Periodic Reporting for period 3 - MIN4ALD (Use of MIN-102 for the treatment of children with cerebral ALD)
Période du rapport: 2021-10-01 au 2022-06-30
The main objective of MIN4ALD is to assess leriglitazone as a treatment for paediatric cerebral adrenoleukodystrophy (cALD) and bring it closer to the market. Leriglitazone is new brain penetrant, full and selective peroxisome proliferator-activated receptor γ agonist. Thanks to its adequate blood-brain barrier penetration and good bioavailability, leriglitazone acts as a disease-modifying therapy reaching adequate central nervous system (CNS) exposure to modulate multiple biological pathways relevant to clinical manifestations of adrenoleukodystrophy (ALD) and potentially in other CNS diseases.
Childhood cALD is a rapidly progressing and devastating disease that occurs in 31-35% of ALD patients with onset typically between age 2 and 12 years of age. The rate at which cALD progresses may vary but is characterized individuals experiencing learning and behavioural difficulties, aggressive behaviour, swallowing difficulties, vision problems, poor coordination, and eventually leading to a vegetative state or death after 2-4 years from disease onset.
There is no pharmacological treatment approved for patients with ALD. If childhood cALD is detected in the early stages patients may undergo Hematopoietic Stem Cell Transplantation (HSCT) to arrest the inflammatory demyelination. The procedure is, however, associated with serious and sometimes fatal complications for the patients, and require finding compatible donors. Since HSCT needs to be performed in early stages of the disease, and requires finding appropriate donors, this option is only available for a portion of paediatric cALD patients. A treatment that would halt or decelerate lesion progression would be extremely beneficial either to avoid the need of HSCT and/or to provide the required time for finding a suitable donor.
Leriglitazone demonstrated strong preclinical proof-of-concept in relevant animal models of CNS diseases related with cALD (neurodegeneration and neuroinflammation). In Phase I studies and a Phase II/III study in adult male ALD patients, leriglitazone showed a favourable benefit-risk profile, with a reduction in myelopathy progression and notably, a reduction of cerebral lesion progression leading to cALD. Only patients on placebo developed cALD during the study. Of importance, leriglitazone showed to be generally well tolerated. At the moment, the marketing authorization application (MAA) and launch preparations for male ALD patients in the EU are underway.
Therefore, the achievement of the current project on paediatric patients would be of great importance as it would allow extending the use of leriglitazone into a patient population with a highly unmet medical need. This is also an outstanding business opportunity that will place the company in a global leading position in the orphan space. The development of better treatment options is a health challenge, with a paramount social impact not only for the orphan diseases community, but for the whole society.
Childhood cALD is a rapidly progressing and devastating disease that occurs in 31-35% of ALD patients with onset typically between age 2 and 12 years of age. The rate at which cALD progresses may vary but is characterized individuals experiencing learning and behavioural difficulties, aggressive behaviour, swallowing difficulties, vision problems, poor coordination, and eventually leading to a vegetative state or death after 2-4 years from disease onset.
There is no pharmacological treatment approved for patients with ALD. If childhood cALD is detected in the early stages patients may undergo Hematopoietic Stem Cell Transplantation (HSCT) to arrest the inflammatory demyelination. The procedure is, however, associated with serious and sometimes fatal complications for the patients, and require finding compatible donors. Since HSCT needs to be performed in early stages of the disease, and requires finding appropriate donors, this option is only available for a portion of paediatric cALD patients. A treatment that would halt or decelerate lesion progression would be extremely beneficial either to avoid the need of HSCT and/or to provide the required time for finding a suitable donor.
Leriglitazone demonstrated strong preclinical proof-of-concept in relevant animal models of CNS diseases related with cALD (neurodegeneration and neuroinflammation). In Phase I studies and a Phase II/III study in adult male ALD patients, leriglitazone showed a favourable benefit-risk profile, with a reduction in myelopathy progression and notably, a reduction of cerebral lesion progression leading to cALD. Only patients on placebo developed cALD during the study. Of importance, leriglitazone showed to be generally well tolerated. At the moment, the marketing authorization application (MAA) and launch preparations for male ALD patients in the EU are underway.
Therefore, the achievement of the current project on paediatric patients would be of great importance as it would allow extending the use of leriglitazone into a patient population with a highly unmet medical need. This is also an outstanding business opportunity that will place the company in a global leading position in the orphan space. The development of better treatment options is a health challenge, with a paramount social impact not only for the orphan diseases community, but for the whole society.
The initial part of the MIN4ALD project focused on the activation and start of the phase II/III clinical trial to assess the efficacy and safety of leriglitazone in paediatric cALD patients, and completed regulatory and ethics submissions to all EU countries participating in the study (Spain, France and Germany). The drug formulation was optimized, quality and safety assays were carried out and all the preparations up to trial launch were performed.
The Phase 2, MT-2-02 study (NEXUS) was initiated during the second-half 2019, and since the project focused on the implementation and development of the clinical trial. Unfortunately, the health emergency related with the COVID-19 pandemic impacted the recruitment of patients requiring international travels, hence causing a delay on the execution of the project. Since the re-opening of the international travels, recruitment quickly speeded-up and is now completed.
The collected data so far shows promising results that are in line with the findings observed in cerebral lesion progression on adult patients and suggest that paediatric cALD patients on treatment may not follow the same course as the natural history. Results need to be taken with caution as more data is being collected. Of importance, leriglitazone showed to be generally well tolerated also in paediatric patients.
