EP4213831A1 - Supplément pour le traitement d'une infection à coronavirus - Google Patents

Supplément pour le traitement d'une infection à coronavirus

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Publication number
EP4213831A1
EP4213831A1 EP20780975.7A EP20780975A EP4213831A1 EP 4213831 A1 EP4213831 A1 EP 4213831A1 EP 20780975 A EP20780975 A EP 20780975A EP 4213831 A1 EP4213831 A1 EP 4213831A1
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EP
European Patent Office
Prior art keywords
day
mmol
use according
dose
composition
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EP20780975.7A
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German (de)
English (en)
Inventor
Adil MARDINOGLU
Jan BORÉN
Mathias Uhlén
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Scandibio Therapeutics AB
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Scandibio Therapeutics AB
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Publication of EP4213831A1 publication Critical patent/EP4213831A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide

Definitions

  • the present disclosure relates to the treatment of a subject that is or has been infected with a coronavirus.
  • Coronaviruses are a large family of ribonucleic acid viruses that typically cause mild to moderate upper respiratory diseases in humans. Members of this family are known to infect animals, including dogs, chickens, cattle, pigs, cats, pangolins, and bats. As far as we know, seven members of this family can infect humans and cause illness. Of these, HC0V-229E, -OC43, -NL63 and -HKUi species cause mild respiratory diseases in humans. However, severe acute respiratory syndrome (SARS) that occurred in late 2002; Middle East Respiratory Syndrome (MERS-CoV) that emerged in 2012; and SARS-C0V-2, which appeared in China in December 2019, are the species that may cause serious respiratory diseases in humans. The epidemic of COVID-19 spread globally in a short time that classified as a pandemic by the World Health Organization (WHO). Since the beginning of the outbreak, infections have expanded rapidly into multiple simultaneous epidemics worldwide.
  • WHO World Health Organization
  • SARS-C0V-2 has 79.5% homology to SARS-C0V-1, the causative agent of SARS in south China; 85% to 96% identity with bat-SL-CoVZC45, a bat SARS-like coronavirus, and 91.02% similarity with SARS- CoV-2-like coronavirus in pangolin named Pangolin-CoV.
  • a population genetic analysis of 103 SARS-C0V-2 genomes from China revealed that causative agent of COVID-19 consists of two evolution types.
  • Type L (70% prevalence in Wuhan), which is derived from the ancestral type S (30% prevalence in Wuhan), is more aggressive and contagious.
  • Zhou et al. investigated the COVID-19 agent through full genome sequencing and phylogenetic analysis, classifying it as a betacoronavirus (a positivesense, single-stranded RNA virus), the same subgenus as SARS-CoV as well as several bat coronaviruses.
  • SARS-C0V-2 uses the same receptor binding (angiotensin-converting enzyme 2 (ACE2)) and cell entry pathway as SARS- CoV-1.
  • ACE2 angiotensin-converting enzyme 2
  • MERS-CoV is less closely related to SARS- C0V-2.
  • SARS-C0V-2 has been found in stool and blood samples, but the rate of transmission, period of infectivity, and duration of viral shedding are uncertain and show great variation.
  • drug repurposing provides an alternative source of data for a novel understanding of metabolic reprogramming in viral infections, as well as the organic compounds with previously unrecognized antiviral behaviours that are possible to expand in unveiling properties of virus biology.
  • drug repurposing identifies formerly undiscovered biomolecular networks, transforming them into novel pharmaceutical targets, even though the determined molecules may not be implemented into clinical trials.
  • Glycine can be synthesized via the interconversion of serine. It has been shown that the serine synthesis is downregulated in patients with NAFLD and supplementation of serine has attenuated alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. Depleted liver GSH is also restored by the administration of N- acetylcysteine as in acetaminophen poising. L-carnitine and nicotinamide riboside that both stimulate the transfer of fatty acids from cytosol to mitochondria have been identified as two additional cofactors that are depleted in patients.
  • N-acetyl cysteine also known as acetylcysteine
  • NAC N-acetyl cysteine
  • acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine and a precursor in the formation of the antioxidant glutathione in the body.
