Periodic Reporting for period 5 - TRIC-TB (Boosting Ethionamide efficacy and lowering the dose with a small molecule transcriptional modulators, to overcoming MDR-TB infections and define a new place for Ethionamide in 1st-line TB treatments.)
Período documentado: 2023-05-01 hasta 2024-02-29
Tuberculosis (TB) is one of the leading causes of death worldwide. Its causative agent is the bacterial pathogen Mycobacterium tuberculosis (Mtb). Until the COVID-19 pandemic, more people were dying of TB each year than of any other disease caused by a single infectious agent. The COVID-19 pandemic has led to reductions in the diagnosis of TB and in access to treatment, reversing years of global progress in reducing the number of deaths. In 2020, the first year-on-year increase (of 5.6%) of TB deaths since 2005 was observed and the total number of TB casualties returned to the level of 2017 with 1.5 million deaths. An estimated 10.6 million people developed TB worldwide in 2022 and an estimated 1.3 million died from TB.
Ethionamide (ETH) and prothionamide (PTH) are valuable drugs in the treatment of TB. However, due to their suboptimal bioactivation within Mtb, high doses are required to achieve clinical efficacy and are typically associated with increasing adverse events, most commonly gastrointestinal intolerance and hepatotoxicity. ETH/PTH are thus unable to realize their full therapeutic potential. Despite this, ETH/PTH are part of a second-line anti-TB regimen for the treatment of MDR-TB and are used in the treatment of TB meningitis (TBM).
The TRIC-TB molecules boost the in vitro and in vivo activity of the pro-drug ETH, resulting in an unprecedented increase of ETH efficacy in vivo. This boosting of activity would allow for lower efficacious doses of ETH in human anti-TB treatments and result in a reduction in dose dependent adverse effects in TB patients. Furthermore, data shows that the boosters overcome pre-existing resistance mechanisms in Mycobacterium tuberculosis against ETH by employing novel bioactivation pathways for ETH.
The overarching objectives of this IMI project are to deliver:
• One Phase 2 ready booster molecule, having a) completed preclinical CTA-enabling studies and b) completed Phase 1 safety PK studies in healthy volunteers: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD).
• One backup molecule on a different chemical series ready for CTA enabling safety toxicology studies.
Ultimately, the results from this project will pave the way for the booster to be integrated into new, improved regimens to treat TB including MDR-TB. A small molecule booster in combination with lower ETH/PTH doses will deliver a better tolerated and more potent drug combination than standard doses of ETH/PTH alone, with the potential to reduce treatment times. This can massively impact the current TB treatment armamentarium and significantly improve both patient experience and treatment outcomes.
Ethionamide (ETH) and prothionamide (PTH) are valuable drugs in the treatment of TB. However, due to their suboptimal bioactivation within Mtb, high doses are required to achieve clinical efficacy and are typically associated with increasing adverse events, most commonly gastrointestinal intolerance and hepatotoxicity. ETH/PTH are thus unable to realize their full therapeutic potential. Despite this, ETH/PTH are part of a second-line anti-TB regimen for the treatment of MDR-TB and are used in the treatment of TB meningitis (TBM).
The TRIC-TB molecules boost the in vitro and in vivo activity of the pro-drug ETH, resulting in an unprecedented increase of ETH efficacy in vivo. This boosting of activity would allow for lower efficacious doses of ETH in human anti-TB treatments and result in a reduction in dose dependent adverse effects in TB patients. Furthermore, data shows that the boosters overcome pre-existing resistance mechanisms in Mycobacterium tuberculosis against ETH by employing novel bioactivation pathways for ETH.
The overarching objectives of this IMI project are to deliver:
• One Phase 2 ready booster molecule, having a) completed preclinical CTA-enabling studies and b) completed Phase 1 safety PK studies in healthy volunteers: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD).
• One backup molecule on a different chemical series ready for CTA enabling safety toxicology studies.
