olesoxime (TRO19622) / Roche - LARVOL DELTA

Spinal Muscular Atrophy: Current Medications and Re-purposed Drugs. (PubMed, Cell Mol Neurobiol) - "This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required."

Journal • Review • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases. (PubMed, Biomolecules) - "Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes."

Journal • CNS Disorders • Pain

Novel combination of Olesoxime/Resveratrol-encapsulated exosomes to improve cognitive function by targeting amyloid β-induced Alzheimer's disease: investigation on in vitro and in vivo model. (PubMed, Inflammopharmacology) - "The behavioral outcomes of Morris water maze test demonstrated that OLX-RSV-loaded exosomes significantly enhanced the APP/PS1 mice's capacity to learn and remember spatial cues. Therefore, we hypothesized that OLX-RSV-loaded exosomes could be a useful and efficient method in the treatment of AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • CASP3

JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam. (PubMed, J Neurol) - P1, P2 | "JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13)...Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017."

Journal • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Pediatrics • Pneumonia • Rare Diseases • Respiratory Diseases

Voltage-dependent anion channels are involved in the maintenance of pig sperm quality during liquid preservation. (PubMed, Theriogenology) - "In contrast, total sperm motility was higher in samples treated with 5 μM TRO19622 than in the control, suggesting that when VDACs channels are inhibited by the lowest concentration of the blocking agent the resilience of pig sperm to liquid storage increases. In conclusion, the current research indicates that mitochondrial function, as regulated by ion channels in the outer mitochondrial membrane like VDACs, is related to the sperm resilience to liquid preservation and may influence cell lifespan."

Journal

Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction. (PubMed, Biomed J) - "The results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Renal Disease • KIM1 • LCN2

Oxysterols in Central and Peripheral Synaptic Communication. (PubMed, Adv Exp Med Biol) - "Overall, oxysterols could be used as "molecular prototypes" for therapeutic approaches. Analogs of 24-hydroxycholesterol (SGE-301, SGE-550, SAGE718) can be used for correction of NMDA receptor hypofunction-related states, whereas inhibitors of cholesterol 24-hydroxylase, cholestane-3β,5α,6β-triol, and cholest-4-en-3-one oxime (olesoxime) can be utilized as potential anti-epileptic drugs and (or) protectors from excitotoxicity."

Journal • CNS Disorders • Epilepsy

Editorial Focus on: "Mitochondrial creatine sensitivity is lost in the D2.mdx model of DMD and rescued by the mitochondrial-enhancing compound Olesoxime". (PubMed, Am J Physiol Cell Physiol) - No abstract available

Journal

JEWELFISH: 24-month safety, pharmacodynamic and exploratory efficacy data in non-treatment-naïve patients with SMA receiving treatment with risdiplam (EPNS 2023) - P2, P2/3 | " JEWELFISH (NCT03032172) is a multicentre, open-label study of daily risdiplam in non-treatment-naïve patients with SMA (inclusion criteria aged 6 months-60 years at enrolment) who were previously enrolled in the MOONFISH study (RG7800) or previously treated with nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®)... JEWELFISH is ongoing at sites across Europe and the USA and is providing important data on the safety, PD and exploratory efficacy of risdiplam in a broad population of non-treatment-naïve patients with SMA."

Clinical • PK/PD data

AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins. (PubMed, Sci Rep) - "To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential."

Journal • PPARGC1A

JEWELFISH: 24-month Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Treatment-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (AAN 2023) - P2, P2/3 | "Design/Methods JEWELFISH (NCT03032172) is a multicenter, open-label study of daily risdiplam in non-treatment-naïve patients with SMA (inclusion criteria aged 6 months–60 years at enrollment) who were previously enrolled in the MOONFISH study (RG7800) or previously treated with nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®)...Based on the exploratory efficacy analysis, an overall stabilization of motor function was observed following 24 months of risdiplam treatment in patients 2–60 years as assessed by the 32-item Motor Function Measure and Revised Upper Limb Module scales (data-cut: 31 January 2022). Conclusions JEWELFISH is ongoing at sites across Europe and the USA and is providing important data on the safety, PD and exploratory efficacy of risdiplam in a broad population of non-treatment-naïve patients with SMA."

