VDP-126 [Assessment] Remedium Bio

Remedium Bio is a regenerative medicine biotechnology company, which has developed the only dose adjustable gene therapy platform technology Prometheus™ and is currently advancing multiple assets with uncorrelated risk to Investigational New Drug (IND) approval.

Longevity Dealflow WG Team

• Senior reviewers: 2 biotech entrepreneurs and 3 biotech VC

• Shepherd: Paolo Binetti

• Squad members: Ryan Spangler, Tovah Wolf

• Sourced by: Paolo Binetti via lifespan.io Longevity Investor Network

Project PI

• Frank Luppino, founder & CEO

Simple Summary

Remedium is a regenerative medicine biotech focused on age-related diseases and large unmet clinical needs . Remedium has multiple assets targeting large unmet clinical needs that show advantages over currently approved products, with significant benefits to healthspan.

The company has also developed a platform gene delivery technology that overcomes limitations of current generation technologies, with the potential to revolutionize therapeutic protein delivery. Prometheus™ is delivered as a simple subcutaneous injection, remains highly localized, and provides durable expression while offering functionality not available with other gene delivery technologies. The platform can deliver a wide range of genetic cargo using a non-antigenic vector and can be easily re-dosed to augment treatment or down-titrated to reduce the level of therapeutic transgene expression.

Remedium’s lead candidate is a first-in-class disease modifying regenerative treatment for Osteoarthritis (OA). The treatment augments expression of an endogenous protein, FGF18, that is critical to the formation and maintenance of healthy cartilage, levels of which are known to decline with age. A single intra-articular injection turns back the clock in the joint, resulting in unprecedented efficacy in a translatable model of primary OA.

Besides knee OA, the Prometheus™ platform is in active preparation for licensing to large pharma and biotech companies and has been evaluated as a first-in-class single injection treatment for obesity and Type 2 diabetes (T2D), where it is promoting weight loss, improving glucose control, and insulin tolerance in a well-established preclinical model of the disease. Remedium’s treatment results in similar efficacy to currently commercially approved ‘daily’ incretins, while minimizing pharmacokinetic sawtoothing, which may drastically improve the treatment’s safety and tolerability.

The Problem

Osteoarthritis

OA is the largest unmet need in rheumatology and the leading cause of joint replacements. To date, however, only one therapeutic approach, repeat and continual FGF18 injections have demonstrated the ability to increase cartilage thickness in placebo controlled clinical studies, while also demonstrating improvement in symptom progression and a complete arrest of progression to joint replacement surgery. That treatment modality, however, is limited by pharmacokinetics of the joints. Since cartilage is avascular, local treatment is required, however, therapeutics delivered locally are rapidly cleared from the joint, limiting efficacy. As such, FGF18 protein injections require up to 12 injections per year in bilateral OA and may need to be sustained indefinitely to prevent reversal of cartilage loss. An ideal approach would utilize a therapeutic that works (FGF18) and deliver it in a means that would produce efficacy without being pharmacokinetically limited by rapid washout (Fig 1).

Protein-based treatments and Gene Therapy

Protein-based treatments have revolutionized medicine, however, they remain expensive to develop and administer and are limited by pharmacokinetic sawtoothing, which results in peaks and troughs that limit safety and efficacy of repeat protein injection therapies.

Gene therapy has the potential to solve these issues, but current generation technologies are extremely expensive and doses cannot be adjusted up or down following initial administration. Moreover, once a gene therapy treatment is administered it cannot be discontinued, preventing its use as a protein replacement therapy (Fig 2).

Type 2 diabetes and Obesity

GLP1 Receptor agonists (GLP1-RAs) have revolutionized treatment of Type 2 diabetes and obesity. Despite their success, however, they remain expensive, and are limited by gastrointestinal side effects that result in a nearly 70% discontinuation rate after the first year of treatment (Fig 3). The side effects have been attributed to the pharmacokinetic spikes following treatment, which do not appear necessary to achieve therapeutic efficacy. Eliminating the pharmacokinetic spikes and reducing the need for daily or weekly injections would result in significant improvements in treatment adherence, maximizing the benefits of this therapy.

