On August 11, 2020, AzurRx (NASDAQ:AZRX) management provided an update for the combination Phase II trial that is evaluating MS1819 in combination with porcine enzyme replacement therapy (PERT). Despite only representing five individuals, the results demonstrated a nine point improvement in the coefficient of fat absorption (CFA) and improvements across the board for stool weight, stools per day and degree of steatorrhea.
MS1819 is recombinant lipase targeting exocrine pancreatic insufficiency (EPI), specifically in cystic fibrosis and chronic pancreatitis patients. It is a synthetic alternative to porcine-derived standard of care. AzurRx is currently advancing two clinical programs examining MS1819: a Phase IIb cystic fibrosis (CF) monotherapy and Phase II CF combination approach. Results for both trials are expected 1H:21.
Combination therapy may be vital to addressing refractory EPI as many patients with severe EPI have difficulty maintaining weight, achieving adequate nutrition and are limited in the quantity of PERT they can take. Adding MS1819 to the PERT regimen may help these patients absorb sufficient calories. A third of CF patients suffering from severe EPI are at the maximum allowed or tolerated dose of PERT. These patients suffer from abdominal pain and difficulty maintaining their body weight due to malnutrition. Many of these patients at the highest dose of PERT are at risk of fibrosing colonopathy, which may occur when daily dosages increase above 10,000 lipase units/kg/day of PERT.
Combination Trial Overview
AzurRx provided positive interim data from its combination trial. While the results only include responses from five patients, results reflected observations taken from three different dose levels with little variability in results. The primary endpoint for the combination trial is the CFA, which measures the digestive system’s ability to metabolize lipids. This done by analyzing fat intake compared with fat excretion. A normal CFA is in excess of 90% and physicians and the FDA generally want to see a CFA of above 80% for a therapy to be deemed effective. Secondary endpoints include coefficient of nitrogen absorption (CNA), which measures protein digestion, stool quantity (mass), steatorrhea, number of stools per day and body mass.
The trial is targeting the enrollment of 24 patients greater than 12 years of age, observed over a period of 100 days. Subjects stop their PERT regimen for two weeks to determine a baseline CFA. If the CFA is below 80%, they are eligible for combination trial enrollment. Subjects are then randomized into the study, beginning with a low dose at 700mg/d then progressing to 1120mg/d and finally 2240mg/d, with CFA measured at each escalation.
Interim readouts for the first five patients were as follows:
Preliminary Readout for Combination MS1819 + PERT1
We note that there does not appear to be any dose dependent response for the varying levels of MS1819. While the number of observations is small, the relationship may be attributed to efficacy saturation.
The CFA increased from below 78% to the high 80% range for all five of the first five patients. The secondary endpoints were consistent with the CFA data. For all doses, the average improvement in CFA was about nine percentage points, which is considered clinically meaningful. This increase could lead to nine pound improvement in weight gain over a year in a young and maturing population. Stool weight and frequency is markedly decreased, as is steatorrhea. Over the brief 45 day dosing portion of the study, patients gained four pounds on average, indicating enhanced nutrition and body mass increase.
Safety and clinical feedback from patients was favorable. Four of the five patients noted that they felt better while on the combination therapy, relative to the symptoms of EPI which are diarrhea, gas and bloating and stomach pain among other discomforts. None of the five patients noted any adverse effects tied to MS1819, and two of two patients reported that abdominal pain returned and stool frequency increased after reverting to PERT only.
The trial plans to enroll 24 patients, with 20 expected to complete the trial. Five patients have completed, and their data was analyzed, a sixth is completing and a seventh has just begun treatment. Trial progress has been slowed by the pandemic and in response, AzurRx has opened 11 new clinical trial sites in Spain and Turkey which are expected to enroll patients by September. These sites are in addition to the six existing trial sites in Hungary. Enrollment targets are expected to be met in 2H:20 and, assuming the trial continues as expected, a Phase III combination study could start by late 2021.
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1. Source: AzurRx Combination Therapy Trial R&D Update Presentation, August 2019