Abstract
Xanthine Oxidase Inhibitors Prevent Metastasis
WO/2019/066469,
Febuxostat and topiroxostat are second-generation xanthine oxidase inhibitors that reduce uric acid production. Febuxostat came into broad use as a treatment for hyperuricemia and gout a decade ago, as a second-line treatment for patients who cannot tolerate allopurinol at the required doses. Febuxostat is as effective as allopurinol in the prevention of tumor lysis syndrome that goes along with massively elevated uric acid levels, 1,2 and it was also reported that febuxostat attenuates cachexia progression and improves survival of tumor-bearing rats. 3 However, no role of xanthine oxidase inhibitors in the prevention of tumor metastasis can be readily found in the literature until the inventors' peer-review companion article 4 that was preceded by this patent document, which focuses on topiroxostat. This agent seems to prevent induction of the metastatic state and cell migration in transwell assays with the 4T1 breast cancer cell line, and in tumor-bearing mice on a high-cholesterol diet. Several figures demonstrate changes in the applicable biomarkers. There is no immediate mechanistic explanation for these observations, but some associations are suggestive: high-plasma urate is both observationally and genetically associated with high cancer incidence. 5 The uric acid transporter SLC2A9 is a direct target gene of the p53 tumor suppressor protein. 6
Better Chances for Patients with Diabetic Heart Disease
WO/2019/069230,
In heart failure with left ventricle impairment, the diastolic phase is compromised but ejection fraction is preserved. There is no treatment for the causes (cardiomyocyte hypertrophy and increased interstitial collagen and calcium deposition within the myocardium) of this diabetes-associated condition, only symptom control. The French biopharma company Poxel believes that its late-stage candidate, imeglimin, might provide a solution. This is an oxidative phosphorylation blocker intended as an antidiabetic that inhibits hepatic gluconeogenesis, increases muscle glucose uptake, and restores normal insulin secretion. 7 Imeglimine has completed phase I and phase II clinical studies involving >1,200 subjects with type 2 diabetes in the United States and Europe (areas where it has been out licensed to Roivant Sciences), and Japan (where it is out licensed to Sumitomo Dainippon Pharma). The rationale is that diabetes causes left ventricular dysfunction early and independently of blood glucose control. 8 Data from obese Zucker rats treated with imeglimine (doses not stated) for 9 and 90 days show left ventricle end-diastolic blood pressure, the left ventricle relaxation constant tau, and end-diastolic pressure–volume relation, cardiac output, and myocardial perfusion changing toward the normal levels seen in lean control rats. This indicates metabolic changes in the myocardium, consistent with the observation that imeglimin improves liver mitochondrial function in a high-fat high-sucrose diet mouse model. 9
From Bowel Inflammation to Diabetes Complications
WO/2019/074406,
Sulfasalazine was originally created with the intent to combine an antibiotic (sulfapyridine) and an anti-inflammatory agent (5-aminosalicylic acid [5-ASA]). Introduced in the mid-20th century, it is on the WHO List of Essential Medicines as a first-line therapy for inflammatory bowel diseases and rheumatoid arthritis. Sulfasalazine and its 5-ASA metabolite act as inhibitors of NF-κB 10 but it also is one of the few established inhibitors of Sxc − (a cystine–glutamate antiporter), which gives it some cancer-sensitizing properties. 11 Nowhere does the literature report that sulfasalazine could counteract the formation of advanced glycation endproducts (AGE), the major mediators of vascular and tissue complications in uncontrolled diabetes. The inventors present limited data that could suggest superiority over aminoguanidine (IC50 values in an in vitro assay, 23.9 μM vs. 765 μM) and pyridoxamine, another AGE formation inhibitor that has been in clinical trials and seems to act through radical scavenging. The inventors show no data concerning the anti-AGE mechanism of sulfasalazine—Note WO/2019/074908 claiming sulfasalazine salts for intractable epilepsy, probably exploiting the cystine–glutamate antiporter activity.
