One-liner: Amplio Pharma is a clinical-stage biotech founded by an experienced pharma team in Sweden with an innovative formulation of methotrexate. The objective: improving this cornerstone drug’s pharmacology toward better treatment of immune-mediated inflammatory disease (IMID), starting with Rheumatoid Arthritis (RA).

Longevity Dealflow WG Team

Reviewers: Tim Peterson, Michael Baran, Sebastian Brunemeier, Matthew ‘Oki’ O’Connor Shepherd: Nina Patrick Other squad members: Mantas Matjusaitis, Paolo Binetti Sourced by: Nina Patrick Project PI: Marguerite Mensonides

Simple Summary

Amplio Pharma was founded in 2020 by three seasoned pharmaceutical executives and is proposing an innovative solution to the growing global issue of immune-mediated chronic inflammatory diseases (IMIDs) that affect up to 20 million people annually and decrease lifespan by up to 10 years if left untreated (1-4). Amplio Pharma’s solution involves adding a pharmacokinetics (PK) enhancer (10, 11) to the anchor treatment for IMIDs, Methotrexate. Methotrexate has a solid track record and has been the gold standard for IMID treatment for decades (5-7). However, as a mono-treatment, it is not effective enough in up to 2/3 of IMID patients (1, 8-9). With the PK enhancer the cellular retention of Methotrexate and in turn the clinical effect and benefit in undertreated IMID patients are increased.

Problem and solution

IMIDs cause daily debilitating pain and fatigue, destruction of joints and other tissues, loss of work productivity, resulting in both a decreased health and life span (4-5). Most patients with IMIDs receive methotrexate as the first choice pharmaceutical to manage their disease. In the majority of these patients (up to 65%), mono-treatment with Methotrexate is insufficient to control the disease and its devastating effects (8, 9). Some of the ones who at first do respond develop resistance to Methotrexate with continued use. Methotrexate can be a very effective treatment for IMIDs, however it is expelled by cells too quickly and therefore can not produce an optimal effect (13-19, 37).

The anti-inflammatory effect of Methotrexate could be dramatically improved if it was retained in the cells. Solution Amplio Pharma’s prospective Methotrexate Forte increases the efficacy through retention of Methotrexate with a pharmacokinetic enhancer.

Methotrexate has been used to treat RA since the late 1940s, and both the mechanism of action and the safety profile are well understood (5, 6). Methotrexate is expelled from cells by the transporters, including the ABCG2 transporter. Patients with defective ABCG2 transporters have a better response rate to Methotrexate. The safety profile seen in patients with defective ABCG2 is the same as it is in patients with normal functioning ABCG2 (15). Amplio Pharma’s PK enhancer is an inhibitor of ABCG2. It is the natural compound, Novobiocin, which was discovered in the mid-1950s. Several drug products of Novobiocin have previously been approved for use in human and veterinary medicine, and like Methotrexate, its pharmacology and the safety profile are well understood (20-25). Amplio Pharma has been granted the patent WO18/220101 (26) by the EPO - the application is pending in the US - for this drug combination (composition of matter patent), its use, formulation and ultimate product. Using their own bootstrapped funds, Amplio Pharma has demonstrated in-house that their Methotrexate Forte:

• Produces a 2-fold increase of half-life,
• Does not cause any other effects in the dose levels needed to alter the pharmacokinetics of Methotrexate
• Has a PK profile similar to Methotrexate when concomitantly administered (Cmax and half life of Methotrexate and Novobiocin are similar) .

