[VDP-48] Ikaria Therapeutics assessment

One liner: Overview of Ikaria Therapeutics, a pre-clinical project to develop a first-in-class therapy for knee osteoarthritis.

This proposal is based on the supporting documents provided by Ikaria, as well as questions and answers to their team, 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 : Tim Peterson, Sebastian Brunemeier

Shepherd : Tim Peterson

Other squad members : Paolo Binetti,

Simple Summary

Ikaria has a joint rejuvenation therapy nearing clinical development based on controlled-release of fenofibrate via injection into the knee. Fenofibrate, a lipid-lowering agent, approved by the FDA for treating dyslipidemia, has been shown to work on age-related diseases. Initial in-vitro and in-vivo studies are promising. The principal investigator (PI) is a world expert on joint ageing and has a strong team, ready to spin off a biotech company and advance the therapy into the clinic.

This proposal is based on the supporting documents provided by Ikaria, questions and answers to their team, and senior reviews.

Problem

Osteoarthritis (OA) is a serious, chronic degenerative joint disease that causes pain, structural changes in the joint tissues, and in the long-term, disability in the people affected. It occurs when the cartilage that cushions the ends of bones in your joints gradually deteriorates.

OA incidence increases with age and affects twice as many women as men (see figure below). This disease is potentially related to two hallmarks of ageing: cellular senescence and loss of proteostasis.

Currently, no disease-modifying therapies exist for OA, with treatments (e.g., NSAIDS) targeting symptoms only. Surgery is the last resort therapy but associated with a lot of pain and complications.

Opportunity

With 240 million people affected by OA worldwide and no disease-altering therapeutics currently available, there is a large market opportunity. There is a strong public health need to reduce reliance on pain medications/opioids for knee OA.

The knee is the most affected joint, therefore it has been selected as the primary target of this project.

An effective therapy would represent a first-in-class drug that could be expanded to other joints and to cover different health areas, mainly those related to age-related diseases.

Solution

The applicants propose a new formulation of Fenofibrate (FN) in microspheres as an intra-articular injection (i.e., IA-FN).

Fenofibrate is an approved drug (sold under the brand names Tricor, Fenobrat, etc.) for mainly dyslipidemias, operating as a PPARα agonist, in particular in chondrocytes, the cells responsible for cartilage formation.

The applicants propose a new formulation of FN in microspheres as an IA-FN, a disruptive innovation that provides an extended-release from microspheres for 3 months. The procedure involves local injection that avoids systemic side effects.

This approach is supported by the results of preliminary studies carried out by the team:

  • Clinical efficacy of oral FN (O-FN) in a retrospective knee OA cohort of 4796
  • Preclinical efficacy of both O-FN and IA-FN in surgically-induced OA in-vivo in mice

In addition, there is an ongoing Phase 2, Randomised, Double-blind, Placebo-controlled Study to evaluate the efficacy and safety of oral FN on quality of life measurements in 216 patients with knee OA.

Since FN is an approved drug with a safe profile, and microspheres are an approved technology for drug delivery, there is a relatively short regulatory path for the IA-FN formulation.

Intellectual Property

IP is specifically on the intra-articular injection of the novel formulation of FN, IA-FN.

Team

Project leader, Beatriz Carames: Currently Cartilage Biology Unit Group Leader at the Institute of Biomedical Research of A Coruña (INIBIC). Relevant expertise in mechanisms related to OA. BEATRIZ CARAMÉS | SEFAGIA.

Beatriz is supported by clinical and pharmacological expertise within the team:

  • Francisco J. Blanco MD, PhD is a Professor of the Medicine Department at the University of A Coruña UDC, a Rheumatologist at the University Hospital of A Coruña (Spain), and a Scientific Director of INIBIC
  • Eduardo Domínguez PharmD, PhD is a Senior Researcher at Genomic Medicine group at University of Santiago de Compostela (USC)
  • Patricia Díaz PharmD, PhD is an Assistant Professor at Department of Pharmaceutical Technology at USC
  • Uxía Nogueira PharmD, PhD. Uxía is a Research Associate in the Cartilage Biology Unit at INIBIC.

Most of the team was previously affiliated with Scripps Research.

Financing

This project has already been funded with 1.5 M€ in 2021 by the Spanish Government and the Foundation for Research in Rheumatology, enabling discovery, as well as preliminary validation.

