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Avenue Therapeutics Initiates Phase 1b/2a Clinical Trial of AJ201 for the Treatment of Kennedy's Disease (Spinal and Bulbar Muscular Atrophy)

Friday, July 28, 2023

Avenue Therapeutics, Inc. (Nasdaq: ATXI) has initiated a Phase 1b/2a clinical trial for their lead drug candidate, AJ201, which is designed to treat spinal and bulbar muscular atrophy (SBMA), commonly known as Kennedy's Disease. SBMA is a progressive neurodegenerative disease for which no approved treatments currently exist.

The company has announced the dosing of the first patient in the clinical trial, and they expect to complete enrollment by the end of 2023 or early 2024. The potential topline data from this trial is anticipated to be available in 2024.

AJ201 has demonstrated promising safety results in Phase 1 clinical data involving healthy volunteers. Preclinical studies using mouse models have also shown positive efficacy signals, such as improvements in motor function, degradation of mutant androgen receptors (AR) - the disease-signaling protein - and activation of the Nrf1 and Nrf2 pathways.

The ongoing Phase 1b/2a clinical trial aims to evaluate the safety and tolerability of AJ201 in approximately 24 patients with clinically and genetically defined SBMA. Patients will be randomly assigned to receive either AJ201 (600 mg/day) or placebo. Secondary endpoints of the study include measuring pharmacodynamic data to observe changes from baseline in mutant AR protein levels in skeletal muscle and analyzing changes in fat and muscle composition seen on MRI scans. These secondary endpoints are believed to be biomarkers indicating the likelihood of longer-term clinical improvement.

The development of AJ201 is of great significance, considering the lack of approved treatments for SBMA. Avenue Therapeutics' goal is to demonstrate that AJ201 can effectively reduce the accumulation of mutant AR aggregates, decrease neuroinflammation, protect cells from oxidative stress, and ultimately improve clinical outcomes for SBMA patients. Their commitment lies in providing impactful therapies to those suffering from neurologic diseases.

Spinal and bulbar muscular atrophy (SBMA) is a rare neuromuscular disease primarily affecting males and is caused by a genetic mutation on the X chromosome. The condition is a result of a trinucleotide CAG repeat expansion in the androgen receptor (AR) gene, leading to the production of a mutant polyglutamine (polyQ) AR protein. These mutant proteins form aggregates, which contribute to muscular atrophy, particularly in the limbs and bulbar region of the body.

The weakening of the bulbar muscles can cause difficulties in chewing, speech, and swallowing, putting patients at risk of choking or inhaling foods and liquids, which can lead to airway infections. SBMA also affects limb muscles, resulting in challenges with walking and an increased likelihood of injuries from falls.

The prevalence of SBMA is rare, and various prevalence rates have been cited in scientific literature. However, a recent study utilizing genetic analysis estimated a disease prevalence of approximately 1 in 6,887 males.

Currently, there are no approved treatments for SBMA by regulatory agencies such as the U.S. Food and Drug Administration or the European Medicines Agency, leaving patients with limited options for managing the disease.

AJ201 is a novel and pioneering therapeutic under development for the treatment of spinal and bulbar muscular atrophy (SBMA). The drug's mechanism of action involves targeting multiple pathways to modify the progression of SBMA effectively. It aims to achieve this by promoting the degradation of the abnormal androgen receptor protein associated with the disease. Additionally, AJ201 stimulates the Nrf1 and Nrf2 pathways, which play crucial roles in protecting cells from oxidative stress, a factor that can lead to cell death.

In its initial evaluation in a Phase 1 study involving 72 healthy volunteers, AJ201 exhibited a remarkable safety and pharmacokinetic profile. Presently, the drug is being investigated in a Phase 1/2a multicenter, randomized, double-blind clinical trial at six different clinical sites across the United States. The main objectives of this trial are to assess the safety of AJ201, gather pharmacokinetic and pharmacodynamic data, and evaluate the clinical response in SBMA patients.

AJ201's potential goes beyond treating SBMA, as it has been granted Orphan Drug Designation by the FDA for various polyglutamine (polyQ) diseases, including Huntington's disease and spinocerebellar ataxia. PolyQ diseases constitute a group of neurodegenerative disorders caused by expanded CAG repeats in specific proteins. One of the pathological hallmarks of these diseases is the aggregation of mutant proteins in affected tissues. The disease progression is thought to be influenced by neuroinflammation, oxidative stress, and disrupted protein quality control mechanisms.

AJ201's development is based on the rationale that by modulating multiple cellular pathways, it can enhance the degradation of mutant AR aggregates, trigger antioxidant and heat shock responses, and increase proteasome expression, which collectively present a promising treatment approach for SBMA and other polyQ diseases.

Avenue holds an exclusive license for AJ201 from AnnJi Pharmaceuticals for specific regions, including the United States, Canada, European Union, Great Britain, and Israel. This underscores the company's dedication to advancing this potential therapeutic option to benefit patients affected by these challenging neurodegenerative conditions.

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