2-Hydroxy-Octadecene-9-Cis-Oate for use in the treatment of oncological pathologies and neuropathic pain.

Abstract

The present invention relates to the compound 2-hydroxy-octadecene-9-cis-oate for use in the treatment of oncological pathologies including grade IV glioblastoma with native IDH, grade 3 glioma, embryonal tumour, pituitary tumour, meningioma, haemangiopericytoma, haemangioblastoma, mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, rectal cancer, urachal cancer, adenocarcinoma of the bladder and oesophageal cancer, and for the treatment of neuropathic pain caused by diabetic peripheral neuropathy, spinal cord injury, post-herpetic neuralgia, chemotherapeutic agent, antitumour agent, cancer, fibromyalgia or hepatitis. The present invention also relates to the pharmaceutical composition comprising 2-hydroxy-octadecene-9-cis-oate.

Description

1 / 76 2-Hydroxy-Octadecene-9-Cis-Oate for use in the treatment of oncological pathologies and neuropathic pain. TECHNICAL FIELD OF THE INVENTION

[001] The present invention relates to the use of 2-hydroxy-octadecene-9-cis-oate (HOCO), a monounsaturated fatty acid derivative hydroxylated at the alpha carbon, its salts or esters, for the treatment of oncological pathologies of the central nervous system and related pathologies and for the treatment of neuropathic pain caused by said oncological pathologies, due to their treatment with antitumor agents, chemotherapeutic agents, as well as diabetic peripheral neuropathy, post-herpetic neuralgia, neuropathic pain after nerve or spinal cord injury, due to fibromyalgia or hepatitis. FUNDAMENTALS OF THE INVENTION

[002] Dietary lipids, including fatty acids, can regulate the lipid composition of cell membranes. Alterations in membrane lipid composition are known to influence cell signaling, which can lead to the development of diseases, or reverse them, as well as prevent them. Similarly, therapeutic, nutraceutical, or pharmacological interventions focused on regulating membrane lipid levels can prevent and reverse (cure) pathological processes. Petition 870250089276, dated 10 / 01 / 2025, p. 10 / 92 2 / 76

[003] Currently, it is known that cell membranes are related to multiple cellular processes. On the one hand, they support proteins involved in cell signaling that regulates important organic parameters. This signaling, mediated by numerous hormones, neurotransmitters, cytokines, growth factors, etc., activates membrane proteins (receptors), which propagate the received signal into the cell through other proteins (peripheral membrane proteins), some of which are also located in the membrane. Since (1) these systems function as amplification cascades and (2) membrane lipids can regulate the location and function of such peripheral proteins (plasma membrane or inner membrane or active or inactive cytoplasm), the lipid composition of membranes can have a large impact on cellular functionality.In particular, the interaction of certain peripheral proteins, such as G proteins, protein kinase C, RAS protein, etc., with the cell membrane depends on the membrane's lipid composition. Conversely, the lipid composition of cell membranes is influenced by the type and amount of lipids ingested. It follows that lipid intake can regulate the lipid composition of membranes, which in turn can control the interaction (and therefore the activity) of important cell signaling proteins. Petition 870250089276, dated 10 / 01 / 2025, page 11 / 92 3 / 76

[004] In the state of the art, tests have been carried out demonstrating the therapeutic activity of 2-hydroxyoctadecene-9-cis-oate (HOCO), a monounsaturated fatty acid derivative hydroxylated at the alpha carbon, in the treatment of various diseases.

[005] There are patients suffering from various types of cancer with poor prognoses and unmet medical needs. Similarly, there are patients suffering from neuropathic pain, in whom treatment with conventional analgesics is not sufficiently effective and who therefore have unmet medical needs. In view of this, there is a need to offer new treatments for these patients. DESCRIPTION OF THE INVENTION

[006] Thus, the expression “pharmaceutically acceptable salt” refers to a salt or ester of a compound that also possesses the desired pharmacological activity of the original compound from which it is derived.

[007] The term "maintenance treatment" or "maintenance therapy" is defined as a therapeutic treatment administered as a complement to a main or primary treatment or therapy, with the purpose of both preventing or delaying the recurrence of the disease, which has been completely or partially remitted after treatment with a primary treatment or therapy, and delaying the Petition 870250089276, dated 10 / 01 / 2025, page 12 / 92 4 / 7 6 Development of a disease after the end of treatment with a primary therapy.

[008] The expression “effective amount” or “therapeutically effective amount” refers to the amount of a drug that provides a therapeutic effect without causing unacceptable toxic effects to the patient. The effective amount or dose of the drug depends on the compound and the condition or disease being treated, including, for example, the age, weight and clinical condition of the patient being treated, the route of administration, the patient’s medical history, the severity of the disease and the potency of the compound administered.

[009] The term “RANO” (from the English Response Assessment in Neuro-Oncology) refers to the criteria for evaluating response in neuro-oncology, which are used in clinical trials and in clinical practice (Brandsma and van den Bent).

[0010] The term “RECIST” (from the English Response Evaluation Criteria In Solid Tumors) refers to the evaluation criteria in solid tumors, which are used in patients with primary and / or metastatic cancer or recurrent metastatic disease (Lencioni et al.).

[0011] The term “PR” (from the English Partial Response) refers to a partial response and corresponds to a decrease in Petition 870250089276, dated 10 / 01 / 2025, page 13 / 92 5 / 76 size of a tumor or cancer grade in the body in response to treatment. Also called partial remission.

[0012] The term SD (from the English Stable Disease) refers to a stable disease, when the cancer does not decrease or increase in severity.

[0013] The term AE (Adverse Event) refers to an adverse effect, understood as an unexpected medical problem that occurs during treatment with a drug or other therapy. Side effects are mild, moderate, or severe and may have causes other than the drug or therapy being used. Also called an adverse event.

[0014] The term NCI-CTCAE (from the English National Cancer Institute-Common Terminology Criteria for Adverse Events) refers to the common terminological criteria for adverse events of the National Cancer Institute of the United States.

[0015] The problem of the state of the art consists in providing a compound for use in the treatment of various types of cancer with poor prognosis and / or low life expectancy and in the treatment of neuropathic pain, caused by diabetic peripheral neuropathy, post-herpetic neuralgia, spinal cord injury, chemotherapeutic agent, antitumor agent, cancer, fibromyalgia or hepatitis.

[0016] The present invention provides a solution to the aforementioned technical problem. Petition 870250089276, dated 10 / 01 / 2025, p. 14 / 92 6 / 76

[0017] The present invention provides the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of a selected oncological pathology from the group consisting of glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthangustrocytetoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma.small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma of the colon, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, pancreatic neuroendocrine cancer, adenocarcinoma of the, Petition 870250089276, dated 10 / 01 / 2025, page 15 / 92 7 / 76 pancreas, chondrosarcoma of the uterus, adenocarcinoma of the cecum, adenocarcinoma of the bladder, esophageal cancer and metastatic small cell esophageal cancer, which is administered at a dose of 500 mg / day to 16,000 mg / day.

[0018] 2-hydroxy-octadecene-9-cis-oate (HOCO) is a monounsaturated fatty acid with the formula COOH-CHOH- (CH2) 6-CH=CH- (CH2) 7-CH3

[0019] The present invention also provides the use of the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of a selected oncological pathology from the group consisting of glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthanastrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, papilloma of the choroid plexus, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, Petition 870250089276, dated 10 / 01 / 2025, page 16 / 92 8 / 76 pancreatic neuroendocrine cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmotic colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, pancreatic neuroendocrine cancer, pancreas, chondrosarcoma of the uterus, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer and metastatic small cell esophageal cancer, wherein said compound, salt or ester is administered at a dose of 500 mg / day to 16,000 mg / day.

[0020] The present invention further provides a method of treating a selected oncological pathology from the group consisting of glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthoastrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, Petition 870250089276, dated 10 / 01 / 2025, page 17 / 92 9 / 76 choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmotic colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic microcytic esophageal cancer. comprising administering the compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, to an individual at a dose of 500 mg / day to 16,000 mg / day.

[0021] In phase I clinical trials with the sodium salt of HOCO (HOCOS, COONa-CHOH-(CH2) 6-CH=CH-(CH2) 7-CH3) as monotherapy in patients with various types of cancer who did not respond to antitumor therapy, the safety and efficacy of the compound against these types of cancer were observed (Example 1). Petition 870250089276, dated 10 / 01 / 2025, page 18 / 92 10 / 76

[0022] Brain tumors have different molecular and cellular characteristics, and therefore their treatment varies according to the type of tumor. Furthermore, it has been proven that pediatric brain tumors differ from tumors in adults, mainly from a molecular point of view, which means that their treatment is different from that applied to adult patients. When the brain tumor originates from glial cells, it is called a glioma and is classified, according to the type of glial cell involved, into astrocytomas, ependymomas, and oligodendrogliomas. Astrocytomas originate from connective tissue cells called astrocytes. They are the most common primary intraaxial tumors. It is the most common type of glioma. Ependymomas develop from ependymal cells that line the ventricles. They represent 2% of all brain tumors. They are the most common in children. Oligodendrogliomas are formed from oligodendrocytes, the supporting cells of the brain.They represent between 1% and 2% of all brain tumors. They are more common in adults.

[0023] Glioblastoma is an astrocytoma that develops in the brain, cerebellum, or spinal cord. Glioblastomas account for about 15% of all brain tumors. Therefore, they are one of the most common types of primary brain tumors. Glioblastomas can affect people Petition 870250089276, dated 10 / 01 / 2025, page 19 / 92 Glioblastomas occur in 11 / 76 of any age, but are more common in adults. They are very aggressive, grow rapidly, and can spread throughout the brain. They rarely spread outside the brain. Due to these characteristics, glioblastoma can be very difficult to treat and is usually not curable. In this sense, the average overall survival (OS) of patients with glioblastoma is about 14 months with the current standard treatment, which consists of radiotherapy and temozolomide, a treatment that has not changed in the last 20 years.

[0024] At the time of conducting the human trials completed in the present invention, glioblastomas were considered high-grade gliomas (III and IV), defined by genetic and epigenetic alterations. Grade IV glioblastomas may present various mutations. The type of grade IV glioblastoma with native isocitrate dehydrogenase (IDH) enzyme is the most aggressive and, currently, there are no effective treatments against this subtype of glioblastoma.

[0025] In embodiments of the compound, salt or ester for use in the invention, the oncological pathology is selected from the group consisting of oligoastrocytoma, glioblastoma, oligodengroglioma, ependymoma, xanthoastrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical teratoid rhabdoid tumor, tumor of Petition 870250089276, dated 10 / 01 / 2025, page 20 / 92 12 / 76 cranial and spinal nerve, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectosigmoid junction cancer, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial cancer, neuroendocrine pancreatic cancer, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, Esophageal cancer and metastatic small cell esophageal cancer.

[0026] In embodiments of the compound, salt or ester for use in the invention, the glioblastoma is a grade IV glioblastoma multiforme with native isocitrate dehydrogenase (IDH) enzyme.

[0027] In embodiments, the compound, salt or ester for use of the invention is for use in the treatment of native IDH grade IV glioblastoma multiforme in an individual with methylation of the methylguanine methyltransferase (MGMT) gene promoter. Petition 870250089276, dated 10 / 01 / 2025, p. 21 / 92 13 / 76

[0028] In embodiments of the compound, salt or ester for use in the invention, the salt is sodium salt.

[0029] In embodiments of the compound, salt or ester for use in the invention, the ester is methyl ester or ethyl ester.

[0030] In embodiments of the invention, the compound, salt or ester is administered orally.

[0031] In embodiments of the invention, the compound, salt or ester is administered at a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day. Preferably, the compound, salt or ester of the invention is administered at a dose of 2,100 mg / day or 12,000 mg / day.

[0032] In embodiments of the invention, the compound, salt or ester is administered in two doses per day, in doses selected from the group consisting of 250 mg, 500 mg, 1,000 mg, 2,000 mg, 4,000 mg, 6,000 mg and 8,000 mg.

[0033] In embodiments of the invention, the compound, salt or ester is administered in three doses per day, in doses selected from the group consisting of 1,050 mg, 2,100 mg, 4,000 mg and 4,200 mg. Petition 870250089276, dated 10 / 01 / 2025, page 22 / 92 14 / 76

[0034] In embodiments of the invention, the compound, salt or ester is administered at a dose of 2,100 mg / day, in three daily doses of 700 mg each.

[0035] In embodiments of the invention, the compound, salt or ester is administered at a dose of 12,000 mg / day, in three daily doses of 400 mg each.

[0036] In embodiments of the invention, the compound, salt or ester is used as a first-line treatment.

[0037] In embodiments of the compound, salt or ester for use of the invention, first-line treatment comprises 4-week cycles, wherein each cycle comprises administering the compound, salt or ester daily during the first three weeks of each cycle and wherein no treatment is administered during the fourth week.

[0038] In embodiments of the invention, the compound, salt or ester is used as a pre-surgical or post-surgical treatment to reduce the size of a tumor.

[0039] In embodiments of the compound, salt or ester for use in the invention, the individual receiving the treatment has been previously treated with at least one and up to five different lines of chemotherapy treatment.

