One-liner: Amplio Pharma is a clinical phase-1-ready 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.
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 a team of 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 life expectancy 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). The addition of the PK enhancer increases the cellular retention of Methotrexate which in turn could increase its clinical effect and benefit the undertreated IMID patients.
Problem and solution
Problem
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).
With conventional Methotrexate, the concentration of Methotrexate molecules in an immune cell is too low to inhibit chronic on-going pro-inflammatory activities in the target cells. The anti-inflammatory effect of Methotrexate could be dramatically improved if it was retained in the cells.
Solution
Amplio Pharma’s prospective Methotrexate Forte drug product increases the efficacy and retention of Methotrexate with a pharmacokinetic enhancer.
Methotrexate has been used to treat Rheumatoid arthritis 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. The product has favorable pharmacodynamic and physicochemical properties and has the potential to significantly increase the clinical efficacy of Methotrexate.
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 plasma profile similar to Methotrexate when concomitantly administered (Cmax and half life of Methotrexate and Novobiocin are similar) .
Opportunity
IMIDs
100% of patients with an IMID start with Methotrexate, as it is the 1st choice treatment for IMIDs. 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). Ever since that became known, the physicians are much more cautious in prescribing them. This is reflected in current sales, KOLs in interviews and prospective sales 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 drug product, Methotrexate Forte, by looking at the historical market for traditional Methotrexate (28, 29). In 2022 the value of theMethotrexate 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, what makes Amplio Pharma’s drug product so unique is that they have identified a PK enhancer, Novobiocin, that has been known to be safe in humans since its discovery in the mid 1950s.
Novobiocin has never been suggested for use of a PK enhancer, and Amplio Pharma saw the opportunity and 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%. THis overall probability of success is 5-fold higher than the regular probability from start of Phase I to market authorization which is about 11% (30).
Furthermore, Novobiocin and Methotrexate are highly soluble in aqueous solutions making the drug combination suitable for subcutaneous injection. This administration route is both the most effective and provides a drug product with attractive CoG margins.
Rheumatoid Arthritis, and to a certain extent Psoriasis Vulgaris, are the most obvious disease areas to test Amplio Pharma’s hypothesis and quickly come to a drug product. In addition to Rheumatoid Arthritis, Amplio is assessing cancer, systemic sclerosis and systemic lupus as other market opportunities for Methotrexate Forte.
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Cancer - High-dose Methotrexate is approved for the use in several different types of cancer, ranging from Acute lymphocytic leukemia (ALL) to lung cancer to breast cancer and Non-Hodgkin lymphoma. The pharmacokinetics: active uptake in the target cells and active elimination from the target cells is the same and the same transporters are involved in cancer cells and immune cells. Therefore, in principle oncology patients may very well benefit from Methotrexate Forte.
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Systemic Sclerosis (dSSc) - an orphan autoimmune disease with no approved treatments. In this rare and deadly disease, doctors often prescribed Methotrexate. There have been clinical studies that hinted at a benefit, but unfortunately for these patients these studies never reached significance (31).
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Systemic Lupus Erythematosus (SLE) - The only approved drugs are two expensive biologics. Older clinical studies hint that Methotrexate treatment may help control the damage caused by active disease (32).
Relation to Longevity
Immune-mediated inflammatory disease (IMID), such as Rheumatoid arthritis, is an age-related disease. Onset of Rheumatoid arthritis occurs between 30 and 60 years of age (33). Currently Methotrexate is the cornerstone treatment for IMIDs like rheumatoid arthritis and psoriasis.
The Center for Disease Control (CDC) directly points to “age” as the first and foremost risk cited for the development of rheumatoid arthritis. 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 autoimmune diseases, such as rheumatoid arthritis. 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 (both small molecules and biologics). 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 spanning from early R&D to marketing & sales and including in-licensing of technologies. They have the network and connections to approach Pharma partners with clinical data.
- COO, Head of Business Development, Marguerite Mensonides (PhD) at marguerite@amplio-pharma.com, co-founder, co-owner and inventor
- CEO, Karin von Wachenfeldt (PhD) at karin@trulylabs.com, co-founder, co-owner and inventor
- CSO, Charlott Brunmark (PhD) at charlott@trulylabs.com, co-founder, co-owner and inventor
Other key contributors are Henrik Fenger, board member and Lars Bukhave (PhD) board member, who both bring in-depth marketing and sales knowledge of new and value-added medicines.
Funding
The founders of Amplio Pharma have personally funded the development of Methotrexate Forte since 2017. To continue its development and begin clinical studies, the founders need to seek external capital.
Amplio Pharma seeks a total of $250,000 to submit a clinical trial application and begin clinical trials.
- Asking $100,000 from VitaDAO. Amplio Pharma is open to both an equity deal or a deal via the “Sponsored Research Agreement” template agreement provided by Molecule.
- The team has reviewed the terms in the Sponsored Research Agreement and they have a preference for this deal structure. They believe it is a fair agreement that many investors may also want to participate in. The structure of this deal would be a share of royalties from the sales of the drug
- VitaDAO is already leveraging our network to accelerate Amplio Pharma to reach their fundraising goal. Amplio Pharma is pitching Capital Cell on VitaDAOs recommendation.
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).
Strengths
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The first DeSci-funded project to go into human clinical trials.
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Patented drug combination with protection until 2037
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Low-risk as the safety profile of both drug components has been well studied and known for over 50 years
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Fast development at a low cost
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Subcutaneous injectable drug product has attractive COGS with margins of 80-95% of list price
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Can charge a premium price for the drug product due to increased response rate and improved clinical efficacy
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The founders are seasoned pharmaceutical executives
Risks
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Currently stuck in the “Valley of Death” for two reasons:
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(1) 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.