The Solution

RMD1101 Regenerative Treatment for OA

RMD1101 is a single, intra-articular injection delivering the FGF18 transgene to arthritic joints, facilitating regeneration that has been confirmed in a clinically translatable model of OA. The single injection treatment of RMD1101 was able to preserve cartilage and subchondral bone geometry in the destabilized medial meniscus model of OA. RMD1101 demonstrated dose-dependent increases in cartilage thickness relative to the placebo control (PBS) as well as compared with the positive control (FGF18 protein treatment, rhFGF18) (Fig 4).

RMD1101 also showed improved safety, as shown in Fig 5.

The breadth and consistency of response to RMD1101 are unprecedented in the treatment of OA and demonstrated in Fig 6 showing histology from all joints collected in the in vivo efficacy study. There is clear and extensive degeneration in the vehicle / PBS treated joints (top row) and near-normal cartilage appearance of the RMD1101 / High Dose gene therapy treated joints (bottom row).

Prometheus™ Dose Adjustable Gene Therapy Platform

Remedium has developed the solution to the challenges constraining gene therapies (unadjustability of the treatment dose following initial administration) and recombinant protein treatments (cost and pharmacokinetic sawtoothing caused by repeat injections). The Prometheus™ dose adjustable gene therapy platform (Fig 7) technology for the first time enables the replacement of a number of subcutaneous protein injection therapies as a single injection. The treatment is durable, adjustable, highly localized, does not impact any life- or function-sustaining organ and is non-antigenic, facilitating re-dosing. Most importantly, the treatment can be easily scaled and produced at a fraction of the cost of even the current protein therapies.

In vivo testing of Prometheus™ confirms its ability to deliver transgenes to the subcutis and that the treatment can be easily augmented by repeat dosing, following initial administration (Fig 8). Studies show the treatment remains durable over a period of half a year, without any observed transgene expression decline. The mechanism for enabling said durability, delivery vector, genetic constructs, and means of dose adjustment are proprietary and exclusive to Remedium.

Moreover, the system can be easily down-titrated following initial administration. Fig 9 shows reduction of reporter gene expression in a dose-dependent manner. This can be accomplished via pharmacological or physical methods that are safe and exceptionally well tolerated. As the technology is highly scalable, a single treatment cost could be as low as $50 per injection at scale. Remedium is currently advancing this platform to in vivo efficacy and finalizing the licensing package to enable partnerships with large pharma and biotech companies in the first half of 2024.

Prometheus™ has a large cargo capacity and is versatile: initial proof of concept studies have demonstrated the ability to express incretins (GLP1 Receptor Agonists), insulin, and full-length monoclonal antibodies. Future efforts will focus on supplementation of longevity factors, suppression of chronic inflammation, and enzyme replacement therapies (Fig 10).

RMD1202 Treatment for Obesity and Type 2 diabetes

Remedium’s second pipeline asset is an innovative treatment for Obesity and Type 2 diabetes, utilizing Prometheus™. RMD1202 has been evaluated in a well-established high fat diet (HFD) and Streptozotocin induced model of late-stage Type 2 diabetes, where it has demonstrated the ability to deliver the same efficacy as daily Exenatide (GLP-1 Receptor Agonist) injections over the 4-wk study period. Statistically significant improvement in weight loss, and glucose / insulin tolerance relative to control are shown in Fig 11.

The treatment produced the aforementioned efficacy on top of an outstanding safety profile and is anticipated to nearly completely eliminate pharmacokinetic spikes associated with repeat GLP-1 RA peptide injections, which are the main drivers of gastrointestinal side-effects causing treatment discontinuation. Thus, the approach is anticipated to be not only cost effective and simpler to administer, but also better tolerated.