A Repurposed Biological
WO/2019/076883,
Pulmonary disease due to nontuberculous mycobacteria (NTM) first came to prominence with the HIV epidemic but is now recognized to be a major cause of chronic lung disease, and especially bronchiectasis, in apparently immunocompetent people. It typically requires treatment with at least three high-dose antibiotics for a minimum of 18 months, which has an overall success rate of no more than 50%. The inventors claim that refractory cases can benefit from inhalation of nebulized GM-CSF, which is not particularly surprising: GM-CSF (used to speed bone marrow repopulation and to treat neutropenia induced by chemotherapy for myeloid leukemia) is known to stimulate alveolar macrophages, causing protection against mycobacterial infection by enhancing cytokine production. 12 GM-CSF pathway overexpression during acute Mycobacterium tuberculosis infection contributes to an efficient M1 response 13 and an inhalable formulation has been used to treat Mycobacterium abscessus infection in cystic fibrosis patients. 14 Interestingly, GM-CSF production is already enhanced in NTM patients, 15 but apparently not to a sufficient degree. In one of the three case reports that are presented, administration of aerosolized sargramostim (yeast-produced recombinant GM-CSF; 250 μg twice daily every second week) to a cystic fibrosis patient resulted in clinically highly significant improvements in forced vital capacity and expiratory volume.
Rebastinib for Facioscapulohumeral Muscular Dystrophy
WO/2019/084499,
This patent application illustrates one of the relatively rare cases wherein a third party claims an investigational drug candidate for a repurposed use. Genea Biocells (San Diego, CA), a neuromuscular disease-focused preclinical stage company, has latched on rebastinib, 16 a TIE2 immunokinase inhibitor in early-stage clinical development for metastatic solid tumors by Deciphera Pharmaceuticals, Inc. (Waltham, MA). Other specifically mentioned compounds include the kinases sorafenib and imatinib, and the immune modulator doramapimod. The claims are for the treatment of facioscapulohumeral muscular dystrophy, 17 a rare disease caused by hypomethylation and inappropriate muscle expression of DUX4, a double-homeodomain retrogene that is epigenetically repressed in normal somatic tissues. 18 Inhibitors of the Src, Tie, Abl, Trk, Fit, Yes, Fak, and PRKDC kinase families are claimed to be suitable for downregulating DUX4 activity, and some of these general claims are supported by in vitro data. Most of the data are for rebastinib, which Genea calls GBC0905 in its repurposed use for which the U.S. Food and Drug Administration granted orphan drug status in 2018.
An Antipsychotic for Chemotherapy Diarrhea
WO/2019/085827,
Bacterial β-glucuronidase is a pivotal factor in the almost intractable diarrhea that occurs as a dose-limiting side effect of the colorectal cancer drug, irinotecan: this enzyme converts the non-toxic primary metabolite of irinotecan into a secondary toxic metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). 19 The inventors have embarked on a virtual screening effort to identify inhibitors of the bacterial (but not the mammalian) enzyme among known drugs, identified norclozapine (the major active metabolite of the antipsychotic clozapine) as an excellent candidate, and verified this in vitro (IC50 ∼10 nM). The problem is that SN-38 is the major active metabolite of irinotecan that not only contributes much to its anticancer effects but also has anti-inflammatory activity through the TLR4 receptor. 20 For the peer review companion article, see Chen et al. 21 Also see the inventors' closely related earlier work with amoxapine in Kong et al. 22
Ketanserin and Antidepressants for Hemorrhagic Virus Fever
WO/2019/088926,
European approval for the first protective vaccine against dengue virus infection came in late 2018, followed by U.S. Food and Drug Administration approval in May 2019; however, these approvals were issued with major restrictions and the World Health Organization recommended use only in people who are known to have had a previous infection. In contrast, there is still no specific treatment for dengue fever. One of its major complications is thrombocytopenia that results from the release of mast cell serotonin into the circulation, an event that also occurs with other hemorrhagic viruses. Instead of just inhibiting serotonin release from mast cells by mast cell stabilizers such as ketotifen 23 or 5-HT1A receptor antagonists, the inventors propose to additionally inhibit serotonin uptake by platelets using serotonergic antidepressants (fluoxetine, paroxetine, and citalopram) and inhibition of serotonin activity on platelets with 5-HT2A receptor antagonists (such as ketanserin, ritanserin, pindolol, risperidone, or quetiapine), Erk pathway inhibitors, or serotonylation inhibitors. Figures show data for thrombocytopenia prevention (without effect on viremia) for ketanserin and fluoxetine in mice infected with dengue virus type 2 and Japanese encephalitic virus. Impeding platelet activation could also prevent vascular leakage, 24 another major complication in hemorrhagic dengue fever. Obviously, other inhibitors of pathways involved in platelet activation, such as those targeting platelet glycoprotein llb/llla or the adenosine receptor, could also be utilized. For the peer review companion article, see Masri et al. 25 Notably, another mode of platelet activation by dengue virus works through binding of a nonstructural viral protein to TLR4 receptors. 26