  • administration of acetylcysteine replenishes glutathione stores.
  • Glutathione may act as endogenous neuromodulator, may also modulate the redox state of the NMDA receptor complex, activate ionotropic receptors that are different from any other excitatory amino acid receptor, and which may constitute glutathione receptors, potentially making it a neurotransmitter.
  • N- acetylcysteine is a prodrug of glutathione, it may modulate all of the aforementioned receptors as well. It confers antioxidant effects and is able to reduce free radicals.
  • Acetylcysteine also possesses some anti-inflammatory effects possibly via inhibiting NF-KB and modulating cytokine synthesis.
  • NAC has two approved indications: (1) treatment of paracetamol (acetaminophen) overdose associated liver damage, and (2) to loosen thick mucus in individuals with cystic fibrosis or chronic obstructive pulmonary disease.
  • NAC has also been tested for contrast induced nephropathy, infertility, cystic fibrosis, ischemic heart diseases, HIV, hypercholesterolemia and schizophrenia. It is probably beneficial in any kind of acute hepatic failure. NAC usage in liver disease is discussed below.
  • NAC is a thiol compound that acts directly as a free radical scavenger and as a precursor to reduced glutathione (GSH). This molecule has been shown to reduce the number and effect of COPD exacerbations and also the inflammatory response in epithelial cells exposed to the H5N1 influenza A virus.
  • NAC improves inflammatory response and oxidative stress in patients with community-acquired pneumonia compared to conventional therapy.
  • HDX aspartic acid-P-hydroxamate, an inhibitor of endogenous SO2 generating enzyme
  • HDX failed to promote alveolar epithelial cell radical generation, PARP upregulation, caspase-3 activation or apoptosis, suggesting that the downregulated SO2 pathway markedly facilitated the oxidative stress and thus likely induced apoptosis.
  • NAC is soluble in water and alcohol, and practically insoluble in chloroform and ether. It is a white to white with light yellow cast powder and has a pKa of 9.5 at 30 °C. NAC is stable in gastric and intestinal fluids and rapidly absorbed after oral administration. It is not affected by food intake. It reaches peak plasma concentration in 30-60 minutes after application. The distribution volume (Vd) is between 0.33 and 0.47 L/kg, which is evident in extracellular fluids and passes primarily to the lung, kidney, and liver. After oral administration, 48% of the amount passed to the blood is determined in the lungs. The rate of binding to plasma proteins is about 50%. NAC is extensively liver metabolized, and 22-30% is excreted in urine in the form of sulfate and taurine. NAC has a half-life of 5.6-6 hours in adults.
  • NAC is available as intravenous and oral formulations.
  • the IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries including the United States.
  • Daily dose of NAC is 200 mg capsules taken 3 times a day (morning, lunch, evening) or a single dose of 600 mg (3 capsules) in the evening.
  • the loading dose is -140 mg/kg
  • the maintenance dose is 70 mg/kg every 4 hours (17 doses).
  • NAC has been tested in various doses.
  • NAC supplementation has been given at a dose of 2700 mg/day for 6 months in a double-blind randomized controlled trial.
  • NAC supplementation is used to enhance performance in elite sport.
  • a recent review of the literature evaluated the effect of NAC supplementation.
  • the typical daily dose of NAC reported was 5.8 g/day; with a range between 1.2 and 20.0 g/day.
  • effect of NAC supplementation on oxidative stress status and alveolar inflammation was analyzed in a double-blind, randomized clinical trial using a dose of 1800 mg/day for 4 months.
  • NAC was administered in oral doses of 6,000- 8,000 mg daily for several months. It had a good safety profile, adverse effects were minimal and not significantly associated with NAC ingestion.
  • NAC is contraindicated in patients with previous allergic/anaphylactoid reaction to acetylcysteine. Patients with acute asthma attacks can also not use NAC. Pregnancy risk category of NAC is B. There is insufficient data on the usage in pregnancy and lactation. Therefore, it should only be used if it is very necessary. Drug interaction with acetylcysteine is very rare. Minor interactions have been reported with parenteral nitro-glycerine and oral forms of nitrates. NAC has no effect on the use of vehicles and machinery.
