New methods

Abstract

Valproic acid, or a compound of Formula (I), or a pharmaceutically acceptable salt thereof: [Refer to original abstract doc for image] wherein R1 is H or D and D is deuterium, for use in the treatment

Description

The present invention relates to compounds for use in the treatment and / or prevention of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), and vessel related fibrosis (e.g. small vessel related fibrosis). Background of the invention Valproic acid, which is commonly abbreviated VPA, is a well-known compound that was first used as an anticonvulsant to treat seizures, and it is also used to treat mania in patients with bipolar disorder and to prevent migraine headaches. In addition, VPA is an inhibitor of histone deacetylases (HDAC) and thus can alter gene expression. As such, VPA has recently been investigated as a potential anticancer therapeutic. It is not clear, however, if the ability of VPA to act as an HDAC inhibitor is related to its ability to treat seizures, bipolar disorders and prevent migraines. Although administration of VPA may provide therapeutic benefits, there are significant toxicities that have been associated with VPA. Indeed, VPA administration can be associated with significant liver toxicity, including acute hepatic liver failure. In particular, there is mounting evidence that a common metabolite of VPA, 4-ene-VPA (depicted below) is at least partly responsible for the toxicity associated with VPA. COOH 4-ene-VPA Novel compounds useful for treating abnormal conditions associated with excess thrombus formation, fibrin deposition, epilepsy, bipolar disease and / or histone deacetylation are described in PCT / GB2022 / 053318. PAH is a progressive and life-threatening condition characterized by elevated blood pressure in the pulmonary arteries, leading to heart failure and, ultimately, death if untreated. Despite advancements in understanding the pathophysiology of PAH, current therapeutic options remain limited and primarily focus on symptom management rather than addressing the underlying causes of the disease. Recent research has identified several key molecular and genetic factors contributing to the development and progression of PAH. Notably, mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene have been implicated in both familial and sporadic forms of the disease (Ghigna et a!., Eur Respir J 2016; 48: 1668-1681). Additionally, the presence of plexiform lesions, a hallmark of severe PAH, varies significantly across different patient populations, suggesting a complex interplay of genetic and environmental factors. Patients with abnormal conditions associated with PAH and / or IPF, such as those experiencing plexiform lesions, artery vessel occlusion, and / or vessel related fibrosis, are particularly difficult to treat. There therefore remains a need for improved treatments and / or prevention of an abnormal condition associated with PAH and / or IPF. Summary of the Invention It is an object of the present disclosure to overcome or at least mitigate one or more of the aforementioned disadvantages. Further, it is an object of the present disclosure to provide advantages and aspects not provided by hitherto known techniques. Thus, the present invention of the present disclosure provides at least one compound of Formula I wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), and vessel related fibrosis (e.g. small vessel related fibrosis) and a combination thereof. Brief Description of the Drawings FIGURE 1 depicts a work plan for a PAH induction protocol wherein D, day; IV, intravenous administration; PO, per os administration; RV, right ventricle; RVSP, right ventricular systolic pressure; SBP, systolic blood pressure; SC, subcutaneous administration; W, week. FIGURE 2 depicts arteriolar changes based on the Heath-Edward's grading system (grade 0 to grade 4) on lung arterioles with diameter <100pm. FIGURE 3 depicts representative 40x photomicrographs of arterioles (H&E staining). Proportion of Grade 0 to Grade 4 (A, B and C) for each experimental group, wherein cd, day, kg, kilogram; mg, milligram; W, week. FIGURE 4 depicts the state of occlusion in lung arterioles with diameter <100 pm, wherein mg / kg, milligramm per kilogram; SuHxNx, Sugen + 3 weeks hypoxia + 3 weeks normoxia. FIGURE 5a and b depicts global arterial score (GAS) against the total and estimated unbound exposures (based on day 41 data). Detailed Description of the Invention According to a first aspect of the invention, there is provided a compound of Formula (I) wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof. The compound for use, method or use according to the first aspect of the invention are hereinafter interchangeably referred to as "uses of the invention" or "methods of the invention". According to an alternative first aspect of the invention, there is provided A method of treating and / or reducing the