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Sequence sPecific ELImination of shiga-Toxin E. Coli

Periodic Reporting for period 3 - SPELITEC (Sequence sPecific ELImination of shiga-Toxin E. Coli)

Reporting period: 2021-04-01 to 2022-03-31

The SPELITEC project aims at developing a first-in-class medicinal product to treat patients infected by Shiga toxin-producing Escherischia coli (STEC).

STEC bacteria primarily infect young children and are responsible for severe bloody diarrhea with serious complications (kidney failure, death). STEC outbreaks can have devastating consequences as seen with the German outbreak of 2011 that killed more than 50 people. Despite the severity of the disease, STEC infections remain an unmet medical need: antibiotics are contraindicated as they may favor the production of toxin by STEC bacteria and worsen the situation, and no other treatment strategy has been approved to treat this condition so far.

In this context the SPELITEC project aims at developing EB003, a new class of highly specific antimicrobial able to target and eliminate STEC bacteria while preventing the production of Shiga toxins. Such product will bring the following advantages to patients and society:
- It will eliminate STEC pathogens from the intestines of infected patients early in the course of the disease.
- It will display an excellent safety profile and its unparalleled specificity will leave all non STEC bacteria (including beneficial microbes from the microbiota) unharmed
- It will cure patients' bloody diarrhea and prevent the serious complications of the disease (kidney failure and death).
- It will reduce the risk of STEC outbreaks as the efficient elimination of the STEC pathogen in patients’ intestines will prevent its spread to the community.

To achieve this goal, the main objectives of the SPELITEC project were:
- To transition from a laboratory-scale to an industrial-scale production of the EB003 compound to meet clinical needs
- To confirm the efficacy of EB003 in various preclinical models in vitro and in vivo.
- To confirm the safety of EB003 in regulatory toxicology models
- To obtain validation from regulatory agencies to perform first clinical trials in humans.

At the end of the final period, we can draw the following conclusions for the SPELITEC project:
- the manufacturing process of the EB003 compound has been successfully transferred to a CDMO, with production of a 100L-scale batch in GMP-like conditions ;
- the efficacy of EB003 has been demonstrated in-vitro (killing experiments on clinical strains) and in-vivo (decolonization and symptom mitigation proven in various mice and rabbit models) ;
- the safety of EB003 has been assessed and confirmed in vitro (on eukaryotic cells through transfection studies) and in-vivo (preliminary and secondary GLP-like toxicology studies) ;
- interactions with regulatory agencies have helped us assess the regulatory requirements for EB003's entry in clinics, and confirmed the quality of EB003's preclinical package.
Since the beginning of the SPELITEC project Eligo achieved the following:

The manufacturing process of EB003 active substance was entirely transferred from a laboratory scale to an industrial scale (100L) compatible with clinical requirements (GMP).
→ It is the first time such a manufacturing process is put in place for that type of product. This is a great milestone for the project and significantly increases EB003’s chances of success in the clinic.

EB003 active substance was tested on a large collection of >100 STEC bacteria isolated from infected patients and representative of the current clinical epidemiology.
→ Eligo could demonstrate that the active substance of EB003 was active on >95% of the collection and could confirm its ability to eliminate STEC bacteria very efficiently (more than 99,99% of the STEC bacteria are eliminated upon treatment). These critical results suggest that EB003 will be active on the vast majority of STEC bacteria infecting patients.

EB003 active substance was tested in a human gut simulator.
→ Eligo could demonstrate that EB003 were successfully released from formulation in the targeted intestinal compartment, that the released particles were active in situ and could induce a significant antimicrobial effect on the targeted bacterial strain. This milestone contributes to demonstrate the efficacy, safety and stability of EB003.

EB003 active substance was tested on human cells and during two GLP-like toxicology studies.
→ Eligo could demonstrate EB003's innocuity on human cells and its safe bio-distribution and shedding profiles. This milestone contributes to demonstrate the safety of EB003.

EB003 active substance was tested on animal models of STEC infections.
→ Eligo could demonstrate the ability of the EB003 active substance to eliminate >99,9% of STEC bacteria from the intestine of mice only 6h after oral administration of the treatment (decolonization model). These results were confirmed in STEC infected infant rabbits. This is a great milestone showing that EB003 has the best chances to target and eliminate STEC in the intestines of patients.
→ Eligo could demonstrate symptoms mitigation in a model of STEC-infected infant rabbits after oral administration of EB003. This milestone demonstrated the in-vivo efficacy of EB003 in a clinically-relevant context.

EB003 received Orphan Drug Designations by the EMA and the FDA, and regulatory agencies were engaged to assess its preclinical package
→ the path to enter the clinics has been significantly derisked, leaving Eligo in a good position to move forward phase 1 clinical trials

Awareness around STEC infections was raised through diverse interactions
→ Eligo communicated on the project during conferences and interactions with investors and funding bodies
→ Eligo secured its freedom-to-operate through patenting
→ Eligo engaged KOLs and leading clinical experts to ensure a successful development path and maximum impact for patients.

Overall, during the three reporting periods, we demonstrated that EB003 can efficiently and safely eliminate recent STEC strains in vitro and in vivo and we secured our ability to produce EB003 at an industrial scale to meet clinical needs and to enter the clinics in the near future.
Key next steps for the SPELITEC project will be to advance the development of EB003 towards first clinical trials in humans by:
- Obtaining the authorization from regulatory agencies to perform clinical studies in humans.