Regulus Therapeutics acknowledged today that clinical development of its nonalcoholic steatohepatitis (NASH) candidate AZD4076 (RG-125) is being halted by AstraZeneca—one of three Regulus pipeline candidates whose clinical programs are being scuttled.
Regulus said development is also being halted on its lead RNA interference (RNAi) candidate RG-101, or anti-microRNA-122 (anti-miR-122), for hepatitis C virus (HCV), as well as its RGLS5040 (anti-miR-27) for cholestatic disease—in addition to AZD4076 (RG-125), which is indicated for NASH in type 2 diabetes/pre-diabetes.
AZD4076 (RG-125) is a N-acetylgalactosamine (GalNAc)-conjugated anti-miR-103/107 oligonucleotide that AstraZeneca selected for development in 2015 under an up-to-$526 million strategic alliance announced by the companies three years earlier to discover, develop, and commercialize compounds targeting three miRNA targets in cardiovascular diseases, metabolic diseases, and oncology.
Under that alliance, AstraZeneca paid $28 million to Regulus, consisting of a $25 million equity investment (made concurrent with Regulus’ IPO in 2012) and a $3 million up-front payment. Regulus earned a $2.5 million milestone payment in April 2015 for the clinical candidate selection and was eligible to receive up to $495.5 million in future milestone payments.
Eight months later, AZD4076 entered Phase I clinical development, earning Regulus a $10 million milestone payment. At the time, the companies said that the candidate had been shown to improve insulin sensitivity and glucose tolerance in animal models.
In the third quarter of 2016, AstraZeneca launched a Phase I/IIa, randomized, single-blind, placebo-controlled, multiple ascending dose study in subjects with type II diabetes and nonalcoholic fatty liver disease (NAFLD). The study is anticipated to be complete in December 2017, Regulus said in its Form 10-Q quarterly report for the first quarter, filed May 5.
The termination becomes effective in 12 months, at which point AstraZeneca’s rights to AZD4076 will revert to Regulus.
HCV, Cholestatic Disease Candidates Also Scuttled
Regulus also said it was halting development of RG-101, which has been under an FDA clinical hold placed last year following the company’s disclosure that a second serious adverse event (SAE) of jaundice occurred in a hepatitis C virus (HCV) patient with end-stage renal disease on dialysis who was enrolled in its on-going Phase I U.S. study, 117 days after receiving a single dose of RG-101.
In January, Regulus acknowledged that the clinical hold would remain in effect for most of this year, after the FDA requested final safety and efficacy data from ongoing RG-101 clinical and preclinical studies before reconsidering whether to lift the hold. The company said at the time that data will be available once current study protocols are complete through 48 weeks of follow-up, which is anticipated in Q4.
RGLS5040, an unconjugated inhibitor of mR-27, has been halted “based on a positioning of the compound with respect to the competitive landscape coupled with the results from repeat pharmacology studies as part of IND-enabling work,” Regulus said.
Regulus’ pipeline cuts come more than a month after the company said it would eliminate 30% of its workforce —approximately 30 jobs—in a restructuring that included the immediate resignation of president and CEO Paul Grint, M.D., who was succeeded by Joseph P. “Jay” Hagan, who was COO.
At the time, Regulus said it would focus on RG-012, a candidate for Alport syndrome being developed with Genzyme, a Sanofi company. Today, Regulus said it is on track to launch Phase II studies for RG-012—the HERA study, aimed at achieving proof-of-mechanism data by the end of 2017 and interim data in mid-2018, and a study assessing RG-012 renal tissue pharmacokinetics, target engagement, and downstream effects on genomic disease biomarkers, with data anticipated by year end.
“We are squarely focused on taking the steps necessary to advance our pipeline and continue building shareholder value,” Hagan said in a statement. “To that end, we recognize that we must be disciplined in our investment choices and focus our resources and capital on our most promising discovery and development programs, including the application of important development, regulatory, and commercial considerations.”