Abstract
Radotinib For Creutzfeldt–Jakob Disease
In sporadic prion disease, the cellular prion protein PrPC, which is required for normal cellular function, is transformed into pathogenic PrPSc by post-translational processing; this induces a conformational change that creates multiple protease-resistant beta sheet structures. 1 Upon ingestion, PrPSc is absorbed by macrophages and follicular dendritic cells and begins to convert local PrPC when it reaches the spleen through the intestinal wall nerves and ultimately accumulates throughout the brain where it causes spongiform encephalopathy, variant Creutzfeldt–Jakob disease. Continuing from their earlier patent application (WO/2018/026150) that claimed radotinib for Parkinson's disease, 2 the inventors have now shown that this multityrosine kinase inhibitor (used for treating Philadelphia chromosome-positive chronic myeloid leukemia, as Supect®) 3 also is effective in prevention and treatment of prion disease. In an animal model (Syrian golden hamsters intraperitoneally infected with the 263K strain of scrapie), radotinib (100 mg/kg p.o.) significantly prolonged survival, with the surviving animals showing no clinical symptoms and very little prion deposition in the brain compared with deceased animals. The rare genetic diseases, Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia, are caused by mutations of the PRNP gene; these might also respond to Bcr-Abl kinase inhibitors, especially to those with good brain penetration, as seems to be the case with radotinib. Note Chinese Patent CN-102406648A claiming imatinib for Parkinson's disease, which was the original inspiration for Il-Yang's investigations, and a later report on its neuroprotective effects in prion infection. 4
Cutamesin, A σ1 Receptor Agonist, For Mitochondrial Diseases
A group of rare hereditary diseases comprising Friedreich's ataxia, Leber's optic neuropathy, MELAS (encephalomyopathy with lactic acidosis and stroke-like syndrome), Leigh encephalopathy, MERRF (red ragged fibers with myoclonus epilepsy syndrome), and others are caused by mutations of mitochondrial (and sometimes also nuclear) genes encoding proteins that are involved in the mitochondrial electron transport system. 5 Analogs of ubiquinone and radical scavengers (such as edaravone) are marginally effective for some symptoms, but cannot restore dysfunctional energy production by the respiratory chain. The inventor proposes σ1 receptor agonists as a solution. This receptor, which is linked circumstantially to a wide variety of signal transduction pathways, is mainly expressed on the endoplasmic reticulum and can associate with mitochondrial membranes to form mitochondria-associated membranes, structures that regulate Ca2+, lipid, and metabolite exchange between the endoplasmic reticulum and mitochondria. 6,7 The preferred compound is cutamesine (SA 4503), which MS Science has in-licensed from Santen Pharmaceuticals; it was in Phase II clinical trials for the treatment of Alzheimer's disease, poststroke recovery, 8 and depression, but has not yet been reported to act in mitochondrial disease. Provided data show cutamesine protecting rat retina-derived RGC-5 cells against the mitochondrial toxin rotenone. Neuromuscular features, often with multisystem involvement, predominate among the consequences of the more than 200 gene defects that cause mitochondrial diseases; this might give cutamesine applicability beyond central nervous system (CNS) conditions.
An Sglt2 Inhibitor Antidiabetic For a Difficult Form of Heart Failure…
Heart failure with (relatively) preserved ejection fraction (HFpEF) was once believed to represent a minority of heart failure cases, but actually it is at least on par with the classical type, which is characterized by a reduced ejection fraction. HFpEF mortality is high (up to 15% annually in community settings) and there is no disease-modifying treatment. 9 Sodium–glucose cotransporter 2 (SGLT2) inhibitors, a relatively new class of antidiabetic drugs that includes dapagliflozin, have demonstrated significant reductions in mortality and heart failure-related hospitalization in patients with type 2 diabetes and cardiovascular disease. Benefits of these drugs in heart failure should extend to patients without diabetes: SGLT2 inhibition promotes diuresis, leading to plasma volume contraction and reduced preload, and decreases in blood pressure, arterial stiffness, and afterload. 10 A 2018 article describes a mathematical model predicting that dapagliflozin would produce a twofold greater reduction in interstitial fluid volume compared with blood volume than the loop diuretic, bumetanide. 11 In August 2019, Chinese researchers reported that 9 weeks of dapagliflozin treatment decreased hypertension and reversed left ventricular concentric remodeling in a porcine model of HFpEF, partly by restraining the sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation, 12 but the July 2018 priority date of AstraZeneca's present patent application clearly preceded this. The clinical trial protocol that is described here seems to be the one for the Phase III DELIVER study (NCT03619213), which evaluates dapagliflozin 10 mg versus placebo; it commenced in August 2018, is recruiting its envisaged 6,100 patients, and is scheduled for completion in June 2021. For more repurposing of SGLT2 inhibitors, see WO/2020/020896, discussed below.
