Aldeyra Therapeutics, Inc. announced advancement of its RASP modulator platform, including the expected submission to the FDA of a proposed expansion of the Phase 2 clinical trial of the investigational RASP modulator ADX-629 in Sjögren-Larsson Syndrome to include pediatric patients, initiation of a Phase 2 clinical trial of ADX-629 in moderate alcoholic hepatitis, submission of an IND application of the investigational RASP modulator ADX-246 for a Phase 1 clinical trial that is expected to be expanded to include atopic dermatitis patients, anticipated submission of an IND application of the investigational RASP modulator ADX-248 for a Phase 1/2 clinical trial in patients with the dry form of age-related macular degeneration (AMD) and dark adaptation deficit, and initiation of a preclinical program of RASP modulators in metabolic disease. Sjögren-Larsson Syndrome is a rare inborn error of metabolism due to mutations in fatty aldehyde dehydrogenase, leading to accumulation of fatty alcohols and fatty aldehydes. The disease is characterized clinically by cognitive delay, spasticity, and dermal compromise.

There is no FDA-approved therapy for Sjögren-Larsson Syndrome. ADX-629, administered twice daily over 90 days, has completed initial clinical testing in three adult patients in an investigator-sponsored clinical trial. Broad-based normalization of the majority of abnormal metabolomic signatures was observed along with reduction in accumulation of fatty alcohols.

A proposed expansion of the clinical trial to include pediatric patients is expected to be submitted to the FDA in the first half of 2024. Moderate alcoholic hepatitis is a common disease that leads to significant morbidity and mortality due to hepatic compromise and related complications. There is no FDA-approved therapy for alcoholic hepatitis.

In preclinical models of ethanol toxicity, ADX-629 decreased hepatic levels of RASP, triglycerides, and inflammatory cytokines. In a sequence-randomized, double-masked, placebo-controlled crossover Phase 2 clinical trial announced last year, relative to placebo, ADX-629 reduced dermal flushing (P=0.0007), increased Romberg test balance time (P=0.02), and lowered levels of the ethanol RASP metabolite acetaldehyde (P=0.03) following acute exposure to alcohol. The moderate alcoholic hepatitis Phase 2 clinical trial is intended to assess the activity of ADX-629, administered orally twice daily over 90 days, initially in approximately 10 patients.

The primary endpoint is safety and tolerability; secondary endpoints include liver function biomarkers, model for end-stage liver disease (MELD) score, hospitalization, and mortality rate. Top-line results from the first patient cohort are expected in the second half of 2024. Atopic dermatitis is a common disease characterized by immune dysregulation that leads to hyperreactivity to endogenous and exogenous factors, potentially including RASP.

There is no widely accepted oral therapy for the treatment of patients with mild to moderate atopic dermatitis. Recently announced results from a 90-day, open-label Phase 2 clinical trial of orally administered ADX-629 in eight mild to moderate atopic dermatitis patients demonstrated statistically significant and clinically relevant improvement in investigator-assessed and patient-reported outcomes across a number of different physiological and psychosocial assessments, including complete resolution of affected body surface area observed in one patient and elimination of itching reported by two patients. Based on the results of the clinical trial, an IND application of next-generation investigational RASP modulator ADX-246 for a Phase 1 clinical trial in healthy volunteers has been submitted to the FDA and is expected to be expanded to include clinical testing in patients with atopic dermatitis.

The clinical trial is anticipated to be initiated in the first half of 2024, and top-line results are expected in the second half of 2024. AMD is a common disease, the so-called dry form of which is characterized by accumulation of toxic metabolites in the retina and visual deficit, typically beginning with difficulty seeing in low-light settings. Metabolites of RASP are associated with compromise in dark adaptation.

Based on data demonstrating that RASP modulation reduces accumulation of toxic metabolites in a preclinical model of AMD, an IND application of next-generation investigational RASP modulator ADX-248 is expected to be submitted in 2024. The Phase 1/2 clinical trial is anticipated to enroll dry AMD patients with dark adaptation deficit. Highlighting the advancement of the RASP platform and the selection of key clinical indications for future development, Aldeyra released a focused pipeline.

The previously announced programs of ADX-629 in chronic cough and idiopathic nephrotic syndrome have been de-prioritized due to regulatory and trial feasibility challenges, respectively. In addition, a new preclinical RASP modulator program in metabolic disease has been announced, supported by a number of clinical trials with ADX-629 that demonstrated a reduction in triglycerides and cholesterol. Based on Special Protocol Assessment feedback received from the FDA last week on reproxalap in dry eye disease, Aldeyra has amended the proposed clinical trial protocol and statistical analysis plan.