Clinical • PK/PD data • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Lysosomal Ca as a mediator of palmitate-induced lipotoxicity. (PubMed, Cell Death Discov) - "Chelation of cytoplasmic Ca or blockade of mPT with olesoxime or decylubiquinone (DUB) suppressed lipotoxicity. Dantrolene or DUB also inhibited lipotoxic death of hepatocytes in vivo induced by administration of ethyl palmitate together with LPS. These results suggest a novel pathway of lipotoxicity characterized by mPT due to lysosomal Ca release which was supplemented by ER → lysosome Ca refilling and subsequent SOCE, and also suggest the potential role of modulation of ER → lysosome Ca refilling by dantrolene or other blockers of ER Ca exit channels in disease conditions characterized by lipotoxicity such as metabolic syndrome, diabetes, cardiomyopathy or nonalcoholic steatohepatitis."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study. (PubMed, Neurol Ther) - P1, P2 | "The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients."

Journal • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Pediatrics • Pneumonia • Rare Diseases • Respiratory Diseases

Mitochondrial creatine sensitivity is lost in the D2.mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime. (PubMed, Am J Physiol Cell Physiol) - "Grip strength, voluntary wheel-running and fibrosis were unaltered by Olesoxime. In summary, locomotor and respiratory muscle mitochondrial creatine sensitivities are lost during early stages in D2.mdx mice but are preserved by short-term treatment with Olesoxime in association with specific indices of muscle quality suggesting early myopathy in this model is at least partially attributed to mitochondrial stress."

Journal • CNS Disorders • Duchenne Muscular Dystrophy • Fatigue • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy • Myositis

Safety update: Risdiplam clinical trial development program (WMS 2022) - P2, P2/3 | "JEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®)...Here we will present updated safety analyses from the risdiplam studies, including safety data from the RAINBOWFISH study. Safety data from across the risdiplam studies will add to the understanding of the long-term safety profile of risdiplam."

Clinical

JEWELFISH: 24-month safety and pharmacodynamic data in non-treatment-naïve patients with spinal muscular atrophy (SMA) (WMS 2022) - P2, P2/3 | "JEWELFISH (NCT03032172) is a multicenter, open-label study that assesses the safety, tolerability and pharmacokinetic/pharmacodynamic (PD) relationship of daily risdiplam in non-treatment-naïve patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®)...Here we will present the month 24 results from JEWELFISH for the first time. The JEWELFISH study is ongoing at sites across Europe and the USA and is providing important data on the safety and PD of risdiplam in a broad population of non-treatment-naïve patients with SMA."

Clinical • PK/PD data • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Traumatic and Diabetic Schwann Cell Demyelination Is Triggered by a Transient Mitochondrial Calcium Release through Voltage Dependent Anion Channel 1. (PubMed, Biomedicines) - "TRO19622 treatment alleviated peripheral nerve defects and motor deficit in diabetic mice. Together, these data indicate that mitochondrial calcium homeostasis is instrumental in the Schwann cell demyelination program and that blocking VDAC constitutes a molecular basis for developing anti-demyelinating drugs for diabetic peripheral neuropathy."

Journal • Diabetic Neuropathy • Pain

Pooled Safety Data from the Risdiplam Clinical Trial Development Program (AAN 2022) - P2, P2/3 | "Design/ Safety data were pooled from three studies within the risdiplam clinical trial program: • FIREFISH (NCT02913482) assesses safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of risdiplam in infants with Type 1 SMA (aged 1–7 months at enrollment) • SUNFISH (NCT02908685) assesses safety, tolerability, PK, PD and efficacy of risdiplam in patients with Types 2/3 SMA (aged 2–25 years at enrollment)• JEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®)... Pooled data across the risdiplam studies suggest risdiplam has a positive benefit-risk profile. This analysis will add to the understanding of the long-term safety profile of risdiplam."

Clinical • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

JEWELFISH: Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (AAN 2022) - P2 | "Design/ JEWELFISH (NCT03032172) is a multicenter, open-label study of daily risdiplam in non-naïve patients with SMA (inclusion criteria aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA®)... JEWELFISH is ongoing at sites across Europe and the US, and will provide important data on the safety, PD and exploratory efficacy of risdiplam in a broad population of non-naïve patients with SMA."