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(2) 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)
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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
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There is no data in support of longer lifespan in model organisms or humans in correlation with methotrexate, novobiocin, nor with their targets
References
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M.K. Desai and R.D. Brinton. Autoimmune disease in women: endocrine transitions and risk across the lifespan. Front. Endocrin. 2019. https://doi.org/10.3389/fendo.2019.00265.
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J.A. Sparks et al. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses’ Health Study. Arthritis Care Res 2016. https://doi.org/10.1002/acr.22752.
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B.N. Cronstein and T.M. Aune. Methotrexate and its mechanisms of action in inflammatory arthritis. Nature Reviews Rheumatology 2020. https://doi.org/10.1038/s41584-20-0373-9
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A.K. Kedia et al. Safety of long-term use of four common conventional disease modifying anti-rheumatic drugs in rheumatoid arthritis. J.R.C.P.E. 2021. https://doi.org/10.4997/JRCPE.2021.306.
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J.F. Smolen et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023. https://doi.org/10.1136/ard-2022-223356.
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R. van Vollenhoven et al. Efficacy and safety of upadacitinib monotherapy in methotrexate-naïve patients with moderately-to-severe active rheumatoid arthritis (SELECT-EARLY): a multicenter, multi-country, randomized, double-bline, active comparator-controlled trial (NCT02706873). Clinical Trial Arthritis Rheumatol. 2020. https://doi.org/10.1002/art.41384.
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C.J. Haagsma et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br. J. Rheumtol. 1997. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. | Rheumatology | Oxford Academic.
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E.D. Eisenmann et al. Boosting the oral bioavailability of anticancer drugs through intentional drug-drug interactions. Basic Clin. Pharmacol. Tox. 2022. https://doi.org/10.1111/bcpt.13623.
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M.J. Rotte. A Toolbox for Personalized Medicine of Methotrexate Therapy in Arthritis. 2014. RePub, Erasmus University Repository: A Toolbox for Personalized Medicine of Methotrexate Therapy in Arthritis.
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S. Kukal et al. Multidrug efflux transporter ABCG2: expression and regulation. Cell Mol. Life Sci. 2021. https://doi.org/10.1007/s00018-021-03901-y.
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J. Gao et al. The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis. Life Sciences 2021. https://doi.org/10.1016/j.lfs.2020.118907.
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R.B. Warren et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J. Invest. Derm. 2008. https://doi.org/10.1038/jid.2008.16.
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Y. Atisha-Fregoso et al. Rheumatoid arthritis disease activity is determinant for ABCB1 and ABCG2 drug efflux transporters function. Plos One 2016. Rheumatoid Arthritis Disease Activity Is Determinant for ABCB1 and ABCG2 Drug-Efflux Transporters Function.
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M. He et al. Hypoxia-inducible factor-2alpha directly promotes BCRP expression and mediates the resistance of OVSCs to adriamycin. Mol. Oncol. 2019. https://doi.org/10.1002/1878-0261.12419.
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P. Krishnamurthy et al. Role of ABCG2/BCRP in biology and medicine. Ann Rev. Pharmacol. Tox. 2006. https://doi.org/10.1146/annurev.pharmtox.46.120604.141238.
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R.W. Robey et al. ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev. 2007. https://doi.org/10.1007/s10555-007-9042-6.
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M. Finland and R.L. Nichols. Novobiocin. Antibiotical et Chemotherapia. 1957 (4) 209-392.
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H.von Graf. Novobiocin-Konzentrationen des Serums nach parenteraler Verabreichung. Dtsch. Med. Wschr. 1961 (86) 1476-1480.
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G.L. Drusano et al. Steady-state serum pharmacokinetics of novobiocin and rifampin alone and in combination. Antimicrobial agents and chemotherapy. 1986. https://doi.org/10.1128/AAC.30.1.42.
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I.I. Raad et al. A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2. Cancer. 1998. https://doi.org/10.1002/(sici)1097-0142(19980115)82:2<412::aid-cncr22>3.0.co;2-0.
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J.R. Murren et al. Phase I and pharmacokinetic study of novobiocin in combination with VP-16 in patients with refractory malignancies. The Cancer Journal 2000, 6 (4) 256-265. PMID 11038146.
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E. Winstead. Can an antibiotic treat cancers that become resistant to PARP inhibitors? Published at https://www.cancer.gov/news-events/cancer-currents-blog/2021/novobiocin-cancer-parp-inhibitor-resistance-1.
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WO 2018/220101 A pharmaceutical composition comprising a combination of methotrexate and novobiocin, and the use of said combination in therapy. https://patentimages.storage.googleapis.com/c7/56/6a/8a37dd916b7998/WO2018220101A1.pdf.
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VitaDAO Senior Review Summary
Four senior reviewers were divided on whether to fund this project. Two of them voted in favor of advancing the project, while the remaining two voted against funding it. Here is a summary:
Qualitative review:
To quantify the level of conviction, they have provided an average score on a scale of 1-5 (with 5 being the highest) for the following criteria -
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
Brief qualitative review summaries:
Reviewer 1:
- “Pros: solid team and IP strategy, very practical solution, and efficient go-to-market. Cons: potentially too boring for many 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 funding. While this funding 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 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 Senior Reviews from the VitaDAO Network
The project went through the review of 15 Capital Cell’ 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 year.
- Team 7.7
- Science 7.5
- Innovation 7.2
- Business Potential 7.3
- Overall Grade 7.6
- Agree
- Agree with revisions (please comment)
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