[0040] In embodiments of the invention, the compound, salt or ester is used as a maintenance treatment.

[0041] In embodiments of the compound, salt or ester for use of the invention, the maintenance treatment comprises cycles Petition 870250089276, dated 10 / 01 / 2025, p. 23 / 92 15 / 76 of 4 weeks, in which each cycle comprises administering the compound, salt or ester daily during the first three weeks of each cycle and in which no treatment is administered during the fourth week.

[0042] In a phase II / III clinical trial that is part of the present invention, first-line treatment with HOCOS combined with radiotherapy and temozolomide was investigated in newly diagnosed patients with native grade IV glioblastoma multiforme (Example 2). Treatment of various cancer types with HOCOS, in combination with various chemotherapeutic agents, was investigated in cell line assays (Example 3).

[0043] In embodiments of the compound, salt or ester for use of the invention, the treatment comprises: - a chemoradiotherapy phase lasting 6 to 7 weeks, comprising administering radiotherapy daily, 5 days a week; administering a second chemotherapeutic agent at a daily dose of 75 mg / m2 starting on the first day of radiotherapy; and administering the compound, salt or ester at a dose of 12,000 mg / day for 4 weeks starting from week 3, counted from the beginning of radiotherapy; - a 4-week treatment rest period; - a maintenance period of 6 cycles of 4 weeks each, in which each cycle comprises administering the second chemotherapeutic agent at a daily dose of 150 to 200 mg / m2, in Petition 870250089276, dated 10 / 01 / 2025, p. 24 / 92 16 / 76 first five days of each cycle; administer the compound, salt or ester at a dose of 12,000 mg / day during the first three weeks of each cycle, and during the fourth week no treatment is administered; and - a monotherapy phase of 4-week cycles, in which each cycle comprises administering the compound, salt or ester at a dose of 12,000 mg / day during the first three weeks of each cycle and in which no treatment is administered during the fourth week, with said cycles continuing indefinitely as maintenance therapy.

[0044] In the previous embodiment and in other subsequent embodiments, determined daily doses were expressed in mg / m2, based on the body surface area of ​​the individual to be treated, as is usual in the state of the art.

[0045] In preferred embodiments of the compound, salt or ester for use in the invention, the treatment comprises: - a chemoradiotherapy phase lasting 6 to 7 weeks, comprising administering radiotherapy daily, 5 days a week; administering temozolomide at a daily dose of 75 mg / m2 from the first day of radiotherapy; and administering HOCOS at a dose of 12,000 mg / day for 4 weeks starting from the third week, counted from the beginning of radiotherapy; - a 4-week rest period; Petition 870250089276, dated 10 / 01 / 2025, page 25 / 92 17 / 76 - a 4-week maintenance period with 6 cycles, in which each cycle comprises administering temozolomide at a daily dose of 150 to 200 mg / m2 for the first five days of each cycle; administering HOCOS at a dose of 12,000 mg / day during the first three weeks of each cycle, and during which no treatment is administered during the fourth week; and - a monotherapy phase with 4-week cycles, in which each cycle comprises administering the compound, salt or ester at a dose of 12,000 mg / day during the first three weeks of each cycle and in which no treatment is administered during the fourth week, with said cycles continuing indefinitely as maintenance therapy.

[0046] In embodiments of the compound, salt or ester for use in the invention, radiotherapy is administered at a daily dose of 2 Gy.

[0047] In some embodiments, the compound, salt or ester of the invention is for simultaneous, separate or sequential use in combination with a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib and cisplatin.

[0048] In some embodiments, the compound, salt or ester for use of the invention is for simultaneous, separate or sequential use in combination with temozolomide, in the treatment of Petition 870250089276, dated 10 / 01 / 2025, p. 26 / 92 18 / 76 glioblastoma. Preferably, the glioblastoma is a native IDH grade IV glioblastoma multiforme.

[0049] The invention also provides the compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of neuropathic pain, which is administered at a dose of 500 mg / day to 16,000 mg / day.

[0050] Neuropathic pain is not conventional pain triggered by specific analgesic pain receptors, characteristic of cuts, blows, burns, and the like. Neuropathic pain can originate from various types of events, including neuronal injury, nerve injury of the central and / or peripheral nervous system, a chemotherapeutic agent, an antitumor agent, cancer, diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia, and hepatitis.

[0051] Most patients suffering from this type of neuropathic pain are treated with several very potent and toxic drugs, with very modest therapeutic results. An example is spinal cord injury, which has proven resistant to treatment with opioids, a family of drugs that are generally very potent for other types of pain (Rodgers et al.). Thus, patients with neuropathic pain receive anticonvulsants, anxiolytics, Petition 870250089276, dated 10 / 01 / 2025, page 27 / 92 19 / 76 antidepressants, opioids and even anesthetics, which allows them to tolerate it only momentarily.

[0052] The present invention also provides the use of the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a drug for the treatment of neuropathic pain.

[0053] The present invention further provides a method for treating neuropathic pain, comprising administering an effective amount of the compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, to an individual.

[0054] In embodiments of the compound, salt or ester for use in the invention, neuropathic pain is caused by neuronal damage or nerve damage to the central and / or peripheral nervous system. Preferably, the neuronal damage is a spinal cord injury.

[0055] In embodiments of the compound, salt or ester for use in the invention, neuropathic pain is caused by a cause selected from the group consisting of a chemotherapeutic agent, an antitumor agent and cancer. Preferably, the antitumor agent is an alkaloid. More preferably, the alkaloid is vincristine.

[0056] In embodiments of the compound, salt or ester for use in the invention, neuropathic pain is caused by a cause selected from the group consisting of diabetic neuropathy Petition 870250089276, dated 10 / 01 / 2025, page 28 / 92 20 / 76 peripheral, post-herpetic neuralgia, spinal cord injury, chemotherapeutic agent, antitumor agent, cancer, fibromyalgia, and hepatitis.

[0057] In some embodiments, the compound, salt or ester for use of the invention in the treatment of neuropathic pain is administered at a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day. Preferably, the compound, salt or ester of the invention is administered at a dose of 2,100 mg / day or 4,200 mg / day.

[0058] In preferred embodiments of the compound, salt or ester for use in the invention, neuropathic pain originates from a cause selected from the group consisting of diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia and hepatitis.

[0059] In embodiments, the compound, salt or ester of the invention is for simultaneous, separate or sequential use in combination with at least one other active ingredient selected from the group consisting of pregabalin, an opioid analgesic, a steroid analgesic, a non-steroidal analgesic, a cannabinoid analgesic, an anticonvulsant, an anxiolytic, an anesthetic and an antidepressant. Petition 870250089276, dated 10 / 01 / 2025, p. 29 / 92 21 / 76

[0060] In embodiments, the compound, salt or ester of the invention is for simultaneous use, separately or sequentially in combination with at least one other active ingredient selected from the group consisting of lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dulcolax, alprazolam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, acetylcysteine, metoclopramide, metamizole, teicoplanin, dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, triazides, losartan, metamizole, sucralfate, lactitol, pancreatin, dimethicone, bethanechol, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, cinitapride, quetiapine, betmiga, valproate, lacosamide, lidocaine, metamizole, finasteride, acetylsalicylic acid,enalapril, metformin, liraglutide, trospium, tramadol, celcoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, dexamethasone, dexketoprofen, losartan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, clorazepate, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone, acyclovir, lidocaine, nystatin, delorazepam, acid, Petition 870250089276, dated 10 / 01 / 2025, page 30 / 92 22 / 76 alendronic acid, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

[0061] The present invention also provides a pharmaceutical composition comprising the compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, for use in the treatment of an oncological pathology, selected from the group consisting of glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthangastrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroidal plexus tumor, choroidal plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma,Bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, rectal adenocarcinoma. Petition 870250089276, dated 10 / 01 / 2025, page 31 / 92 23 / 76 metastatic, metastatic sigmotic adenocarcinoma of the colon, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, chondrosarcoma of the uterus, adenocarcinoma of the cecum, adenocarcinoma of the bladder, esophageal cancer and metastatic small cell esophageal cancer, wherein the compound, salt or ester is administered at a dose of 500 mg / day to 16,000 mg / day.

[0062] In embodiments of the pharmaceutical composition of the invention, the oncological pathology is selected from the group consisting of oligoastrocytoma, glioblastoma, oligodengroglioma, ependymoma, xanthoastrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical teratoid rhabdoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, lung cancer small cell carcinoma, rectal cancer, rectosigmoid junction cancer, adenocarcinoma Petition 870250089276, dated 10 / 01 / 2025, page 32 / 92 24 / 76 metastatic rectal cancer, metastatic sigmoid colon adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial cancer, neuroendocrine pancreatic cancer, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

[0063] In embodiments of the pharmaceutical composition of the invention, glioblastoma is a grade IV glioblastoma multiforme with native isocitrate dehydrogenase (IDH) enzyme.

[0064] In embodiments, the pharmaceutical composition of the invention is for use in the treatment of assay-native grade IV glioblastoma multiforme in an individual with methylation of the methylguanine methyltransferase (MGMT) gene promoter.

[0065] In embodiments of the pharmaceutical composition of the invention, the salt is sodium salt (HOCOS).

[0066] In embodiments of the pharmaceutical composition of the invention, the ester is a methyl ester or an ethyl ester.

[0067] In embodiments of the pharmaceutical composition of the invention, the compound, salt or ester is administered in a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day. Preferably, Petition 870250089276, dated 10 / 01 / 2025, page 33 / 92 25 / 76 The compound, salt or ester of the invention is administered at a dose of 2,100 mg / day or 12,000 mg / day.

[0068] In embodiments, the pharmaceutical composition of the invention further comprises a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib and cisplatin.

[0069] In embodiments, the pharmaceutical composition of the invention further comprises temozolomide, for use in the treatment of glioblastoma. Preferably, the glioblastoma is a native IDH grade IV glioblastoma multiforme.

[0070] The present invention also provides a pharmaceutical composition comprising the compound 2-hydroxyoctadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, for use in the treatment of neuropathic pain, wherein the compound, salt or ester is administered at a dose of 500 mg / day to 16,000 mg / day.

[0071] In embodiments of the pharmaceutical composition of the invention, neuropathic pain is caused by neuronal damage or nerve damage to the central and / or peripheral nervous system. Preferably, the neuronal damage is a spinal cord injury. Petition 870250089276, dated 10 / 01 / 2025, p. 34 / 92 26 / 76

[0072] In embodiments of the pharmaceutical composition of the invention, neuropathic pain is caused by a cause selected from the group consisting of a chemotherapeutic agent, an antitumor agent, and a carcinogen. Preferably, the antitumor agent is an alkaloid. More preferably, the alkaloid is vincristine.

[0073] In embodiments of the pharmaceutical composition of the invention, neuropathic pain is caused by a selected cause from the group consisting of diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia and hepatitis.

[0074] In embodiments of the pharmaceutical composition of the invention for use in the treatment of neuropathic pain, the compound, salt or ester is administered at a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 14,000 mg / day and 16,000 mg / day. Preferably, the compound, salt or ester of the invention is administered at a dose of 2,100 mg / day or 4,200 mg / day.

[0075] In embodiments, the pharmaceutical composition of the invention further comprises at least one other active ingredient selected from the group consisting of pregabalin, an opioid analgesic, a steroidal analgesic, a non-steroidal analgesic, a cannabinoid analgesic, a Petition 870250089276, dated 10 / 01 / 2025, p. 35 / 92 27 / 76 an anticonvulsant, an anxiolytic, an anesthetic, and an antidepressant.

[0076] In embodiments, the pharmaceutical composition of the invention further comprises at least one other active ingredient selected from the group consisting of lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dulcolax, alprazolam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, acetylcysteine, metoclopramide, metamizole, teicoplanin, dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, triazides, losartan, metamizole, sucralfate, lactitol, pancreatin, dimethicone, bethanechol, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, cinitapride, quetiapine, betmiga, valproate, lacosamide, lidocaine, metamizole, finasteride, acetylsalicylic acid, enalapril, metformin, liraglutide, trospium, tramadol,celcoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, dexamethasone, dexketoprofen, losartan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, clorazepate, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone Petition 870250089276, dated 10 / 01 / 2025, page 36 / 92 28 / 76 acyclovir, lidocaine, nystatin, delorazepam, alendronic acid, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

[0077] In embodiments, the pharmaceutical composition of the invention further comprises 1 to 20% (w / w) of an antioxidant, 0.01 to 10% (w / w) of a sweetener, 0.1 to 20% (w / w) of a gelling agent and 0.01 to 10% (w / w) of a flavoring, the sum of the percentages of all ingredients in the pharmaceutical composition (including the active ingredient(s)) being 100% (w / w).

[0078] In embodiments, the pharmaceutical composition of the invention further comprises 20 to 80% (w / w) of a diluent, 0.1 to 20% (w / w) of an antioxidant, 0.01 to 10% (w / w) of a sweetener, 0.1 to 20% (w / w) of a gelling agent and 0.01 to 10% (w / w) of a flavoring, the sum of the percentages of all ingredients in the pharmaceutical composition (including the active ingredient(s)) being 100% (w / w).