  • L-carnitine is a naturally occurring substance required in mammalian energy metabolism. It is a carrier molecule that facilitates the transport of long-chain fatty acids across the inner mitochondrial membrane, thereby delivers substrate for oxidation and subsequent energy production.
  • Carnitine deficiency is characterized with very low L-carnitine levels in plasma and tissues and may be either primary or secondary.
  • Primary carnitine deficiency is an autosomal recessive disorder caused by a deficiency in the plasma membrane carnitine transporter and leads to urinary carnitine wasting.
  • SLC22A5 mutations can also affect carnitine transport and decrease carnitine levels.
  • Secondary carnitine deficiency is associated with various causes like inadequate intake, decreased synthesis due to liver disorders, loss of carnitine during diarrhoea, diuresis or haemodialysis.
  • the clinical presentation consists of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycaemia, and/or cardiomyopathy.
  • Associated symptoms include hypotonia, muscle weakness and failure to thrive.
  • carnitine supplementation may rapidly alleviate signs and symptoms.
  • L-carnitine is indicated in the treatment of primary and secondary L-carnitine deficiency. It may also be used in patients taking certain drugs (such as valproic acid for seizures or antibiotics for tuberculosis), or during medical procedures (haemodialysis for kidney disease) that deplete the body's L-carnitine. (27)
  • L-carnitine has also been tested in heart failure, ischemic heart diseases, peripheral arterial diseases, HIV, male infertility, anorexia, chronic fatigue syndrome and fatigue associated with chronic diseases and chronic obstructive pulmonary disease. It is also used as a replacement supplement in strict vegetarians, dieters, and low-weight or premature infants. In athletes, carnitine has been used to improve performance, but beneficial effects in athletes is not consisted in all studies.
  • Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone.
  • the absolute bioavailability of levocarnitine is ⁇ 15-16%.
  • the mean distribution half-life is ⁇ 0.6 hours and the mean apparent terminal elimination halflife is 17.4 hours.
  • Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) is a mean of 4.00 L/h.
  • Levocarnitine is not bound to plasma protein or albumin when tested at any concentration.
  • Major metabolites are trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-y-butyrobetaine, primarily in faeces (0.44% to 45% of the administered dose).
  • Urinary excretion of levocarnitine is about 4 to 8% of the dose.
  • Faecal excretion of total carnitine is less than 1% of the administered dose.
  • a levocarnitine dosage of 1 to 3 g/day has been recommended for a 50 kg subject.
  • L-carnitine supplementation has been given at a dose of 6 g/ day for 2 weeks.
  • Several studies have tested if L-carnitine supplementation promotes weight loss in obese subjects (4 g/L, 8 weeks).
  • Efficacy and effectiveness of carnitine supplementation for cancer-related fatigue has recently been tested in a systematic literature review and meta-analysis (nine studies used a dose between 2 to 6 g per day).
  • Impact of L-carnitine supplementation on plasma lipoprotein(a) concentrations have been analysed in a recent systematic review and meta-analysis of randomized controlled trials (studies used 2-4 g/day).
  • L-carnitine is usually well tolerated.
  • Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhoea.
  • carnitine supplements can cause nausea, vomiting, abdominal cramps, diarrhoea, and a “fishy” body odor.
  • Rarer side effects include muscle weakness/mild myasthenia in uremic patients and seizures in those with seizure disorders.
  • Gastrointestinal adverse reactions with levocarnitine may be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.
  • NAD consuming activities and cell division necessitate ongoing NAD synthesis, either through a de novo pathway that originates with tryptophan or via salvage pathways from three NAD+ precursor vitamins, nicotinamide riboside, nicotinamide, and nicotinic acid.
  • NAD generation is vital since it is linked to several redox reactions in the body. NAD plays a central role in energy metabolism and oxidative phosphorylation and is a key component of many metabolic pathways for carbohydrates, lipids, and amino acids.
  • NR has been used as an NAD+ precursor vitamin.
  • NR is considered a form of vitamin B3 (niacin) and it is available as an over-the-counter dietary supplement, and approved as food ingredient in enhanced water products, protein shakes, nutrition bars, gum and chews at no more than 0.027% by weight.
