Drug Repurposing Patent Applications April

Abstract

A Tricyclic Antidepressant Blocks Metastasis

International Patent Application WO/2020/065113, Imipramine for Use as an Inhibitor of FASCIN1 Overexpression (Inventors: Conesa Zamora P, Perez Sanchez H, Luque Fernández I, Montoro Garciá S, Albuquerque González B, Campioni Rodrigues P, et al.; applicant: Fundación Universitaria San Antonio, Spain; Fundación para la Formación e Investigación Sanitarias, Spain; Universidad de Granada, Spain; published: April 2, 2020).

The best thing a pharmacologist can say about cancers is that they overexpress a multitude of molecular targets: A significant expression difference to normal tissue, and a high importance for the overexpressed protein for tumor growth and metastasis, should create a high potential for selective targeting of the malignant tissue. By these criteria fascin1, a strongly overexpressed protein in many solid tumors that binds and crosslinks actin bundles should be an excellent cancer target: It is a key protein in the formation of filopodia and invadopodia that makes tumor cells invasive and motile, whereas it is absent from most normal epithelial cells.¹ Indeed, fascin1 expression in tumors is positively associated with metastasis and mortality.² Migrastatin and its macroketone analogs (e.g., MGSTA-6) are considered typical fasc1 inhibitors³ but their potential in oncology is limited by their complex structure. A few small-molecule inhibitors have been published: imidazofurane carboxamides⁴ and loosely related compounds disclosed in WO/2015/127125. Finding that the old tricyclic antidepressant, imipramine (an aminergic neurotransmitter reuptake inhibitor with multiple additional actions on various central nervous system receptors) also is a fascin1 inhibitor is still surprising. The inventors conducted pharmacophoric modeling based on the nucleus of the migrastatin structure, tested it against a 9,591 compound subset of the DrugBank library, and selected imipramine among the hits for inhibitory activity testing in cell migration assays, organotypic invasion of fibroids, and the zebrafish larvae invasion model. In most of these, imipramine was as effective or better than migrastatin. They suggest it might be especially effective against serrated adenocarcinoma of the colon.⁵ For the peer review companion paper, see Albuquerque-González et al. ⁶

Erythromycin-Derived Antibiotics Kill Senescent Cells

International Patent Application WO/2020/072598, Azithromycin and Roxithromycin Derivatives as Senolytic Drugs (Inventors: Sotgia F, Lisanti MP; applicant: Lunella Biotech, Inc., Canada; published: April 9, 2020).

Senolysis—either the selective elimination of senescent cells or the disruption of their SASP (senescence-associated secretory phenotype) secretome—is one of the key approaches toward longevity and health in old age.⁷ Using the bromodeoxyuridine (BrdU) induced model of fibroblast senescence through controlled DNA damage, the inventors identified two macrolide antibiotics of the erythromycin family, azithromycin and roxithromycin, as senolytic drugs. Remarkably, erythromycin showed no such activity whereas telithromycin (a ketolide) did, indicating a complex mechanism that is not dependent on the presence of sugar moieties. In the xCELLigence real-time assay system, azithromycin preferentially targets and senescent cells in BrdU-damaged MRC-5 human lung fibroblast cultures, inducing both aerobic glycolysis and autophagy (as measured by the Seahorse XFe96 metabolic flux analyzer). These effects were also seen with azithromycin and non-immortalized BJ human fibroblasts. However, their characteristic is biphasic; mitochondrial oxygen consumption rates are inhibited at 50 μM and stimulated at 100 μM. There was little effect on non-senescent fibroblasts at either concentration. For the peer review companion paper, see Ozsvari et al. ⁸ For more drug repurposing from Lunella Biotech, see WO/2019/108729 [discussed in vol. 18(3) of ASSAY] and Fiorillo et al. ⁹ for triple combinations of doxycycline, azithromycin, and ascorbic acid for eradicating cancer stem cells by targeting mitochondria.

Connectivity Mapping Suggests a Former Gerd Drug Candidate for Nonalcoholic Steatohepatitis

International Patent Application WO/2020/077186, AZD3355 (Lesogaberan) for Treatment and Prevention of Nonalcoholic Steatohepatitis (NASH), Liver Fibrosis, and Other Liver Conditions (Inventors: Dudley J, Friedman S, Readhead B, Becker C, Bhattacharya D; applicant: Icahn School of Medicine at Mount Sinai, USA; published: April 16, 2020).