Opportunity

OA is the largest unmet clinical need in rheumatology and is estimated to impact 1 in 7 adults, as the leading cause of joint replacements worldwide. The market for OA and related treatments are estimated at over $50B globally (Fig. 12).

Type 2 diabetes and Obesity are highly prevalent conditions that adversely impact longevity and healthspan. Current estimates place the market for T2D and Obesity at over $30B US.

The ability of the platform to replace monoclonal therapies, treatments for diabetes and rheumatoid arthritis, atopic dermatitis, enzyme replacement therapies, and augment lost protein expression to enhance longevity can result in a plethora of highly lucrative partnerships for the company.

Relevance to Longevity

As we age, several critical to function genes decline in the level and quality of gene expression. A number of them, such as FGF18, FGF21, and Alpha-Klotho, have been implicated in promoting healthspan and lifespan. Prometheus™ is an effective method of replacing proteins adversely impacted by age-related decline, whereas traditional gene therapy approaches are immunogenic, extremely expensive, cannot be re-dosed, and cannot be adjusted following initial administration.

Remedium’s lead candidate is a regenerative therapy for the treatment of OA, a characteristic disease of aging where cartilage is lost over time causing loss of joint function. Remedium technology is therefore well positioned to prevent health related decline in the age-related degenerative pathology of the joint and translate to other areas of healthspan and lifespan.

IP Roadmap

Remedium maintains a robust IP portfolio for its lead OA gene therapy, and pipeline products. To enable the optimal level of IP protection, Remedium has contracted Wolf Greenfield, a biotech-focused IP firm with specific expertise in gene therapy. The Remedium team has extensive and diversified expertise ideating, drafting, submitting, and defending IP with nearly 190 patents and pending applications. IP is ideated internally and Remedium performs internal freedom to operate and patentability assessments prior to preparing provisional applications. Its lead OA PCT has been published and is in national filing stages. In addition, Remedium has a portfolio of 7 provisional patents covering the lead indication, platform technology, and pipeline assets that enable extensive protection of its innovative technology. See the pipeline in Fig. 13.

Planning and Milestones

The series-A two-year planning to bring the three key assets to clinical trials is provided in Fig. 14.

Budget

Remedium is currently raising a $15M Series A round. Through the end of 2024, Remedium is planning the following use of capital:

OA IND-enabling work: $6.3M focused on toxicology batch production, IND-enabling preclinical study completion, and preparation of the IND submission.

PrometheusTM Development: $2.0M focused on full platform characterization and enablement of licensing for partnered therapeutic indications.

General R&D and SG&A: $1.8M to support pipeline assets and operational activities including R&D, Operations, External Manufacturing, Quality, and Regulatory.

BD, IP, Software, Office, Misc: $1.1M to support partnership activities, IP advancement to national phases and PCT applications, software, office space and other expenses.

Remedium has developed 3 assets and a platform technology through in vivo efficacy on a total initial raise of approximately $3.5M and plans to continue highly efficient use of capital into the future to maximally extend runway and enable maximum value creation for the investors.

Financing and VitaDAO Fundings Terms

Remedium was founded in 2021 and raised an expanded seed round of approximately $3.5M, of which over $1M was committed by the CEO. All funds to date have been invested as a SAFE (20% discount, $25M cap). Remedium is a Delaware corporation, currently raising a Series A, targeting a $15M raise and has identified a reputable VC to lead the round. Remedium’s current investors include the LongevityTech Fund, MicroVentures, Angel Star Ventures, Primo Medical Group, Sherwood Ventures, Apis Health Angels, Guindy Alumni Angels, as well as several prominent angel investors who are/were former biotech industry executives. For a limited time, Remedium is continuing to accept investments under the SAFE to bridge closing of the Series A.

An allocation of $50k is available for VitaDAO community.