  • Human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study, and single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans.
  • Niacin has been reported to alleviate LPS-induced acute lung injury, possibly by preventing the depletion of NAD.
  • a randomized controlled study determined the short-term effects of extended-release niacin (ERN) on endothelial function, measured by flow-mediated vasodilation (FMD) of the brachial artery, in HIV-infected adults with low HDL-c.
  • FMD flow-mediated vasodilation
  • PARP enzymes are enzymes that induce natural immunity against mouse hepatitis virus (MHV), which is used as a coronavirus infection model. MHV infection has been shown to increase NAD and NADP in natural immune cells. Study data show that overexpression of virally induced PARP and PARP10 depress host cell NAD metabolism and NAD + enhancement strategies differ in restoring PARP10. These data showed that, not nuclear NAD +, but the cytoplasmic NAD+ increase can regulate antiviral PARP functions that support the natural immune response to other viruses and coronaviruses susceptible to PARP-mediated antiviral activity.
  • a typical dose maybe 100-250 mg taken before the first meal of the day.
  • a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested.
  • the lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.
  • Flushing is the most sensitive end point of nicotinic acid effects, but after ingestion of supplemental nicotinamide, no cases of flushing or glucose intolerance have been reported and only one case of hepatitis was reported following the ingestion of greater than 3 g/ day for several days. Such side-effects have not been reported for NR.
  • NR was not defined as genotoxic but data on the use of NAD during pregnancy and breast-feeding is inadequate.
  • European Food Safety Authority (EFSA) EFSA has issued a positive opinion of nicotinamide riboside chloride as a novel food on August 07, 2019. And a dose of 230 mg/ day in pregnant and lactating women is permissible (EFSA Opinion: https://www.efsa. europa.eu/en/efsajournal/pub/5775).
  • L-serine is generally classified as a non-essential amino acid, however under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine.
  • HSAN1 Hereditary sensory and autonomic neuropathy type 1
  • SPT serine palmitoyl transferase
  • L-serine has been shown to decrease the macrophage- and neutrophil-mediated inflammatory responses in mice during Pasteurella multocida infection.
  • L-serine administration has been reported to reduce body weight by decreasing orexigenic peptide expression and reduces oxidative stress and inflammation during aging in mice, possibly by modulating the Sirti/NFicB pathway.
  • IL-6 and the number of GFAP- and Iba-i-positive cells) by L-serine treatment has been shown to lead to neuroprotection in mice after traumatic brain injury.
  • the study subjects were randomized to L-serine (400 mg/kg/day) or placebo for one year. All participants received L-serine during the second year. Analysis of vital signs, physical examination findings, and clinical laboratory examinations, did not reveal adverse effects of L-serine. Thus, long-term L-serine supplementation did not reveal adverse effects of L-serine.
  • Serine supplementation (three daily doses of 5 g of L-serine [i.e., 190 mg/kg]) has also been shown to be safe even in pregnancy, as shown by in pre- and postnatal treatment of 3-phosphoglycerate-dehydrogenase deficiency.
  • the present inventors have recently integrated kinetic data from human turn-over studies using stable-isotope technique with experimentally derived flux data to simulate the dynamics of liver metabolism of subjects with varying degree of hepatic steatosis using personalized liver genome-scale metabolic models (GEMs).
  • GEMs liver genome-scale metabolic models
  • the correlations between the predicted intracellular fluxes of the liver and hepatic steatosis were assessed to identify underlying molecular mechanisms that are disturbed in subjects with NAFLD.
  • the systems level analysis indicated that altered NAD+ and GSH metabolism (with increased demand for NAD+ and GSH in NAFLD) was a prevailing feature in NAFLD.
  • the present inventors modelled and validated if it would be possible to reverse hepatic steatosis by boosting the NAD+ and GSH metabolism (as described above). Advanced modelling was performed to clarify the molar relationship of the co-factors needed for optimal efficiency. It was found that the metabolites serine, L- carnitine, NAC and NR in a molar ratio of 30:4:4:1 may effectively promote NAD+ and GSH metabolism and decrease the amount of hepatic steatosis.
