VDP-85 [Assessment] HDAX Therapeutics

[divyacohen]

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.

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 funnel link

Airtable | Everyone's app platform

Pitch Deck

HDAX.pdf Airtable - To review when ready [internal, shared]

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)

Link

Update from HDAX team since Pitch to VitaDao

Link

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

Vote:

Here we’ll vote if the Longevity-Dealflow WG’s assessment should go on-chain.

If it succeeds here, the VITA token holders will ratify the WG’s assessment (positive or negative) via a decentralized vote.

• Agree
• Revisions Requested (Details in Comments)
• Disagree

[bowtiedshrike]

The full summaries are behind a Google sign-in.

It would be helpful if the WG assessment (positive or negative) was included under “Vote” to reduce confusion.

If there’s an HDAC6 inhibitor that isn’t toxic, that would have widespread application even if you only believe a third of the HDAC6 literature.

It isn’t clear what disease-specialists are on the team. Are these all medicinal chemists, or is there CMT expertise?

Are there any preliminary data showing any of these compounds work in the CMT mouse (and which CMT mouse model?), or is it all PK and tox data so far? It would be nice to see some promising data in a few mice to show that the team can assess the necessary endpoints, and that there is improvement in the endpoints before going to heroic lead optimization measures. Any issues in the preliminary study would also improve lead optimization because the team would know what needs to be fixed.

[Paolo]

Hi bowtiedshrike, thank you for the valuable comments, as usual. Here are a few points on the info provided:

• we don’t usually provide the full reviews but just a digest, which still need to process, I added the subscores and will hopefully publish a qualitative digest today. In the meanwhile I have removed the link
• any other link that you are interested in, I encourage you to request access, and let me know if you still have issues
• we usually include the WG assessment before the vote, because it’s a different thing, it’s a summary of the evaluations performed by our senior reviewers. I have reworded the title to avoid confusion.

[Paolo]

Excellent write-up @divyacohen!

[bowtiedshrike]

Oh right, this is an assessment for partner organizations. The Humanity one is also listed as an assessment, but that would be a direct VitaDAO investment?

I understand the desire for diplomacy, but it would be helpful to see by the vote a reminder if we’re voting to ratify an assessment for partner orgs vs an assessment that will lead to VitaDAO investments.

Why is the conviction score lower than ALL of the other quantitative scores save novelty? Is this a case of ‘sounds well and good, but HDAC6 inhibitors have all failed so far and there’s no preliminary data showing they work here?’

[longevion]

Assessments of companies that are also raising equity but not (yet) willing to sign a deal with VitaDAO to co-develop one or more of their assets

It’s crowdsourced intelligence as a public good. Any investor can use it.

Here we’ll vote if the Longevity-Dealflow WG’s assessment should go on-chain.

If it succeeds here, the VITA token holders will ratify the WG’s assessment (positive or negative) via a decentralized vote.

Funding proposals are separate

@bowtiedshrike

Why is the conviction score lower than ALL of the other quantitative scores save novelty? Is this a case of ‘sounds well and good, but HDAC6 inhibitors have all failed so far and there’s no preliminary data showing they work here?’

While the company might be great in each individual area, the Senior Reviewers might not be thinking that it’s fit for VitaDAO’s community / mission of accelerating early stage longevity research towards commercialization, maybe because the company can have no issue fundraising from trad VCs, so focus should be on others

[bowtiedshrike]

I’ve noticed a range of opinions on fit and mission for VitaDAO.

This is the first I’ve heard as ability to attract funding as a negative factor. This kind of pre-clinical work seems to be in line time-wise with other proposals made, though a bit earlier stage than some of the others. Also relevance scored a 4, which sounds like mission relevance (and with which I agree). If (and that’s a huge if) this HDAC6 inhibitor lives up to some of the HDAC6 hype, it would be huge.

I also agree with the low conviction score (too many other HDAC6 inhibs are toxic/failed), but surprised to see it lower than feasibility/data and market advantage.

[nabanita]

Although the founding team has PhDs in biological/medicinal chemistry and biophysics, we have recently recruited Dr. Ahmet Hoke, Director of Neuromuscular Division, and Professor of Neurology and Neuroscience at Johns Hopkins School of Medicine has joined our SAB in February 2023. Dr. Hoke is a key figure in the neuropathy space, both as a clinician scientist, and also as an advisory member of prior biotech companies in similar disease space with successful exists. He was in the SAB of Disarm Therapeutics, which focused on neuropathy, and was acquired by Eli Lily in 2020.

[nabanita]

We have shown efficacy of HDAX molecules in Human iPSC Model of Charcot-Marie-Tooth Disease. In comparison to current clinical candidate CKD-504 of Chong Kun Dang Pharmaceuticals, our asset shows improved activity at 1/100th the concentration and at 1/4th the time point. Please see our response to senior reviewers for the recently generated data.

Additionally, in primarily cultured cortical neurons we have been able to show that HDAX asset shows healthy neurite outgrowth despite a dose escalation. In contrast, clinical candidate competitor ricolinostat (Regenacy Pharmaceutical) shows significant dose-dependent toxicity and decrease in neurite outgrowth. Please see our response to senior reviewers for the new data.

[nabanita]

Our HDAC6-targeting platform is unlike any previous effort in the industry and academia. We have been able to develop a unique, 2-site binding mechanism that enables us to form a second direct bond in the HDAC6 pocket, resulting in our improved biochemical profile. All attempts to target HDAC6 has only been through a singular interaction. We’ve been able to show improved drug residence times and resulting safety and efficacy improvements with our distinguished way of drug target engagement.

Although most HDAC isoforms (histone deacetylases) are primarily epigenetic regulators, HDAC6 is not. HDAC6 does not deacetylase histones; its substrates are alpha-tubulin, Miro1 and cortactin - thus making it important in axon transport and mitochondrial regulation, not epigenetics. HDAC6 has never been truly selectively targeted successfully in the biopharma industry, so the historical failure of the other epigenetics modulating HDAC isoforms cannot be used in the context of selective HDAC6 inhibition. In addition, HDAC6 knockout mice are viable and fertile with a normal life span (unlike knockout of other HDACs), and are deemed to be safer therapeutic targets. Due to these aforementioned reasons, many large pharma are currently actively looking for HDAC6 assets (Novartis, Eli Lily, Takeda, Abbvie), and we are already in discussion with them to align our development plan with a strategic alliance/exit in mind.

[Paolo]

I have just added the qualitative part of the senior reviews digest

[bowtiedshrike]

Would you please add their response, or is that coming?