tolcapone (CRX-1008) / Corino Therap, SOM Biotech - LARVOL DELTA

CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis. (PubMed, Amyloid) - "Tolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis."

Journal • Amyloidosis

[VIRTUAL] TOLCAPONE LEVELS AND TTR STABILIZATION IN CEREBROSPINAL FLUID OF PATIENTS WITH LEPTOMENINGEAL AMYLOID TTR MUTATIONS (ISOA 2020) - "CRX-1008 up to 200 mg three times daily for 28 days was well tolerated by clinical and biochemical measures in patients with LMA-related vTTR. Results of serum and CSF CRX-1008 drug level determinations, and TTR tetramer stabilization assays before and after 100 mg and 200 mg TID dosing, will be presented."

Clinical • Amyloidosis • CNS Disorders • Epilepsy • Movement Disorders • Parkinson's Disease • Ventriculomegaly

Corino Therapeutics Announces Presentation of New Clinical Research Finding at the XVII International Symposium on Amyloidosis (PRNewswire) - P1, N=10; NCT03591757; "...Dr. John Berk, M.D...is presenting positive findings from a proof-of-concept study of oral CRX-1008...at the XVII International Symposium on Amyloidosis....The results confirm that CRX-1008 is a potent TTR stabilizer in both plasma and CSF using established ex vivo assays. CRX-1008 normalized TTR concentration in plasma with an overall mean increase in plasma TTR tetramer concentration of 55%. Significant concentrations of drug penetrated into the CSF....'These new clinical research findings suggest that CRX-1008 may be the first hope for patients with hATTR-leptomeningeal, treating both peripheral and central manifestations of hATTR,' said Dr. John Berk....CRX-1008 was well tolerated in patients with no drug related adverse events or safety concerns."

Media quote • P1 data • Amyloidosis • CNS Disorders

Membrane bound catechol-O-methytransferase is the dominant isoform for dopamine metabolism in PC12 cells and rat brain. (PubMed, Eur J Pharmacol) - "Comparison of the effect of a MB-COMT selective inhibitor LI-1141 on dopamine metabolism in wild type and MB-COMT knockout PC12 cells allowed us to confirm the selectivity of LI-1141 with respect to MB-COMT in cells. Under conditions in which LI-1141 was shown to inhibit only MB-COMT but not S-COMT, it effectively changed dopamine metabolites similar to the effect induced by tolcapone, a non-selective COMT inhibitor, suggesting that selective inhibition of MB-COMT will be effective in blocking dopamine metabolism, providing an attractive therapeutic approach in improving cognition for patients."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • Vascular Neurology

Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder. (PubMed, J Exp Pharmacol) - "While the vast majority of these trials involve neuromodulation and psychotherapeutic approaches, only a small proportion (around 20%) involve the investigation of new pharmacological approaches (tolcapone, nabilone, psilocybin, troriluzole, nitrous oxide, rituximab, naproxen, and immunoglobulins). Here, we provide a comprehensive review of investigational and experimental drugs to treat OCD."

Journal • Review • Immunology • Inflammation • Mood Disorders • Obsessive-Compulsive Disorder • Psychiatry

Safety and efficacy of tolcapone in Parkinson's disease: systematic review. (PubMed, Eur J Clin Pharmacol) - "Literature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium."

Clinical • Journal • Review • CNS Disorders • Hepatology • Liver Failure • Movement Disorders • Parkinson's Disease

Effects of Cortical Dopamine Regulation on Drinking, Craving, and Cognitive Control (clinicaltrials.gov) - P2; N=90; Recruiting; Sponsor: Medical University of South Carolina; Trial completion date: Dec 2020 ➔ Jun 2021; Trial primary completion date: Dec 2020 ➔ Jun 2021

