One liner: HDAX is a preclinical-stage drug discovery company targeting a class of proteins implicated in neuropathies and inflammation with novel small molecules having potentially superior drug properties

This proposal is based on the supporting documents provided by HDAX Therapeutics, as well as questions and answers, and senior reviews.

If this goes on-chain, the VITA token holders will ratify the WG’s assessment via a decentralized vote

Longevity Dealflow WG team

Scientific & business evaluation : Tuan Dinh, Tim Peterson, Diane Seimetz, Joppe Nieuwenhuis

Shepherd : Divya Cohen

Other squad members : Paolo Binetti, Tim Peterson, Ryan Spangler, Nina Patrick

Simple Summary

HDAX Therapeutics is a small molecule preclinical stage drug discovery company developing a targeted therapeutics platform for safe and efficacious treatment of Histone Deacetylase (HDAC)-driven pathologies such as neuropathies and cancers with high unmet medical need. They have started with HDAC6, whose knock-down also increased the lifespan of animal models in recent literature

With the novel compact bitopic binding mechanism it has developed, HDAX overcomes common drug discovery challenges including weak binding, off-target toxicities, and poor pharmacokinetic profiles that have hampered the drug development of previous attempts in this field. In particular, their lead HDAC6 inhibitor can cross the blood-brain-barrier, enabling Central Nervous System (CNS) disease targeting that is not possible with competing molecules, including clinical candidates.

HDAX is a spinout from Prof. Patrick Gunning’s lab at University of Toronto, a leading professor in his field and serial entrepreneur (Janpix, Dunad, & Dalriada Therapeutics). Up to date they have won several startup competitions, raised $340k, and patented the chemical composition of their lead compound. HDAX is seeking funding to cover part of the clinical nomination phase of their HDAX6 compound, including lead optimization and testing in indication-specific animal models.

Problem

HDAC6 is a validated clinical target whose inhibition can be an effective and safe strategy to treat brain/nerve pathologies such as cancers, neuropathies, and neurodegeneration. Unfortunately, to date, there are no FDA-approved HDAC6-targeting drugs and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are five HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated brain diseases, urging for the development to address these challenges.

Opportunity

The HDAX technology has the potential to be applicable in amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), chemotherapy-induced peripheral neuropathy (CIPD), diabetic-induced peripheral neuropathy (DIPN), and Charcot-Marie-Tooth neuropathy (CMT), as implicated in preclinical studies [1]. Similarly, all these indications lack a curative treatment and thus, presents as an opportunity to become the first-in-class, breakthrough therapy.

The interest for HDAC inhibitors is confirmed by deals in past years. For example, in 2019 Rodin Therapeutics, a pre-clinical company developing a first-in-class, orally-available, brain-permeable, HDAC2 therapeutics (HDAC-CoREST complex inhibitor, RDN-929) for brain diseases driven by synaptic loss and dysfunction, was acquired by Alkermes in a deal worth $100M upfront cash plus up to $850M depending on development candidate achieving clinical and regulatory milestones and sales thresholds.

Besides aging-related diseases, HDAC proteins are promising targets to improve healthspan [2] and lifespan, as recently shown specifically for HDAC6 homologs in c. elegans and drosophila [3], [4]. The data below, taken from [3], showcases lifespan extension and rescue of climbing score (a measure of locomotive function) after genetic inhibition of HDAX6 (via RNAi) in drosophila.

Solution

HDAX Tx’s lead compound avoids the fallacies of past HDAX6 inhibitors though the rational design of a patented, dual coordinated mechanism of action which has resulted in superior selectivity and potency. This was achieved via a novel dual-coordination of thecatalytic Zn2+ metal at the HDAX6 enzyme active site by directly engaging the hydroxamate moiety in the first-shell coordination sphere, and an indirect second-shell coordination via the metal-bound histidine ligand.

This multi-coordination ligand increases HDAC6 affinity and selectivity and affords a unique chemotype that has generated HDAXTx’s most potent and selective analogs. Through their rational, iterative structure activity relationship (SAR) studies, HDAX has also improved the pharmacokinetics of their lead compounds to achieve impressive in vivo bioavailability with plasma concentrations >5,000 ng/mL and brain concentration >3,000 ng/mL following 20 mg/kg IP dosing in mice studies via treatment of new generation of compounds.

Furthermore, HDAXTx has demonstrated preliminary safety through in vivo tolerability, Ames test, and hERG binding studies to reveal the potential for use in chronic diseases. These molecules are being advanced to in vivo studies in Charcot-Marie-Tooth disease mice models, and the company anticipates more subsequent in vivo studies in preparation for clinical validation of this novel class of inhibitors.