…And Another Sglt2 Inhibitor for a Genetic Kidney Disease
If a patient presents with glomerular hematuria with no obvious cause and bilateral, high-tone, sensorineural hearing loss and with lenticonus, or fleck retinopathy, Alport syndrome should be suspected. This is a rare genetic disease caused by mutations in any of the three COL4A genes that impair production, deposition, or function of the collagen IV network, the major collagenous constituent of mature basement membranes in the glomerulus, cochlea, cornea, lens, and retina.
13
To date, there is no curative treatment and despite interventions with renin–angiotensin system blockers, most patients with Alport syndrome will continue to face progressive loss of kidney function. The inventors claim that the antidiabetic SGLT2 inhibitor, empagliflozin (Jardiance®, codeveloped by Eli Lilly and Boehringer Ingelheim under a 2011 alliance) should provide a more effective option. This is not surprising: the antidiabetic mechanism of sodium–glucose cotransporter 2 inhibitors rests on their ability to increase urinary glucose excretion and diuresis in general; their positive effect on renal hemodynamics makes them nephroprotective.
14
Based on interim results from the EMPA-KIDNEY trial (NCT03594110), which also enrolled patients without diabetes, the FDA granted Jardiance Fast Track designation for the treatment of chronic kidney disease in March 2020. The outline of a clinical study comparing empagliflozin with placebo as add-on therapy with standard of care in patients with Alport syndrome (not yet found on
Warfarin, Ciclopirox, and Dihydroartemisinin For Retinitis Pigmentosa
In retinitis pigmentosa, disease progression is relatively protracted; therefore, pharmacological interventions aimed at slowing rod photoreceptor cell death have been widely investigated. 15 Neurotrophic factors, antiapoptotic agents, nutritional supplements, and antioxidants have been shown to provide neuroprotective effects in animal models, but these benefits translate to patients only to a very limited degree if at all. 16 HTS campaigns have generated promising leads, but the anticoagulant, warfarin, the antifungal, ciclopirox olamine, or the antimalarial, dihydroartemisinin, had so far not been among them. The inventor used a rho:YFP-NTR zebrafish larva model of metronidazole rod photoreceptor ablation to screen the Johns Hopkins Drug Library (∼3,000 largely human-approved compounds). This is an application of the ARQiv phenotypic drug discovery platform, which had evaluated over 500,000 transgenic larval zebrafish to identify drugs that stimulate an increase in the number of insulin-producing pancreatic beta cells. 17,18 TUNEL staining of larvae indicating primary hits and tests in primary mouse retinal cell cultures and rd1 mouse retinal explants validated the above-mentioned three compounds as cross-species neuroprotectants, capable of promoting photoreceptor survival in both fish and mouse models of retinitis pigmentosa. Combinatorial assays at optimal concentrations demonstrated additive effects in less than half of the tested compound pairs, indicating that complementary signaling pathways regulate cell death during this form of retinal degeneration. None of the three agents supported rod photoreceptor regeneration. For a discussion of WO/2020/040327 claiming ciclopirox for treating HBV infection, see below.