Regarding the dissemination and exploitation of the results, because ALD is an orphan disease, the communication has been performed specially through the orphan disease community in specific meetings/conferences with investigator, KOLs, prescribers and experts in cALD. Additional dissemination activities for the coming months are planned once all patients reach the 6 months treatment as this is a key timepoint of the study. This will allow patients, caregivers, heath care practitioners and in general, the orphan disease community learning about the outcome of the MIN4ALD project.
To ensure the exploitation of the results, Minoryx has been prosecuting the current patent portfolio and has filed new patents to protect results and increase the valuation of the company.
The Phase 2, MT-2-02 study (NEXUS) was initiated during the second-half 2019, and since the project focused on the implementation and development of the clinical trial. Unfortunately, the health emergency related with the COVID-19 pandemic impacted the recruitment of patients requiring international travels, hence causing a delay on the execution of the project. Since the re-opening of the international travels, recruitment quickly speeded-up and is now completed.
The collected data so far shows promising results that are in line with the findings observed in cerebral lesion progression on adult patients and suggest that paediatric cALD patients on treatment may not follow the same course as the natural history. Results need to be taken with caution as more data is being collected. Of importance, leriglitazone showed to be generally well tolerated also in paediatric patients.
Regarding the dissemination and exploitation of the results, because ALD is an orphan disease, the communication has been performed specially through the orphan disease community in specific meetings/conferences with investigator, KOLs, prescribers and experts in cALD. Additional dissemination activities for the coming months are planned once all patients reach the 6 months treatment as this is a key timepoint of the study. This will allow patients, caregivers, heath care practitioners and in general, the orphan disease community learning about the outcome of the MIN4ALD project.
To ensure the exploitation of the results, Minoryx has been prosecuting the current patent portfolio and has filed new patents to protect results and increase the valuation of the company.
MIN4ALD Phase 2 SME Instrument project is aimed at pushing Minoryx to successfully reach a market-ready product. Since there is a gap in the market to be filled in X-ALD as currently there is no approved treatment for this condition, MIN4ALD’s impact could be significant. If successful, Minoryx would be in a leading position due to the strong mechanism of action of MIN-102, which has broad effects and a high potential to treat different forms of X-ALD, such as cALD.
As a part of MIN4ALD Minoryx is currently running the phase II, open-label clinical trial in paediatric cALD patients to validate the solution. The study will provide an assessment of the effects of MIN-102 on cALD disease progression prior to HSCT, the only approved treatment for this indication, or experimental ex-vivo autologous stem cell transplant.
cALD can be detected prior to the development of clinical symptoms via regular surveillance using magnetic resonance imaging (MRI) of the brain. Detection of the first brain MRI abnormalities precedes the onset of significant clinical symptoms by at least 6 months to 1 year. Specifically, the current protocol assesses whether MIN-102 has at the capacity to arrest disease progression at two critical timepoints: i) 24 weeks after inclusion in the study, when historical data suggests that the majority of cerebral lesions has converted from non-inflammatory to inflammatory, or if Gd+ at baseline, when in the majority of patients there is rapid growth of lesions, and ii) 96 weeks after inclusion in the study, with a long-term confirmatory assessment on the effect on disease progression where based on natural history the majority of patients should present clear clinical progression.
Regarding the social-economic benefits, MIN4ALD will impact patients, prescribers and hospitals as it could provide a less aggressive treatment for these patients. On the other hand, it will impact pharma companies due to the huge potential of the treatment which will bring an increase in sales, access to new markets and a financial risk reduction. In addition, MIN4ALD addresses EU challenges aligned with the EU Regulation on Orphan Medicinal Products and contributes to the EU Health Strategy as it will improve patient care management, reduce overall cost of healthcare and reduce the burden on society.
As a part of MIN4ALD Minoryx is currently running the phase II, open-label clinical trial in paediatric cALD patients to validate the solution. The study will provide an assessment of the effects of MIN-102 on cALD disease progression prior to HSCT, the only approved treatment for this indication, or experimental ex-vivo autologous stem cell transplant.
cALD can be detected prior to the development of clinical symptoms via regular surveillance using magnetic resonance imaging (MRI) of the brain. Detection of the first brain MRI abnormalities precedes the onset of significant clinical symptoms by at least 6 months to 1 year. Specifically, the current protocol assesses whether MIN-102 has at the capacity to arrest disease progression at two critical timepoints: i) 24 weeks after inclusion in the study, when historical data suggests that the majority of cerebral lesions has converted from non-inflammatory to inflammatory, or if Gd+ at baseline, when in the majority of patients there is rapid growth of lesions, and ii) 96 weeks after inclusion in the study, with a long-term confirmatory assessment on the effect on disease progression where based on natural history the majority of patients should present clear clinical progression.
Regarding the social-economic benefits, MIN4ALD will impact patients, prescribers and hospitals as it could provide a less aggressive treatment for these patients. On the other hand, it will impact pharma companies due to the huge potential of the treatment which will bring an increase in sales, access to new markets and a financial risk reduction. In addition, MIN4ALD addresses EU challenges aligned with the EU Regulation on Orphan Medicinal Products and contributes to the EU Health Strategy as it will improve patient care management, reduce overall cost of healthcare and reduce the burden on society.