[0079] The pharmaceutical composition of the present invention may be in the form of a gastro-resistant compound to prevent the degradation of its components by the low pH of the gastric environment. The pharmaceutically acceptable excipient or carrier includes, among others, diluents, antioxidants, sweeteners, gelling agents, flavorings, fillers or other vehicles, such as silica. Petition 870250089276, dated 10 / 01 / 2025, page 37 / 92 29 / 76 anhydrous colloidal and glyceryl monostearate. The pharmaceutical composition may be in the form of a capsule, powder, tablet, emulsion, suspension, solution, or any other pharmaceutical form, packaged in a blister, bottle, paper sachet, polyester, polyethylene and / or aluminum, or any other type of container. To produce the pharmaceutical composition of the invention, conventional techniques may be used to prepare pharmaceutical compositions. For example, the compound, salt, or ester of the invention described herein may be mixed with a carrier, or diluted by a carrier, or enclosed in a carrier that may be in the form of an ampoule, capsule, envelope, paper, polyethylene and / or aluminum, or other packaging. When the carrier is a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.Some examples of suitable diluents are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of fatty acids, pentaerythritol fatty acid esters, polyethylene, hydroxymethylcellulose, and... Petition 870250089276, dated 10 / 01 / 2025, page 38 / 92 30 / 76 polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical composition of the invention may also include humectants, antioxidants, emulsifying and suspending agents, preservatives, sweeteners, and flavorings. The pharmaceutical composition of the invention may be formulated to provide rapid, sustained, or delayed release of the compounds described herein after administration to the patient, using methods well known in the art.

[0080] The pharmaceutical composition of the invention can be a solid composition or a liquid solution.

[0081] The pharmaceutical composition of the invention can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salts to influence osmotic pressure, buffers and / or coloring substances and the like, which do not react adversely with the compounds described in this document.

[0082] Throughout the description and claims, the terms comprising, “comprising” and their variants have a non-limiting meaning and therefore should not exclude other technical features. The terms comprising, comprising and their variants, throughout the description and Petition 870250089276, dated 10 / 01 / 2025, p. 39 / 92 31 / 76 of the claims specifically include the terms “consists of”, “consisting of” and their variants.

[0083] As used in this document and in the claims, the singular form “o(a)” includes references to plural forms, unless the content clearly indicates otherwise.

[0084] Unless otherwise defined, all technical and scientific terms used throughout the description and claims have the same meaning as commonly understood by those skilled in the art in the field of the invention. BRIEF DESCRIPTION OF THE FIGURES

[0085] Figure 1. Pharmacokinetic profile of HOCOS at different doses. The graphs represent the serum [HOCOS] logarithm (ng / ml) of patients after administration of the first dose on the first day of treatment (day 1, black) and the steady state after 21 days of treatment (day 21, gray) at doses of 500 mg / day (bid), 1,000 mg / day (bid), 2,000 mg / day (bid), 4,000 mg / day (bid), 8,000 mg / day (bid), 12,000 mg / day (tid), and 16,000 mg / day (bid), orally. These daily doses were divided into two (bid) or three (tid) daily doses. These results demonstrate the good absorption of HOCOS at different doses in patients with different types of cancer (see Table 2). Petition 870250089276, dated 10 / 01 / 2025, p. 40 / 92 32 / 76

[0086] Figure 2. Antitumor efficacy during monotherapy with HOCOS. In a phase I / II clinical trial, the safety and efficacy of HOCOS were studied in patients with different types of cancer (Table 2). In these patients (assigned with a code), tumor volume was determined at the end of the clinical trial (% of volume relative to initial diagnosis). (A) Tumor volume of patients with glioblastoma relative to baseline volume at recruitment (0%). Dashed lines describe the upper and lower limits for considering tumor progression, stable disease, and tumor regression according to RANO criteria. (B) Tumor volume in patients with non-glioblastoma tumors relative to baseline volume (0%).In both graphs, the gray bars represent patients treated with HOCOS and with stable disease or tumor regression who did not meet all RANO or RECIST criteria, and the black bars represent patients treated with HOCOS and with stable disease or tumor regression who met all RANO or RECIST criteria.

[0087] Figure 3. Example of response to HOCOS treatment. (A) Magnetic resonance imaging (MRI) of a patient with glioblastoma, showing tumor size at baseline (images in the first column on the left) and progression during the period HOCOS was administered as monotherapy (phase I / II clinical trial), at 4 months. Petition 870250089276, dated 10 / 01 / 2025, page 41 / 92 33 / 76 (images in the second column from the left), 9 months (images in the third column from the left), 21 months (images in the fourth column from the left), and 32 months (images in the fifth column from the left). The tumor appears as the white area within the white circle in the middle of the normal neural tissue (gray). The patient experienced sustained tumor regression over time (according to RANO criteria) for three years on monotherapy with HOCOS 500 mg orally twice daily (1,000 milligrams per day, orally, twice daily). Transverse (upper scans) and sagittal (lower scans) brain MRI scans show reduction of the glioblastoma (within the white circle) over the period of treatment with HOCOS monotherapy. (B) Effect of HOCOS (black dots) in a murine model (immunocompromised mice) of human pancreatic cancer (MIAPaCa-2 cells).The image shows how the treatment slows the growth rate of pancreatic cancer compared to the control (white dots).

[0088] Figure 4. Efficacy of HOCOS as first-line standard treatment in combination with temozolomide and radiotherapy in newly diagnosed patients with trial-grade IV native glioblastoma. In a phase II / III clinical trial, the safety and efficacy of HOCOS in combination with TMZ and other drugs were evaluated. (A) Survival Petition 870250089276, dated 10 / 01 / 2025, page 42 / 92 34 / 76 total patients (OS), which corresponds to the time between diagnosis and death. Treatment with HOCOS (black bars) significantly increases OS. (B) Progression-free survival (PFS), which corresponds to the time (in months) between diagnosis and the increase in tumor size according to RANO criteria.The gray bars show survival in patients treated with the current standard of care (SoC), consisting of radiotherapy for 6 weeks and temozolomide for 6 months; the white bars show survival in the clinical trial with the current standard of care plus HOCOS or placebo (approximately 50% of each treatment concomitant with temozolomide for 6 months and monotherapy thereafter); and the black bars are the extrapolation of survival of patients treated with HOCOS plus the standard of care, considering that in the clinical trial patients were randomized with a 1:1 ratio between the HOCOS and placebo groups. In addition, patients were administered other drugs mentioned in the present invention during treatment.

[0089] Figure 5. Safety and efficacy of HOCOS in the treatment of neuropathic pain in patients with spinal cord injury. (A) To assess the pharmacological safety of the product, it is studied whether an adverse effect (AE) is related to the treatment or not. Medical researchers determined whether the Petition 870250089276, dated 10 / 01 / 2025, page 43 / 92 35 / 76 Adverse effects (AEs) were either treatment-related or unrelated. The Phase I / II clinical trial in patients with spinal cord injury consisted of 4 groups to which patients were randomly assigned. The first group received placebo (n = 9), the second group received 1,050 mg of HOCOS divided into three doses of 350 mg each (n = 11), the third group received 2,100 mg of HOCOS divided into three doses of 700 mg each (n = 11), and the fourth group received 4,200 mg of HOCOS divided into three doses of 1,400 mg each. All patients also received pregabalin along with other drugs mentioned in the present invention. The bars from the left show all adverse effects in patients treated with placebo or different doses of HOCOS (P w / AE). The bars on the right show the adverse effects in patients that the clinical investigators identified as directly related to treatment (P w / RTAE) with HOCOS or with placebo.(B) In order to determine the efficacy of HOCOS versus placebo in patients with neuropathic pain caused by spinal cord injury, the VAS (Visual Analogue Scale) was used. Pain in the total patient population (panel B) was determined during the screening visit, during the baseline visit (V1), at the end of the first month (V2), second month (V3) and third month of treatment (V4) and after one month without treatment (V5, follow-up). The reduction between baseline and endpoint was measured. Petition 870250089276, dated 10 / 01 / 2025, page 44 / 92 36 / 76 of the trial was calculated in the total patient population as V1-V4. After the end of the trial, V5-V4 was analyzed, which had to be positive in all cases, since, upon discontinuation of treatment, an increase in pain is expected, attributed both to the drug and the placebo effect. Graph B shows the pain values ​​(VAS) in patients who received 0.0 (placebo), 1,050, 2,100, or 4,200 milligrams daily of HOCOS. (C) Since the sensation of neuropathic pain can fluctuate over time, may be reduced, and may even disappear naturally, a pain assessment was performed at the end of the experimental treatment period (V5). The trial lasted approximately 6 months between screening and V5, and it was observed that some patients showed a continuous trend in pain reduction that continued after the end of treatment (between V4 and V5). It was expected that between V4 and V5 there would be an increase in pain sensation, even (although to a lesser extent) in the placebo group.This abnormal behavior was eliminated in a second analysis, removing patients with pain reduction between V4 and V5 or with other abnormalities, such as erratic values. In this censored population, results very similar to those of the total population were obtained, but statistically significant (two-way ANOVA, Fisher's least significant difference test - Fisher's LSD). (D) Pain values ​​on the VAS scale measured in responding patients, which are the patient population. Petition 870250089276, dated 10 / 01 / 2025, page 45 / 92 37 / 76 uncensored subjects who experienced a reduction in pain of more than 1 point on the pain scale (between V1 and V4) and who experienced an increase in pain after the completion of treatment (between V4 and V5). Results show the ± mean values ​​for each group and time point. A two-tailed ANOVA followed by a Fisher post-hoc LSD analysis was used to determine the significance of the data. *p < 0.05 relative to baseline pain. (E) VAS values ​​in patients with a probability of more than 90% suffering from neuropathic pain, based on the PainDetect test, performed on all patients. Pain reduction was statistically significant at doses of 2,100 mg / day and 4,200 mg / day. The dose of 2,100 mg / day was the most appropriate, showing reductions from the first month, becoming significant from the second month and reaching a maximum in the third month of treatment, with a reduction in VAS values ​​from about 7 to about 3.(F) Among the patient population with a greater than 90% probability of suffering from neuropathic pain, the percentage of responders (reduction in the VAS scale > 1.5 points) in the placebo group (treated with pregabalin and other drugs, but not with HOCOS) was only 25%. On the other hand, all groups of patients treated with HOCOS showed a treatment response rate greater than 40%, with the 2,100 mg / day group again showing the highest response rate, at 80%. Petition 870250089276, dated 10 / 01 / 2025, page 46 / 92 38 / 76

[0090] Figure 6. Efficacy of HOCOS measured in thermal hyperalgesia using the “tail movement” test against vincristine-induced neuropathic pain. (A) Animals were first treated with 0.0 (control), 0.5, 0.75, or 1 mg / kg of vincristine (cumulative dose over 10 days). Vincristine is a drug used in cancer chemotherapy and is associated with the onset of neuropathic pain. Then, the same animals were treated orally with saline solution (0 mg / kg HOCOS) or HOCOS (400 mg / kg) for 28 days. Latency time in the indicated animal groups was measured after 28 days of treatment. HOCOS was shown to increase latency time in the tail movement test, which is interpreted as a reduction in neuropathic pain. Values ​​were expressed as % of response time to stimulus on day 28 of treatment versus baseline (day 1).(B) Effect of HOCOS on thermal hyperalgesia caused by vincristine (1 mg / kg) and measured by the tail movement test. This hyperalgesia is a result of neuropathic pain, and the heat reaction time in animals is shown on the first day and after 7 weeks of treatment with HOCOS. This demonstrates that vincristine induced reactions in the response time to thermal discomfort, which was not altered by vehicle treatment, but treatment with HOCOS significantly altered it from 5 weeks of treatment onwards. Furthermore, after 7 weeks of treatment, the animals treated with... Petition 870250089276, dated 10 / 01 / 2025, page 47 / 92 39 / 76 vincristine followed by treatment with HOCOS showed no significant differences compared to animals that did not receive vincristine.

[0091] Figure 7. Efficacy of HOCOS measured in mechanical allodynia using the Von Frey test against vincristine-induced neuropathic pain. To identify the effect of HOCOS against other types of neuropathic pain besides those caused by spinal cord injury, the effect was studied using the Von Frey test. (A) The pressure threshold (grams) that induces the plantar reflex in animals previously treated with vincristine (VC, cumulative dose of 1 mg / kg over 10 days) and after 1, 14, 21, and 28 days of treatment in the absence (0 mg / kg) or presence of HOCOS (400 mg / kg). (B) Results of animals previously treated with 0 (control), 0.5, 0.75, or 1 mg / kg of vincristine and subsequent treatment in the absence (0 mg / kg) or presence of HOCOS (400 mg / kg) for 28 days. Results were expressed as grams of pressure. What percentage of pressure is relative to the control? DESCRIPTION OF THE MODALITIES Example 1: Phase I / II clinical trial in patients with glioblastoma and other advanced cancers.