  • suitable daily supplementation doses are 24.7 g serine (0.0078 x 30 moles), 5.1 g of L- carnitine (given in the stable salt form of 7.46 g L-carnitine tartrate) (0.0078 x 4 moles), 5.1 g of NAC (0.0078 x 4 moles) and 2 g of NR (0.0078 moles). This is further discussed below.
  • ODE differential equation
  • Model fit to the mean plasma serine level predicted that a twice-daily dose of 12.4 g serine might produce a desired long-term increase in mean plasma serine concentration of 100%. Doses up to 400 mg/kg/day (around 25-30 g/day) have been studied in humans and shown to be safe.
  • L-carnitine deoxycarnitine gamma-butyrobetaine, 4- trimethylammoniobutanal, 3-hydroxy-N 6,N6,N6- trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine
  • composition for use in a therapeutic method, said composition comprising:
  • nicotinamide riboside quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/ or nicotinate.
  • the therapeutic method is a method of treatment of a subject that is or has been infected with a coronavirus or a method of treatment of a subject suffering from a SARS.
  • Figure 1 shows a Kaplan-Meier graph of the proportion of patients in the treated group and the placebo group that had symptoms on each day.
  • a composition for use in a therapeutic method is: a method of treatment of a subject that is or has been infected with a coronavirus, typically a severe acute respiratory syndrome-related coronavirus; or a method of treatment of a subject suffering from a severe acute respiratory syndrome (SARS).
  • a coronavirus typically a severe acute respiratory syndrome-related coronavirus
  • SARS severe acute respiratory syndrome
  • SARS is a viral respiratory disease of zoonotic origin caused by a severe acute respiratory syndrome coronavirus.
  • the SARS is COVID-19.
  • the severe acute respiratory syndrome-related coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-C0V-2).
  • composition of the first aspect comprises:
  • nicotinamide riboside quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate.
  • the composition comprises A), B), C) and optionally D).
  • group A serine and glycine are preferred.
  • the most preferred substance in group A) is serine, which is typically provided as L-serine.
  • N-acetyl cysteine (NAC) and cysteine are preferred.
  • the most preferred substance in group B) is NAC.
  • the substance of group C) is preferably carnitine, optionally in the form of a carnitine salt, such as carnitine tartrate.
  • the substance of group C) is L-carnitine, optionally in the form of a L-carnitine salt, such as L-carnitine tartrate.
  • the substance of group D) is preferably nicotinamide riboside (NR).
  • the substance(s) of group A) is preferably included in a higher molar amount than the substance(s) of group D).
  • the molar ratio of A) to D) is normally between 250:1 and 1.5:1 and typically between 150:1 and 3:1.
  • the molar ration is between 90:1 and 10:1, more preferably between 50:1 and 20:1.
  • the molar ratio of A) to B), considering efficacy and toxicity, is typically between 20:1 and 1:4, such as between 16:1 and 1:4, preferably between 12:1 and 1.5:1 and more preferably between 10:1 and 3:1.
  • A) to C), considering efficacy and toxicity, is normally between 150:1 and 1:1, typically between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1.
  • the composition of the first aspect is a solid, such as a solid powder. Such a powder can be mixed with water, e.g. by the patient/consumer, a nurse or a physician.
  • the composition of the first aspect is an aqueous solution or suspension (“cocktail”), which facilitates convenient oral administration. Such an aqueous solution or suspension is preferably ready to drink.
  • the composition is a powder comprising:
  • D) nicotinamide riboside wherein the molar ratio of A) to B) is between 16:1 and 1.5:1, preferably between 10:1 and 3:1, the molar ratio of A) to C) is between 100:1 and 2:1, preferably between 30:1 and 3:1, more preferably between 15:1 and 4:1; and the molar ratio of A) to D) is between 150:1 and 3:1, preferably between 90:1 and 10:1, more preferably between 50:1 and 20:1.
  • the composition is a powder comprising: A) serine;
  • D) nicotinamide riboside wherein the molar ratio of A) to D) is between 90:1 and 10:1, preferably between 50:1 and 20:1, more preferably between 40:1 and 20:1.
