EpiOUTAUT – EPIGENETIC MODULATORS TO AMELIORATE CORE SYMPTOMS IN RARE SUBTYPES OF AUTISM SPECTRUM DISORDER

Market

It is estimated that worldwide one in 160 children has an ASD. This high prevalence
appears to be increasing globally due to improved awareness, diagnostic tools and
reporting. ASD is a chronically underserved market with a clear opportunity for
companies to capitalize on this market by developing and launching an effective
drug that treats a core symptom. ASD market is expected to grow with a CAGR of
4.3% from 2018 to 2026. North America generated a revenue of $1,911.7 mln in
year 2018 and is expected to grow through 2026. Europe is anticipated to be the
second most prominent region in terms of revenue. 7Dup prevalence has been
estimated at 1:7,500-1:20,000, qualifying as a rare disease [ORPHA:96121] thus
providing the opportunity to get market exclusivity through the Orphan Drug
Designation. There are more than 6000 rare diseases affecting 30 million EU
citizens. 80% of rare diseases are of genetic origin and are often chronic and
life-threatening.

Current technology limitations

Current ASD treatment guidelines advise the use of pharmacologic intervention
to manage disruptive behavior and to improve compliance with behavioral
interventions rather than treat core symptoms. The most common prescribed
pharmacologic classes are anti-psychotic drugs, antidepressants, stimulants, and
anticonvulsants. The only two FDA approved treatments are the atypical
antipsychotic drugs, risperidone and Abilify, for the treatment of irritability.
Several companies are developing novel first-in-class drugs by focusing on
various targets and mechanisms of action being mainly the modulation of
neurotransmission at the synapse or alteration of the levels of serotonin at the
synapse. One example is Latuda, developed by Dainippon Sumitomo Pharm, that
has an antagonistic effect on dopamine and serotonin receptors. Another
product is an enzyme replacement therapy, CM-AT, developed by Curemark, that
targets a dysfunctional digestive system in ASD children. Prof. Testa’s project
aims at developing first-in-class pharmacological agents to treat core symptoms
in rare autistic syndromes by targeting key genetic lesions and pathogenic
pathways.

Our technology and solutions

Prof. Giuseppe Testa’s group has developed a unique collection of
patient-specific neuronal models - disease avatars - including differentiated
neurons and brain organoids, starting from pluripotent stem cells reprogrammed
from skin fibroblasts of 7DupASD patients, representing uniquely relevant
models exploitable for the identification of novel druggable targets.
Dysregulation of chromatin remodelling has been identified as a new potential
target playing a critical role in the cognitive profile of 7DupASD patients. These
findings allowed to identify IEO proprietary anti-LSD1 (Lysine-specific histone
demethylase 1A) compounds as potential novel 7DupASD treatment.
Proof-of-Concept studies showed that LSD1 inhibition reverts the ASD-relevant
social deficits in 7DupASD mouse models. The effect of LSD1 inhibitors on
7DupASD core sociality symptoms and the availability of a platform of disease
models for other rare neurodevelopmental disorders allows to expand the
application of this treatment to other ASD syndromes sharing the same core
symptoms and converging on the same molecular mechanisms.

Roadmap

Future goals to be achieved include:
1) Regulatory preclinical studies,including full toxicology studies and GMP manufacturing of theclinical candidate;
2) Definition of regulatory approval path, includingOrphan Drug Designation;
3) Design and development of a phase I/IIclinical trial in 7DupASD patients.

Importantly, collaborations with specialized clinical centers and a worldwide 7DupASD patients’families association have already been established that will providethe clinical expertise and infrastructure, along with the patientcohorts, to design and prepare the first clinical trials of the LSD1inhibitor in 7DupASD.