose-escalation phase 1b clinical trial investigating APL-2 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) were presented at the 60th ASH Annual Meeting & Exposition in San Diego, California.

Among the highlights, significant reductions in lactate dehydrogenase (LDH), total bilirubin, and absolute reticulocyte count (ARC) stood out among the significant and sustained increases in hemoglobin without transfusions.

“PNH affects close to 5000 people in the United States alone and is a disease, when left untreated, has about a 35% 5-year mortality,” Cedric Francois, MD, PhD, CEO of Apellis, told Rare Disease Report^®. “APL-2 inhibits the C3 target and does it systemically with subcutaneous injections.”

In the early clinical trial conducted in New Zealand, Thailand, Malaysia, and Hong Kong, investigators evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of multiple subcutaneous injections of APL-2 in patients with PNH.

At screening, patients have to have hemoglobin levels < 105 g/L (normal range [NR] 119-180), LDH levels >2 times upper limit of normal (x ULN), and ≥ 1 blood transfusion in the prior 12 months. Three patients will be enrolled into Cohort 1, and up to 20 patients will be enrolled in Cohort 2 and administered 180 mg/d or 270 mg/d of APL-2, respectively.

Changes from baseline in hemoglobin, LDH, ARC, total bilirubin, and transfusion requirements are serving as efficacy assessments. Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score is also being measured.

Per data entries recorded July 24, 2018, Cohort 1 has been fully recruited, and Cohort 2 has had 17 patients dosed, 15 of whom have been administered APL-2 for >28 days and 9 of whom have been administered for >84 days.

Investigators noted that the, “Data is summarized for 14 (and 10) subjects in Cohort 2 who have received 270 mg/d of APL-2 for at least 28 (and 84) days; not included in the summary are 2 subjects who have not yet reached Day 28 and one subject who had underlying metastatic ovarian cancer with a chronic low gastrointestinal bleed, unknown at time of screening, resulting in artificially low hemoglobin and high LDH levels determined to be unrelated to PNH.”

At baseline, hemoglobin was 84 g/L (range 55-110), which increased to 110 (74-135) and 116 (71-145) g/L at Days 29 and 85 respectively. This increase demonstrated a mean increase in hemoglobin of 29 g/L and 33 g/L.

One hundred percent of patients experienced increases in hemoglobin levels at Day 29; 57% achieved levels within the normal range.

Of the 10 subjects with Day 85 data available, hemoglobin increases were made. Patients received a total of 67 transfusions (average 4.8 per year per patient; range 0 to 15) in the 12 months prior to APL-2 dosing.

No transfusions have been reported for any patient during the APL-2 treatment period, with the exception of 2 patients, both of whom were administered a single transfusion within the first 2 weeks of treatment i.e. before APL-2 had reached steady state concentration.

“Mean baseline LDH of 2459 I/U (9.8x ULN) was reduced to 197 I/U (0.8x ULN) by Day 29. Mean baseline ARC and total bilirubin were reduced from 193 to 89 10^9/L (NR 30-100 10^9/L) and 39 umol/L to 10 umol/L (NR 3-15 umol/L), respectively.”

At Day 29, 13 of the 14 patients (92%) had LDH and bilirubin within the normal range, and 11 (79%) had ARC in the normal range.

Currently, APL-2 has been reported as well-tolerated, with no observance of significant infections or thromboembolic events.

Due to progression of aplastic anemia related to underlying PNH, 1 subject was withdrawn from the study due to progression of aplastic anemia related to underlying PNH. More than 5000 SC doses of APL-2 ≥ 270 mg/day have been administered in clinical trials in patients with PNH, representing a cumulative systemic exposure of >700 patient weeks of APL-2 treatment.

Reflecting on the positive results, Dr. Francois commented on the potential of APL-2 for the treatment of patients with PNH. “On one hand, we get very good improvements in hemoglobin levels. In pharmacology, we have about 24 patient years in which these patients did not need a single transfusion.

Compared to eculizumab (Soliris), for example, where close to 40% of patients continue to require transfusions over a 1-year period, and on average, you should think 2 units per patient, per year that are needed in the PNH population on C5 inhibitors to keep the hemoglobin a reasonable range. Should APL-2 prove to be safe product and continues to show efficacy, we think we have something that will be valuable to this patient population.”

The study, titled “2314 Inhibition of C3 with APL-2 Results in Normalisation of Markers of Intravascular and Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH),” was presented at the 60th ASH Annual Meeting & Exposition.