Team

The team has over 50 years experience in biotechnology with a focus on biologics, regenerative medicine, and gene therapy. The leadership is comprised of seasoned industry executives who have a track record taking companies from a market cap of $6M to $1B and developing / industrializing / licensing products to global pharma and biotech giants including JNJ, Bohringer Ingelheim, and Sanofi (Fig. 15).

The company has additionally hired a cadre of top clinical and scientific advisors in the therapeutic areas of focus. Their advisors have a wealth of scientific expertise in the disease areas, extensive experience in clinical development, and the clinical background necessary to drive product design (Fig. 16).

Pitch

Slide Deck: https://drive.google.com/open?id=1n-wE_j4YrS50g9LhmdhCx6ZvUIFcSJuH&usp=drive_fs

Pitch recording: https://drive.google.com/file/d/12cfxJ52I487emQmDN5pKefHInNUqZgVK/view

Highlights

• Prometheus™: a unique platform technology capable of delivering peptides to antibodies as a single injection, adjustable dose gene therapy, at a fraction of the cost of current treatment, applicable to a wide range of potential longevity interventions.

• RMD1101: regenerative gene therapy for the treatment of Osteoarthritis based on the only clinically validated mechanism of therapeutic activity – FGF18.

• RMD1202: single injection, which performs as well as daily GLP-1 RA injections in a translatable model of T2D, without the pharmacokinetic spikes that drive the discontinuation causing side effects.

• Team: the leadership team is comprised of seasoned industry veterans with extensive background successfully developing, industrializing, facilitating approval, and licensing blockbuster therapies.

Risks

Risks for Remedium Bio are standard corporate risks associated with a preclinical biotech including:

• Manufacturing / CMC

• Toxicology IND-enabling studies

• Regulatory

• financing risks associated with the current market environment

Remedium has undertaken several risk mitigation strategies to reduce risk associated with its programs, including:

1. Utilization of 2 contract development and manufacturing organizations to scale-up the lead candidate product and produce Toxicology / IND-enabling preclinical study batch.

2. Completion of extensive biodistribution/safety/efficacy testing in relevant preclinical models to maximally derisk IND-enabling GLP studies.

3. Utilization of proven technological elements with clinical level validation, e.g. the FGF18 transgene has been clinically confirmed as functional in a placebo controlled randomized trial.

4. Pursuit of a tiered intellectual property strategy where multiple technological elements (e.g. formulations, doses, genetic constructs) are protected in subsequent applications to optimally secure IP.

5. Maximally efficient use of funds through reliance on academic collaborations for research and development activities with internalization of only critical to function staff.

References

Please see the Discourse proposal for the list of references.

Senior Review Digest - Quantitative

Below is the average scores out of 5 per category from 5 reviewers, who all recommended that the project should be advanced for token-holders vote.

Average Scores

• Team Expertise: 4.4
• Feasibility & Data: 4.0
• Commercial Potential & Impact: 4.6
• Novelty & Market Advantage: 4.0
• IP Defensibility: 3.5
• Relevance to Longevity: 4.0
• Deal Terms: 3.6
• General Conviction Score 4.2 (for reference, the average score of past funded projects is 3.7)

Senior Review Digest - Qualitative

Each reviewer was asked whether they would endorse the project, below are their answers.

Reviewer 1 I would suggest funding the project, mainly because of its potential applications in gene therapy and longevity therapeutics. It could provide a safer way for several gene therapies. Additionally, VitaDAO could think of finding synergies with other portfolio companies as a gene delivery system and so on.

Reviewer 2 I like the concept of innovative platforms, but with the little information I have right now I would be hesitant to support it. That's mainly driven by the poor understanding of the platform technology, so once that has been cleared, I could.

Reviewer 3 Yes, based on what little i know, I'm very excited about this project.

Reviewer 4 Yes, for a 50k check. Advice is to wait for a lead investor because this project will need a large amount of capital to hit the key value inflection milestone.

Reviewer 5 Yes. In fact, I am planning to introduce a corporate venture and two funds to consider investing