Ultimately, the results from this project will pave the way for the booster to be integrated into new, improved regimens to treat TB including MDR-TB. A small molecule booster in combination with lower ETH/PTH doses will deliver a better tolerated and more potent drug combination than standard doses of ETH/PTH alone, with the potential to reduce treatment times. This can massively impact the current TB treatment armamentarium and significantly improve both patient experience and treatment outcomes.
Two pre-clinical candidates, BVL-GSK038 and BVL-GSK098, both with adequate properties for candidate selection, resulted from an extensive Lead Optimization program that was completed before the start of the project.
The more advanced molecule, BVL-GSK098, successfully achieved the first TRIC-TB objective, the delivery of a Phase 2 ready drug candidate. The backup compound, BVL-GSK038, was produced in sufficient quantities to be ready for CTA-enabling studies, achieving the second project objective.
In the first project year, the synthetic route for the backup compound was optimized and BVL-GSK038 was produced in sufficient quantity and purity, achieving milestone 1 (MS1).
In the second project year, BVL-GSK098 completed the 28-day toxicology and safety pharmacology studies, so called CTA-enabling studies. Due to the favourable profile, the compound was endorsed to enter the first-in-human (FIH) studies. For the FIH study, the oral formulation was optimized and BVL-GSK098 was filled in capsules. The CTA was filed in 2020, achieving MS2.
In 2022, TRIC-TB successfully completed Phase 1 clinical trials. BVL-GSK098 was generally safe and well tolerated and showed a linear pharmacokinetic (PK) profile at therapeutically effective doses in healthy volunteers, achieving MS3 (Phase 2a ready).
Finally, a regulatory acceptable sub-chronic toxicology package has been generated for BVL-GSK098. The safety-margin to the anticipated therapeutic human dose is more than 10-fold. With the successful completion and reporting of the toxicology studies, MS4 was achieved, allowing BVL-GSK098 to enter Phase 2b trials.
There were some deviations from the original workplan, partially the result of the COVID-19 pandemic and the subsequent inflation of the costs of the planned studies. The team appropriately applied contingency measures to prioritize the continued development of BVL-GSK098 while removing deliverables associated with development of the backup compound BVL-GSK038 through GA amendment procedures.
The project results have been extensively disseminated. Twenty-eight presentations and posters were presented at international conferences within the project duration.
BioVersys received U.S. FDA Qualified Infectious Disease Product (QIDP) designation and Orphan Drug Designation (ODD) for BVL-GSK098 and ETH fixed-dose combination for treatment of TB. These qualifications reflect the the potential for bETH to improve treatment options for patients who have TB.
BVL-GSK098 seamlessly transitioned into Phase 2a study (funded by EDCTP), studying the early bactericidal activity (EBA), safety, tolerability and PK of ETH alone and in combination with BVL-GSK098 in TB patients. The consortium members from TRIC-TB are also involved in the EBA study. This is rewarding for the team that has worked together for many years on the development of BVL-GSK098 and a prime example of the project’s sustainability.
In summary, TRIC-TB has met and even exceeded all the objectives as described in the grant agreement, and the development of the BVL-GSK098 continues beyond the IMI funding.
The more advanced molecule, BVL-GSK098, successfully achieved the first TRIC-TB objective, the delivery of a Phase 2 ready drug candidate. The backup compound, BVL-GSK038, was produced in sufficient quantities to be ready for CTA-enabling studies, achieving the second project objective.
In the first project year, the synthetic route for the backup compound was optimized and BVL-GSK038 was produced in sufficient quantity and purity, achieving milestone 1 (MS1).
In the second project year, BVL-GSK098 completed the 28-day toxicology and safety pharmacology studies, so called CTA-enabling studies. Due to the favourable profile, the compound was endorsed to enter the first-in-human (FIH) studies. For the FIH study, the oral formulation was optimized and BVL-GSK098 was filled in capsules. The CTA was filed in 2020, achieving MS2.
In 2022, TRIC-TB successfully completed Phase 1 clinical trials. BVL-GSK098 was generally safe and well tolerated and showed a linear pharmacokinetic (PK) profile at therapeutically effective doses in healthy volunteers, achieving MS3 (Phase 2a ready).