likelihood of occurrence of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject in need of treatment thereof, said method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ri is either H or D and wherein D is deuterium, or valproic acid, or a pharmaceutically acceptable salt thereof, wherein the abnormal condition associated with PAH and / or IPF is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof. According to a further alternative first aspect of the invention, there is provided the use of a compound of Formula (I) wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof. Compounds of Formula (I) may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in international patent application WO 2023 / 118846 and GB patent no. GB 2613900. The contents of WO 2023 / 118846 and GB 2613900 are incorporated by reference. The phrase "compounds of the invention" as used herein means any one or more of the specific compounds of Formula I or valproic acid. In particular embodiments, the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain compounds of the invention, Ri is either H or D and wherein D is deuterium. In a particular embodiment, there is provided compounds of Formula (I) where Ri represents H. In a further embodiment, there is provided compounds of Formula (I) where Ri represents D (i.e. deuterium). Specific compounds of the present invention include compounds la and / or lb and pharmaceutically acceptable salts thereof: Compound la may be referred to herein as 2-(Propyl-2z2,3z3-c / 4)pentanoic-4z4z5,5-c / 4 acid, 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid or 4,4,5,5-Tetradeutero-2-(2,2,3,3-tetradeuteropropyl)valeric acid (compound la) and compound lb may be referred to herein as 2-(Propyl-2,2z3z.3-d4)pentanoic-2,4z4z5z5-d5 acid or 2,4,4,5,5-Pentadeutero-2-(2,2,3,3-tetradeuteropropyl)valeric acid (compound lb). The compounds of the present invention are novel derivatives of valproic acid (VPA), in which specific hydrogen atoms have been replaced with deuterium isotopes (2H) (represented as "D" in Formula I, compound la and compound lb). The inventors have unexpectedly found that valproic acid having the specific deuteration patterns of Formula I have a surprising metabolic profile that reduces levels of a known toxic metabolite of VPA as well as increased safety profile that both treats conditions associated with excess fibrin deposition and / or thrombus formation as well as reducing excessive blood loss often seen in drugs targeting these conditions. In alternative embodiments, the compound is valproic acid, or a pharmaceutically acceptable salt thereof. The terms "the compounds of the invention" and "a compound as described herein" are used interchangeably and can be used to indicate: the compound of Formula I, compound la, compound lb or valproic acid. The compounds of the present invention include pharmaceutically acceptable salts of the compounds of Formula I or valproic acid. The phrase "pharmaceutically acceptable salt(s)," as used herein includes but is not limited to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. The compounds described herein are acidic in nature and are capable of forming salts with e.g. various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Particular examples of pharmaceutically acceptable addition salts include those derived from metals such as calcium, magnesium, potassium or, preferably sodium. In certain embodiments, such salts may be present as a "hemi-salt" (i.e. in a 2:1 ratio of compound to counterion). The compounds described herein may also for complexes with various amines. Examples of amines include, alkylamines, aminoalcohols (e.g. 2-(dimethylamino)ethanol), basic amino acids (e.g. lysine), quartenary amines (e.g. choline). The compounds of the invention defined herein are known to be beneficial in the treatment of a variety of disease, as disclosed in US patent application US 2017 / 020874, international patent applications WO 2016 / 055797 and WO 2023 / 118846, and GB patent GB 2613900. The inventors have discovered that the compounds of the present invention are surprisingly effective at treating and / or preventing certain abnormal conditions associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) as is evidenced by the data in the examples which show that a dose dependent decrease of grade 3 and grade 4 arterioles as well as a dose dependent decrease in the proportion of partially to closed vessels in favour of open vessels following administration of a compound of the invention. Accordingly, these data indicated that the compounds of the invention are useful in treating abnormal conditions associated with PAH and / or IPF, specifically, plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), vessel related fibrosis (e.g. small vessel related fibrosis) and a combination thereof. As noted below, the compounds of the present invention are also unexpectedly