Lesogaberan is a peripherally restricted high-affinity GABAB receptor-specific agonist whose development for refractory gastroesophageal reflux disease was discontinued, because Phase II studies showed no meaningful efficacy whereas paresthesia was a problematic adverse event.¹⁰ In immunodeficient mice xenografted with human islets, oral lesogaberan promoted human β cell replication and islet cell survival, suggesting potential utility in diabetes.¹¹ The inventors' disclosure of its potential utility for nonalcoholic steatohepatitis (NASH) and liver fibrosis is particularly surprising, because GABA has been reported to exacerbate these conditions in a mouse model..¹² Lesogaberan was identified in silico as a promising candidate compound for NASH, liver cirrhosis, and hepatocellular carcinoma through a modified connectivity mapping approach, that is, comparison of its transcriptomic signature (generated by exposing A549 and MCF7 cell lines to two distinct concentrations and vehicle) to the transcriptional profiles representing 310 distinct human diseases. In a second step, the same analysis was performed for all 1,309 compounds in the connectivity map against the NASH signatures within the disease transcriptome library; it was found that the connectivity scores ranked in the top 1% of predictions for NASH. Cell culture assays were then performed in immortalized human hepatic stellate (LX-2) cells and primary human hepatic stellated cells, which were assessed for fibrogenic protein expression after treatment with lesogaberan (0–300 nM) for either 24, 48, or 72 h. At 48 h of treatment with 30 nM, bPDGF-R, TGFb-R1, and TIMP1 were downregulated; cytotoxicity was apparent only with 300 nM. In human liver slices, at least one of the pro-fibrotic genes was downregulated after 24 h in the majority of 10 samples.

Idebenone and Benzbromarone Target Goblet Cells Vial TMEM16

International Patent Application WO/2020/078813, Compound for Use in the Treatment of a Disease Characterized by Dysregulated Mucus Production and/or Secretion (Inventor: Kunzelmann K; applicant: Universität Regensburg, Germany; published: April 23, 2020).

This invention is related to inhibitors of TMEM16 proteins, preferably of TMEM16A and/or TMEM16F. TMEM16A (anoctamin 1) is a Ca²⁺-activated chloride channel in the airways and the intestine and has been associated with goblet cell metaplasia; its expression is strongly upregulated in cystic fibrosis, and it co-occurs with mucus hypersecretion. TMEM16F has been proposed to be essential for Ca²⁺-dependent scramblase activity. Taking note that the old antihelmintics niclosamide and nitazoxanide are potent TMEM16A antagonists that fully dilate bronchial airways,¹³ and considering that the failed Alzheimer drug candidate and approved Leber's hereditary optic neuropathy drug idebenone¹⁴ as well as the uricosuric benzbromarone¹⁵ also inhibit TMEM16A, the inventors investigated these compounds for inhibiting basal (i.e., ATP-induced) mucus secretion to treat cystic fibrosis, ulcerative colitis, and irritable bowel syndrome. The common target in these diseases are the goblet cells, which, though clearly different in the airways and the intestinal tract, share critical features such as low pH and high Ca²⁺ content in their secretory granules. A murine model of regio-specific TMEM16A knockout in the airway epithelium and freshly excised colonic segments mounted in a vertical perfusion chamber, with mucus induced by inhaled ovalbumin and perfusion with methacholine, respectively, were used as test systems. The results are quite impressive; for example, benzbromarone was effective in the knockout mice when injected i.p. at only 1 mg/kg for 5 days. Mice homozygous for a cystic fibrosis CFTR mutation support the effect of cystic fibrosis. In the intestinal explant model, both intraperitoneal and oral application of niclosamide completely inhibited ATP-induced release of mucus.

Fibrates for Neurodegenerative Diseases

International Patent Application WO/2020/082941, Use of Gemfibrozil and Derivative Thereof for Treatment and/or Prevention of Neurodegenerative Disease (Inventors: Yao Y, Luo R, Li G, Su L, Yang J, Zhang D; applicant: Kunming Institute of Zoology Chinese Academy of Sciences, China; published: April 30, 2020).

