Regulus Therapeutics (RGLS) last week announced positive topline results from the third cohort of patients in its Phase 1b MAD study of RGLS8429 for the treatment of ADPKD. RGLS8429 is a novel, next generation oligonucleotide for the treatment of ADPKD designed to inhibit miR-17 and to preferentially target the kidney.
The double-blind, placebo-controlled trial is evaluating RGLS8429 treatment across three different weight-based dose levels and one fixed dose level, including measuring changes in urinary polycystins 1 and 2 (PC1 and PC2), htTKV, cyst architecture, and overall kidney function.
The sixteen subjects in the third cohort were randomized 3:1 to receive either 3 mg/kg of RGLS8429 or placebo every other week for three months.
RGLS8429 was found to be well tolerated with no safety concerns.
Continued evidence of a mechanistic dose response was observed, based on measurement of urinary PC1 and PC2.
The 3 mg/kg dose demonstrated more consistent increases in PC1 and PC2 across patients compared to earlier cohorts.
Percent change from baseline in PC1 and PC2 demonstrated a dose response across all doses tested, with statistical significance seen at 3 mg/kg compared to placebo.
Exploratory MRI imaging analysis suggested RGLS8429 reduced htTKV at 3 mg/kg after three months of dosing.
70% of subjects demonstrated reductions in htTKV following completion of the 3 mg/kg dose level.
Regulus is now enrolling a fourth cohort of up to 30 patients, who will receive an open label fixed dose of 300 mg every other week for three months. In addition to PC1 and PC2 and safety, imaging biomarkers will also be evaluated.
Most analysts seemed happy with the result - Cannacord Genuity (which recently commenced coverage of PYC) raised its price from $11 to $28 - and the RGLS share price was initially up 38% premarket on the day of the announcement. But instead of rising, the share price tanked instead – now down 30%, from $2.51 to $1.76.
It’s unclear what prompted the sell-off. Jones Research, which commenced coverage of RGLS just a few weeks before the announcement, maintained its price target at $8. It speculated that the share price drop was likely due to questions around dose response, eGFR benefit, and magnitude of reduction in htTKV compared with Cohort 2. However, in the opinion of Jones Research, the sell-off was an overreaction.
Perhaps recent history has left investors especially wary.
Regulus, which was established in 2007 by Alnylam and Isis Pharmaceuticals (now Ionis), has suffered setbacks in its kidney programs over the last couple of years. In late 2021, the Company discontinued development of its first-generation compound, RGLS4326, for the treatment of ADPKD. Off-target CNS effects were seen with RGLS4326 at the top doses tested in chronic preclinical toxicology studies and the Company subsequently shifted development to the “safer” RGLS8429.
The following year, Sanofi walked away from a Regulus therapy for the genetic kidney disease, Alport syndrome. The french pharma's exit followed termination of a Phase 2 trial after a 24 week interim analysis failed to demonstrate improvement in kidney function between the Regulus drug and placebo. Had the Phase 2 trial successfully completed, Regulus would have received a US$25m milestone payment from Sanofi.
Regulus is now hopeful that the data from its latest Phase 1 MAD study will form the basis for a potentially pivotal Phase 2/3 study under an Accelerated Approval regulatory pathway, yet to be discussed with the FDA.
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