[0092] An open-label, multicenter, phase I / II clinical trial (without placebo) was conducted in patients with glioblastomas (high-grade with native or mutated IDH) and high-grade gliomas and other advanced solid tumors in Petition 870250089276, dated 10 / 01 / 2025, page 48 / 92 40 / 76 continuous growth phase. All included patients gave their written informed consent and were also receiving the concomitant medication listed in the present invention. The trial was conducted in accordance with the Declaration of Helsinki and the International Council on Harmonization Guidelines on Good Clinical Practice and was approved by the Research Ethics Committee or Ethics Committees of the participating institutions. The trial was designed by Laminar Pharmaceuticals SA, in collaboration with the trial researchers.

[0093] The primary objectives were to determine the safety and tolerability of HOCOS administered as monotherapy, to describe the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and to identify the recommended dose for treatment. Secondary objectives included characterizing the unique and steady-state pharmacokinetic profiles of HOCOS in a continuous daily dosing regimen and evaluating the preliminary antitumor efficacy of HOCOS.

[0094] The disease was documented by imaging with computed tomography or magnetic resonance imaging. Tumors were evaluated at baseline and every two cycles. Petition 870250089276, dated 10 / 01 / 2025, page 49 / 92 41 / 76 of treatment until disease progression, according to RANO criteria for glioblastomas, gliomas and other tumors of the nervous system, or RECIST 1.1 for solid tumors in other tissues and organs.

[0095] Patients over 18 years of age with histologically or cytologically confirmed advanced solid tumors, including glioblastomas, and various types of high-grade gliomas refractory to standard treatment, or for which there is no standard treatment (Table 2), who had previously been treated with more than one (up to five) different lines of cancer treatment and no longer responded to conventional treatments, were included. In the glioma cohort, patients with grade 3 or 4 malignant gliomas who had relapsed or progressed after first- or second-line standard treatment were included, with progressive disease being defined according to RANO criteria.

[0096] The main exclusion criteria included having received anticancer therapy in the four weeks prior to the start of treatment (six weeks for mitomycin and nitrosoureas and two weeks for palliative radiotherapy and surgery); unresolved NCI-CTCAE grade > 1 from prior anticancer therapy; gastrointestinal dysfunction that could alter drug absorption; history of hyperlipidemia and / or need for lipid-lowering therapy; Petition 870250089276, dated 10 / 01 / 2025, pp. 50 / 92 42 / 76 significant uncontrolled cardiovascular disease; and recent intracranial or intratumoral bleeding on computed tomography or magnetic resonance imaging.

[0097] HOCOS was administered as a dry powder and accompanied by a series of excipients (Table 1), in polyester, aluminum and low-density polystyrene sachets, and was reconstituted as an oral suspension in water between 30 minutes and 2 hours after a meal, in 21-day cycles. The suspension contained the amount of HOCOS and excipients indicated in Table 1 for the different dose levels. Table 1. HOCOS formulations for cancer treatment HOCOS Compound Dose 0 g (placebo) 0.125 g 0.25 g 0.5 g 1 g 2 g 3 g 4 g HOCOS Cellulose 0.000 0.125 0.250 0.500 1.000 2.000 3.000 4.000 Microcrystalline 4.0 3.875 3.750 3.500 3.000 2.000 1.000 - Mannitol 3.680 3.680 3.680 3.680 3.680 3.680 3.680 3.680 Citric Acid 0.011 0.015 0.030 0.060 0.115 0.225 0.330 0.350 Sucralose 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050 Xanthan Gum 0.100 0.100 0.100 0.100 0.100 0.100 0.100 0.100 Mango Flavor 0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 Total Weight 8.141 8.145 8.16 8.19 8.245 8.355 8.46 8.48 Water for Reconstitution 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml 100 ml ml

[0098] The initial dose was 250 mg twice daily (bid), i.e., 500 mg daily. A standard 3+3 dose escalation design was used with seven cohorts (total daily dose from 500 mg to 16,000 mg, see Table 2). The doses of 500, 1000, 2000, 4000, 8000, and 16000 mg daily Petition 870250089276, dated 10 / 01 / 2025, pp. 51 / 92 43 / 76 were obtained by administering twice daily (bid), while the 12,000 mg daily dose was obtained by administering 4,000 mg three times daily (tid). Three patients per dose level were enrolled and observed for any dose-limiting toxicity (DLT) during the first treatment cycle. They were moved to higher dose levels if no DLT was observed in any patient. Three additional patients were included at a given dose level if 1 in 3 patients experienced DLT. As a standard safety measure, within each cohort, patients were enrolled with an interval of 1 week or more between the first patient and subsequent patients.

[0099] To be evaluated for dose escalation decisions, patients had to have taken more than 80% of the trial drug and not have undergone a DLT during the DLT observation period.

[00100] The cohort's dose escalation decisions were also based on a clinical review of all relevant available data from contemporary and previous dose cohorts. The maximum administered dose was defined as the dose level at which a DLT was observed during the treatment cycle in more than 33% of evaluable patients, and the maximum tolerated dose (MTD) was defined as the highest dose level below the former. Petition 870250089276, dated 10 / 01 / 2025, pp. 52 / 92 44 / 76

[00101] Treatment was maintained until clinical or radiological disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. Modifications to the treatment regimen, dose delays of up to 14 days, and up to 2 dose reductions due to toxicity were permitted. Dose increases were permitted in patients who had obtained clinical benefit with their initial or current dose, at the investigator's discretion and during a visit with the medical monitor.

[00102] Pharmacokinetics were assessed by HPLC in tandem MS to measure HOCOS concentrations. Pharmacokinetic profiles (pre-dose and 1, 2, 4, 6, and 8 hours post-dose) were measured on cycle 1, days 1, and 21. This included blood pharmacokinetic exposure (dose, concentration, maximum concentration [Cmax], area under the plasma time curve [AUC]) and population pharmacokinetic parameters (volume of distribution [Vd] and clearance [CL]). In the dose-escalation cohorts, pre-dose trough levels were also measured on days 8 and 15. In the extended safety cohort, only the day 1 pharmacokinetic profile was measured. A final pharmacokinetic sample was collected at the final trial visit.

[00103] The maximum predicted sample size was determined by modeling the clinical criteria of Petition 870250089276, dated 10 / 01 / 2025, pp. 53 / 92 45 / 76 interruption of dose escalation, with additional patients in the two extended safety cohorts.

[00104] The population for efficacy analysis included all patients who received at least 80% or more of the doses administered in cycle 1 and who underwent at least one tumor assessment in the trial. Responses were summarized descriptively using frequency distributions. Median progression-free survival (PFS) was estimated by Kaplan-Meier analysis. Progression-free survival at 6 months (PFS, i.e., the percentage of patients alive and progression-free 180 days after treatment initiation) was also determined.

[00105] The population for pharmacokinetic analysis included patients who received HOCOS and provided at least one blood sample for pre-dose and post-dose pharmacokinetic assessment. Pharmacokinetic parameters were summarized by descriptive statistics. Individual and mean concentration versus time profiles were presented on linear and logarithmic scales. A potency model was used to test dose proportionality. Results

[00106] 54 patients were treated at 5 research centers in the United Kingdom and Spain (Table 2). No patients were withdrawn due to an adverse event (AE) or Petition 870250089276, dated 10 / 01 / 2025, pp. 54 / 92 46 / 76 a serious adverse event (SAE) occurred in both the dose-escalation and expansion phases of the trial. Thirty-two patients (15 with glioblastoma / glioma and 17 with other advanced solid tumors) were treated in the first 7 cohorts and included in the dose-escalation phase (500 mg / day to 16,000 mg / day) of the trial. Subsequently, 22 patients (12 with glioma and 10 with advanced solid tumors) were included in the expansion cohort (cohort 8), and all patients received the trial drug at a dose of 12,000 mg / day. Of these patients, 44 were evaluated to assess the efficacy of HOCOS, since, to evaluate this parameter, patients had to have undergone at least two radiological analyses.

[00107] The mean cumulative dose was 318,571.4 mg (1,143 to 2,912,571 mg) and the mean duration of treatment was 41 days (2-989). Dose escalation ranged from 500 to 16,000 mg / day. HOCOS was rapidly absorbed, with exposure proportional to the dose (Figure 1). Promising activity was observed in patients with high-grade gliomas. The clinical trial was highly positive, as none of the 21 patients with glioblastoma and high-grade gliomas experienced serious adverse effects, and the mean PFS was 40 days, with responses lasting up to 3 years. The PFS at 18 months in these patients had a life expectancy of some Petition 870250089276, dated 10 / 01 / 2025, pp. 55 / 92 47 / 7 6 weeks was a hopeful 18.5%. On the other hand, patients with other solid tumors in different organs had a PFS of 42 days on average. In conclusion, HOCOS demonstrated a very good safety profile and encouraging preliminary activity in this population of patients with malignant brain and other organ tumors that are difficult to treat and have a very low life expectancy. It should be noted that these patients are in continuous tumor progression and have already stopped responding to any type of therapy; therefore, both the interruption of disease progression (stable disease, SD) and partial responses (tumor reductions: partial response, PR) are considered positive responses to therapy.

[00108] In the group of patients with glioblastomas and gliomas, a decrease in the brain-specific protein of astroglial cells (glial fibrillary acidic protein, GFAP) was observed in 12 of 15 patients (80%) on day 8 of cycle 1 (4 hours after the dose), with a median percent change from baseline of -20.1%. In this context, GFAP levels correlate with tumor volume and constitute a potential biomarker for glioma. The trend was less pronounced in cycle 2, on day 1 (pre-dose), with a decrease in GFAP observed in 8 of 13 (61.5%) patients and a median percent change from baseline of -10.51%. Petition 870250089276, dated 10 / 01 / 2025, pp. 56 / 92 48 / 76

[00109] Twenty-one (21) patients with glioblastoma or glioma and other neurological tumors (Table 2) underwent radiological evaluation (MRI) at baseline and at least once after baseline. In this patient population, both partial responses (PR) and stable disease (SD) were observed according to RANO criteria (Figure 2A, Table 2). One patient had a sustained partial response for more than 3 years with 1,000 mg of HOCOS daily between cycle 1 and cycle 44, and then with 12,000 mg daily between cycle 45 and cycle 48 (Figure 2A and Figure 3A). All patients received two lines of treatment without bevacizumab. The median PD was 40 days, with 18.5% of patients having a disease-free period of 6 months or more.

[00110] In addition, another 24 patients with other advanced solid tumors were included in the trial in the target population for treatment. In these patients, reductions in tumor size were also observed in some and stabilization of the disease in others (Figure 2B, Table 2), with the mean time to tumor stabilization being 42 days.

[00111] In this first phase I / IIA clinical trial in humans, HOCOS monotherapy was well tolerated, and the most frequent adverse effects were diarrhea, nausea, and vomiting, which occurred infrequently and could be controlled with medication. The events were related to Petition 870250089276, dated 10 / 01 / 2025, pp. 57 / 92 49 / 76 dose and predictable, given the health status of the patient population, as well as the nature of the HOCOS oral suspension formulation. There were no adverse events attributable to the trial drug or adverse events resulting in death. Therefore, HOCOS was well tolerated at a dose of 4,000 mg three times a day (12 grams orally, three times a day).

[00112] Monotherapy with HOCOS has demonstrated promising antitumor activity in patients with high-grade glioma (grade 3) and glioblastoma (grade 4) and other cancers. It was observed that patients with glioblastoma, glioma, and other types of cancer showed PR or SD according to RANO criteria, with clinical benefit lasting more than 6 months in 5 patients, including one patient with grade IV glioblastoma who had been pre-treated but did not respond to any further treatment and who showed a response lasting more than 3 years (Figure 3A). The 6-month progression-free survival (PFS) rate in the glioma population was 18.5%, which is surprising for this type of patient, who no longer responds to any treatment when the disease is progressing and whose death usually occurs within a few months after recurrence.