Opportunity

Amplio Pharma’s candidate drug product contains Methotrexate, the anchor 1st choice pharmaceutical, and therefore can target the complete IMID patient population (7). Methotrexate is expected to remain the 1st choice treatment in the coming years despite the entry of TNF-biosimilars and generic versions of the JAK inhibitors. JAK inhibitors severely increase the risk for serious cardiovascular problems (EMA Statement), and physicians have grown more cautious in prescribing them. Despite earlier predictions, experts no longer foresee a replacement/decrease in the use of Methotrexate. (7, 28, 29). It is possible to realistically estimate the market opportunity for Amplio Pharma’s Methotrexate Forte, by looking at the historical market for traditional Methotrexate (28, 29). In 2022 the value of the Methotrexate market (US and EU5) was $568 million, with 64% of that value coming from the parenteral Methotrexate market (pre-filled syringes and autoinjectors). Traditionally, PK enhancers, like other excipients, require a full pre-clinical and clinical development program to ensure the safety of their use (27). However, Amplio Pharma’s team recognized that through Novobiocin, they would have a PK enhancer that has been known to be safe in humans since its discovery in the mid 1950s. Upon seeing this opportunity Amplio Pharma moved quickly to secure a patent for the composition of a drug product that contains both the anchor drug, Methotrexate, and the specific PK enhancer, Novobiocin. The European patent was granted in 2021 and the US patent is pending. Amplio Pharma can leverage the extensive pharmacology, pharmacokinetic and safety studies performed on both Methotrexate and Novobiocin, qualifying for an abbreviated clinical development program, saving time and money, and at strongly reduced risks by using well-known and well-documented compounds in their drug product. For these reasons, Amplio Pharma estimates their overall probability of success in passing clinical trials and bringing Methotrexate Forte to the market to range from 70% to 95%, which is >5-fold higher than the regular probability from start of Phase I to market authorization which is about 11% (30). Novobiocin and Methotrexate are highly water soluble, the drug combination is suitable for subcutaneous injection. This administration route is both the most effective and provides a drug product with attractive CoG margins. RA, and to a certain extent Psoriasis Vulgaris (Pso), are the most obvious disease areas to test Amplio Pharma’s hypothesis and quickly come to a drug product. In addition to RA, Amplio is assessing cancer, systemic sclerosis and systemic lupus as other market opportunities for Methotrexate Forte (31, 32).

Relation to Longevity

Immune-mediated inflammatory disease (IMID), such as RA, are age-related diseases. Onset of RA occurs between 30 and 60 years of age (33). Currently Methotrexate is the cornerstone treatment for IMIDs like RA and Pso. The Center for Disease Control (CDC) directly points to “age” as the first and foremost risk cited for the development of RA. This statement is well illustrated by Safiri S. et al, 2019 (33) in the figure below:

A recent review from April 2022 (34) addressed the effect of aging on the host immune system and the relationship between aging and the onset of IMIDs, such as RA. Successful treatment with Methotrexate is strongly correlated with the expansion of healthy T-cells (35, 36) and an improvement in quality of life. In contrast, unsuccessful treatment leads to a decrease in quality of life due to chronic pain and fatigue, destruction of joints, damage of several internal organs, with devastating physical and emotional consequences. This chronic pain stops the patients from engaging in other known longevity-enhancing activities such as strength training and cardio activities. It has also been documented that untreated IMIDs shortens lifespan in a compelling study of morbidity and mortality in nurses over 35 years (4).

Plan & IP Roadmap

• Amplio Pharma is ready to start clinical evaluation of their concept/hypothesis.
• Their patent WO2018/220101, a composition of matter patent, discloses the technology as such.
• In the immediate future, Amplio Pharma plans to develop and submit a clinical trial application to evaluate the pharmacokinetic profile of the PK enhancer following subcutaneous administration of several ascending dosing strengths.
• This data will allow Amplio Pharma to select the appropriate dose of the PK enhancer for concomitant administration with Methotrexate and measure subsequent clinical efficacy enhancement

Team

The Amplio Pharma team are seasoned pharmaceutical executives with expertise in both R&D as well as in-licensing drug products. The founders have a uniting interest in sustainable development of drug products that bring about true increases in health and life span of humanity. Each member of Amplio Pharma’s founding team individually has 25+ years in the pharmaceutical industry. They have the network and connections needed to approach Pharma partners with clinical data.