beneficial in treating pulmonary arterial hypertension (PAH) in subjects refractory to treatment for PAH with a previously ceased or ongoing treatment regimen. Accordingly, the invention provides methods of using the compounds of the present invention for treating / preventing abnormal conditions associated with PAH and / or IPF, said abnormal conditions being plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), or vessel related fibrosis (e.g. small vessel related fibrosis) and a combination thereof. In other words, the present invention provides methods of treating / preventing abnormal conditions associated with PAH and / or IPF, said abnormal conditions being specifically, plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), or vessel related fibrosis (e.g. small vessel related fibrosis) and a combination thereof. The methods of treatment of abnormal conditions associated with PAH and / or IPF comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof. As indicated herein, the compound of the invention may be provided in the form of a pharmaceutical composition. There is also provided use of a compound as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment / prevention of an abnormal condition associated with PAH and / or IPF, said abnormal conditions being plexiform lesions, artery vessel occlusion (e.g. small artery vessel occlusion), or vessel related fibrosis (e.g. small vessel related fibrosis) and a combination thereof. In particular embodiments, the subject in need of uses or methods of the invention is a subject suffering from pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension (PAH) is a subgroup of pulmonary hypertension and is categorized by World Health Organization (WHO) as group 1. PAH is a condition characterised by elevated blood pressure in the pulmonary arteries and pulmonary arterioles which is caused by narrowing and thickening of tiny arteries of the lung. Commonly, a mean pulmonary artery pressure greater than 20 mmHg in a subject as measured by a right heart catheterization is required for the diagnosis of PAH. The WHO define the severity of a subject's pulmonary hypertension (PH) symptoms by functional classes: • Class I - symptom-free when physically active or resting • Class II -no symptoms at rest, but normal activities such as climbing the stairs, grocery shopping or making the bed cause some discomfort and shortness of breadth • Class III - resting may be symptom free but normal chores around the house are greatly limited due to shortness of breath or feeling tired • Class IV - symptoms at rest and severe symptoms with an activity. Class I is the mildest and Class IV the most severe form of PH. Assigning a functional class helps the PH healthcare team to understand how the patient is affected by their condition. A goal of PH treatment is to make everyday living easier, so it is very important to have an accurate picture of how PH is affecting a patient's daily life. The New York Heart Association (NYHA) has classified symptoms relevant for PHPAH in the following classes: Classi- Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV - Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and / or fatigue may even be present at rest. Discomfort is increased by any physical activity. In particular embodiments, the subject in need of uses or methods of the inventions is suffering from Class I, Class II, Class III or Class IV pulmonary hypertension (PH) according to the WHO or NYHA. In particular, suffering from Class III / IV or Class IV. Pulmonary arterial hypertension (PAH) is further subdivided into various categories based on the cause, including idiopathic PAH (e.g. non-responders at vasoreactivity testing, acute responders at vasoreactivity testing), heritable PAH, PAH associated with drugs and toxins, PAH associated with specific diseases (e.g. connective tissue disorders (CTD), HIV infection, portal hypertension, congenital heart diseases, or schistosomiasis), PAH with features of venous or capillary (PVOD / PCH) involvement, persistent PAH in the newborn, and PAH in long-term responders to calcium channel blockers. Thus, in particular embodiments, the subject in need of uses or methods of the invention may be a subject suffering from idiopathic pulmonary arterial hypertension (PAH), heritable PAH, PAH associated with drugs and toxins, PAH associated with specific diseases, PAH with features of venous or capillary involvement, persistent PAH in the newborn, or PAH in long-term responders to calcium channel blockers. Subjects suffering from pulmonary arterial hypertension (PAH) may have, or be at risk having, a condition involving fibrosis. The fibrosis may be primary or secondary fibrosis or both, remodelling and repair, fibrosis associated with cardiovascular disease, inflammatory disease, fibrosis associated with activation of the Renin-Angiotensin-System, the mineral corticoid receptor and PAI-1 