Further funding would support regulatory approval application of IA-FN for OA as a new indication, as well as a Phase I safety trial in individuals with knee OA. The workplan, milestones, and budget breakdown provided by the team are clear and reasonable.

The budget is below.

Concept Total Description
Staff Cost 138,000€ Project Manager junior (PhD, MBA): 32.000€ / year (2 years); Scientific operations (PhD): 37.000€ / year (2 years)
Consumables 50.000€
Services 312.000€ Asphallion: Regulatory roadmap for the development of a new formulation of FN (IA-FN). Budget: 50.000€; Preclinical regulatory for IA-FN trial: CRO for IA-FN formulation (GMP preparation). Budget: 100.000€; Manufacturing of microspheres formulation. Budget: 75.000€; SCReN: Complete management and monitoring of the IA-FN trial will be subcontracted to SCReN to serve as “CRO” for the trial. Budget: 90.000€ (SCReN is the CRO subcontracted for the ongoing FN trial).
Total 500.000€

Ikaria is open to VitaDAO terms, including IP-NFT, royalties, equity blend of deal structure.

Additional information

Deck: PRESENTATION_INVESTORS_BC.pdf - Google Drive

Project Summary: Written Summary.pdf - Google Drive

Publications:

  • “Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy”, U. Nogueira-Recalde, I. Lorenzo-Gómez, F. J. Blanco, M. I. Loza, D. Grassi, V. Shirinsky, I. Shirinsky, M. Lotz, P. D. Robbins, E. Domínguez, B. Caramés, EBioMedicine, 2019
  • “Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis”, C. Vinatier, E. Domínguez, J. Guicheux, B. Caramés, Frontiers in Physiology, 2018
  • “Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA”, M. K. Lotz and B. Caramés, Nat. Rev. Rheumatol, 2011

The authors in bold are Ikaria team members.

Highlights

  • OA represents a significant market with a clear medical need.
  • Fenofibrate (FN) is a safe drug that has been shown to work for several age-related conditions, so the chance that it also works for OA is high.
  • The team has produced strong supportive evidence of efficacy of the proposed solution OA, both in mice and humans.
  • Sound scientific team.

Risks

  • FN is not a new therapy and is-off patent. The use of microspheres to deliver drugs is not new. So the IP strategy could have some risks.
  • Being based in Spain makes fundraising for further clinical trials harder.
  • Long study durations in arthritis.

Longevity WG scientific evaluation digest

The 4 senior reviewers have expressed a vote in agreement to fund this proposal. Here is the digest:

Quantitative reviews:

To quantify the level of conviction, they have provided a score on a scale of 1-5 (with 5 being the highest).
The average score was 4.0/5

Brief qualitative review summaries:

1) “Strong supportive evidence of FN’s potential in OA therapy, both in mice and humans”

2) “Address a clear unmet need. OA is a classic age-driven disease”

3) “Well-established, focused team with a formulation for osteoarthritis (OA). Safe bet”

4) “Clear budget, conscientious team”, “Strong patent position on fenofibrate joint injection”

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
  • Agree with revisions (please comment)
  • Disagree

0 voters

2 Likes

I’m confused about the IP. If the IP already exists, they would transfer full rights to VitaDAO? Or would the agreement be for future IP? The only thing patentable here is the delivery to the knees with the microspheres? Or do they have IP on the current formulation and plan to get more IP on a new formulation in contract to Asphallion? Are there any data with the new formulation?

From a data standpoint, the release doesn’t look like 3 months; more like 2, with the bulk of the release over about 2 weeks. Presumably this is part of the proposed formulation work to refine the microparticles so the logistic curve has a more even release?

Do regulatory agencies buy pre-clinical data like that shown? If I were reviewing those data for a paper, I would not buy the 100 mg/kg/day dose, and want a more reasonable dose done instead. 100 mg/kg daily is 6.8 g/day for a 150# person (assuming exact translation); yet the microsphere dosing is 1-10 ug. Is the oral efficacy just that lousy?

The GW PPARa agonist worked better in the in vitro trials. Why was FN advanced instead of the GW compound?

1 Like

Interesting project with a solid team behind, thanks for the write up @Paolo!