[00113] The encouraging clinical response observed in a population with such a poor prognosis and needs Petition 870250089276, dated 10 / 01 / 2025, pp. 58 / 92 50 / 76 clearly unmet medical criteria support the therapeutic efficacy of this product. Table 2. Patients treated in the clinical trial with HOCOS monotherapy. Patient Code Dose (g / day) Pathology Number of cycles Number of previous treatments 010101 0.5 Mesothelioma 2 1 020102 0.5 Mesothelioma 15 2 010103 0.5 Glioblastoma 2 2 030201 1 Glioblastoma 1 4 010202 1 Glioblastoma 49 2 030203 1 Glioblastoma 2 4 020204 1 Pancreatic Adenocarcinoma 2 2 030301 2 Glioblastoma 2 2 010302 2 Glioblastoma 2 1 020303 2 Small cell lung cancer (SCLC) 2 4 030401 2 Endometrial adenocarcinoma 2 5 020402 4 Rectal adenocarcinoma Metastatic adenocarcinoma 2 8 010403 4 Rectal 1 3 010404 4 Glioma 1 1 010501 8 Colon adenocarcinoma 2 5 030502 8 Uracal adenocarcinoma 2 12 020503 8 Metastatic sigmotic adenocarcinoma of the colon 2 9 010601 12 Metastatic rectal cancer 3 6 030602 12 Glioblastoma 1 4 030603 12 Glioblastoma 9 2 030604 12 Colon adenocarcinoma 1 11 030605 12 Oligoastrocytoma 1 2 010606 12 Glioblastoma 9 2 030607 12 Astrocytoma 3 3 020608 12 Adenocarcinoma of the rectosigmoid junction 2 12 010701 16 Glioma G3 1 2 030702 16 Astrocytoma 2 2 020703 16Pleural mesothelioma 1 4 010704 16 Uterine chondrosarcoma 1 4 030705 16 Endometrial adenocarcinoma Metastatic lung adenocarcinoma 2 7 020706 16 2 3 030707 16 Anaplastic astrocytoma 3 4 013001 12 Glioblastoma 2 3 033002 12 Glioblastoma 2 1 053003 12 Glioma 1 1 013004 12 Oligodendroglioma 14 2 033005 12 Glioblastoma 1 4 013006 12 Glioblastoma 10 2 033007 12 Glioblastoma 2 6 033008 12 Gliosarcoma 3 9 013009 12 Gliomatosis cerebralis 2 2 023010 12 Glioblastoma 1 2 Petition 870250089276, dated 10 / 01 / 2025, pp. 59 / 92 51 / 76 033011 12 Glioblastoma 1 5 013012 12 Glioblastoma 2 1 024001 12 Metastatic colorectal adenocarcinoma 2 4 034002 12 Metastatic colon adenocarcinoma 4 7 034003 12 Rectal adenocarcinoma 2 8 014004 12 Colorectal carcinoma 2 6 044005 12 Distal bile duct adenocarcinoma 7 3 024006 12 Metastatic small cell esophageal cancer 1 3 014007 12 3 6 034008 12 Rectal cancer 3 14 044009 12 Bladder adenocarcinoma 2 4 014011 12 Cecal adenocarcinoma 2 5

[00114] Monotherapy with HOCOS, prescribed as salvage treatment in cancer patients previously treated with other agents, has demonstrated promising antitumor activity, along with a manageable safety profile that is considerably less toxic than other chemotherapies; which makes it an ideal candidate for first-line treatment of gliomas, grade IV glioblastomas with native assay, and other types of cancer.

[00115] Treatment with HOCOS has not only been shown to be effective in humans, but also in animal models of various types of human cancer, such as pancreatic cancer. Figure 3B shows the antitumor effect of HOCOS on the growth of human pancreatic cancer (MIAPaCa-2 cells) in immunocompromised mice. In this case, pancreatic cancer is a very aggressive type of cancer, with a high mortality rate and a very short life expectancy. Petition 870250089276, dated 10 / 01 / 2025, pages 60 / 92 52 / 76 Thus, patients with distant pancreatic cancer have a 5-year survival rate of 3%. This survival rate is slightly higher in patients with regional pancreatic cancer (16%), with localized cancer having the best prognosis (5-year survival expectancy of 44%). Inclusion criteria

[00116] Patients with glioblastoma / glioma and other tumor types were included in this phase I / II clinical trial. These patients received HOCOS monotherapy at the doses indicated in Table 2. The inclusion criteria for these patients were as follows: - Able and willing to provide written informed consent. - Male or female patients aged 18 years and older. - With advanced solid neoplasia, confirmed histologically or cytologically, refractory to standard treatment or for which there is no standard therapy. Inclusion criteria for patients with neurological tumors

[00117] - To have a diagnosis of glioblastoma, grade 3 or 4 malignant glioma, or similar neurological tumors that recur (relapse) or progress after standard first- or second-line treatment or subsequent lines of treatment. Petition 870250089276, dated 10 / 01 / 2025, pp. 61 / 92 53 / 76 - A truly progressive disease, confirmed according to RANO criteria. Life expectancy of at least 12 weeks. ECOG performance status of 0-2. - Ability to swallow and ingest oral medications. - Ability to perform appropriate imaging tests of the tumor, using computed tomography or magnetic resonance imaging, to assess the progression of the disease. - Hematological values ​​at screening / baseline: hemoglobin 7 90 g / L (9 g / dL) or 5.6 mmol / L, absolute neutrophil count 7 1.5 x 109 / L, platelets 7 100 x 109 / L. - Coagulation values ​​at screening / baseline: International Normalized Ratio (INR) ≥ 1.5, Partial Thromboplastin Time (PTT) ≥ 2 x Upper Limit of Normal (ULN). - Liver function test values ​​at screening / baseline: total bilirubin ≥ 1.5 x ULN - unless explained by a genetic syndrome such as Gilbert's syndrome; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 2.5 x ULN. - Value of renal function tests in screening / baseline: serum creatinine 1.5 x ULN. Petition 870250089276, dated 10 / 01 / 2025, pp. 62 / 92 54 / 76 - No history of corrected QT interval (QTc) prolongation and normal QTc interval at screening / baseline (QTc < 450 ms). - Female patients (or male patients whose partner is) without the potential to procreate (defined as > 2 years after last menstruation or surgically sterile), female patients with the potential to procreate with a negative serum pregnancy test within 7 days before the first dose of HOCOS or within 14 days, followed by a negative confirmatory urine pregnancy test within 7 days before the first dose of HOCOS, and using (or if male and not surgically sterile, whose partner is using) effective non-hormonal contraceptive methods (non-hormonal intrauterine contraceptive device, barrier contraceptive method along with spermicidal gel). Inclusion criteria for patients with solid tumors other than glioblastoma / glioma

[00118] - The presence of lesions suitable for biopsy (mandatory for glioma-free patients enrolled in the extended safety cohort and highly desirable for glioma-free patients enrolled in the dose escalation phase). Example 2: First-line clinical trial in patients with newly diagnosed glioblastoma using HOCOS in combination with temozolomide and radiotherapy. Petition 870250089276, dated 10 / 01 / 2025, pp. 63 / 92 55 / 76

[00119] Following the good results of the phase I / II clinical trial, a phase II / III trial was conducted in newly diagnosed glioblastoma patients. This clinical trial was conducted in a double-blind, placebo-controlled format. 27 patients were included in this trial. Of the total patients, 50% were randomly assigned to the placebo group and the other half to the HOCOS group, without the physician or patient knowing who was taking placebo or verum. Two of the recruited patients dropped out of the trial before starting treatment, therefore they were not valid for the analysis. Patients with newly diagnosed glioblastoma or grade IV glioma and with native (mutation-free) isocitrate dehydrogenase (IDH) enzyme and MGMT gene promoter methylation were included in the trial. All patients concomitantly received, in addition to temozolomide, other drugs mentioned in the present invention.In addition, patients received chemotherapy following the protocol outlined above.

[00120] The treatment used in the clinical trial consisted of 5 phases: Step 1. Treatment of the patient with surgery to remove the glioblastoma. Step 2. Subject the patient to chemoradiotherapy lasting 6 to 7 weeks, comprising the administration of radiotherapy in daily fractions of 2 Gy, 5 days a week; Petition 870250089276, dated 10 / 01 / 2025, pp. 64 / 92 56 / 76 temozolomide at a dose of 75 mg / m2 per day, administered concomitantly with radiotherapy; HOCOS at doses of 12,000 mg / day or placebo. Step 3. 4-week washout period, during which HOCOS and temozolomide radiotherapy are discontinued. Stage 4. Maintenance period of 6 cycles, where each cycle lasts 4 weeks and each cycle consists of administering temozolomide (150 to 200 mg / m2) and HOCOS (12,000 mg / day) or placebo daily during the first three weeks of each cycle and then 7 days of rest without treatment for each cycle. Stage 5. Maintenance monotherapy, 4-week cycles consisting of administering HOCOS (12,000 mg / day) or placebo daily during the first 3 weeks of each cycle, followed by a 7-day washout period without treatment, wherein said cycles continue permanently as maintenance therapy until the tumor shows progression, according to RANO criteria.

[00121] The clinical trial conducted was a randomized, double-blind, placebo-controlled, two-arm parallel trial (1:1 ratio) to evaluate the efficacy and safety of HOCO sodium salt versus placebo in newly diagnosed patients with glioblastoma (grade IV glioma) and native trial patients. In all arms, patients received the Petition 870250089276, dated 10 / 01 / 2025, pp. 65 / 92 57 / 76 standard treatment (temozolomide and radiotherapy) along with different drugs mentioned in the present invention were randomized to receive placebo (arm A) or a dose of 12,000 mg / day of HOCOS (arm B).

[00122] This trial evaluates progression-free survival (PFS), defined as the period of time when glioblastoma is diagnosed and when tumor growth is observed, based on RANO criteria. In addition, the time to life from diagnosis, termed overall survival (OS), is studied. Results

[00123] The overall survival (both OS and PFS) of 24 patients was monitored over a period of 36 months. Figure 4 shows the results of this trial. The 1:1 randomization (1 patient treated with placebo for each patient treated with HOCOS) indicates that half of the patients received an investigational product (HOCOS) and the other half received placebo. Figure 4A shows the overall survival (OS) of the patients participating in the trial conducted in the present invention (black bars: combined HOCOS + temozolomide), compared to the standard treatment survival (SoC, gray bars: temozolomide only). As can be seen, the overall survival of patients in the mixed population treated with temozolomide plus HOCOS or placebo is much higher (60%, 44% and 36% survival at 17, 28 and 36 months after the Petition 870250089276, dated 10 / 01 / 2025, pp. 66 / 92 58 / 76 diagnosis, respectively) than that of standard treatment with temozolomide as the sole chemotherapy (survival rates of 38%, 9.4%, and 1.4% at 17, 28, and 36 months post-diagnosis, respectively). A similar increase is observed in progression-free survival (Figure 4B), given that the PFS percentages at 17, 28, and 36 months were 28%, 24%, and 8%, respectively, while with standard treatment the PFS was 18%, 2.8%, and 0.35%, respectively. These data clearly indicate that patients treated with HOCOS plus temozolomide obtain additional therapeutic benefit from treatment with temozolomide as the sole chemotherapeutic agent. Considering that approximately half of the patients are treated with HOCOS and the other half are treated with placebo, the potential percentage of patients benefiting from this new chemical compound was calculated as: 0.5 x (% HOCOS) + 0.5 x (% SoC) = % MIN

[00124] Where % MIN is the percentage of patients with survival (PFS or OS, as the case may be) in the mixed population of patients treated and not treated with HOCOS in the trial of the present invention, % SoC is the percentage of patients appearing in the trials performed with standard treatment (temozolomide only), and % HOCOS is the percentage of patients with survival (PFS or OS, as the case may be) that would be achieved if all patients with grade IV glioblastoma multiforme with IDH Petition 870250089276, dated 10 / 01 / 2025, pp. 67 / 92 59 / 76 native patients were treated with HOCOS (plus temozolomide and the drugs mentioned in the present invention). In this equation, % HOCOS is the only unknown. The % MIN data are obtained from the present trial and the % SoC data were obtained from the literature (meta-analysis with all trials conducted in patients with glioblastoma and treated with temozolomide). This calculation, which indicates the therapeutic potential of HOCOS, clearly demonstrates the therapeutic benefit of this compound, since the survival rates, i.e., OS and PFS values, at 36 months were 70.6% and 15.7% for HOCOS + temozolomide and only 1.4% and 0.35% for temozolomide alone (Figure 4). These results indicate that HOCOS produces a marked and significant increase in the life expectancy of patients with native IDH grade IV glioblastoma, and that its combined use with temozolomide can save many lives.Furthermore, its oral administration and the absence of adverse effects mean that HOCOS can be administered permanently as the sole antitumor maintenance therapy, whereas temozolomide can only be administered for 6 months because of its toxicity. Example 3. Trials in cell lines with HOCOS in combination with other compounds in the treatment of various types of cancer.