Trial completion date • Trial primary completion date

Analysis of Reproducibility and Robustness of a Human Microfluidic Four-Cell Liver Acinus MicroPhysiology System (LAMPS). (PubMed, Toxicology) - "Further experiments to study the effects of Terfenadine (10 μM), Tolcapone (88 μM), Trovafloxacin (150 μM with or without 1 μg/mL lipopolysaccharide), Troglitazone (28 μM), Rosiglitazone (0.8 μM), Pioglitazone (3 μM), and caffeine (600 μM) were carried out over 10 days. With respect to drug effects, both cell types demonstrated comparable and more human-relevant effects in LAMPS, as compared to 2D cultures. Overall, these studies show that LAMPS is a robust and reproducible in vitro liver model, comparable in performance when seeded with either primary human hepatocytes or iPSC-derived hepatocytes, and more physiologically and clinically relevant than 2D monolayer cultures."

Journal • Hepatology • TNFA

Tissue and interspecies comparison of catechol-O-methyltransferase mediated catalysis of 6-O-methylation of esculetin to scopoletin and its inhibition by entacapone and tolcapone. (PubMed, Xenobiotica) - "Rats, dogs, pigs, and sheep are high COMT activity species, in contrast to humans, mice, and rabbits; COMT activity is highest in the liver. Both entacapone and tolcapone are potent COMT inhibitors, but their inhibition mechanisms differ."

Journal

A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors (clinicaltrials.gov) - P=N/A; N=26; Completed; Sponsor: University of California, San Francisco; N=154 ➔ 26

Clinical • Enrollment change • MRI

Artificial intelligence approach fighting COVID-19 with repurposing drugs. (PubMed, Biomed J) - "Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches...Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • Novel Coronavirus Disease

Targeting transthyretin - mechanism-based treatment approaches and future perspectives in hereditary amyloidosis. (PubMed, J Neurochem) - "The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo...Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome remaining limitations, including application burden, side effects, and blood-brain permeability."

Journal • Review • Amyloidosis • Hepatology • Liver Failure • Pain

Tolcapone in Obsessive Compulsive Disorder (clinicaltrials.gov) - P2/3; N=20; Recruiting; Sponsor: University of Chicago; Trial completion date: Aug 2020 ➔ Nov 2020; Trial primary completion date: Aug 2020 ➔ Nov 2020

Clinical • Trial completion date • Trial primary completion date • Mood Disorders • Obsessive-Compulsive Disorder • Psychiatry

Augmenting Frontal Dopamine Tone Enhances Maintenance over Gating Processes in Working Memory. (PubMed, J Cogn Neurosci) - "Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for first-order stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance."

Clinical • Journal

Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice. (PubMed, Neuropharmacology) - "Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer. (PubMed, Int J Mol Sci) - "Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers."

Journal • Amyloidosis • Pain

Addition of Tolcapone in Intrajejunal Levodopa Infusion Therapy Requires a Pronounced Dose Reduction. (PubMed, Mov Disord Clin Pract) - No abstract available

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] Enhancing Frontal Dopamine Tone Improves Working Memory Maintenance (ANA 2020) - "Resting state fMRI data demonstrated that the degree to which tolcapone improved performance in individual subjects correlated with increased connectivity between a region important for first-order stimulus-response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the bilateral intraparietal sulcus and left fusiform gyrus. Together these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance."

Clinical • CNS Disorders

Analysis of an Integrated Human Multi-organ Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics. (PubMed, Anal Chem) - "Untargeted metabolomics identified 18 key biomarkers significantly changed in human brain MPS after tolcapone dosing, which were mainly associated with perturbation of tryptophan and phenylalanine metabolism (BH4 cycle), glycerophospholipid metabolism, energy metabolism, and aspartate metabolism. This is the first example of successfully combining drug metabolism, metabolomics and cell engineering to capture complex human physiology and the multi-organ interactions; the results we present here could be a step toward using analytical chemistry to advance the utilization of human-on-a-chip for testing both drug efficacy and toxicity in a single system."