  • the concentration of A) is typically 0.20-2.4 mmol/ml, preferably 0.40-2.4 mmol/ml and more preferably 0.60-2.4 mmol/ml;
  • the concentration of B) is normally 0.09-0.90 mmol/ml, typically 0.09-0.54 mmol/ml, preferably 0.11-0.40 mmol/ml and more preferably 0.013-0.30 mmol/ml; and/or
  • the concentration of D) is typically 0.006-0.12 mmol/ml, preferably 0.012-0.08 mmol/ml and more preferably 0.018-0.07 mmol/ml.
  • the concentration of C) is normally 0.009-0.38 mmol/ml, typically 0.009-0.19 mmol/ml, preferably 0.016-0.16 mmol/ml and more preferably 0.028-0.12 mmol/ml.
  • the solution or suspension of the first aspect may be provided in a package for convenient handling and distribution. Further, the volume of such a package may be such that drinking the whole contents of the package at once or during a single day results in oral administration of appropriate doses of the substances in the solution or suspension.
  • the volume of the package is 25-1000 ml. The volume is preferably 50-500 ml. When it is intended that the consumer/ patient shall drink more than one package per day, the volume is typically relatively low, such as 25-500 ml, preferably 25-400 ml.
  • the packaged solution or suspension comprises 48- 478 mmol of A).
  • the dose of A) is effective, but not toxic.
  • A) is serine in an amount of 5-50 g, more preferably 10-50 g.
  • the packaged solution or suspension comprises 2.0-39.2 mmol of D) when D) is NR and 2.0-196 mmol of D) when D) is not NR.
  • the dose of D) is effective, but not toxic.
  • D) is NR in an amount of 0.5-10 g, more preferably 1.5-6 g.
  • the composition of the first aspect is a powder, it may also be packaged.
  • the powder maybe provided in unit dose packs. It follows from the discussion above that such a unit dose may comprise 48-478 mmol of A) and/ or 2.0-39.2 mmol of D) when D) is NR and 2.0-196 mmol of D) when D) is not NR.
  • such as packed powder preferably comprises serine in an amount of 5- 50 g and/or NR in an amount of 0.5-10 g. More preferably, such a packed powder comprises serine in an amount of 10-50 g and/or NR in an amount of 1.5-6. o g.
  • the substances of the present disclosure are preferably a significant part of the composition of the first aspect.
  • the substances included in groups A)-D) may amount to at least 10 %, such as at least 25 %, such as at least 50 % of the dry weight of the composition of the first aspect.
  • the weight of serine is at least 10 %, such as at least 25 %, such as at least 40 % of the dry weight of the composition of the first aspect.
  • composition of the first aspect may comprise one or more tasting agent(s), such as one or more sweetener(s) (e.g. sucralose) and/or one or more flavor agent(s). It may also comprise a lubricant, such as a polyethylene glycol lubricant (e.g. Polyglykol 8000 PF (Clariant)).
  • a lubricant such as a polyethylene glycol lubricant (e.g. Polyglykol 8000 PF (Clariant)).
  • the therapeutic method comprises oral administration of the composition.
  • the therapeutic method of the first aspect may further comprise administration of an anti-viral drug.
  • the therapeutic method of the first aspect further comprises administration of chloroquine or hydroxychloroquine.
  • the daily dose maybe in the range of 100-1200 mg, such as 200- 1000 mg.
  • hydroxychloroquine maybe given for a period of 2-8 days, such as 3-7 days.
  • the therapeutic method may for example comprise administration, such as oral administration, of:
  • the method of treatment may for example comprise administration, such as oral administration, of:
  • C) may be administrated in a dose of 12-100 mmol/ day, such as 16-75 mmol/day, such as 20-50 mmol/day
  • the daily dose may be reached by administrating one or more doses per day to the patient.
  • the number of daily doses is one, two or three.
  • the patient may consume a drink formed from the composition in powderous form one, two or three times per day.
  • Each dose or drink preferably comprises no more than 4.78 mmol/kg of A).
