VDP-81 [Funding]: Amplio Pharma

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


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.


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) .



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.

  • 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.

  • 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).

  • 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


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.

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.


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).


  • 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 product has attractive COGS with margins of 80-95% of list price

  • Can charge a premium price for the drug product due to increased response rate and improved clinical efficacy

  • The founders are seasoned pharmaceutical executives


  • Currently stuck in the “Valley of Death” for two reasons:

  • (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.

  • (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)

  • 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


  1. M. vd Meeberg et al. A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis. BJCP 2022. https://doi.org/10.1111/bcp.15579.

  2. K.B. Almutairi et al. The prevalence of rheumatoid arthritis: a systematic review of population-based studies. J. Rheumatol. 2021. https://doi.org/10.3899/jrheum.200367.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. J. Krauss and F. Bracher. Pharmacokinetic enhancers (boosters) – escort for drugs against degrading enzymes and beyond. Sci. Pharm. 2018. Sci. Pharm. | Free Full-Text | Pharmacokinetic Enhancers (Boosters)—Escort for Drugs against Degrading Enzymes and Beyond.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. M. Finland and R.L. Nichols. Novobiocin. Antibiotical et Chemotherapia. 1957 (4) 209-392.

  21. H.von Graf. Novobiocin-Konzentrationen des Serums nach parenteraler Verabreichung. Dtsch. Med. Wschr. 1961 (86) 1476-1480.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. EMA/CHMP/158268/2017 Guideline on clinical development of fixed combination medicinal products.

  28. 2021 Datamonitor market analysis and forecast: Rheumatoid Arthritis

  29. 2022 Global Data market analysis and forecast: Rheumatoid Arthritis

  30. D.W. Thomas et al. Clinical development success rates 2006-2015. 2016. Published and supported by Informa, Amplion and the Biotechnology Innovation Organization (BIO).

  31. F.H. van den Hoogen et al. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br. J. Rheumatol. 1996. https://doi.org/10.1093/rheumatology/35.4.364.

  32. R. Sakthiswary and E. Suresh. Methotrexate in systemic lupus erythematosus: a systemic review of its efficacy. Lupus 2014. https://doi.org/10.1177/0961203313519159.

  33. S. Safiri et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: a systematic analysis of the Global Burden of Disease study 2017. Ann Rheum. Dis. 2019. https://doi.org/10.1136/annrheumdis-2019-215920.

  34. T.V. Zhao et al. T-cell aging-associated phenotypes in autoimmune disease. Front. Aging 2022. https://doi.org/10.3389/fragi.2022.867950.

  35. A. Abou-Raya et al. The Role of Regulatory T Cells (CD4+CD25+FOXP3) in Methotrexate Unresponsiveness in a Cohort of Naive Rheumatoid Arthritis Patients. ACR Convergence 2021. https://acrabstracts.org/abstract/the-role-of-regulatory-t-cells-cd4cd25foxp3-in-methotrexate-unresponsiveness-in-a-cohort-of-naive-rheumatoid-arthritis-patients/.

  36. A.P. Cribbs et al. Methotrexate restores regulatory T cell function through demethylation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis & Rheumatology 2015. https://doi.org/10.1002/art.39031.

  37. P. Breedveld et al. The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7- Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models. Mol. Pharmacol. 2007. https://doi.org/10.1124/mol.106.028167.

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)
  • Disagree

0 voters


Incredible write up @ninapatrick and team!


What share of royalties will go to VitaDAO? If royalties end up being 2%, if VitaDAO got 25%, that would be 0.5% rate overall, correct?

How well does the drug have to do in Europe/US in order for VitaDAO to recoup 1x, 2x or 10x of the initial investment at these rates?

What is the market size for RA in Europe only? If the US does not grant the patent, how dead is the project? Also in the US, doesn’t the IRA limit patent protection on this type of patent?

Improving healthspan, especially vs these chronic diseases, seems within scope for VitaDAO to me.

On one hand, methotrexate can’t become obsolete fast enough. On the other hand, that doesn’t seem like it will happen any time soon, so strategies to extend and improve it seem reasonable.


I will leave the royalty question and recouping of the initial investment to somebody from Molecule, but can try to answer your other questions/address your other concerns:

The eIRR of the Methotrexate Forte, including only rheumatoid arthritis (disease) and Europe (geography) is 69%.

The EU5 markets tend to represent ca. 35-40% of the total European market, both in volume and in value. This is due to the reference pricing that the different memberstates use to set the national list price for products. According to Global Data’s market analysis for Rheumatoid Arthritis, ca 70% of the total annual sales of sc methotrexate came from the EU5.