Gemfibrozil is an old lipid-lowering agent, still available as a generic one, but as all fibrates it has been almost totally eclipsed by the statins. Recently, it started a second career in the rare disease field as an approved drug for the supportive treatment of neuronal ceroid lipofuscinosis,¹⁶ a group of neuronal lipid storage disorders collectively known as Batten disease (see WO/2018/126000). Gemfibrozil has also been reported to stimulate ADAM-10-mediated proteolysis of the amyloid precursor protein, explained by the fact that the ADAM10 promoter harbors PPAR-responsive elements, thereby linking to gemfibrozil's PPAR-α agonist action, which is responsible for its antidyslipidemic activity.¹⁷ Taken together, this prior art that precedes the patent application's October 2018 Chinese priority date can be supposed to make patentability of gemfibrozil for neurodegenerative diseases difficult, especially for Alzheimer's disease. Nevertheless, the applicant decided to try, also for Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The claims are extended to fenofibrate, which has similar prior art for Alzheimer's.¹⁸ For the peer review companion paper, see Luo et al. ¹⁹ In the meantime, others have confirmed that gemfibrozil not only reduces amyloid pathology in a mouse model of Alzheimer's disease but also improves memory²⁰—a fact that the present patent application also discloses by showing Morris water maze data.

A Beriberi Drug for Retinal Diseases

International Patent Application WO/2020/091430, Composition for Prevention or Treatment of Macular Degeneration (Inventors: Park DH, Lee IK; applicant: Kyungpook National University Industry-Academic Cooperation Foundation, Korea; published: May 5, 2020).

Age-related macular degeneration continues to be the leading cause of legal blindness in industrialized nations, although VEGF inhibitor antibodies and binding proteins have made the exudative form of choroidal neovascularization treatable. The present inventors have demonstrated that fursultiamine (thiamine tetrahydrofurfuryl disulfide, TTFD), which is used in the treatment of thiamine deficiency,²¹ reduces the increased expression of the angiogenesis promoter HIF-1α in the ARPE-19 retinal pigment epithelial cell line under hypoxic conditions, and it inhibits choroidal vascular endothelial cell growth in the ex vivo mouse choroid sprouting assay. In both models, the effect of fursultiamine became apparent at 20 μM, and it was complete at 100 μM. In the murine in vivo laser-induced choroidal neovascular model, 50 mg/kg was administered orally for 8 days from 1 day before to 1 week after laser irradiation; angiography showed the size of the choroidal neovascular lesions to be significantly reduced. Ophthalmological effects have not been reported for fursultiamine itself, but the potential benefits of thiamine in diabetic retinopathy (also an exudative retinal disease) are known: It corrects the increase in MMP-2 activity induced by high glucose, while increasing the expression of TIMP-1, an inhibitor of matrix metalloproteases.²² However, fursultiamine is no newcomer to drug repurposing: It has been investigated for autism spectrum disorders,²³ and WO/2013/084532 (Nagasaki University) claims benign prostate hyperplasia and non-neurogenic overactive bladder as new therapeutic indications.

Intravenous Meloxicam for Patients with Platelet Dysfunction

International Patent Application WO/2020/097338, Methods of Treating Subjects Having Platelet Dysfunction with IV Meloxicam (Inventors: Mack RJ, McCallum S; applicant: Baudax Bio, Inc., USA; published: May 14, 2020).

Classical nonsteroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit cyclooxygenase-1, thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation. Meloxicam, a long-acting oral NSAID, also inhibits COX-1 but because of its preference for COX-2 its repression of TxA2 formation does not reach levels that decrease platelet function in humans, even at supratherapeutic doses.^24,25 On the other hand, it does not interfere with the antiplatelet action of acetylsalicylic acid.²⁶ This has been known for at least 20 years. The inventors suggest using an i.v. formulation of meloxicam to provide a faster onset of action and prevention of acute postoperative pain in patients with a genetic platelet dysfunction (Von Willebrand disease, Glanzmann disease, Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, or Bernard-Soulier syndrome); with acquired conditions that compromise platelets: cirrhosis, uremia, systemic lupus; or in patients on long-acting anticoagulants. Whole blood samples from eight healthy subjects treated with 30 mg/mL i.v. meloxicam were analyzed by using the collagen with adenosine diphosphate (CADP) reagent cartridge, confirming that there were no statistically significant differences in PFA-100 closure time values between the individuals receiving meloxicam and untreated controls. Although this is not drug repurposing in the strict sense, it illustrates how changing the route of administration can extend the therapeutic utility of an old drug.

A Discontinued Anorectic Drug for Rett Syndrome

International Patent Application WO/2020/105005, Methods of Treating Rett Syndrome Using Fenfluramine (Inventors: Galer BS, Megargel B; applicant: Zogenix International Ltd., United Kingdom; published: May 28, 2020).