A Common Antifungal Might Eradicate Hepatitis B Virus Infection
The antifungal, ciclopirox, is no newcomer to drug repurposing; it has been claimed for retinitis pigmentosa in WO/2020/036658 (discussed above), for congenital erythropoietic porphyria in WO/2018/078081, for bladder cancer in WO/2016/077346, and for diabetic ulcers in WO/2003/088966—to name just a few examples. Ciclopirox modulates many enzymes and key pathways, most of which are at least indirectly influenced by its key activity, chelation of iron. 19 Its activity extends to inhibition of herpesviruses 20 and human immunodeficiency virus 21 and—as the present document shows—also to hepatitis B virus where it is said to be able to remove the viral cccDNA, which makes infection persistent—which is not achieved by current HBV drugs. 22 Ciclopirox does not reduce HBV core protein expression, but binds to it at several sites (in particular at Y118) and ultimately inhibits capsid assembly. HBV DNA discharged from HepG2.2.15 cells, and cccDNA and rcDNA present in the cells were reduced during ciclopirox treatment at 10 μM, a concentration that was not cytotoxic. Ciclopirox synergizes with entecavir (a deoxyguanosine analog) and tenofovir (a nucleotide analog reverse transcriptase inhibitor) and could become an important addition to orally active drug cocktails that actually eradicate the infection. For the peer review companion article, see Kang et al. 23
A Discontinued Insomnia Drug For Inflammatory Bowel Diseases
Gaboxadol is a δ-selective GABAA receptor agonist 24 that a Merck & Co.–Lundbeck partnership had pushed into Phase III insomnia trials before ending the development in March 2007. Gaboxadol (which is hallucinogenic at higher doses) was picked up by Ovid Therapeutics, which recoded it OV101. While the company is actively developing gaboxadol for Angelman syndrome (Phase III) and Fragile X syndrome (Phase II) under claims made in WO/2017/015049, it has been very busy filing patent applications covering various other repurposed uses: WO/2018/144827 (tinnitus); WO/2018/217718 (depression); WO/2019/028234 (diabetes); and WO/2019/055369 (narcolepsy). The current document makes claims for inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, and asthma (and is followed by WO/2020/061410 for Tourette syndrome and stuttering and WO/2020/097045 for movement disorders). That GABAA receptors regulate stress and inflammation is well known, but the mechanisms are as complex as the receptor itself: pharmacologic activation of α3-GABAA receptors induces colon inflammation in mice, whereas ligands at α1/4/5-GABAARs are anti-inflammatory. 25,26 Outlines for possible clinical studies in inflammatory bowel syndrome and asthma are presented, but there are no data to support the claims. While there is limited evidence for GABAA receptors containing δ-subunits being expressed in the gut, intestinal actions of gaboxadol might be explained by the gut–brain axis. Delta subunits are present in airway smooth muscles, and muscimol, the parent compound of gaboxadol, relaxes their histamine-induced contraction. 27
A Topical Statin For a Disfiguring Dermatological Condition
Inflammatory linear verrucous epidermal naevus (ILVEN) is a rare cutaneous hamartoma of unknown etiology, often confused with the equally unusual linear variant of psoriasis and first reported in the scientific literature 50 years ago. 28 The bands of intensely erythematous, inflammatory, and pruritic papules are benign, but highly resistant to noninvasive treatments of all types, whether topical, systemic, or laser (to which normal epidermal nevi tend to respond well). The genetics of ILVEN, which is mostly sporadic, has not been explored systematically; in particular, the condition has not previously been proposed to be a disorder of the cholesterol pathway or linked to a defect in normal cholesterol metabolism. This is precisely what the inventor suggests for a subset of cases in whom a combination of an HMG-CoA reductase inhibitor (simvastatin) and cholesterol, applied topically (2% w/w in Unguentum Merck, twice daily for a minimum of 3 months), produced good response. Of the 13 treated patients, 4 had clear improvements that were prolonged in 3 of the cases. Whole-exome sequencing suggests that mutations in NSDHL (coding for a cholesterol biosynthesis enzyme that is associated with the X-linked CHILD syndrome when mutated 29 ) and PMVK (coding for phosphomevalonate kinase; mutations are associated with porokeratosis, which responds to lovastatin/cholesterol 30 ) are present in responders. The association does not seem to be a strong one, but ILVEN patients have (statistically significant) lower average levels of cholesterol than non-ILVEN controls.
Discontinued Potassium Channel Openers Might Treat Sleep Apnea
Sleep apnea is a common medical condition present in a significant fraction of the adult population and particularly frequent in the morbidly obese. Treatment of severe cases (associated with significantly increased cardiovascular mortality) with continuous positive airway pressure masks and other devices is effective, but it disturbs sleep. Investigations of potential drug therapies have centered on increasing ventilatory drive, altering the arousal threshold, increasing stability of the ventilatory control system, or preventing airway collapse. 31 Here is a different idea: KCNQ (Kv7) potassium channel openers such as retigabine (also known as ezogabine) or flupirtine. Both agents had been marketed worldwide as CNS agents, but were withdrawn: GlaxoSmithKline pulled its retigabine-based anticonvulsant, Potiga®/Trobalt®, in 2017 because of ophthalmic side effects, and the European Medicines Agency withdrew market approvals for all flupirtine-based analgesics (which had never been available in the United States) in 2018 because cases of serious hepatotoxicity continued to be reported despite previous restrictions in use. Less pronounced KNCQ openers (diclofenac and meclofenamic acid) and various investigational agents are also claimed, and a study protocol to investigate peripheral chemoreceptor sensitivity with a KCNQ channel opener is presented. Open KCNQ channels hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells; they have been suggested as therapeutics for resistant hypertension, which is frequently associated with sleep apnea. 32,33 It would be interesting to see what a peripherally restricted drug of this type could achieve in sleep apnea.