Biomarker • Journal • Metabolic Disorders • Solid Tumor

[VIRTUAL] Levodopa Dose Equivalency for Opicapone and Safinamide (MDS Congress 2020) - "After comparison with other COMTi, tolcapone and entacapone, the conversion factor for opicapone 50 mg should be “levodopa dose x 0,4 LED”.In the two RCT of safinamide the combine improvement in ON time without troublesome dyskinesias was 0,63 h, placebo time discounted. The LED proposed for opicapone 50 mg is “total levodopa dose x 0,4 mg LED” and for safinamide 50 or 100 mg is “100 mg LED”."

CNS Disorders • Parkinson's Disease

Effects of Tolcapone on Decision Making and Alcohol Intake in Alcohol Users (clinicaltrials.gov) - P2; N=62; Completed; Sponsor: Jennifer Mitchell; Active, not recruiting ➔ Completed; Trial completion date: Jun 2020 ➔ Nov 2019

Trial completion • Trial completion date

[VIRTUAL] Investigating the effects of the catechol-O-methyltransferase inhibitor tolcapone on learning and memory in diazepam-challenged rats (ECNP 2020) - "Tolcapone, a COMT inhibitor, antagonizes the amnestic effect of diazepam in the hippocampal-dependent step-through passive avoidance test. This is probably due to the enhancement of the effect of dopamine in that particular brain structure."

Preclinical • Alzheimer's Disease • CNS Disorders • Insomnia • Parkinson's Disease • Sleep Disorder

COMT-catalyzed palmitic acid methyl ester biosynthesis in perivascular adipose tissue and its potential role against hypertension. (PubMed, J Pharmacol Exp Ther) - "Furthermore, in in vitro enzymatic assays in the presence of COMT and S-5'-adenosyl-L-methionine (AdoMet), the stable isotope [C]-PA was methylated to form [C]-PAME in incubation medium or the Krebs-Henseleit solution containing 3T3-L1 adipocytes or rat PVAT...[C]-PA methylation to form [C]-PAME in 3T3-L1 adipocytes and rat PVAT was blocked by various COMT inhibitors, such as S-(5'-adenosyl)-L-homocysteine, adenosine-2',3'-dialdehyde, and tolcapone...COMT-dependent PAME biosynthesis is involved in AT-1 receptor-mediated blood pressure regulation, as evidenced by the reversal of decreased PAME biosynthesis in PVAT by losartan in hypertensive rats. This finding might help in developing novel therapeutic or preventive strategies against hypertension."

Journal • Cardiovascular • Hypertension

Targeting COVID-19 in Parkinson's patients: Drugs repurposed. (PubMed, Curr Med Chem) - "The most common under trial drugs for COVID-19 are Remdesivir, Favipiravir, Chloroquine and Hydroxychloroquine, Azithromycin along with adjunct drugs like Amantadine with some monoclonal antibodies. Presently, clinically US FDA approved drugs in PD includes Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), Dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), Monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), Amantadine and Antimuscarinic drugs...Conclusion and relevance of this review focus on the drugs that can be tried for the PD patients with SAR CoV-2 infection, in particular, Amantadine approved by all developed countries a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and antiParkinson properties. The significant prognostic adverse effect of SARS-CoV-2 on PD and the..."

Clinical • Journal • CNS Disorders • Infectious Disease • Movement Disorders • Novel Coronavirus Disease • Parkinson's Disease • CTSL

Development of a PC12 cell-based assay for screening catechol-O-methyltransferase inhibitors. (PubMed, ACS Chem Neurosci) - "Incubation of PC12 cells with tolcapone, a highly potent and selective COMT inhibitor, increased the concentrations of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) while reducing the metabolites 3-methoxytyramine (3-MT) and homovanillic acid (HVA) in the cell culture medium. These results match the known in vivo effects of COMT inhibition in rodents. Together, these data support the continued use of PC12 cells as an in vitro screen that bridges cell-free enzyme assays and more costly in vivo assays."

Journal • Neuroendocrine Tumor • Oncology • Solid Tumor