Regarding the effect of the inflation reduction act (IRA) on patents: as far as we are aware, the act does not limit the time of exclusivity (patent protection) of a composition-of-matter patent, as these patents are not “extended” patents.


Methotrexate is quite toxic and this approach is unlikely to ever be useful for longevity.

The project may have merits as a symptom palliation approach for RA and other indications, but is outside of the scope for VitaDAO as a longevity accelerator.

Palliating symptoms of disease is not equivalent to extending healthspan. If that were true, then investing in opioids would qualify as healthspan extension.

Healthspan extension means you slow the pace of aging, and ideally also median lifespan in animal studies.


Thank you for adding the Senior Review Summary to which we would like to add some of our reflections as well as the overall rating from Capital Cell’s BioExpert review group (see end of post).

When we discussed the possibility to raise funds with VitaDAO, one of our first questions addressed the interpretation of longevity and whether this included patients with chronic life-shortening or life-threatening diseases where successful treatments might indeed shorten the lifespan of a particular set of cells that had gone “rogue” with the objective to shift the health span and the life span back again to a state where treated patients experience a health and life span of a healthy individual. In the case of patients that suffer from immune-mediated inflammatory disesase, the pain and fatigues seriously interfer with any physical activities. This is something that the patients with active, unsuccessfully treated disease experience every day. This comes on top of the ongoing damage caused to internal organs, incl. the heart, that are the main cause behind the increased mortality seen in these patients.
This is why it was such a devastating finding that JAK-inhibitors increase the risk of cardiovascular events! And contrary, Methotrexate has been found to be cardioprotective in these patients. It is why we enclosed the literature references both the mortality of the disease (4) and on the safety of low-dose MTX (6).
Successful treatment of IMIDs directly results in an increase in health span and life span of these patients.
Methotrexate momentarily is and will remain the first treatment that patients who have develop IMIDs.

From that perspective, we have felt a moral obligation to have a drug product that provides the optimal benifit/risk ratio possible, where as much of the given dose not only reaches the target “rogue” cells but actually remains within these cells as long as possible. This can be achieved by the addition of the 2nd component of Methotrexate Forte, Novobiocin.
Neither Methotrexate nor Novobiocin themselves can be viewed as substances that in principal increase the longevity of a cell.
However, together, when taken at a given dose (5-30 mg) at a given interval (once weekly) via a given administration route (subcutaneous), they have the potential to increase the longevity - both health span and life span - of patients with IMIDs.
Methotrexate Forte has the potential to double the number of responders from less than 30% at 6 months treatment to up to 60%. And we flatly disagree with the notion that this is a small, incremental improvement just because we have been smart enough to select a well-known, safe and highly water-soluble substance as our PK enhancer!

A moral obligation, however, is not enough for successful drug development. It is what drives our passion, but it will not drive our success. For that we need the buy in from other groups of stakeholders.

The first important group of stakeholders are the doctors and patients. The acknowledgement that we are marching in the right direction comes come from the words from Prof. Dr. Bart vd Bemt, a Dutch KOL from the St Maarten clinic in the south-east of the Netherlands. He has declared willing to act as the Principal Investigator in our first clinical study. His words: “Yes! There are two things that drive the efficacy of treatments and hence the well-being of my patients and the most important one is optimum pharmacokinetics of the drug so I can have the best efficacy/safety ratio. My clinic treats 1000 patients here in the south-east of the Netherlands and I start all of them on MTX”. The other thing that drives the efficacy is the compliance, which is typically 70% when a drug is administered with an autoinjector, compared to 55% when it comes as a tablet (29).

The second most important group of stakeholders are the investors and their trust in the commercial potential of the candidate drug product. As to the commercial potential, we know from the BD representatives of several pharmaceutical companies that the exclusivity guaranteed by our IP and human proof-of-concept data will be enough to bring them to the table. For several of these companies, Methotrexate (as Metoject or Nordimet) is the breadwinner.

And to conclude: the overall rating from the BioExpert review group of Capital Cell
(15 independent reviewers with backgrounds in life science and fundraising/investment):

  • team 7.7/10
  • science 7.5/10
  • innovation 7.2/10
  • business potential 7.3/10

overall grade: 7.6/10

1 Like

I agree with Marguerite on this one. Blocking chronic inflammatory diseases is the difference between being able to function and not being able to function, which is the definition of healthspan. Also, as she notes, chronic inflammation does increase damage, which will shorten lifespan. It’s not a matter of ‘feeling good’ vs ‘feeling bad’, but a functional difference. Functionality/quality of life is what healthspan aims to measure.