Allopurinol May Preferentially Act on Certain Cancers
Rapidly dividing cancer cells rely heavily on the purine de novo pathway for synthesis of adenine and guanine, whereas normal cells favor the less resource-intensive salvage pathway. Enzymes in the purine biosynthesis pathway are therefore good potential targets for cancer therapeutics, especially if they are overexpressed in many cancers, such as the bifunctional phosphoribosylaminoimidazole Succinocarboxamide Synthetase (PAICS), 34 which participates in steps 6 and 7 and whose crystal structure has just become available. 35 This patent document seems to rely completely on a bioinformatic correlation between the PAICS gene expression as documented in the U.S. National Cancer Institute's Cancer Genome Atlas (which has molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types) and allopurinol sensitivity of cancer cell lines or actual cancers. Such correlations can be readily obtained from the literature, but without proof of a causal relationship (which the patent document does not offer), they might be spurious. For example, men chronically treated with allopurinol as a gout treatment may, 36 or may not, 37 have a lower risk of contracting prostate carcinoma, which requires PAICS expression for proliferation and invasion. 38 Similar cases could be made for lung and colon cancer. Allopurinol, an inhibitor of xanthine oxidoreductase and uric acid synthesis, reduces oxidative stress—which would also be a factor to correct for. See Geneheal's WO/2019/113724 for similar claims for the alcohol-aversive agent, disulfiram.
Antihyperlipidemic Pcsk9 Blockers For Allergy
Besides its canonical role as a natural inhibitor of the low-density lipoprotein receptor, PCSK9 is involved in inflammation as a critical regulator of the innate immune response. 39 Mice with a PCSK9 gain-of-function mutation display a reduction of blood and spleen regulatory T cells and a concomitant increase of CD3+/CD45+ T cells in their lungs. 40 The inventors have obtained preliminary data from oral allergy induction experiments in wild-type and PCSK9 knockout mice and show that under basal condition and in the absence of a particular stimulus, PCSK9 deficiency significantly increases the percentage of regulatory T cells in the spleen, mesenteric lymph nodes, and Peyer's patches. Moreover, inventors have shown the effect of allergic challenge in primary human bronchial epithelial cells on PCSK9 expression and secretion. House dust mite allergens strongly increase PCSK9 mRNA levels and intracellular PCSK9 protein content. It follows that PCSK9-blocking monoclonal antibodies (evolocumab, Amgen's Repatha®; alirocumab, Sanofi's Praluent®; and other inhibitors and therapeutic vaccines in clinical development—or discontinued—for statin-resistant hypercholesterinemia or sepsis) could be beneficial in asthma and other allergic diseases. However, no data are presented to actually demonstrate such a therapeutic effect.
Antabuse Has Distinct Influence on Inflammatory Airway Responses
Disulfiram (tetraethyldisulfane dicarbothioamide, an inhibitor or hepatic aldehyde dehydrogenase) has been used as an alcohol-aversive drug since the 1950s and is still widely used as a second-line drug to support postwithdrawal abstinence in alcoholics. It is also one of the drugs with the most extensive repurposing claims, which span the range from various cancers (WO/2015/120254, WO/2019/227530, WO/2019/113724, and others) to ophthalmology to HIV infection and rare diseases such as adenylosuccinase deficiency (WO/2019/113724). Although some putative effects of alcoholism drugs on the immune system have been reported, the literature holds nothing on their effects on Group 2 innate lymphoid cells (a relatively minor cell population comprising non-T–non-B cells, nuocytes, and natural helper cells) that are an important source of type-2 effector cytokines. 41 Suppressing the activity of these ILC2 cells could be important in inflammatory conditions. The inventors have found that disulfiram can reduce IL-5, IL-13, and eosinophils and modulate Th2 cells in the murine model of ovalbumin-induced asthma. The claims focus on eosinophilic respiratory diseases. This seems to be the only document discussing direct benefits of disulfiram for the general immune system, although the compound can lead to tumor-specific immune responses through induction of immunogenic cancer cell death. 42