Reporting a phase II, open-label study assessing the safety and efficacy of MS1819-SD, a recombinant lipase, for the treatment of exocrine pancreatic insufficiency

Abstract

Background: Chronic pancreatitis is the most common cause of exocrine pancreatic insufficiency (EPI) in adults. EPI is a deficiency in exocrine pancreatic enzymes resulting in an inability to maintain normal digestion. This inadequate digestion, especially fat malabsorption, occurs when intraduodenal levels of lipase fall below 5–10% of normal enzyme output. Furthermore, in EPI due to chronic pancreatitis, decreased bicarbonate output leads to impairment of micelle formation of fats. Fat maldigestion is compounded by decreased pancreatic secretion of lipase and colipase, further dampening hydrolysis of intraluminal fat. Methods: A multicenter, Phase II, open-label, non-randomized study was conducted to investigate the safety of escalating doses (280 mg/day, 560 mg/day, 1120 mg/day and 2240 mg/day) of MS1819 Spray Dried (MS1819-SD, a lipase produced by the LIP2 gene of Yarrowia lipolytica using recombinant DNA technology) in patients with chronic pancreatitis (NCT03481803) and decreased fecal pancreatic elastase-1 (FE-1). Patients ‘washed-out’ their standard of care treatment for EPI establishing a baseline. Each patient subsequently received escalating doses of MS1819-SD in 2-week increments. The total treatment phase ranged from 48 to 60 days. Safety was assessed by adverse event (AE) incidence, including clinical or laboratory abnormalities, and efficacy was determined using Coefficient of Fat Absorption (CFA) change from baseline. Systemic exposure and immunogenicity potential of MS1819 were investigated in patients’ serum. Results: A total of 11 patients (9 males, 2 females) were enrolled in France, Australia and New Zealand. The study mean age was 59.2 years (11.19 standard deviation [SD]) and mean weight was 70.6 kg (12.84 SD). Disease etiology was alcoholism in 4 patients, idiopathic in 3 patients, genetic in 2 patients, auto-immune in 1 patient and gallstone induced pancreatitis for 1 patient. In the highest dose group (2240 mg/day) 4/10 patients reported an AE. One serious AE occurred at this dose but it was not considered to be treatment related (pre-planned removal of stent). A drug-related AE was reported at the 1120 mg dose (slight hepatic cytolysis, mild in nature). No circulating MS1819 was detected hence the mechanism of this adverse event cannot be explained or related to systemic exposure. MS1819 immunogenicity was observed in some patients with post-treatment anti-drug antibodies (ADAs) detected. However, some pre-existing ADAs were also detected and the incidence of ADAs was mild (3/10 patients) with moderate ADA titers. Increases in CFA were reported with all doses of MS1819-SD, these increases were particularly high in patients with baseline CFA <40%. Comparing CFA with FE-1 (24 patients with both recorded at screening) a positive spearman rank correlation of 0.64 (p < 0.001) was obtained. Although the study was not powered to detect a difference in efficacy parameters, the least square mean increase in CFA was 21.8% with MS1819-SD 2240 mg (p = 0.002; per protocol analysis). Conclusion: In general, a favorable safety profile was reported at all doses of MS1819-SD included in the study. Statistically significant and clinically meaningful increases in CFA compared to baseline were recorded. Although the efficacy analysis was pre-planned, the study was not powered to demonstrate differences in the groups and only a small number of patients were included. Favorable trends were also observed on other evaluated endpoints, including the Bristol stool scale, number of daily evacuations and stool weight. Additional studies are warranted to further evaluate the use of MS1819-SD to treat EPI in patients with chronic pancreatitis or cystic fibrosis.