I would go further and say that limiting chronic inflammatory diseases is where most of the longevity gains will be made. This is the premise behind the Humanity app we’re discussing in the other VDP–improve behaviors to cut CVD/diabetes/sarcopenia risks. But autoimmune diseases are a top 20 killer for women 5-65, and you can’t eat and lift your way out of RA, lupus, etc.

It may be helpful to have a discussion about scope and/or portfolio for VitaDAO. Either more clearly define the scope (we only want longevity increasers which the FDA does not want to approve) or decide what ratio of money goes to what types of research (chronic inflammation gets 25%, senescence gets 20%, longevity enhancers get 15%, behavior modifying approaches get 30%, etc).

What you’re proposing is no different from the traditional pharma model which has failed to slow the pace of aging.

Targeting the downstream consequences of aging (reducing inflammation) is symptom-focused.

There’s a place for targeting symptoms, but we aim to target the root cause of multiple age-related diseases (e.g., the primary Hallmarks of Aging).

We can let the rest of the non-longevity pharma world finance ‘me too’ pharmacokinetic plays to mitigate the toxicity of a known generic drug. It’s a good idea, but just not LongBio.

Regarding the dichotomy of “either we fund geroprotectors which extend lifespan OR we develop drugs for specific diseases.” We can develop drugs that accomplish both of our goals:

  1. Targets the root cause of aging
  2. Has ‘lead indications’ that are approvable by FDA and other regulators for specific diseases. This is followed by ‘label expansion.’

Behavior modifying approaches and apps are getting lots of funding already, not really where the ‘unmet need’ or valley of death lies – that’s in developing new medicines that directly target aging.

A less toxic methotrexate is not a geroprotector. It may be a good idea, but it’s never going to be a longevity drug in the way that rapamycin s (e.g., reduces inflammation while also extending healthy lifespan across species).


Thanks Marguerite. I speak for a few of us who believe it’s a good idea to mitigate the toxicity of methotrexate.

But the benefit will only be for patients with autoimmune diseases. And it won’t dramatically improve the efficacy of the drug, we hope it will mitigate some of the toxic side effects of methotrexate.

Methotrexate is very toxic, even with the perfect formulation – it’s not a drug that extends healthy lifespan in the general population, can be used prophylactically, and prevents multiple age-related diseases. This is what we call a ‘geroprotector.’

It’s also the kind of project that is eminently fundable for traditional investors or pharmas – because it’s a pretty straightforward repurposing/formulation type approach.

We have an obligation to fund longevity research, and treating the symptoms of particular diseases is outside of the scope of our mandate.

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Chronic inflammation is a “primary hallmark of aging”, not a “downstream consequence”. I would go so far as to argue cell senescence, mitochondrial dysfunction, genomic instability and many of the others are downstream consequences of chronic inflammation arising from an immune system that can no longer provide adequate surveillance by killing the dysfunctional cells and promoting regeneration of new cells.

Plus you can worry about targeting some ‘root cause of aging’, but Listeria, Group B strep, SARS-CoV2, flu and many others will still destroy old people. And these are diseases immunocompetent adults barely notice, if at all.

But this is why I think there should be some consensus on what scope/portfolio is. To use Saava’s Quality Adjusted Life Years (QALYs) measures at a population level, a friendlier methotrexate will be bigger than rapamycin is. Plus a focus on the general population will lead to a focus on behavior, CVD, diabetes and hypertension only because those will have the biggest impacts. Though I agree we need to know Total Addressable Market for this and other interventions.

I also favor taking some lower risk deals with increased likelihood of success, assuming the terms for VitaDAO are good. Hence my questions about royalties, returns under certain scenarios and the risk assessment. If we fund a lower risk venture that does return the principal, we helped them for the cost of tying up the capital for a while, which gives VitaDAO a W, and helps sustain the model. Even if people say ‘track record of Ws doesn’t matter’, it still matters, especially for attracting other strategic partners.

You think Pfizer (and others) doesn’t have a number for either deals they get, Ws, or other metric within some timeframe to decide if they will dump more money into VitaDAO’s approach? And given that this is “eminently fundable for traditional investors or pharmas”, it means it is more likely to be acquired by them later, which means a VitaDAO-backed venture had an exit, possibly to one of these strategic partners.

To use a lab analogy, it’s like having trainees work on at least two projects: one that has potential to get into Nature or Science, and a second that has a guarantee of being published at least in JBC (and these days with MDPI and Frontiers, you can go there for an even lower bar).


@SB23 honest question, and unrelated to Amplio, are you saying VD finances exclusively projects targeting root causes?

This proposal did not pass phase 3 and will not be implemented by the DAO