  • the method of treatment may for example be carried out for a period of at least one week.
  • the first administration of the composition of the first aspect is carried out within 48 hours, such as within 24 hours, of the diagnosis of a coronavirus infection, such as a SARS-C0V-2 infection.
  • a coronavirus infection such as a SARS-C0V-2 infection.
  • Such a diagnosis may be RT-PCR-based.
  • substances comprising
  • the therapeutic method is: a method of treatment of a subject suffering from a severe acute respiratory syndrome (SARS); or a method of treatment of a subject that is or has been infected with a coronavirus, typically a severe acute respiratory syndrome-related coronavirus.
  • SARS severe acute respiratory syndrome
  • a method of treating a subject comprising administration to the subject of:
  • nicotinamide riboside quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate D-ribonucleoside, nicotinamide and/or nicotinate.
  • the subject of the method is a subject suffering from a SARS or a subject that is or has been infected with a coronavirus.
  • the embodiments and examples of the first and second aspect apply to the third aspect mutatis mutandis.
  • the subject of the first, second and third aspect is preferably a human subject.
  • a mixture of the four substances was produced in Turkey according to GMP regulations by Pharmactive Company, Istanbul (www.pharmactive.com.tr/en/anasayfa.html) according to EU standards and packed according to GMP rules with the appropriate dosage.
  • the mixture was produced as a soluble powder packed in 60 mL HDPE plastic bottles with screw caps.
  • the mixture contained strawberry aroma.
  • Placebo products were produced at Pharmactive company using identical HDPE plastic bottles. Placebo products contained to be dissolved in 200 mL water.
  • the scope of the trial is 400 volunteering patients (men and women) aged 18 years or older, who have been diagnosed with COVID-19, meet all the inclusion criteria and do not meet any of the exclusion criteria.
  • 100 patients were randomized and recruited. Provided that the statistical evaluation of the data obtained from the 100 patients are found to be satisfactory, a second stage of the study including an additional 300 patients will be carried out.
  • - Severe liver disease e.g. Child Pugh score > C, AST>5 times upper limit
  • the study subjects were randomized on a 3:1 basis.
  • the study was open- labeled.
  • a web-based randomization system was used to assign a randomization code for each patient.
  • the investigator or another responsible person at the investigational site entered the web-based randomization system specific to the study through assigned username and password. After entering patient-related information (patient number, date of birth, patient initials), the system provided a randomization code for the future use.
  • the first treatment (initial loading dose) was administrated by the responsible investigator based on the randomisation assignment. The remaining treatments were administered by the patient at home. Hydroxychloroquine treatment was administered at an initial dose of 2x400 mg (oral) followed by 400 mg/day (2x200 mg oral) for a total of 5 days.
  • the present disclosure can present results from the first stage of the clinical trial. On average, the patients of the treated group were asymptomatic after 6.6 days. In contrast, the patients of the placebo group were on average asymptomatic after 9.3 days.

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Abstract

La présente divulgation porte sur une composition destinée à être utilisée dans une méthode thérapeutique de traitement d'un sujet qui est ou qui a été infecté par un coronavirus, ladite composition comprenant : A) de la sérine, de la glycine, de la bétaïne, de la N-acétylglycine, de la N-acétylsérine, de la diméthylglycine, de la sarcosine et/ou de la phosphosérine ; B) de la N-acétylcystéine, de la cystéine et/ou de la cystine ; C) facultativement de la carnitine, de la désoxycarnitine, de la gamma-butyrobétaïne, du 4-triméthylammoniobutanal, de la 3-hydroxy-N6,N6,N6-triméthyl-L-lysine, de la N6,N6,N6-triméthyl-L-lysine et/ou de la lysine ; et D) du nicotinamide riboside, du quinolinate, du désamino-NAD+, du nicotinate D-ribonucléotide, du nicotinamide D-ribonucléotide, du nicotinate D-ribonucléoside, du nicotinamide et/ou du nicotinate.
EP20780975.7A 2020-09-18 2020-09-18 Supplément pour le traitement d'une infection à coronavirus Pending EP4213831A1 (fr)

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