Rett syndrome, a chronically progressive X-linked genetic disorder, mostly results from spontaneous mutations in MECP2, a gene coding for a methyl CpG binding protein that is essential for correct neuronal function.²⁷ More than 40 binding partners have been identified, including transcriptional co-repressors, activators, and other factors involved in the regulation of gene expression. There is no causative treatment for Rett syndrome, although many approaches have been attempted.²⁸ The inventors suggest fenfluramine, a serotonergic stimulant originally developed and marketed as an anorectic but discontinued due to valvular heart disease; in June 2020, the U.S. FDA approved Zogenix formulation for the treatment of otherwise intractable seizures in Dravet syndrome patients.²⁹ According to the invention, stimulation of 5-HT1a, 5-HT1d, 5-HT2a, 5-HT2c, and σ-1 receptors treat not only the seizures but also the stereotypes, compulsions, and self-injurious behaviors that frequently trigger them. A maximum of 0.8 mg/kg/day after titration in 2 weeks of increments starting with 0.2 mg/kg/day is expected to be effective in an investigator-initiated trial that will investigate the antiepileptic potential. Although these doses are low compared with anorectic doses, they are within the known antiepileptic range.³⁰ Patentability will hinge on the demonstration that fenfluramine has more than merely anticonvulsant actions in Rett syndrome.

An Asthma Drug for a Painful Chronic Hand Condition

International Patent Application WO/2020/109230, Montelukast for the Treatment of Erosive Hand Osteoarthritis (Inventors: Monfort Faure J, Verges Milano J, García Alonso F, Ramentol Massana J, Sanchez García JA, Sanz Menéndez N, et al.; applicant: MMC Intellectual Property Institute, S.L., Spain; published: June 4, 2020).

Erosive osteoarthritis of the hand is distinct from the form that affects the hips and knees; genetic risk factors, pathogenesis, and disease course seem to be substantially different.³¹ Intramuscular injections of clodronate are an effective treatment³² but are burdened with the side effects of this first-generation bisphosphonate. There is evidence for an association with a genomic region containing an IL-1β single-nucleotide polymorphism,³³ which could explain the strong inflammatory component of the disease. The inventors claim that montelukast, a leukotriene receptor antagonist approved for the maintenance therapy of allergic conditions such as asthma, rhinitis, and urticaria, could provide a superior alternative when administered orally at 10–50 mg/day. Montelukast has already been reported to show effect in a murine meniscus destabilization model of knee osteoarthritis.³⁴ Two clinical trials (which do not seem to have been registered in the clinicaltrials.gov or EudraCT databases) are described where patients were administered 10 or 20 mg/day (if they did not respond to 10 mg/day) for 3–16 months. Highly significant reductions in pain and functionality scores as well as in radiological parameters are said to have been achieved. Topical formulations are also claimed. Hydroxychloroquine is another agent that has been clinically investigated as a repurposing candidate for erosive osteoarthritis of the hand but was ineffective.³⁵

A Uricosuric for a Rare Disease: and for Cancer

International Patent Application WO/2020/119784, New Application of Febuxostat and Derivatives Thereof (Inventors: Zhu W, Pan W; applicant: Geneheal Biotechnology Co. Ltd., China; published: June 18, 2020).

Adenylosuccinate lyase is an important enzyme in the complicated and energy-intense de novo purine synthesis pathway. Loss-of-function mutations of its gene affect purinosome assembly and cause adenylosuccinate lyase (ADSL) deficiency,³⁶ a rare autosomal recessive metabolic disorder where its two substrates (N-succinylcarboxamide-5-aminoimidazole ribonucleotide [SAICAR] and succinyladenosine) accumulate. Inhibitors of PAICS (the SAICAR synthetase) could provide relief in ADSL (purines would still be available through the salvage pathway), but they could also be a treatment for PAICS-overexpressing quickly growing tumors with a high purine demand.³⁷ Of at least equal importance is the fact that SAICAR activates the M2 isoform of pyruvate kinase; the SAICAR-PKM2 complex phosphorylates more than 100 human proteins (mostly other kinases), and it is required for sustained proliferative signaling of cancer cells.³⁸ As a follow-up to a series of SAICAR-related patent applications starting with WO/2018/059212, Geneheal has now turned its attention to febuxostat, a second-generation xanthine oxidase inhibitor used as a second-line uricosuric. The document provides no data but states that febuxostat reduced the formation of SAICAR and succinyladenosine in cultures of MD231 breast cancer and H1299 lung cancer cell lines, as well as rescuing the normal phenotype in a Caenorhabditis elegans ADSL model. In this context, it is interesting that French researchers claimed the older uricosuric, allopurinol for ADSL treatment in WO/2018/029430 [reviewed in ASSAY Vol. 16(5)]. Besides being a xanthine oxidase inhibitor, allopurinol also inhibits the purine salvage pathway enzyme, hypoxanthine phosphoribosyl transferase.³⁹

The First Approved NASH Drug: Soon for Liver Cancer?