[00125] In addition to monotherapy treatments, both in humans and in human and animal cancer cells Petition 870250089276, dated 10 / 01 / 2025, pp. 68 / 92 60 / 76 experimental studies shown in Figures 2A, 2B and 3A and 3B, the combinatorial treatments between HOCOS and other compounds go beyond what is shown in Figure 4. This is possible for two reasons. The first is that HOCOS is a very harmless (non-toxic) compound and there is no risk of increasing the significant and dangerous adverse effects that other antitumor drugs have. The second is that the mechanism of action of HOCOS is completely different from that of other drugs and, therefore, its effects can be additive. To study the potential use of HOCOS in combination therapies, human glioblastoma cells from the U118, SNB19, and SF268 cell lines, human mesothelioma cells NCI-H2021, and pancreatic cancer cells BxPC-3 (pancreatic adenocarcinoma) and MIAPaCa-2 (pancreatic neuroendocrine cancer) were cultured in the absence or presence of different chemotherapeutic agents and combinations of HOCOS with said compounds.The compounds used in this assay were temozolomide, thiamine, gemcitabine, fluoroacil, oxplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib, and cisplatin. The results obtained show that the combination of HOCOS with temozolomide is approximately 3 times more potent than HOCOS alone (Table 3). Furthermore, it was observed that all combinations used showed antitumor potency superior to that of a single drug, both in glioblastoma and pancreatic cancer. Therefore, since HOCOS is a compound... Petition 870250089276, dated 10 / 01 / 2025, pp. 69 / 92 61 / 76, with no toxicity at therapeutic doses and a mechanism of action different from other antitumor drugs that increases their potency, it can be used in combination therapies with other drugs for the treatment of glioblastoma or other types of cancer. Table 3. Efficacy of HOCOS combined with other antitumor drugs Compound IC50 Combination IC50 Cell and cancer type Thiamine 15.35 mM Thiamine + 200 μΜ HOCOS 5.75 mH Glioblastoma SNB19 HOCOS 1,119 μΜ HOCOS + 300 μΜ Temozolomide 472 μΜ Glioblastoma SF268 Etoposide 2.08 μΜ Etoposide + 150 μΜ HOCOS 1.25 μΜ Glioblastoma Irinotecan 14.96 μΜ Irinotecan + 150 μΜ HOCOS 5.47 μΜ Glioblastoma U118 Imatinib 234.4 nM Imatinib + 150 μΜ HOCOS 169.8 nM Glioblastoma U118 Gemcitabine 7.8 nM Gemcitabine + 300 μΜ HOCOS 5 nM BxPC-3 Pancreas HOCOS 450.1 μΜ HOCOS + 2 μΜ fluoroacyl + 2 μΜ oxyplatin + 1 μΜ irinotecan 201.1 μΜ MIAPaCa-2 Pancreas Folfirinox 1 μΜ HOCOS + Folfirinox 0.4 μΜ BxPC-3 Erlotinib 16.03 μΜ Erlotinib + 150 μΜ HOCOS 6.27 μΜ A549 Lung Cisplatin 16.37 Cisplatin + 150 HOCOS 5.47 μΜ NCI-H2021 Mesothelioma Example 4: Clinical trial in patients with neuropathic pain caused by spinal cord injuries.

[00126] A clinical trial was conducted with HOCOS in people with spinal cord injury suffering from neuropathic pain. The aim of the trial was to demonstrate the pharmacological safety (absence of toxicity) and pharmacological efficacy against neuropathic pain in patients with nerve injury. In this clinical trial, the average neuropathic pain of the patients who participated in the research was between 7 and 8, with 10 being considered the maximum pain possible and 0 the absence of pain, according to the VAS scale. Therefore, it is a population Petition 870250089276, dated 10 / 01 / 2025, pp. 70 / 92 62 / 76 with high chronic pain. A pain that, despite the many analgesics used, is not alleviated since it is a different pathology from conventional pain.

[00127] In a population of 44 patients, patients were randomly segregated (double-blind) into 4 groups. HOCOS tablets were administered at doses of 0 (placebo), 1,050, 2,100 or 4,200 milligrams per day (in 3 doses and orally) and neuropathic pain was recorded according to the VAS scale as a measure of effectiveness. In addition, all patients received the concomitant medication described in the present invention. The composition of said tablets is described in Table 4. Table 4. Composition of HOCOS tablets for the treatment of neuropathic pain. COMPONENTS QUANTITY PER TABLET (mg) PLACEBO (mg) Active ingredient (AHO) 350.0 0.0 Microcrystalline cellulose 331.0 681.0 Mannitol 255.0 255.0 Hydroxypropylcellulose SSL 24.0 24.0 Croscarmellose sodium 60.0 60.0 Sodium glycolate (starch) 60.0 60.0 Hydroxypropylcellulose LH11 60.0 60.0 Sodium lauryl sulfate 12.0 12.0 Ascorbic acid 30.0 30.0 Sodium stearyl fumarate 18.0 18.0 Pure water q.s. q.s. Total weight in base tablet 1,200 mg 1,200 mg Coating: Opadry® con II 88A18002 White Polyvinyl alcohol - Hydrolyzed particulate (E-120) Talc (E-553b) 48 mg 48 mg Titanium dioxide (E-171) Fatty acid esters - glycerol Sodium lauryl sulfate Pure water q.s.q. Total weight of coating length 1.248 mg 1.248 mg Petition 870250089276, dated 10 / 01 / 2025, pp. 71 / 92 63 / 76

[00128] To select patients who met the inclusion requirements for the trial, primarily those with spinal cord injury, neuropathic pain, and receiving pregabalin treatment, patients underwent a screening visit (SV). Once selected for the trial, an initial visit (V1) was conducted during which they were informed about the trial, their pain was quantified, they received the necessary medication for one month, and a blood sample was collected to assess the patient's baseline status. After 1, 2, and 3 months of treatment, visits V2, V3, and V4 were conducted, respectively, to assess treatment efficacy and collect blood samples. From V4 onwards, medication was discontinued, and a visit was conducted after one month without treatment (V5).Therefore, visit V5 was one in which an increase in pain level was expected in all patients, both in those in whom the treatment worked and stopped taking the product, and in those patients who experienced a placebo effect. In all visits, screening and V1 to V5, pain was measured using the VAS scale (Table 5). Petition 870250089276, dated 10 / 01 / 2025, pp. 72 / 92 64 / 76 Table 5. Neuropathic pain data (VAS scale) in patients with spinal cord injury. HOCOS dose (g / day) Patient code sv VI V2 V3 V4 (EoT) V5 (EoS / FU) SV-V4 VI-V4 V5-V4 0a HPT012 5 6, 7 4.5 3.2 4 1 1 2.7 -3 0 HPT018 6, 6 5.7 5.5 8 7 7.5 -0.4 -1.3 0.5 0 HTP025 6, 7 5.8 5.1 5.5 5 5.4 1.7 0.8 0.4 0 HIG029 9 9 5 3 2 1 7 7 -1 0 HPT034 8.8 8.4 8 7.5 7 5.5 1.8 1.4 -1.5 0 HPT037 9.6 9.6 9,2 9 9,5 9,2 0,1 0,1 -0,3 0 HUC047 6, 5 6, 5 7 8 8 7 -1,5 -1,5 -1 0 HVH049 6, 5 7 7 6, 5 6 6, 5 0,5 1 0,5 0 HPT063 6, 77 6, 84 5.54 2.44 1 4.3 5.77 5.84 3.3 1.05 HPT002 5.6 6. 6 6. 4 6. 7 6. 3 6. 1 -0.7 0.3 -0.2 1.05 HVH008 7.8 6. 5 3 3 2 4 5.8 4.5 2 1.05 HPT011 7.8 4 7.3 2.5 6. 7 7 1.1 -2.7 0.3 1.05 HPT017 5.2 3.5 3.8 1.4 4 6.2 1.2 -0.5 2.2 1.05 HUC021 7.05 7.5 7 7.7 7.5 4 -0.45 0 -3.5 1.05 HPT032 8.2 8.2 7.5 7.5 6, 7 7.8 1.5 1.5 1.1 1.05 HPT039 4.5 4.7 4.7 6. 5 6. 5 8 -2 -1.8 1.5 1.05 HPT046 8.2 8.6 8.4 7.5 7 7.5 1.2 1.6 0.5 1.05 HLM051 8.9 8.9 6.2 4.9 7.7 9.4 1.2 1.2 1.7 1.05 HIG056 7 7 5 4 5 5 2 2 0 1.05 HPT058 6 5 4.7 5.5 4.4 4.5 1.6 0.6 0.1 1.05 HPT061 10 9 8 6. 73 7.2 8 2.8 1,8 0.8 2.1 HPT001 6, 5 6, 5 8.1 7.1 7.35 7.3 -0.85 -0.85 -0.05 2.1 HVH005 6, 4 5 4 3 2.5 8 3.9 2.5 5.5 2.1 HIG024 7.5 7.5 7.5 6 6 6 1.5 1.5 0 2.1 HPT031 4 5 2.5 1.4 2.6 2 1.4 2.4 -0.6 2.1 HIG033 8 8 1 2 2 1.5 6 6 -0.5 2.1 HIG035 7 7 7 7.5 5 6 2 2 1 2.1 HLM042 7.7 7.7 6.5 4 2.7 8.2 5 5 5.5 2.1 HPT052 5.2 4.5 6.5 3.5 4 4 1.2 0.5 0 2.1 HPT060 6.66 6.67 7.52 5.43 5.37 8.49 1.29 1.3 3.12 2.1 HPT062 10 10 6.2 5.7 8.3 MD 1.7 1.7 2.1 HPT066 3.9 5.1 6 3.7 1.7 3.1 2.2 3.4 1.4 4.2 HPT007 5 5 4 4.5 5 MD 0 0 4.2 HVN014 6, 5 6, 5 4.5 4.5 5 6.5 1.5 1.5 1.5 4.2 HPT022 8.3 8.4 8.4 8 8.8 8.8 -0.5 -0.4 0 4.2 HVH027 6 6 6 6 6 6 0 0 0 4.2 HLM041 6.2 6.2 4.4 6 5.7 5.2 0.5 0.5 -0.5 4.2 HUC044 7 7 6 4 1.7 4.5 5.3 5.3 2.8 4.2 HUC045 8.5 10 7 7.2 5 9 3.5 5 4 4.2 HVN050 8.7 9 9 8.7 6, 6 7.8 2.1 2.4 1.2 4.2 HVR053 8.5 7.6 7.8 5.2 5.4 7 3.1 2.2 1.6 4.2 HPT059 4.4 5.7 3 3.7 6, 7 6, 7 -2.3 -1 0 4.2 HIG064 5 5 7 5 9 3 -4 -4 -6, Petition 870250089276, dated 10 / 01 / 2025, pp. 73 / 92 65 / 76 4.2 HVR065 7.4 8.1 8.1 8 7.2 8.9 0.2 0.9 1.7 Measuring the adverse effects of HOCOS

[00129] In this clinical trial, HOCOS produced fewer adverse events per patient (P w / AE) than placebo: 1 adverse event per placebo patient versus 0.5 adverse events per patient treated with HOCOS (Figure 5A). Furthermore, treatment-attributable adverse events were also higher in patients receiving placebo (0.44 adverse events per patient related to placebo treatment, P w / RTAE) than in patients receiving HOCOS (0.08 adverse events per patient related to HOCOS treatment, P w / RTAE) at the optimal dose (2,100 milligrams per day). The reduction of more than 80% in this parameter in the group with the dose selected for subsequent treatments (2,100 milligrams daily) suggests that HOCOS is safe (non-toxic) and, moreover, protects against general health problems and / or problems derived from another drug mentioned in this invention in patients with spinal cord injury.Thus, these data indicate that HOCOS has a positive effect on the overall health of patients with spinal cord injury (paraplegia and tetraplegia). Measuring the effectiveness of HOCOS against neuropathic pain.

[00130] The efficacy of HOCOS against neuropathic pain in patients with spinal cord injury was determined using the Petition 870250089276, dated 10 / 01 / 2025, pp. 74 / 92 The 66 / 76 VAS scale consists of a straight line whose ends define "no pain" (0 on the scale) and "worst possible pain" (10 on the scale) (Haefeli and Elfering). The patient is asked to rate the intensity of their pain between these two points. Scales with lengths between 5 and 20 cm were used, although the best results were obtained with lengths of 10 to 15 cm. In this clinical trial, the efficacy of HOCOS was evaluated in 44 patients with spinal cord injury and neuropathic pain using two baseline measures: the screening visit (SV) and the first visit (V1), in which the patient had not yet received medication. Oral treatment lasted 3 months, and pain was assessed after one month (V2), two months (V3), and three months (V4) of treatment. V4 was also referred to as the End-of-Treatment (EoT) visit. Patients remained off medication for one month and were subsequently evaluated at a fifth visit (V5), also called the End of Trial visit (EoS).

[00131] Efficacy analysis was performed on both the “Total Population” of the trial (44 patients: Figure 5B) and a “Censored Population” of patients with objectively persistent pain (34 patients in whom, after treatment interruption, a HOCOS withdrawal effect with increased pain was observed: Figure 5C). The parameter selected to censor patients was pain behavior between visits 4 and 5. As the trial Petition 870250089276, dated 10 / 01 / 2025, pp. 75 / 92 The clinical trial shown in the present invention lasted approximately 6 months, from patient screening to the EoS (Experimental Assessment of Pain). It is possible that several patients entered a cycle of pain reduction spontaneously and naturally. Patients who experienced pain reduction due to treatment experienced increased pain after the treatment period ended; therefore, those patients whose pain decreased at the end of treatment, between V4 and V5, were censored. This censoring was performed equally in all experimental groups. Furthermore, pain was analyzed in the censored responder group, those who had a pain reduction greater than 1 point on the VAS scale (Figure 5D). As can be seen, there is a significant reduction in patients treated with HOCOS, especially in the 2.1 gram daily group (700 milligrams 3 times a day, Tables 4 and 5). This difference is significant when censored patients, whose pain does not increase between V4 and V5, are eliminated.There are no major differences in the absolute reduction values ​​between the 3 analyses performed with (1) all patients (Figure 5B), (2) uncensored patients (Figure 5C), and (3) censored responder patients (Figure 5D), indicating that the overall reduction in pain is not affected by this type of analysis. The statistical significance, however, improves between these analyses, which shows that more homogeneous patient populations are studied. Petition 870250089276, dated 10 / 01 / 2025, pp. 76 / 92 68 / 76

[00132] As discussed above, neuropathic pain differs from other types of pain and is caused by different molecular and cellular mechanisms. The PDQ questionnaire allows us to determine whether the pain suffered by the patient is neuropathic or not. In a further post-hoc analysis, it can be observed that patients receiving treatments of 2,100 mg / day and 4,200 mg / day had significant reductions in neuropathic pain levels measured by the VAS (Figure 5E). In this case, the dose of 2,100 mg / day (po, tid) was the most effective, with the decrease in pain being evident from the first month of treatment and significant from the second month. After 3 months of treatment with 2,100 mg / day, the VAS values ​​in these patients with a high probability of suffering from neuropathic pain were approximately half compared to the beginning of treatment (Figure 5E). In this subpopulation of patients, it was observed that the percentage of responders in the placebo group (0 mg / day) was only 25% (Figure 5F).In contrast, 80% of patients who received 2,100 mg / day of HOCOS responded to treatment, and those who received 1,050 mg / day and 4,200 mg / day responded 37% and 55%, respectively (Figure 5F).