Intellectual Property

Team Dr. Nabanita Nawar, PhD – CEO & cofounder, nabanita@hdaxtx.com

Dr. Pimyupa Manaswiyoungkul, PhD – COO & cofounder, pimyupa@hdaxtx.com

Prof Patrick Gunning, PhD - Scientific Advisor & cofounder, patrick.gunning@utoronto.ca

Dr. Olasunkanmi Olaoye, PhD - VP Drug Discovery & cofounder, tobi.olaoye@mail.utoronto.ca

Dr. Elvin de Araujo, PhD – CINO & cofounder, e.dearaujo@mail.utoronto.ca

Dr. Roman Fleck - Executive chairman, romanfleck@gmail.com

The founders have known each other for 4-10 years and all of them have initially met at the University of Toronto. Patrick Gunning is a Professor of Chemistry at the University of Toronto. CEO Nabanita Nawar and VP Drug Discovery Tobi Olaoye and COO Dr. Pimyupa Manaswiyoungkul graduated from Prof Patrick Gunning’s lab with PhD’s in medicinal chemistry. CINO Dr. Elvin De Araujo is the research manager and former post-doc at the Gunning Group. All members have collaborated in multiple academic projects and scientific innovations under the supervision of Patrick Gunning, which has resulted in over a dozen high-impact peer-reviewed publications and patents.

Research Plan

HDAXTx aims to use the funding to conduct IND-enabling animal trials in indication-specific animal models. Upon gaining additional insights into the pharmacodynamics of our molecules in animals, we will be utilizing the funding to accelerate lead optimization for clinical candidate nomination by the end of 2022.

The 12 month milestones for this project is focused on clinical candidate selection. Although the current lead molecules already display commendable drug-like properties, further refinement to improve brain exposure will most likely enhance the efficacy and allow the molecules to achieve a broader dosing regimen. To accomplish these priorities, the project has 2 main goals:

Goal 1: Lead optimization towards clinical candidate selection. Evaluate top molecules for efficacy, safety and pharmacokinetic profile. ($50,000)

Goal 2: Evaluate compound tolerability and efficacy in indication-specific animal models. ($200,000)

Success of goal 1 may result in additional IP generation pending the improvements which has led to meaningful results. This clause has been captured under our favorable option for exclusive licensing from the University of Toronto, whom will be supporting the pursuant of the development of any novel findings originating from goal. Similarly, success of goal 1 may lead to the opportunity to employ an additional PDF in cellular/animal biology to accelerate the completion of goal 2, contributing to the growing life science sector in Ontario.

Financing

To date HDAXTx has won 10 programs at 9 different pitch competitions, securing over a combined amount of $340,000 in non-dilutive funding.

In this round HDAXTx is raising $2M in notes with various investors to fund clinical candidate validation (see above), R&D expansion, and business development.

Bibliography

• [1] “HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy”, 2021
• [2] “From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs”, 2019
• [3] “Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism”, 2021
• [4] “Immunosuppression Induced by Brain‑Specific HDAC6 Knockdown Improves Aging Performance in Drosophila melanogaster”, 2022

#Additional information

Airtable

Pitch Deck HDAX.pdf

NDA Restricted Information Available Under NDA here

(*Please note access will only be granted once this NDA template is signed and added to this folder. Please email divyacohen@gmail.com once you’ve completed these steps)

Other Files (science papers, competitors etc)

Update from HDAX team since Pitch to VitaDao

Highlights

• Peripheral Neuropathy represents a significant market with a clear medical need.
• HDAC6 is a validated target in Alzheimers and peripheral neuropathy.
• HDAXTx’s drug candidate has higher brain permeability, low toxicity, and efficacy than others in the market.
• The team is strong, consisting of medicinal chemists from one of the leading medchem labs in the world.

Risks

• Early in validation. So far mouse studies have only been completed in cancer models (previous indication explored by HDAX) rather than peripheral neuropathy.
• Being based in Canada makes fundraising for further clinical trials harder.

Longevity WG scientific evaluation digest

Qualitative evaluation HDAX has good initial in vitro and in vivo data, with good safety, strong sensitivity, good PK profile, strong HDAC6 binding. Strong literature supporting the connection between HDAC6 and age-related diseases, including cancer and neurodegeneration: targeting HDAC is popular and a strong fit with VitaDAO. Most HDAC trials/drugs are related to oncology. Inhibition of HDAC6 can restore normal nerve function in peripheral neuropathies. The HDAX team has relevant background in research and drug development, the founders have known each other and worked together for a long time. The company was spun out from the lab of Prof. Patrick Gunning, a serial entrepreneur, secured dilutive funding and got some exposures at pitch competitions. Some IP is already established.

However, HDACs have a long history of failure in biopharma. Several HDAC-inhibiting drugs with selectivity for HDAC6 are already in clinical development, one recently completed their Series B financing round, another has brain-penetrant, small molecule, selective HDAC6 inhibitors. While HDAX’s limited available data support the differentiation with competitors to a certain extent, the medical relevance is unclear at this stage.

In summary, this is an early-stage, high-risk opportunity in a promising space with significant competition.

Quantitative evaluation The reviewers have scored the proposal on different aspects including general conviction, on a scale of 1-5 (with 5 being the highest). Here are the average scores:

• Novelty: 2.5
• Feasibility & Data: 3
• Relevance: 4
• Science Team: 4
• Market Advantage: 3
• IP Potential: 4
• Conviction score: 2.75