Finally, a regulatory acceptable sub-chronic toxicology package has been generated for BVL-GSK098. The safety-margin to the anticipated therapeutic human dose is more than 10-fold. With the successful completion and reporting of the toxicology studies, MS4 was achieved, allowing BVL-GSK098 to enter Phase 2b trials.
There were some deviations from the original workplan, partially the result of the COVID-19 pandemic and the subsequent inflation of the costs of the planned studies. The team appropriately applied contingency measures to prioritize the continued development of BVL-GSK098 while removing deliverables associated with development of the backup compound BVL-GSK038 through GA amendment procedures.
The project results have been extensively disseminated. Twenty-eight presentations and posters were presented at international conferences within the project duration.
BioVersys received U.S. FDA Qualified Infectious Disease Product (QIDP) designation and Orphan Drug Designation (ODD) for BVL-GSK098 and ETH fixed-dose combination for treatment of TB. These qualifications reflect the the potential for bETH to improve treatment options for patients who have TB.
BVL-GSK098 seamlessly transitioned into Phase 2a study (funded by EDCTP), studying the early bactericidal activity (EBA), safety, tolerability and PK of ETH alone and in combination with BVL-GSK098 in TB patients. The consortium members from TRIC-TB are also involved in the EBA study. This is rewarding for the team that has worked together for many years on the development of BVL-GSK098 and a prime example of the project’s sustainability.
In summary, TRIC-TB has met and even exceeded all the objectives as described in the grant agreement, and the development of the BVL-GSK098 continues beyond the IMI funding.
The expected result until the end of the project is to deliver a booster molecule having completed Phase 1 SAD and MAD studies and long-term toxicology studies in animals. In addition, the PK/PD should be sufficiently characterized to be ready for Phase 2a studies in TB patients.
Current TB therapies are a combination of four or more drugs and treatment times range from 6-18 months depending on the resistance profile of Mtb. The potential impact of the TRIC-TB booster molecule for patients and society are:
1. The combination of booster and low dose ETH/PTH allows for a safer and better tolerated dose of this fast-acting anti-TB drug, without differentiating potency on drug resistant or sensitive strains. This could result in ETH/PTH being a valuable treatment for MDR, extensively drug-resistant (XDR) and isoniazid (INH) mono-resistant TB treatment.
2. In addition, the TRIC-TB consortium is expanding the indication and use ETH and BVL-GSK098 for treatment of TB meningitis since both ETH and the booster molecules cross the blood brain barrier.
3. We seek to replace isoniazid (INH) in first line therapy. This would offer an important benefit to patients, payers and society, since INH is associated with rapid resistance development and increasing rates of resistance. We can improve patient care as describe in 1) and also reduce costs of TB therapy for healthcare stakeholders. Furthermore, by reducing resistance development, we can reduce resistance dissemination.
4. We aim to contribute to global sustainability goals for responsible use of antibiotics, by exploring the full potential of an existing antibiotic.
Current TB therapies are a combination of four or more drugs and treatment times range from 6-18 months depending on the resistance profile of Mtb. The potential impact of the TRIC-TB booster molecule for patients and society are:
1. The combination of booster and low dose ETH/PTH allows for a safer and better tolerated dose of this fast-acting anti-TB drug, without differentiating potency on drug resistant or sensitive strains. This could result in ETH/PTH being a valuable treatment for MDR, extensively drug-resistant (XDR) and isoniazid (INH) mono-resistant TB treatment.
2. In addition, the TRIC-TB consortium is expanding the indication and use ETH and BVL-GSK098 for treatment of TB meningitis since both ETH and the booster molecules cross the blood brain barrier.
3. We seek to replace isoniazid (INH) in first line therapy. This would offer an important benefit to patients, payers and society, since INH is associated with rapid resistance development and increasing rates of resistance. We can improve patient care as describe in 1) and also reduce costs of TB therapy for healthcare stakeholders. Furthermore, by reducing resistance development, we can reduce resistance dissemination.
4. We aim to contribute to global sustainability goals for responsible use of antibiotics, by exploring the full potential of an existing antibiotic.