International Patent Application WO/2020/128815, Saroglitazar for the Treatment of Hepatocellular Carcinoma (Inventors: Jain MR, Giri S; applicant: Cadila Health care Ltd., India; published: June 25, 2020).

Saroglitazar, a dual PPAR-α/γ agonist and a flagship research product of Zydus Cadila, was the first glitazar to be marketed anywhere; the Indian government approved it in June 2013 for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes not controlled by statins. Indian approval for therapy of nonalcoholic steatohepatitis followed in March 2020, but there are no U.S. or European approvals yet. Given the fact that hepatocellular carcinoma (HCC) frequently develops on the basis of cirrhosis, which is a feature of NASH, both conditions probably being due to disrupted PPAR-γ pathways,^40,41 the present move to claim saroglitazar for HCC is a logical one. Cadila shows convincing data from a murine model: C57BL/6 male mice were administered a choline-deficient, l-amino acid-defined, high-fat diet and HCC was induced by one-time intraperitoneal administration of diethylnitrosamine. Treatment with saroglitazar (1 or 3 mg/kg) was initiated after 8 weeks of diet initiation and continued for 27 weeks. The high-dose group had 40% and 44% lower ALT and AST serum levels, respectively, when compared with the elevated levels of these hepatic injury markers seen in disease controls not treated with saroglitazar, and no liver tumors were observed while these were present in more than 93% of controls. Even the 1 mg/kg dose reduced their prevalence to 20%. If translatable to clinical practice, these results would be extremely important: HCC, a cancer with limited pharmacotherapeutic options, is one of the few common malignancies with rising incidence.⁴²

A Discontinued Parkinson Disease Drug Candidate for Cancer

International Patent Application WO/2020/132325, Methods for Treating Cancer Using Tozadenant (Inventor and applicant: Kostrub C; published: June 23, 2020).

After the death of five patients from agranulocytosis and associated severe adverse events in a Phase III Parkinson's disease clinical trial of the A_2A receptor antagonist tozadenant (SYN-115), Acorda Therapeutics, Inc., announced discontinuation of the candidate drug in November 2017. With its Executive Director Preclinical Safety and Pharmacology as the inventor-applicant, the company now attempts repurposing for cancer, an obvious choice given the role of purinergic receptors in general,⁴³ and A_2A receptors in particular,⁴⁴ in malignancies. That antitumor immune responses evoked by PD-1 immune checkpoint blockade could be enhanced by tozadenant in mouse models was reported years ago.⁴⁵ The treatment claimed here is standalone, with maximum human oral doses (calculated based on the efficacious doses in the in the AT-3ova CD73⁺ breast tumor mouse model) in the range of only 0.6–0.9 mg, administered daily or in even longer intervals. This is a well-chosen model; high CD73 expression is associated with anthracycline resistance and a poor prognosis in triple-negative breast cancers.⁴⁶ Synergy with anti-PD-1 monoclonal antibodies was also confirmed in the murine CT26 colon carcinoma and B16F10 CD73 melanoma mouse models.

Footnotes

Abbreviations Used

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Drug Repurposing Patent Applications April–June 2020

Abstract

A Tricyclic Antidepressant Blocks Metastasis

Erythromycin-Derived Antibiotics Kill Senescent Cells

Connectivity Mapping Suggests a Former Gerd Drug Candidate for Nonalcoholic Steatohepatitis

Idebenone and Benzbromarone Target Goblet Cells Vial TMEM16

Fibrates for Neurodegenerative Diseases

A Beriberi Drug for Retinal Diseases

Intravenous Meloxicam for Patients with Platelet Dysfunction

A Discontinued Anorectic Drug for Rett Syndrome

An Asthma Drug for a Painful Chronic Hand Condition

A Uricosuric for a Rare Disease: and for Cancer

The First Approved NASH Drug: Soon for Liver Cancer?

A Discontinued Parkinson Disease Drug Candidate for Cancer

Footnotes

Abbreviations Used

References