Some comments:

  1. Answering the comment above, it’s important to clarify that the passing of this proposal wouldn’t mean that VitaDAO itself invests 500000€. What the community is voting here is to ratify the publically available assessment of Ikaria by the Longevity Working Group, so other investors (some of them very alligned with VitaDAO’s interests) can use it to make their decisions. Something similar to what was done with Rubedo (VDP-15 Rubedo.Life assessment) and Repair Bio ([VDP-46] Repair Biotechnologies).
  1. Considering point 1, I think this part of the proposal is rather confusing, and I would suggest rewording, as well as the addition of a section explaining what the passing of the proposal would mean as in Repair Bio’s proposal.
  1. In addition to the point above and the not-so-clear sustained release of the microparticles, I would add as a risk that there isn’t any evidence that the local delivery of FN to the joint will have similar efficacy than systemic exposure by oral administration, even if the doses are comparable (which seems also unclear). FN has systemic effects (eg. reduction of LDL cholesterol, reduction of tryglycerides, increased ketogenesis…) that could have a positive impact in osteoarthritis but wouldn’t be achieved by local administration. I definitely see the local administration as worth exploring, but it doesn’t seem such a “safe bet” to me as the evaluation suggests.
1 Like

Thanks for the clarification. Assessment-as-a-service is new and interesting.

How is VitaDAO compensated for this service? Does the Canadian non-profit pay for the services rendered? If the Canadian non-profit invests and the company succeeds, does VitaDAO get a finder’s fee for helping to select a winner?

1 Like

See Table 1:

How can we learn more about the safety profile of this product? - is the planned dose range for the Ph1 within the observed dose range from previous oral approaches? Is there any chronic dose large animal data to mimic the 3 mon extended release? PPARs have a history of safety issues due to the systemic nature they work, would be interested to see more data on the proposed therapeutic window and IND enabling package.

Interested to hear more about IP & freedom to operate? How much patent life would this product have? Is there underlying IP which could bring legal action once there is a commercial product? Are there many example of pharma buying reformulated products - to my knowledge this is often not a prioritized transaction unless the data is transformative. Realistically who is the buyer if clinical data is favorable.

Lastly, re Use of Proceeds - how where can one run a Ph1 for <0.5euro and a Ph2 for 2-5M euro with 216 patients? Is there a government subsidy? Can this data be used for future FDA interactions or the study would need to be re-run in the US?

2 Likes

Is knee cartilage repair not too specific for VitaDAO?
It seemed to me that VitaDAO was more focused on project funding that increases lifespan and health span in general.
So yes, osteoarthritis is linked to aging but often also cancer, yet we do not fund cancer-related research.

Hi @RUM It’s a good point but a common misconception. One can’t get a drug approved by regulators on the basis of it extending life or Healthspan. One has to target a disease. Fortunately the geroscience hypothesis states that if one targets a core aging process, which Ikaria is doing in going after a fatty acid oxidation promoting drug, then it should work for multiple diseases. Thus, if the drug proves useful in osteoarthritis, the uses could extend to other conditions thus in aggregate fulfilling the goal to extend lifespan and Healthspan.

2 Likes

Hi @scienceman, please have the answers from Ikaria to your comments.

  1. How can we learn more about the safety profile of this product? - is the planned dose range for the Ph1 within the observed dose range from previous oral approaches? Is there any chronic dose large animal data to mimic the 3 mon extended release? PPARs have a history of safety issues due to the systemic nature they work, would be interested to see more data on the proposed therapeutic window and IND enabling package.

safety profile?

Our product is a specific combination of Fenofibrate (FN) and Poly Lactic-Co-Glycolic Acid (PLGA) microspheres with extended-release properties for intra-articular administration with a safety profile established in preclinical mice models. Clinical safety profile will be evaluated in Ph1 trial. FN is an approved drug and PLGA is an approved component of many long-acting drug formulations, both have a very well characterized safety profile and dose range. The long-term safety record in both clinical trials and real time world of oral FN is favorable (1-3), while PLGA microspheres are approved as an extended-release injectable suspension to deliver triamcinolone acetonide (TCA) to manage osteoarthritis knee pain (4,5). Therefore, one should expect a good safety profile for IA-FN, since microspheres are biodegradable (carbon and water) and a minimal systemic exposure of FN (directly delivered in the synovial fluid) is expected.

Dose?