Cardiac Arrythmia has a New Treatment Option
WO/2019/095056,
Pharmacological treatments for cardiac dysfunction exclusively target the deleterious neurohormonal activation and fibrosis but address arrythmia only insufficiently. The ryanodine receptor blocker dantrolene, which inhibits calcium release from the sarcoplasmic reticulum, 27 was originally intended as a general muscle relaxant for spasticity, but soon found a more specific use in malignant hyperthermia. 28 In animal models of cardiac arrest, dantrolene is acutely protective against subsequent cardiac arrhythmia 29 ; however this is not useful in therapy. The inventor has found that resynchronizing calcium cycling in cardiac tissue that had been made dyssynchronous leads to better contractile function. As a consequence, he claims chronic dantrolene treatment of patients who are likely to develop dyssynchronous cardiac dysfunction, without regard to whether such a patient has previously experienced a cardiac arrhythmia or cardiac arrest, based on resynchronization of calcium cycling. Data from cardiac stress tests performed in 20 healthy volunteers (mean age 65 ± 9 years) on chronic oral dantrolene are presented; also 10-year retrospective data from patients from the Malignant Hyperthermia Clinic at Toronto General Hospital who received dantrolene for at least 3 months. During a mean of 10.9 ± 6 years follow-up, no major cardiac events (serious arrhythmia, sudden death, or myocardial infarction) were noted. All electrocardiograms revealed sinus rhythm. For the peer review companion article, see Bokhari et al. 30
Benzoic Acid Salts are Antidepressants
WO/2019/103597,
Among the most exciting experiences a drug-repurposing scientist could have is to find promising pharmaceutical potential in a nondrug compound. In the case of benzoic acid salts (which are not only widely used as food additives, but occur naturally in many foods, including milk products), the excitement is not new: it has been known for >70 years that sodium benzoate is a DAAO inhibitor. 31 It can raise synaptic concentrations of D-serine and other D-amino acids, which stimulate the NMDA receptor 32 —and cerebral NMDA hypofunction is implicated in the pathophysiology of major depression. 33 Case reports of drug-naive depressive patients exhibiting volume increases of brain regions critical for depression and cognition upon treatment with sodium benzoate have been published by one of the present inventors. 34,35 Although the obviousness indicators are overwhelming, the peer review record does not seem to contain investigations with benzoic acid salts that have measured behavioral or clinical measures of depression. The inventors report an 8-week pilot clinical trial in patients with major depression treated with sodium benzoate (250–1,500 mg/day) or placebo (n = 20 + 20). The 17-item Hamilton Rating Scale for Depression and the Perceived Stress Scale, but not the Global Assessment of Function, showed significant group differences at endpoint. Some patients also improved on cognitive scores, which is consistent with glutamatergic neurotransmission being involved in cognitive disturbances.
Modified Antibiotics Target Cancer Cell Mitochondria
WO/2019/108729,
Functional mitochondria are required for the propagation of cancer stem cells. Because of the conserved evolutionary similarities between aerobic bacteria and mitochondria, certain classes of antibiotics or compounds having antibiotic activity can inhibit mitochondrial protein translation as an off-target side effect. The inventors have reported earlier that several classes of nontoxic antibiotics could be used to halt cancer stem cell propagation. 36 They have now chemically modified such antibiotics with one or more mitochondria-targeting moieties (tri-phenyl-phosphonium [TPP], fatty acids, or guanidinium) to endow them with enhanced anticancer properties. This is the MITO-ONC-RX technology platform reported in the peer review companion article. 37 Antibiotics from the tetracycline family, erythromycin, as well as chloramphicenol and levofloxacin, can be derivatized in this way. Being modified from the known drugs, these “repurposcins” are technically not repurposed compounds, but they certainly advance and broaden the concept. Data demonstrate the effects of tigecycline TPP derivatives on cell viability and intracellular ATP levels in hTERT-BJl normal fibroblasts and in MCF-7 human breast cancer cells, where mammosphere forming is inhibited.
