AJ201 is a new chemical entity being developed for the treatment of spinal and bulbar muscular atrophy (SBMA), a neurodegenerative disease associated with abnormal aggregation of the androgen receptor (AR) protein with a polyglutamine (polyQ) stretch. At the molecular levels, AJ201 exerts multiple cellular effects, activating nuclear factor erythroid 2-related factor 2 (Nrf2) in response to oxidative damages, Nrf1 to enhance the ubiquitin proteasome system (UPS)-mediated degradation, as well as heat shock factor 1 (Hsf1) to promote protein folding. In an animal model of SBMA, AJ201 alleviated behavioral defects in motor functions, ameliorated muscle atrophy, reduced the accumulation of mutant AR aggregates in muscles and activate the expression of antioxidant enzymes.

Spinal and Bulbar Muscular Atrophy (Kennedy’s Disease)

The genetic defect underlying SBMA is the expansion of a polyQ-encoding CAG repeat in the first exon of the AR gene. SBMA is a rare X-linked disorder affecting approximately 1 in 35,000 males globally. The disease is characterized by a progressive degeneration of the lower motor neurons in the anterior horn of the spinal cord and the brainstem as well as the skeletal muscles. The accumulation of pathological mutant AR aggregates is thought to cause cytotoxicity, excessive oxidative stress and chronic neuroinflammation, leading to the degeneration and death of neurons. Currently, there is only one drug approved for the treatment of SBMA, namely Leuprorelin (an androgen deprivation agent) in Japan. Leuprorelin appeared to delay certain functional decline in SBMA patients. However, the efficacy remained sub-optimal. Given its important role in activating key regulatory pathways responsible for redox homeostasis, UPS-mediated protein degradation and correct protein folding, AJ201 is also being investigated for the treatment of other neurodegenerative disorders or polyQ diseases, such as Huntington’s disease and spinocerebellar ataxia type 2.

Combinational mechanisms of AJ201 to treat neurodegenerative diseases associated with protein aggregations  

Clinical Development

1. Granted 3 FDA orphan drug designations to AJ201 for the treatments of SBMA, HD and SCA
2. Completed IND submission to US FDA in April 2019
3. Phase 1 clinical trial in healthy volunteers (ClinicalTrials.gov Identifier: NCT04392830) has been completed in 2021
4. The first-in-patient trial to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in adults with SBMA is to kick off in 2022(ClinicalTrials.gov Identifier: NCT05517603)
   
   
   Do you have Kennedy’s disease?
   A new clinical trial can help pave the way for the future of SBMA research.
   Now enrolling: a clinical trial for adult males with spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease
   A clinical trial is evaluating an investigational study drug to determine if it is safe and tolerable in adult males 18 years of age or older with Kennedy’s disease.
   What should I know about this clinical trial?
   • To be eligible for this clinical trial, participants must be*:
   – Male and 18 years of age or older
   – Diagnosed with Kennedy’s disease and muscle weakness
   • This clinical trial will consist of at least 6 visits over a period of about 20 weeks
   • Eligible participants will be randomly assigned (by chance) to receive either the investigational study drug (AJ201) or placebo (looks like the investigational study drug but has no active drug in it)
   • The health and safety of participants will be monitored throughout the clinical trial
   • Participant data and information will be kept confidential
   • Clinical trial participants will receive all clinical trial–related procedures and tests and the investigational study drug or placebo at no cost
   * Other inclusion/exclusion criteria will apply.
   To learn more about this clinical trial, please visit clinicaltrials.gov.

References

1. Polyglutamine Repeats in Neurodegenerative Diseases. Annu Rev Pathol 2019 Jan 24; 14:1-27
2. A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet. 2016 May 15;25(10):1979-1989
3. Chapter 17 Kennedy’s Disease. Blue Books of Practical Neurology. Volume 28, 2003, Pages 425-434, cp1-cp2
4. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nature Medicine 2001 Mar;13(3):348-353