Clinical • PK/PD data • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Remyelination therapies for multiple sclerosis: Optimizing translation from animal models into clinical trials. (PubMed, Expert Opin Investig Drugs) - "Limiting the contribution of OPC mediated repair in models of MS would allow the evaluation of remyelination-promoting agents on mature oligodendrocytes. Among remyelinating reagents reviewed, only rHIgM22 targets both OPCs and mature oligodendrocytes."

Journal • Preclinical • CNS Disorders • Inflammation • Multiple Sclerosis • Solid Tumor

[VIRTUAL] Pooled safety data from the risdiplam clinical trial development program (EAN 2021) - P2, P2/3 | " The risdiplam programme consists of four studies across a broad SMA population: • FIREFISH (NCT02913482): a 2-part study assessing safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in infants with Type 1 SMA (inclusion criteria: 1–7 months at enrolment) • SUNFISH (NCT02908685): a 2-part study assessing safety, tolerability, PK, PD and efficacy in patients with Type 2 or 3 SMA (inclusion criteria: 2–25 years at enrolment) • JEWELFISH (NCT03032172), assessing safety, tolerability, PK and PD in patients with SMA (inclusion criteria: six months–60 years at enrolment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec- xioi (ZOLGENSMA®) • RAINBOWFISH (NCT03779334), assessing efficacy, safety, PK and PD in infants (inclusion criteria: birth–6 weeks at first dose) with genetically diagnosed and presymptomatic SMA... This analysis will add to the understanding of the..."

Clinical • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4

[VIRTUAL] JEWELFISH: 12-month safety, pharmacodynamic and exploratory efficacy of risdiplam in non-naïve patients with SMA (EAN 2021) - P2, P2/3 | "JEWELFISH participants have previously received nusinersen (SPINRAZA ®), onasemnogene abeparvovec-xioi (ZOLGENSMA®), olesoxime or RG7800 (RO6885247)... JEWELFISH is ongoing across Europe and the US and will provide important data on the safety, PD and exploratory efficacy of risdiplam in a heterogenous population of non-naïve patients with SMA."

Clinical • PK/PD data • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4

[VIRTUAL] Pooled Safety Data from the Risdiplam Clinical Trial Development Program (AAN 2021) - P2, P2/3 | "Design/ The risdiplam clinical development program consists of four studies in a broad population of individuals with SMA: FIREFISH (NCT02913482) is a two-part study assessing the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in infants with Type 1 SMA (inclusion criteria 1–7 months at enrollment) SUNFISH (NCT02908685) is a two-part study assessing the safety, tolerability, PK, PD and efficacy in patients with Type 2 or 3 SMA (inclusion criteria 2–25 years at enrollment) JEWELFISH (NCT0302172) assesses the safety, tolerability, PK and PD in patients with SMA (inclusion criteria 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA®). This analysis will add to the understanding of the long-term safety profile of risdiplam."

Clinical • CNS Disorders • SMA4

[VIRTUAL] JEWELFISH: Safety and Pharmacodynamic Data in Non-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (AAN 2021) - P2, P2/3 | "JEWELFISH participants previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA®). The JEWELFISH study is ongoing in sites across Europe and the US and will provide important data on the safety and PD of risdiplam in non-naïve patients with SMA."

Clinical • PK/PD data • CNS Disorders • Muscular Atrophy • SMA4

[VIRTUAL] Pooled safety data from the risdiplam clinical trial development program (MDA 2021) - P2, P2/3 | "The risdiplam clinical development program consists of four studies in a broad population of individuals with SMA:FIREFISH (NCT02913482) is a two-part study assessing the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy in infants with Type 1 SMA (inclusion criteria 1–7 months at enrollment)SUNFISH (NCT02908685) is a two-part study assessing the safety, tolerability, PK, PD and efficacy in patients with Type 2 or 3 SMA (inclusion criteria 2–25 years at enrollment)JEWELFISH (NCT0302172) assesses the safety, tolerability, PK and PD in patients with SMA (inclusion criteria 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec-xioi (ZOLGENSMA®).RAINBOWFISH (NCT03779334) assesses the efficacy, safety, PK and PD in infants (inclusion criteria birth-6 weeks at first dose) with genetically diagnosed and presymptomatic SMA. This analysis will..."

Clinical • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4