as well as other systemic diseases. In particular embodiments, the condition involving fibrosis is an interstitial lung disease (ILD). Accordingly, in particular embodiments, the present invention provides a treatment / prevention of an abnormal condition (such as artery vessel occlusion, vessel related fibrosis, or, in particular, plexiform lesions) associated with pulmonary arterial hypertension (PAH) in a subject suffering from, or at risk of, and ILD. A particular ILD to be mentioned is pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), which is associated with increased pulmonary pressure. Thus, in particular embodiments, the subject suffering from PAH in need of uses or methods of the invention may be a subject suffering from, or at risk from, an ILD, such as pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis). In particular embodiments, the subject in need of uses or methods of the inventions is suffering from PAH and IPF. In other embodiments, the subject in need of uses or methods of the invention is a subject suffering from idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause where the lung tissue becomes scarred and stiff, making it difficult to breathe. Symptoms of IPF include the gradual onset of shortness of breath, a persistent dry cough, fatigue, weight loss, and clubbing of finger. Complications of IPF may include pulmonary hypertension, heart failure, pneumonia or pulmonary embolism. Accordingly, in particular embodiments, the subject in need of uses or methods of the inventions is suffering from IPF with pulmonary hypertension. Although all forms of pulmonary arterial hypertension (PAH) share common histopathological features, the presence of certain pulmonary arterial abnormalities and extent of co-existing pulmonary venous involvement differs between the different subgroups. The structural changes in the pulmonary arteries of subject suffering from PAH is classified by a five-grade system: • Grade 0 (GO): normal. • Grade 1 (Gl): medial hypertrophy without intimal changes. • Grade 2 (G2): medial hypertrophy with intimal proliferation. • Grade 3 (G3): medial hypertrophy, intimal proliferation, and fibrosis / fibro-elastosis. • Grade 4 (G4): medial hypertrophy, intimal proliferation, and plexiform lesions (stalk-like branches, angiomatoid lesions, and aneurysm-like lesions). Such structural changes, such as plexiform lesions, in the pulmonary arteries may also be present in subjects suffering from idiopathic pulmonary fibrosis (IPF). Plexiform lesions are a hallmark of severe pulmonary arterial hypertension (PAH), characterised by complex vascular formations originating from remodeled pulmonary arteries (e.g. by stalk-like branches, angiomatoid lesions, and aneurysm-like lesions). The classic plexiform lesion is a peculiar and easily recognisable lesion that is rather typical for PAH (as defined by the WHO). Accordingly, in particular embodiments, the abnormal condition associated with pulmonary arterial hypertension (PAH) is plexiform lesions. In certain embodiments, the subject is suffering from grade 4 pulmonary arteries. In certain embodiments, the subject is suffering from grade 3 pulmonary arteries. In particular embodiments, the subject is suffering from Class I, Class II, Class III or Class IV pulmonary hypertension (PH) according to the WHO or NYHA. In particular, suffering from Class III / IV or Class IV. However, as discussed by Stacher et al Am J Respir Crit Care Med Vol 186, Iss. 3, pp 261-272, Aug 1, 2012, plexiform lesions are generally not present in two of the PAH subgroups: subjects with pulmonary veno-occlusive disease (PVOD), and PAH associated with connective tissue disease (PAH-CTD). Thus, in particular embodiments, the abnormal condition associated with pulmonary arterial hypertension (PAH) is plexiform lesions and wherein the PAH is not PVOD or PAH-CTD. In alternative embodiments, the abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) is artery vessel occlusion. In particular embodiments, the abnormal condition is small artery vessel occlusion. In further alternative embodiments, the abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) is vessel related fibrosis. In particular embodiments, the abnormal condition is small vessel related fibrosis. Disease specific therapies for pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) are associated with improved disease-free survival, symptom scores and mortality. However, in certain cases, the disease may be refractory to therapy and so the subject does not respond to standard treatment. In such circumstances, the subject may require an atrial septostomy or lung transplantation. The inventors have also found that the compounds of the invention are surprisingly effective in treating pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject who is refractory to treatment for PAH and / or IPF with a previously ceased or ongoing treatment