[00133] These results indicate that HOCOS is effective in treating neuropathic pain. It is very important to consider that all patients in this trial were treated Petition 870250089276, dated 10 / 01 / 2025, pp. 77 / 92 69 / 76 with pregabalin and other medications, which achieved only partial pain relief. The reduction observed in patients due to treatment with HOCOS is significant (up to 3 points on the VAS scale) and also occurs in addition to the effect of pregabalin and other drugs. Because HOCOS has a different mechanism of action than other compounds, it can induce this effect both alone and in combination with other medications. In fact, patients in this trial received different drug combinations in each case, so efficacy is not exclusively related to any one combination. In other words, HOCOS may be effective as monotherapy or in combination therapy with pregabalin, opioids, anticonvulsants, anxiolytics, anesthetics, antidepressants, etc.

[00134] In the uncensored population of 2,100 milligrams daily (most effective therapeutic dose), it showed efficacy in 75% of patients, in whom the average effect was approximately a 2-point reduction on the VAS pain scale (Tables 5 and 6). In a previous trial with pregabalin (Cardenas et al.), it was observed that only approximately 50% of patients responded to treatment with an average reduction of 1.2 points on the VAS scale. Therefore, it can be concluded that HOCOS is more effective than pregabalin and, moreover, that its effect overlaps with that of pregabalin, being additive. Petition 870250089276, dated 10 / 01 / 2025, pp. 78 / 92 70 / 76 to this and the other medications mentioned in the present invention.

[00135] The additive effect of HOCOS, along with other drugs, in inducing a marked reduction in neuropathic pain has several interesting considerations that should be highlighted. Firstly, this reduction is greater than that produced by the reference drug for the treatment of neuropathic pain, pregabalin (along with the other drugs mentioned in this document), which reduces neuropathic pain by only 1.2 points on the VAS scale (Cardenas et al.). On the other hand, the percentage of patients responding to pregabalin was 33% in the placebo group and 48% in the pregabalin group, with a difference of 0.82 points between these groups on the VAS scale (Cardenas et al.). In this trial with a daily dose of 2.1 g of HOCOS, there were pain reductions of 1.92 points on the VAS scale between V1 and V4 for the total population.Patient censoring did not result in differences in absolute pain scores, but in the significance of the trial according to the statistical test used (two-way ANOVA, Fisher's LSD test). Regarding the percentage of patients responding to HOCOS treatment in the censored population, reductions greater than 1 VAS point were observed in 55% of patients treated with 1,050 milligrams per day, 75% in those treated with 2,100 mg / day, and 56% in those treated with 4,200 mg / day (Table 6). On the other hand, only 17% of... Petition 870250089276, dated 10 / 01 / 2025, pp. 79 / 92 71 / 76 patients treated with placebo and censored showed marked reductions in neuropathic pain (Table 6). These data clearly indicate that HOCOS is more effective than pregabalin. Furthermore, all patients in this trial were being treated with pregabalin; therefore, the observed effect is additive to that of pregabalin. This additive effect is attributed to the difference in the mechanism of action of both compounds. In the subpopulation of patients with a high probability of presenting neuropathic pain, the effect of the 2,100 mg / day dose of HOCOS at 3 months was very pronounced and significant (Figure 5E). Additionally, with 4,200 mg / day, significant differences in pain reduction were also found, while placebo or low doses (1,050 mg / day of HOCOS) did not produce significant changes in pain scores on the VAS scale in patients with neuropathic pain.This demonstrates that treatment with HOCOS produces a specific pharmacological effect on neuropathic pain in patients with spinal cord injury. Furthermore, after the end of treatment, the increase in the mean VAS score is also consistent with a specific effect of this compound. Finally, in the population of patients with a high probability of having neuropathic pain (>90%) according to the PDQ, the percentage of responders to treatment in the 2,100 mg / day group is markedly higher than in the placebo group (25% and 80%, respectively: Figure 5F). Again, this result... Petition 870250089276, dated 10 / 01 / 2025, pages 80 / 92 72 / 76 demonstrates that treatment with HOCOS is specific and concentration-dependent. Table 6. Total number of patients, uncensored and responders. Dosage Patients Patients Non-responders Patients % of responders (g / day) evaluated censored 1 responders 2 uncensored 0 9 6 1 17 1.05 12 11 6 55 2.1 11 8 6 75 4.2 12 9 5 56 1 patients who did not experience a placebo withdrawal effect HOCOS between V4 and V5 were censored for the second analysis. 2 patients with a marked reduction in pain (VAS analysis V4-V1 > 1). Example 5. Efficacy of HOCOS against neuropathic pain in a vincristine-treated rat model

[00136] The efficacy of HOCOS against neuropathic pain was also investigated in a rat model treated with vincristine (0.5 mg / kg to 1 mg / kg), a drug used in cancer chemotherapy and associated with the onset of neuropathic pain. This model induces peripheral neuropathy similar to that which could be observed in other types of patients, such as those with fibromyalgia, chemotherapy pain, post-herpetic pain, or pain after diabetes or hepatitis, since it does not occur due to traumatic nerve injury. Therefore, this model is different from that of spinal cord injury and is an example of the usefulness of HOCOS in other types of neuropathic pain besides nerve injuries in general, and spinal cord injury in particular. In experimental animals, the Petition 870250089276, dated 10 / 01 / 2025, pages 81 / 92 73 / 76 Pain levels were recorded using analgesimeters based on the reduction of hyperalgesia (exacerbated pain produced by mild stimuli, such as pressure with a toothpick) or allodynia (pain produced by non-painful pressures, such as gentle pressure, the friction of a leaf or a finger on the skin). In this sense, 2 types of tests were performed. (1) The “tail flick” test allows the measurement of thermal hyperalgesia and consists of applying a heat source to the tail, using a laser light beam or similar, and recording the time it takes for the animal to move its tail away from the light beam. The longer the animal can withstand it, the higher the temperature it can withstand and the lower its pain threshold. This test measures the latency or period (seconds) between the onset of the stimulus in the animal and its response to it, so that lower latency values ​​correspond to a higher level of neuropathic pain (Klazas et al.).In this sense, while vincristine reduced latency time in a dose-dependent manner, HOCOS increased this time in treated animals, indicating that it is capable of reversing vincristine-induced neuropathic pain (Figure 6A). In addition to the dose-dependent effect of vincristine, treatment with HOCOS after vincristine treatment (1 mg / kg) had treatment time-dependent effects (Figure 6B). Thus, HOCOS, but not the vehicle, induced recoveries in tail movement values. These results demonstrate that HOCOS is very effective. Petition 870250089276, dated 10 / 01 / 2025, pages 82 / 92 4 / 7 6 in the treatment of neuropathic pain caused by causes other than nerve lesions. Similarly, these results demonstrate the possibility of using HOCOS in the treatment of cancer patients and patients who present with pain induced by antitumor chemotherapeutic agents, such as various alkaloids, including vincristine.

[00137] In addition to thermal hyperalgesia measurements, mechanical allodynia was measured using the Von Frey test. In this test, a non-painful stimulus (e.g., plantar pressure with a plastic fiber) is induced, and the animal's reaction to said stimulus is observed. Figure 5 shows how the effect of HOCOS, measured by the Von Frey test, is very pronounced and significant, while increasing during the treatment period (0-28 days) and remaining even against high doses of the cytotoxic agent (Figures 7A and 7B). Mechanical allodynia is a type of pain that frequently appears in patients suffering from fibromyalgia, chemotherapy pain, post-herpetic pain, or pain following diabetes or hepatitis. Therefore, HOCOS is useful for treating these types of neuropathic pain.

[00138] The tests and results above demonstrate that HOCOS is effective in treating neuropathic pain originating from causes other than nerve or spinal cord injuries. Petição 870250089276, de 01 / 10 / 2025, pág. 83 / 92 75 / 76 REFERÊNCIAS

[00139] Brandsma and van den Bent. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22(6):633-8. doi: 10.1097 / WCO.0b013e328332363e Cardenas et al. A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology. 2013;80(6):533-9. doi: 10.1212 / WNL.0b013e318281546b Haefeli and Elfering. Pain assessment. Eur Spine J. 2006;15 Suppl 1(Suppl 1):S17-24. doi: 10.1007 / s00586-0051044-x Klazas et al. Gabapentin Increases Intra-Epidermal and Peptidergic Nerve Fibers Density and Alleviates Allodynia and Thermal Hyperalgesia in a Mouse Model of Acute TaxolInduced Peripheral Neuropathy. Biomedicines.2022;10(12):3190.doi:10.3390 / biomedicines10123 190. Lencioni et al. Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J Hepatol. 2017;66(6):1166-1172. doi: 10.1016 / j.jhep.2017.01.012. Rodgers et al., Morphine resistance in spinal cord injury-related neuropathic pain in rats is associated with alterations in dopamine and dopamine-related metabolomics. Petição 870250089276, de 01 / 10 / 2025, pág. 84 / 92 76 / 76 Pain. 2022;23(5):772-783. doi: 10.1016 / j.jpain.2021.11.009. Petição 870250089276, de 01 / 10 / 2025, pág. 85 / 92

Claims

1 / 17 CLAIMS 1. 2-hydroxy-octadecene-9-cis-oate compound, or a pharmaceutically acceptable salt or ester thereof, characterized in that it is for use in the treatment of a selected oncological pathology from the group consisting of glioblastoma, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthangastrocytoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuro-glial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, plexus tumor choroidal, choroidal plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer,metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic colonic sigmoid adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, uterine chondrosarcoma, cecal adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer, which is administered at a dose of 500 mg / day to 16,000 mg / day.

2. Compound, salt or ester for use, according to claim 1, characterized in that the oncological pathology is selected from the group consisting of oligoastrocytoma, glioblastoma, oligodengroglioma, ependymoma, xanthoastrocytoma, medulloblastoma, pilocytic astrocytoma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical rhabdoid teratoid tumor, cranial and spinal nerve tumor, mixed neuro-glial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic adenocarcinoma of the lung, small cell lung cancer, rectal cancer, cancer of the rectosigmoid junction, metastatic rectal adenocarcinoma.metastatic sigmotic adenocarcinoma of the colon, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial cancer, Petition 870250080784, dated 09 / 09 / 2025, page 34 / 52 3 / 17 pancreatic neuroendocrine cancer, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

3. Compound, salt or ester for use, according to claim 1 or 2, characterized in that the glioblastoma is grade IV glioblastoma multiforme with native isocitrate dehydrogenase (IDH) enzyme.

4. Compound, salt or ester for use, according to claim 3, characterized in that it is for use in the treatment of native IDH grade IV glioblastoma multiforme in an individual with methylation of the methylguanine methyltransferase (MGMT) gene promoter.

5. Compound, salt or ester for use, according to any one of claims 1 to 4, characterized in that the salt is a sodium salt.

6. Compound, salt or ester for use, according to any one of claims 1 to 5, characterized in that the ester is a methyl ester or an ethyl ester.

7. Compound, salt or ester for use, according to any one of claims 1 to 6, characterized in that the compound, salt or ester is administered orally.

8. Compound, salt or ester for use, according to any of claims 1 to 7, characterized by Petition 870250080784, dated 09 / 09 / 2025, p. 35 / 52 4 / 17 fact that it is administered in a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day.

9. Compound, salt or ester for use, according to any one of claims 1 to 8, characterized in that it is administered at a dose of 2,100 mg / day.

10. Compound, salt or ester for use, according to any one of claims 1 to 8, characterized in that it is administered at a dose of 12,000 mg / day.

11. Compound, salt or ester for use, according to any one of claims 1 to 10, characterized in that the compound, salt or ester is used as a first-line treatment.

12. Compound, salt or ester for use, according to claim 11, characterized in that the first-line treatment comprises 4-week cycles, wherein each cycle comprises administering the compound, salt or ester daily during the first three weeks of each cycle and wherein during the fourth week no treatment is administered.

13. Compound, salt or ester for use, according to any of claims 1 to 12, characterized by the fact that the compound, salt or ester is used as a pre-surgical or post-surgical treatment to reduce the size of a tumor.