The planned dose range for Ph1 is within mid-range used for oral FN (from 40 mg to 200 mg per day). For Ph1 trial of IA-FN, the maximum tolerated dose will be determined by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. Since intra-articular FN is intended to be delivered in the synovial cavity, we are calibrating the dose for humans according to our preclinical studies in mice and the maximum drug loading capacity of microspheres. In such studies, oral FN was administered at 100 mg/kg/body weight/day in drinking water, while intra-articular microspheres were loaded with 1mg and 10 mg of FN. In all three studies, 3 months after treatment, chondroprotection was found and no evidence of toxicity (eg liver, kidney, cartilage) was observed. We are now conducting a Ph2 study assessing as a primary outcome the efficacy of 145 and 200 mg/daily oral FN in 216 patients (3 groups) with knee OA at improving joint pain and function (structure integrity) , as recommended by FDA Guidance for industry for OA.

chronic dose large animal data?

We have not tested the effect of this formulation in large animals. Based on previous knowledge, some in-vivo models are better suited than others for OA, such as the canine, and porcine due to converging molecular mechanisms (6,7). Conducting such studies in mini-pigs in which damage is inflicted by surgery could be useful to generate preclinical evidence before entering regulatory studies and clinical trials.

safety issues of PPARs?

This extended-release intra-articular formulation is intended to be directly delivered in the synovial cavity as microspheres, and a large drug exposure of metabolic tissues is not expected. Indeed, the joint capsule is relatively sealed to prevent leakage of synovial fluid and to give stability, the blood supply is provided by periarticular arterial plexus and vessels in the synovial membrane and subchondral bone, while the cartilage is avascular.

proposed therapeutic window?

Our preclinical and clinical roadmap are aligned to facilitate therapeutic window determination and adjustments to regulatory studies. For example, pharmacodynamics, pharmacokinetics, and toxicology assessments will be carried out for the prioritized formulations showing efficacy. Pharmacodynamics will be studied by monitoring lipids and liver damage over 6 weeks after a single intra-articular administration in mice models; Pharmacokinetics will be studied by calculating Cmax, AUC and T1/2 following IA administration of FN microspheres or equivalent dose of FN into the knee of minipigs. Nonclinical toxicology (eg carcinogenesis, mutagenesis, impairment of fertility) will not be conducted since the administration is local and preliminary PD/PK studies in small animals show limited systemic exposure.

IND enabling package?

Our preclinical studies in vivo provided meaningful and significant dose-dependent responses and the biological evidence to support an investigational new drug (IND) application package as expected in the FDA Draft Guidance.

  1. Interested to hear more about IP & freedom to operate? How much patent life would this product have? Is there underlying IP which could bring legal action once there is a commercial product? Are there many example of pharma buying reformulated products - to my knowledge this is often not a prioritized transaction unless the data is transformative. Realistically who is the buyer if clinical data is favorable.

IP & freedom to operate?

Our Grant of European patent (EP), and examination of the application was filed in February, 2022 and relates to biodegradable microspheres for extended release of fenofibrate, injectable formulations and their use for the treatment of joint related disorders, such as osteoarthritis. It covers composition of matter, methods of manufacture, and methods of use for IA-FN. The composition of matter invention is the result of unique discoveries relating to a narrow drug load specification, a certain release profile of polymers, specific polymer weights and ratios, and efficacy in preclinical models observed within a specific dose-range. A preliminary FTO assessment is favorable and shows low risk to infringe any patent within the landscape.

patent life?

The time to market is the primary factor to be considered in order to estimate the lifespan of this product. If the patent is granted this year as expected, the team would have a period of 1-3 years to complete the clinical development. In parallel to such implementation, we plan to generate IP and trade secrets as additional assets around this mechanism/technology to diversify the risks associated to patent life cycle.

legal action once there is a commercial product?

A detailed FTO analysis will be performed in order to identify the main parties and products that may be competitors. Preliminary assessment does not show any clear overlap of other patents with the delivery technology, manufacturing protocol used for our formulation.

buying reformulated products ?