regimen. Accordingly, in a second aspect of the invention, there is provided a method of treating pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ri is either H or D and wherein D is deuterium, or valproic acid, or a pharmaceutically acceptable salt thereof, wherein the subject is refractory to 5 treatment for PAH and / or IPF with a previously ceased or ongoing treatment regimen. According to an alternative second aspect of the invention, there is provided the compound of Formula I, or a pharmaceutically acceptable salt thereof, 10 wherein Ri is either H or D and wherein D is deuterium, or valproic acid, or a pharmaceutically acceptable salt thereof, for use in a method of treating pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject, 15 wherein the subject is refractory to treatment for PAH and / or IPF with a previously ceased or ongoing treatment regimen. According to a further alternative second aspect of the invention there is provided the use of a compound of Formula (I) wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject, wherein the subject is refractory to treatment for PAH and / or IPF with a previously ceased or ongoing treatment regimen. The skilled person will understand that a "treatment regimen" is a detailed plan for administering a specific treatment and outlines, for example, the dosage, schedule, and duration of the treatment. For example, a treatment regimen comprises administering one or more therapeutic agents for treatment of a relevant condition, e.g. a compound of Formula (I) or valproic acid as defined herein for the treatment of abnormal condition associated with PAH and / or IPF. The skilled person will understand that the term "refractory to treatment" refers to a disease or condition that does not respond to standard treatments. Thus, a subject who is refractory to treatment is a subject suffering from a disease or condition that does not respond to standard treatments. For example, a subject who is refractory to treatment for PAH and / or IPF is a subject suffering from PAH and / or IPF that does not respond to standard treatments, such as the treatments described herein. The skilled person will understand that a "previously ceased" treatment regimen refers to a treatment regimen has been stopped. In other words, the subject of a previously ceased treatment regimen is not currently undergoing said treatment regimen. The skilled person will understand that an "ongoing" treatment regimen refers to a continuous or extended treatment regimen. In other words, the subject of an ongoing treatment regimen is undergoing said treatment regimen. A subject refractory to treatment (i.e. unsatisfactory treatment) for pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) with a previously ceased or ongoing treatment regimen effect can be identified by procedures known to a person skilled in the art. For example, by pulmonary blood pressure and / or pulmonary vascular resistance (PVR) (performed by right-heart catherization, done yearly on some PAH patients), unsatisfactory (e.g. elevated) biomarkers such as brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), unsatisfactory 6 minute walking distance test, or indirectly through an echocardiogram (ECHO) or magnetic resonance imaging (MRI), or a so called risk score that is a composite important for disease progression. One such risk score is the REVEAL risk score, as described in CHEST 2019; 156(2):323-337. An unsatisfactory change in risk score, such as the REVEAL risk score, is an increase by at least 1 or at least 2 units. The aforementioned procedures for identifying a subject refractory to treatment (i.e. unsatisfactory treatment) for pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) may also be used to identify subjects in need of the uses and methods of the first aspect of the invention, i.e. subjects suffering from an abnormal condition associated with PAH and / or IPF. In particular embodiments of the second aspect of the invention, the previously ceased or ongoing treatment failed to sufficiently lower blood pressure in the subject's pulmonary arteries. In particular embodiments of the second aspect of the invention, the subject's pulmonary artery pressure is greater than about 20 mmHg at rest after said previously ceased or ongoing treatment but prior to said administering the compound of Formula I or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments, pulmonary artery pressure is greater than about 25 mmHg, greater than about 30 mmHg, or greater than about 35 mmHg at rest after said previously ceased or ongoing treatment but prior to said administering the compound of Formula I or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the second aspect of the invention, the previously ceased or ongoing treatment is treatment with one or more therapeutic agent selected from the group consisting of PDE5 inhibitors (such as sildenafil and