14. Compound, salt or ester for use, according to any one of claims 1 to 12, characterized in that the individual receiving the treatment has been previously treated with at least one and up to five different lines of chemotherapeutic treatment.

15. Compound, salt or ester for use, according to any one of claims 1 to 10, 13 or 14, characterized in that the compound, salt or ester is used as a maintenance treatment.

16. Compound, salt or ester for use, according to claim 15, characterized in that the maintenance treatment comprises 4-week cycles, wherein each cycle comprises administering the compound, salt or ester daily during the first three weeks of each cycle and wherein during the fourth week no treatment is administered.

17. Compound, salt or ester for use, according to any one of claims 1 to 16, characterized in that the treatment comprises: - a chemoradiotherapy phase lasting 6 to 7 weeks, comprising administering radiotherapy daily, 5 days a week; administering a second chemotherapeutic agent at a daily dose of 75 mg / m2 from the first day of radiotherapy; and administering the compound, salt or ester at a dose of 12,000 mg / day for 4 weeks from week 3 counted from the start of radiotherapy; - a treatment rest period of 4 weeks; - a maintenance period of 6 cycles of 4 weeks, in which each cycle comprises administering the second chemotherapeutic agent at a daily dose of 150 to 200 mg / m2, during the first five days of each cycle; administering the compound, salt or ester at a dose of 12.000 mg / day during the first three weeks of each cycle, and during the fourth week no treatment is administered; and - a monotherapy phase of 4-week cycles, wherein each cycle comprises administering the compound, salt or ester at a dose of 12,000 mg / day during the first three weeks of each cycle, wherein during the fourth week no treatment is administered, wherein said cycles continue indefinitely as maintenance therapy.

18. Compound, salt or ester for use, according to any one of claims 1 to 17, characterized in that it is intended for simultaneous, separate or sequential use in combination with a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxiplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib and cisplatin.

19. Compound, salt or ester for use according to claim 18, characterized in that it is intended for simultaneous, separate or sequential use in combination with temozolomide, in the treatment of glioblastoma.

20. Compound, salt or ester for use, according to claim 19, characterized in that the glioblastoma is a native IDH grade IV glioblastoma multiforme.

21. Compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of neuropathic pain, characterized in that it is administered at a dose of 500 mg / day to 16,000 mg / day.

22. Compound, salt or ester for use, according to claim 21, characterized in that neuropathic pain is caused by neuronal damage or nerve damage of the central and / or peripheral nervous system.

23. Compound, salt or ester for use, according to claim 22, characterized in that the neuronal lesion is a spinal cord lesion.

24. Compound, salt or ester for use, according to claim 21, characterized in that neuropathic pain is caused by a selected cause from the group consisting of a chemotherapeutic agent, an antitumor and carcinogenic agent. Petition 870250080784, dated 09 / 09 / 2025, page 39 / 52 8 / 17 25. Compound, salt or ester for use, according to claim 24, characterized in that the antitumor agent is an alkaloid.

26. Compound, salt or ester for use, according to claim 25, characterized in that the alkaloid is vincristine.

27. Compound, salt or ester for use, according to claim 21, characterized in that the neuropathic pain is caused by a selected cause from the group consisting of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and hepatitis.

28. Compound, salt or ester for use, according to any one of claims 21 to 27, characterized in that it is administered in a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day.

29. Compound, salt or ester for use, according to any one of claims 21 to 28, characterized in that it is administered at a dose of 2,100 mg / day.

30. Compound, salt or ester for use, according to any of claims 21 to 28, characterized by the fact that it is administered at a dose of 4,200 mg / day.

31. Compound, salt or ester for use, according to any one of claims 21 to 30, characterized in that it is for simultaneous, separate or sequential use in combination with at least one other active ingredient selected from the group consisting of pregabalin, an opioid analgesic, a steroidal analgesic, a non-steroidal analgesic, a cannabinoid analgesic, an anticonvulsant, an anxiolytic, an anesthetic and an antidepressant.

32. Compound, salt or ester for use, according to any one of claims 21 to 31, characterized in that it is for simultaneous use, separately or sequentially in combination with at least one other active ingredient selected from the group consisting of lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dulcolax, alprazole lam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, acetylcysteine, metoclopramide, metamizole, teicoplanin, dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazides, losartan, metamizole, sucralfate, lactitol, pancreatin, Petition 870250080784, dated 09 / 09 / 2025, page.41 / 52 10 / 17 dimethicone, bethanechol, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, cinitapride, quetiapine, betmiga, valproate, lacosamide, lidocaine, metamizole, finasteride, acetylsalicylic acid, enalapril, metformin, liraglutide, trospium, tramadol, celcoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, dexamethasone, dexketoprofen, losartan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, clorazepate, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone, acyclovir, Lignocaine, nystatin, delorazepam, alendronic acid, carbamazepine, cortisone, hydrocortisone, cannabidiol, and tetrahydrocannabinol.

33. Pharmaceutical composition characterized by comprising the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, for use in the treatment of a selected oncological pathology from the group consisting of glioblastoma multiforme, astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, oligoastrocytoma, oligodengroglioma, ependymoma, xanthangustrocytetoma, medulloblastoma, low-grade glioma, grade 3 glioma, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, Petition 870250080784, dated 09 / 09 / 2025, page. 42 / 52 11 / 17 atypical rhabdoid teratoid, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma,pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, colon adenocarcinoma, rectal cancer, rectosigmoid junction cancer, rectal adenocarcinoma, metastatic rectal adenocarcinoma, metastatic sigmoid colon adenocarcinoma, colorectal adenocarcinoma, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial adenocarcinoma, neuroendocrine pancreatic cancer, pancreatic adenocarcinoma, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer, wherein the compound, salt, or ester is administered at a dose of 500 mg / day. 16,000 mg / day.

34. Pharmaceutical composition, according to claim 33, characterized in that the oncological pathology is selected from the group consisting of oligoastrocytoma, glioblastoma, oligodengroglioma, ependymoma, xanthoastrocytoma, medulloblastoma, astrocytoma. Petition 870250080784, dated 09 / 09 / 2025, page 1. 43 / 52 12 / 17 pilocytic, pontine glioma, ependymal tumor, subependymoma, cerebral gliomatosis, embryonal tumor, atypical teratoid rhabdoid tumor, cranial and spinal nerve tumor, mixed neuroglial tumor, pituitary tumor, germ cell tumor, meningeal tumor, meningioma, hemangiopericytoma, hemangioblastoma, choroid plexus tumor, choroid plexus papilloma, pineocytoma, pineoblastoma, mesothelioma, pleural mesothelioma, bile duct adenocarcinoma, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, metastatic lung adenocarcinoma, small cell lung cancer, rectal cancer, rectosigmoid junction cancer, metastatic rectal adenocarcinoma,Metastatic sigmoid adenocarcinoma of the colon, metastatic colorectal adenocarcinoma, urachal fistula cancer, urachal adenocarcinoma, endometrial cancer, pancreatic neuroendocrine cancer, uterine chondrosarcoma, cecal adenocarcinoma, bladder adenocarcinoma, esophageal cancer, and metastatic small cell esophageal cancer.

35. Pharmaceutical composition, according to claim 33 or 34, characterized in that the glioblastoma is grade IV glioblastoma multiforme with native isocitrate dehydrogenase (IDH) enzyme.

36. Pharmaceutical composition, according to claim 35, characterized in that it is for use in the treatment of IDH grade IV glioblastoma multiforme Petition 870250080784, dated 09 / 09 / 2025, page 44 / 52 13 / 17 native in an individual with promoter methylation of the methylguanine methyltransferase (Mgmt) gene.

37. Pharmaceutical composition, according to any one of claims 33 to 36, characterized in that the salt is a sodium salt.

38. Pharmaceutical composition, according to any one of claims 33 to 37, characterized in that the ester is a methyl ester or an ethyl ester.

39. Pharmaceutical composition, according to any one of claims 33 to 38, characterized in that the compound, salt or ester is administered in a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 3,150 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 6,300 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 12,600 mg / day, 14,000 mg / day and 16,000 mg / day.

40. Pharmaceutical composition, according to any one of claims 33 to 39, characterized in that the compound, salt or ester is administered at a dose of 2,100 mg / day.

41. Pharmaceutical composition, according to any one of claims 33 to 39, characterized in that the compound, salt or ester is administered at a dose of 12,000 mg / day.

42. Pharmaceutical composition, according to any of claims 33 to 41, characterized in that it further comprises a second chemotherapeutic agent selected from the group consisting of temozolomide, thiamine, gemcitabine, fluorouracil, oxplatin, irinotecan, etoposide, imatinib, folfirinox, erlotinib and cisplatin.

43. Pharmaceutical composition, according to any one of claims 33 to 42, characterized in that it further comprises temozolomide, for use in the treatment of glioblastoma.

44. Pharmaceutical composition, according to claim 43, characterized in that the glioblastoma is a native IDH grade IV glioblastoma multiforme.

45. Pharmaceutical composition characterized in that it comprises the compound 2-hydroxy-octadecene-9-cis-oate, or a pharmaceutically acceptable salt or ester thereof, together with at least one pharmaceutically acceptable excipient or carrier, for use in the treatment of neuropathic pain, wherein the compound, salt or ester is administered at a dose of 500 mg / day to 16,000 mg / day.

46. ​​Pharmaceutical composition, according to claim 45, characterized in that neuropathic pain is caused by neuronal or nerve damage to the central and / or peripheral nervous system. Petition 870250080784, dated 09 / 09 / 2025, pp. 46 / 52 15 / 17 47. Pharmaceutical composition, according to claim 4 6, characterized in that the neuronal lesion is a spinal cord lesion.

48. Pharmaceutical composition, according to claim 45, characterized in that neuropathic pain is caused by a selected cause from the group consisting of a chemotherapeutic agent, an antitumor and carcinogenic agent.

49. Pharmaceutical composition according to claim 48, characterized in that the antitumor agent is an alkaloid.

50. Pharmaceutical composition according to claim 49, characterized in that the alkaloid is vincristine.

51. Pharmaceutical composition, according to claim 45, characterized in that the neuropathic pain is caused by a selected cause from the group consisting of diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia and hepatitis.

52. Pharmaceutical composition, according to any one of claims 45 to 51, characterized in that the compound, salt or ester is administered in a dose selected from the group consisting of 500 mg / day, 1,000 mg / day, 1,050 mg / day, 2,000 mg / day, 2,100 mg / day, 4,000 mg / day, 4,200 mg / day, 6,000 mg / day, 8,000 mg / day, 10,000 mg / day, 12,000 mg / day, 14,000 mg / day and 16,000 mg / day.

53. Pharmaceutical composition, according to any one of claims 45 to 52, characterized in that the compound, salt or ester is administered at a dose of 2,100 mg / day.

54. Pharmaceutical composition, according to any one of claims 45 to 52, characterized in that the compound, salt or ester is administered at a dose of 4,200 mg / day.

55. Pharmaceutical composition, according to any one of claims 45 to 54, characterized in that it further comprises at least one other active ingredient selected from the group consisting of pregabalin, an opioid analgesic, a steroidal analgesic, a non-steroidal analgesic, a cannabinoid analgesic, an anticonvulsant, an anxiolytic, an anesthetic and an antidepressant.

56. Pharmaceutical composition, according to claim 55, characterized in that it further comprises at least one other active ingredient selected from the group consisting of lamotrigine, omeprazole, phenoxypentanoic acid, metformin, ibuprofen, dulcolax, alprazolam, diazepam, baclofen, macrogol, duloxetine, levofloxacin, gabapentin, ceftriaxone, enoxaparin, pantoprazole, paracetamol, ipratropium bromide, Petition 870250080784, dated 09 / 09 / 2025, page. 48 / 52 17 / 17 acetylcysteine, metoclopramide, metamizole, teicoplanin, dexketoprofen, oxybutynin, meropenem, beclomethasone dipropionate, formoterol fumarate, atorvastatin, calcifediol, paroxetine, cyanocobalamin, clonazepam, amlodipine, trazodone, flurazepam, thiazides, losartan, metamizole, sucralfate, lactitol, pancreatin, dimethicone, bethanechol, amitriptyline, lorazepam, vitamin D, lormetazepam, solifenacin, simvastatin, cinitapride, quetiapine, betmiga, valproate, lacosamide, lidocaine, metamizole,finasteride, acetylsalicylic acid, enalapril, metformin, liraglutide, trospium, tramadol, celcoxib, citalopram, sildenafil, tamsulosin, loratadine, tizanidine, vortioxetine, zolpidem, bromazepam, dexamethasone, dexketoprofen, losartan, eslicarbazepine, pentoxifylline, mirabegron, fluoxetine, clorazepate, mirtazapine, rosuvastatin, prednisone, beclamethasone, methylprednisone, acyclovir, lidocaine, nystatin, delorazepam, alendronic acid, carbamazepine, cortisone, hydrocortisone, cannabidiol and tetrahydrocannabinol. Petition 870250080784, dated 09 / 09 / 2025, page. 49 / 52,

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