Antihelminthics and Fungals Target Pulmonary Hypertension
WO/2019/111829,
Idiopathic pulmonary arterial hypertension is a deadly disease, modifiable to a degree by treatment with endothelin receptor blockers, PDE5 inhibitors (sildenafil, a classic case of on-target repurposing), and prostanoids; kinase inhibitors are under investigation for this therapeutic indication. Japanese researchers have now identified other repurposing candidates that are as much off-target as one could imagine: the antihelminthic mebendazole and the antifungal itraconazole. Data obtained with various established animal models show clear effects in terms of size and weight of the right heart ventricle as well as pulmonary circulation pressure. The patent document does not indicate possible mechanisms, but the peer review companion article, 38 published a few months after this document, reveals that mebendazole reduced expression of ADAMTS8. This secreted disintegrin and metalloproteinase is specifically expressed in the lung and the heart and was found to be upregulated in the lungs of mice with hypoxia-induced pulmonary hypertension. In cancer, which resembles the excessive growth of the pulmonary arterial wall in some ways, ADAMTS8 targets Erk, 39 a kinase that is also involved in pulmonary arterial hypertension.
A Muscle Relaxant for Behavioral Problems in Dementia
WO/2019/116091,
Cyclobenzaprine has been in use as a centrally acting muscle relaxant since the late 1970s. The utility of very low dose sublingual tablets (TNX-102 SL) to treat sleep disturbances, especially in the context of fibromyalgia 40,41 and chronic fatigue syndrome, has previously been investigated by the applicant (see WO/2013188847). Tonix is now extending the claims for TNX-102 SL to the prevention or treatment of behavioral and psychological symptoms of dementia (BPSD), with or without interference with sleep, and to cognitive decline or dementia in neurodegenerative conditions. This is an obvious consideration for a brain-penetrant compound that is primarily a 5-HT2 receptor antagonist with additional α1 adrenergic antagonism; atypical antipsychotics, all of which have this type of activity to varying degrees in addition to their dopaminergic antagonism, are frequently used off-label to treat BPSD. The presented data, with sublingual cyclobenzaprine doses from 2.8 mg upward, focus on early-stage clinical studies that had been conducted in patients with post-traumatic stress disorder. A phase III study, NCT03841773, was ongoing in December 2019. A protocol outline for an 8-week clinical study in 160 patients with Alzheimer's disease is presented.—Note that cyclobenzaprine is known for its anticholinergic side effects, 42 which are of course undesirable in impaired cognition but should be irrelevant given the low dose and the partial bypass of the hepatic circulation, minimizing the longer lasting effects of the primary active metabolite, norcyclobenzaprine.
Eradication of Human Immunodeficiency Virus with a Porphyria Drug
WO/2019/123435,
When the human immunodeficiency virus enters a cell, its reverse transcriptase transcribes its RNA genome into a cDNA strand, synthesizes a complementary sense strand, and its integrase component inserts the resulting viral duplex DNA into the cellular genome, where the virus becomes latent and persistent. To eradicate HIV completely, latency-reversing agents must be used to induce HIV provirus expression, thus exposing persistently infected cells to killing by cellular immunity or apoptosis. 43 Inducers of PKC expression, such as nontumorogenic phorbol esters and HDAC inhibitors, or bryostatin are suggested for this purpose. An in vitro synergistic effect of phorbol myristate acetate with Normosang® (a heme arginate 44 drug used for treatment of acute porphyria) on reactivation of latent HIV-l has been reported by the inventors 45 ; the theory being that heme, and probably also heme arginate, acts as a strong “danger signal” for the immune system and at the same time as a reverse transcriptase inhibitor and an immunomodulatory agent. The inventors now claim a method that might achieve the very first cure of HIV-1 infection in humans. In a trial with eight HIV-positive individuals, single doses of Normosang (3 mg hemin per kilogram of body weight i.v.) were administered alone (without added PKC inducers) on top of standard combination antiretroviral therapy. Reactivation of latent HIV-1 was achieved in vivo, followed by decrease of the size of the latent virus cellular reservoir as measured by the population of CD32a+ CD4+ T lymphocytes and as amount of reactivable HIV-l at the RNA level. A decrease to some 68% of initial values was observed in three of four patients after 2 weeks. Obviously, repeated administration of heme arginine can be supposed to be more effective.