Following more than a year of restructuring and recalibration, Regulus Therapeutics Inc. is facing a new partial clinical hold placed by the FDA on its phase I test of RGLS-4326, an oligonucleotide it's developing for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Though the impacted multiple ascending-dose (MAD) study was voluntarily paused by Regulus last year, the agency will now require final reports and analyses of chronic toxicity studies in mice and nonhuman primates to be completed before allowing the company to restart it. Company shares (NASDAQ:RGLS) fell 34.8% Wednesday to 74 cents.

Regulus CEO Jay Hagan said his team has had "productive dialogue" with the regulator resulting in "clear requirements that we believe we can address with data anticipated in the next several months from ongoing studies, augmented by data to be generated from additional studies that we expect to be completed early next year." The company didn't respond to a request for further information.

Trouble for the ADPKD program goes back to at least July 2018, when the La Jolla, Calif.-based company said it voluntarily paused a phase I MAD study in humans due to "unexpected observations" in a mouse chronic toxicity study run in parallel with the phase I trial. Since the MAD study was designed to support starting a phase II proof-of-concept trial in ADPKD in mid-2019, that plan had to be put on hold. Instead, Regulus began a new chronic mouse tox study in September 2018, tweaked in consultation with the FDA.

Interim data from the revised toxicity study was intended to justify restarting the human MAD study. After securing positive interim data suggesting it did so, in January Regulus submitted the results and information from earlier studies, including a nonhuman primate (NHP) tox study, to the FDA. But instead of a green light, the partial clinical hold arrived. To lift it, the regulator wants final reports from the chronic toxicity studies in both mice and NHP and "satisfactory related analyses" to ensure human participants in the phase I MAD study can be safely dosed, Regulus said.

Meanwhile, the company has permission to proceed with any additional single ascending-dose (SAD) studies as part of the process to gather additional supporting information to guide the future development of the program, it said. But since Regulus said Wednesday that it has already completed a SAD study in healthy volunteers up to the planned highest dose, further SAD studies in the near term seem unlikely.

Competition and setbacks

Caused by the mutations in the PKD1 or PKD2 genes, ADPKD is among the most common human monogenic disorders and a leading cause of end-stage renal disease. Otsuka Pharmaceutical Co. Ltd.'s Samsca (tolvaptan) is the only FDA-approved medicine for the indication, but generic entries aren't far behind. Furthermore, Sanofi Genzyme's venglustat and Reata Pharmaceuticals Inc.'s bardoxolone methyl are racing ahead in late-stage clinical development for the treatment of conditions including ADPKD.

RGLS-4326 is designed to inhibit microRNA-17 (miR-17) and preferentially target the kidney. Preclinical studies have demonstrated direct regulation of PKD1 and PKD2 in human ADPKD cyst cells, a reduction in kidney cyst formation, improved kidney weight/body weight ratio, decreased cyst cell proliferation, and preserved kidney function in mouse models of ADPKD, the company said.

Regulus has faced significant headwinds since mid-2016, when excitement over its miR-122 antagonist, RG-101, in April quickly gave way to serious concerns in June. That was when the FDA issued a verbal clinical hold on a phase II test of the candidate in patients with chronic hepatitis C virus following a serious case of jaundice, sending company shares almost 50% lower. A year later, the program was dead. (See BioWorld, June 29 and June 29, 2016, and June 13, 2017.)

Regulus shares continued to struggle, having fallen 78.8% from their year-ago value of $3.51. Since that time, the company has reduced its staff by about 60% and restructured a key collaboration with Sanofi SA. In the latter change, it transitioned further development of its miR-21 programs, including the RG-012 for Alport syndrome, to the Paris-based company. The change downsized associated milestone payments contemplated by the pair's original 2010 deal, but brought in some near-term cash too, leaving Regulus with cash and cash equivalents of $10.3 million at the end of March, bolstered by a raise of $16.7 million through the closing of the first tranche of a $41.8 million private placement in May. (See BioWorld, June 23, 2010.)

It's unclear how long the miR specialist will stick with RGLS-4326 should it encounter further push-back from the FDA or how quickly the program might be able to proceed to phase II should the partial hold be lifted. But either way, with fresh cash and a pipeline of six additional discovery programs spanning indications from nonalcoholic steatohepatitis and glioblastoma to infectious disease, the company's remaining team seems intent on rebuilding.

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