• COO, Head of Business Development, Marguerite Mensonides (PhD), co-founder, co-owner and inventor
• CEO, Karin von Wachenfeldt (PhD), co-founder, co-owner and inventor
• CSO, Charlott Brunmark (PhD), co-founder, co-owner and inventor

Funding

The founders of Amplio Pharma have personally funded the development of Methotrexate Forte since 2017. To continue its development and establish human proof-of-principle, Amplio Pharma seeks a total of $1,000,000. Asking $100,000 from VitaDAO. Amplio Pharma is open to a deal via the “Sponsored Development Agreement” template agreement provided by Molecule. VitaDAO has successfully leveraged its network to accelerate Amplio Pharma to reach their fundraising goal through an introduction to Capital Cell (their BioExpert Network analysis has been added to this proposal). The budget will be used to cover the cost of the creation and submission of the first clinical trial application for the proof of principle trial plus 12 month general runway for the company (PM, IP, on-going fundraising activities), and offers the necessary bridge funding until the $ 1M raise through Capital Cell is finalized later this year.

Strengths

The first DeSci-funded project to go into human clinical trials. Patented drug combination with protection until 2037 Low-risk as the safety profile of both drug components has been well studied and known for over 50 years Fast development at a low cost Subcutaneous injectable drug products have attractive margins where a premium price can be charged for the drug product due to increased response rate and improved clinical efficacy The founders are seasoned pharmaceutical executives

Risks

Currently stuck in the “Valley of Death” for two reasons: Attracting investment to this project has been challenging for the team since the active pharmaceutical agent (APIs) in the drug combination are known, old drugs, which are less attractive to VC who traditionally back novel drugs. Amplio Pharma has discussed the opportunity with several in-licensing representatives within the industry, both API producing (Methotrexate) and companies with a portfolio in the IMID area. The feedback from these industry representatives was a high interest to partner after human proof of concept (Phase II) have been obtained but before running the pivotal superiority trial (Phase III) Methotrexate Forte would compete in the beginning for market share against the gold standard, Methotrexate. A clear demonstration of superiority of the new drug would be needed to shift prescribers from old to new drug product There is no data in support of longer lifespan in model organisms or humans in correlation with methotrexate, novobiocin, nor with their targets

VitaDAO Senior Review Summary

Four senior reviewers were divided (2:2) on whether to fund this project. Qualitative review below (scale 1-5, 5 being the highest): The average overall rating was 2.7/5.

• Novelty & Impact : 2.75/5
• Feasibility & Data : 4/5 with one reviewer voting “Not enough information provided”
• Relevance : 1.75/5
• Science Team : 4.3/5 with one reviewer abstaining
• Market Advantage : 2.6/5 with one reviewer abstaining
• IP Potential : 4/5 Reviewer 1:
• “Pros: solid team and IP strategy, very practical solution, and efficient go-to-market. Cons: potentially too boring for other investors to join in” Reviewer 2:
• “VitaDAO is not a pure venture fund. Returns need to flow back to the DAO to maintain operations. An early high-profile win would not only help to validate VitaDAO as a credible model, but also to attract additional investment. While this investment is not our core mission, it does serve to help grow the DAO and in my view can be a part of a balanced portfolio strategy.” Reviewer 3:
• “This is worth funding by a more traditional investors, but is out of scope for VitaDAO” Reviewer 4:
• “The team is strong.They have their patents in order and what seems like a clear path to market, but the fact they are only modestly improving a medication targeting a disease that progressively worsens as we age is not necessarily enough to be considered innovative or taking significant steps to advancing longevity research.”

External Reviews from the VitaDAO Network

On top of VitaDAO, the project was reviewed by 15 Capital Cell (see funding section above) Bioexperts with high scores. These scores are out of 10 and position Amplio as one of the best teams Capital Cell has seen in the past, with a positive 13/15 vote to invest. Capital Cell’s fundraising has a >93% success rate.

• Team 7.7
• Science 7.5
• Innovation 7.2
• Business Potential 7.3
• Overall Grade 7.6