2023-12-005 - FIRSTGUT2 - NOVEL ENZYME THERAPY FOR INFLAMMATORY BOWEL DISEASE

FIRSTGUT2

2023-12-005

Developing succinate-converting enzyme therapies

TRL3. In vivo demostration of the efficacy of the novel mechanism of action for animal models of Crohn's disease, Type 2 Diabetes and Fatty Liver Disease.

Inflammatory Bowel Disease (IBD) is a chronic uncurable illness. Current treatments still have 40-50% lack of response and are associated to strong safety issues. Elevated succinate is a metabolic feature of IBD-associated dysbiosis, promotes inflammation and plays a role in the development of fibrosis. Moreover, intestinal succinate can reach circulation and trigger systemic inflammation. Previous attempts to modulate succinate effects were directed towards modulating SUCNR1 and have failed, likely because SUCNR1 is also responsible for essential functions that shouldn’t be fully blocked and also because not all the effects of succinate are SUCNR1-mediated. In this context, removing the excess intestinal succinate is a science-driven opportunity to restore the healthy microbiome, diminish inflammation and prevent fibrosis. Based on this needs we are developing an oral gut-restricted monitorable therapy (thanks to the measurement of succinate in faeces and blood) composed by in silico-identified succinate-degrading enzymes.

13500000000

2300000000

1000000000

DIAMET plan is to expand the number and type of succinate-modulating therapies and generate strong patent-protected therapies with solid in vivo proof-of-concept data and big market potential. In present proposal, once good in vivo proof-of-concept data is obtained and the value proposition is well defined, the asset will be transferred to a Pharma Company or to SUCCIPRO, a spin-off who is interested in expanding its succinate-related therapies and develop them until the end of Clinical Phase 2a. The product would not get into the market until 2032-2033. IISPV and SUCCIPRO are currently working on a co-development agreement but still SUCCIPRO will own less than 50% of the asset. Notwithstanding SUCCIPRO is interested in the asset, IISPV Technology Transfer Office will take care of the whole process, ensuring that technology transfer is done under best market conditions and that SUCCIPRO has the necessary resources to guarantee the correct development of the technology, particularly in the event that there was a third party interested in the technology.

Current treatments for IBD differ among countries, but globally there is a pipeline of marketed products that include aminosalycilates and immunomodulators such as azathioprine for mild-to-moderate disease, and biologic therapies for severe cases, of which anti-TNF therapy is the most widely used. Despite the availability of therapies, there remain unmet clinical needs in a number of areas, particularly relating to the efficacy and safety of maintenance therapies: -Efficacy: The Crohn’s & Colitis Foundation estimates that 40–50% of patients with IBD are nonresponders who will need novel targets and therapeutic agents. Indeed, according to GlobalData, of the patients with IBD who initially benefit from anti-TNF treatment, 25–40% develop intolerable adverse events or lose their response within the first year of therapy. - Patient adherence: this can also be an obstacle due to several factors, such as the complexity of dosing regimens, safety and tolerability. - Safety: many therapies are immunosuppressive or carry boxed warnings. Indeed, all anti-TNF drugs carry a boxed warning from the FDA because of an increased risk of opportunistic infections and certain types of cancer. - Biomarkers: There is a lack of objective and robust biomarkers to guide decision making for the most suitable therapy. This strongly affects patient outcomes and the impact of the disease. There remains a need for validated, cost-effective biomarkers to guide the selection of the most appropriate therapies to facilitate clinical management.

We are currently funded by a "Prueba de Concepto" Project and a CaixaIMpulse Award (Second stage). Based on the advice we have received from different experts on Intellectual Property, we aim to complement these projects with a Freedom To Operate Analysis

Contacting Pharma Companies interested in the technology and license the technology to a Pharma Company, taking into account that SUCCIPRO as a co-owner of the technology will hav efirst right of refusal

Get an in vivo-validate lead candidate ready to start the preclinical regulatory phase

Oral administration, enzyme oral therapy with a novel mechanism of action

Regulatory barriers

mid2025: preclinical non-regulatory studies. Identification of the final lead candidate mid2025: License agreemedt to SUCCIPRO or to a bigger Pharma Company (best deal will be sought) mid2025-2026: regulatory preclinical Phase 2027-2028: Phase I and Phase IIa clinical studies 2029-2031: Phase IIb and Phse III Clinical studies 2032: Commercialization

Not filled, patentability study shows that more data is needed to get a robust patent application

IP Sonia Fenández-Veledo

More recently, the academic research team has shown interest in expanding its pipeline of succinate-modulating therapies. More specifically, the team is now focused on developing succinate-converting enzyme therapies, which offer many advantages over previous bacteria-based therapies, including ease of production, better-expected safety profile, and specificity. process.