IA-FN would be a breakthrough disease-modifying since there is nothing than palliative anti-inflammatory products available for OA. As an example of successful commercialization, Flexion therapeutics develop Zilretta, a triamcinolone acetonide extended-release injectable suspension approved on 2017, to manage osteoarthritis knee pain. This product is an agonist of glucocorticoid receptor (GR) that is supplied is supplied as a single-dose kit containing a vial of 32 mg of TCA microsphere powder, a vial of sterile diluent, and a sterile vial adapter for intra-articular administration. Recently, Flexion therapeutics was acquired by Pacira for an equity value of nearly $450m or $630m, which includes debt. The net sales of Zilretta in US were $85.6 million in 2020, $101.1 million in 2021 and $23.6 million in first quarter 2022. This drug is indicated for managing pain by anti-inflammatory mechanisms, while IA-FN delay disease progression by structural chondroprotection through modulating senescence and autophagy, likely leading to anti-inflammatory and pain relief efficacy (8).

Realistically who is the buyer if clinical data is favorable.

If Ph2 data is positive, we expect to engage pharmaceutical companies with strong anti-inflammatory portfolio and a very large market in the chronic disease space, such as Abbvie, Merck & Co., Inc, Pfizer, Eli-Lilly, Novartis or Regeneron. Monoclonal antibodies targeting TNF for rheumatoid arthritis (RA), including Humira or Remicade are among the highest-selling drugs, but they are expensive and have limited efficacy. In a similar situation are NSAIDs, which have low efficacy and are associated to a wide range of side effects. If PPAR agonist is a protective mechanism, it would be a paradigm change, since there are not any disease-modifying products available for OA. The product could also potentially be used in sports medicine, spine degeneration, and chronic joint degeneration. A potential expansion to other joints such as hand or hip will be also considered. Lastly, patients who may likely have more benefits from the treatment will be people who are 65 or older and certain younger people with disabilities.

  1. Lastly, re Use of Proceeds - how where can one run a Ph1 for <0.5euro and a Ph2 for 2-5M euro with 216 patients? Is there a government subsidy? Can this data be used for future FDA interactions or the study would need to be re-run in the US?

Our Ph2 is fully funded by the government, run in our local Hospital and we are applying a similar funding strategy for the intra-articular formulation Ph1 study. We have already in place quotes for manufacturing the formulation (CDMO), for recruiting and monitoring (CDMO, Hospital), as well as for the X-ray and MRI (Hospital). In this funding model some parts are outsourced, some are run in the hospital and the sponsor is public. Indeed, the clinical research plays a fundamental role in Spain within the National Health System, which provides universal coverage and is among the world leaders in quality. The clinical researchers have the necessary expertise to undertake trials with the best quality standards. The existing industry and network is very active and is committed to promote, provide the infrastructure and associated logistics perfectly developed in 872 different centers, in which 513 are Hospitals, 342 are Health Centers and 17 are Phase I Units. The costs are competitive within Europe, the number of clinical trials run is the highest (12,5%), is the second country in terms of recruited patients, and is the 7th regarding the approval time average. The clinical trial data obtained in the Ph2 and Ph1 can be used to support a IND application to EMA and FDA.

References

  1. Takahashi M, et al. Event Monitoring and Evaluation by Community Pharmacists in Japan: A Pilot study on Fenofibrate and Pemafibrate. Curr Drug Saf. 2022 Feb 24.
  2. Park MS, Youn JC, Kim EJ, Han KH, Lee SH, Kim SH, Kim BJ, Kwon SU, Ryu KH. Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter, Randomized, Double-blind, Phase IV Study. Clin Ther. 2021;43(10):1735-1747
  3. Blais JE, Tong GKY, Pathadka S, Mok M, Wong ICK, Chan EW. Comparative efficacy and safety of statin and fibrate monotherapy: A systematic review and meta-analysis of head-to-head randomized controlled trials. PLoS One. 2021 Feb 9;16(2):e0246480.
  4. Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, Ballal R, Hunter D, Clayman M. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am. 2015 Jun 3;97(11):877-88
  5. Paik J, Duggan ST, Keam SJ. Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee. Drugs. 2019 Mar;79(4):455-462. doi: 10.1007/s40265-019-01083-3.
  6. Vincent TL. Of mice and men: converging on a common molecular understanding of osteoarthritis. Lancet Rheumatol. 2020 Oct;2(10):e633-e645.
  7. Samvelyan HJ, Hughes D, Stevens C, Staines KA. Models of Osteoarthritis: Relevance and New Insights. Calcif Tissue Int. 2021 Sep;109(3):243-256.
  8. Szychlinska MA, Ravalli S, Musumeci G. Pleiotropic effect of fibrates on senescence and autophagy in osteoarthritis. EBioMedicine. 2019 Jul;45:11-12.