tadalafil), soluble guanylate cyclase stimulators (such as riociguat), endothelin receptor antagonists (such as aprocitentan, bosentan, macitentan, tezosentansitaxentan, ambrisentan, atrasentan, BQ-123, sparsentan, zibotentan, avosentan, edonentan, and clazosentan), prostacyclins and prostacyclin agonists (such as selexipag, epoprostenol, treprostinil, and iloprost), and long acting calcium channel blockers (such as nifedipine, diltiazem, and amlodipine or a combination thereof. In particular embodiments of the second aspect of the invention, the previously ceased or ongoing treatment is an ongoing treatment, wherein treatment with the compound of Formula I, or a pharmaceutically acceptable salt thereof, thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, is in addition to (i.e. coadministered with) the ongoing treatment. In particular embodiments, the ongoing treatment is treatment with one or more therapeutic agent selected from the group consisting of PDE5 inhibitors (such as sildenafil and tadalafil), soluble guanylate cyclase stimulators (such as riociguat), endothelin receptor antagonists (such as aprocitentan, bosentan, macitentan, tezosentansitaxentan, ambrisentan, atrasentan, BQ-123, sparsentan, zibotentan, avosentan, edonentan, and clazosentan), prostacyclins and prostacyclin agonists (such as selexipag, epoprostenol, treprostinil, and iloprost), and long acting calcium channel blockers (such as nifedipine, diltiazem, and amlodipine or a combination thereof. In particular embodiments, the previously ceased or ongoing treatment is first line treatment with a PDE5 inhibitor (e.g. as described herein) and / or an endothelin receptor antagonist (e.g. as described herein). In particular embodiments, second line treatment is with a prostacyclin and / or prostacyclin agonist (e.g. as described herein). The skilled person will understand that the term "first line treatment" refers to an initial, or primary, therapy recommended for a disease or condition. A "second line treatment" is a therapy provided if the first line treatment is not effective or is responsible for severe side effects. The skilled person would therefore understand that the uses or methods of the second aspect of the invention may be administered to the subject refractory to treatment for PAH after any previously ceased (i.e. after) or any ongoing (i.e. concurrently to) treatment for PAH, including, but not limited to a first line treatment, a second line treatment for PAH, or any further treatment for PAH. The methods of treatment and methods using the compounds of the present invention comprise administering one of more the compounds of the present invention to a subject in need of treatment thereof. Suitable dosage ranges of the compounds of the invention are generally about 0.0001 milligrams / dose to 2000 milligrams / dose of a compound of the invention per kilogram body weight, per day. In specific embodiments of the invention, the dose is from about 0.001 milligram to about 4000 milligrams per kilogram body weight, or from about 0.01 milligram to about 3000 milligrams per kilogram body weight, or from about 0.1 milligram to about 2000 milligrams per kilogram body weight, or from about 0.1 milligram to about 1500 milligrams per kilogram body weight, or from about 0.1 milligram to about 1000 milligrams per kilogram body weight, or from about 1 milligram to about 500 milligrams per kilogram body weight, or from about 1 milligram to about 100 milligrams per kilogram body weight, or from about 1 milligram to about 90 milligrams per kilogram body weight, or from about 1 milligram to about 80milligrams per kilogram body weight, or from about 1 milligram to milligrams per kilogram body weight, or from about 1 milligrams per kilogram body weight, or from about 1 milligrams per kilogram body weight, or from about 1 milligrams per kilogram body weight, or from about 1 milligrams per kilogram body weight, or from about 1 milligrams per kilogram body weight, or from about 1 milligram to milligram to milligram to milligram to milligram to milligram to about about about about about about about 70 60 50 40 30 20 10 milligrams per kilogram body weight, or from about 1 milligram to about 5 milligrams per kilogram body weight. In other embodiments, one of more of the compounds of the present invention are administered at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 7 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg or 100 mg / kg. In other specific embodiments, daily doses are in the range of about 1 to 4000 mg per patient (e.g. 1 to 3000 mg or 1 to 2000 mg per patient), administered in single or multiple doses. Thus, particular treatments that may be mentioned include administering from about 1 to about 4000 mg / day, about 1 to about 3000 mg / day, about 1 to about 2000 mg / day, about 1 to about 1000 mg / day, about 1 to about 900 mg / day, about 1 to about 800 mg / day, about 1 to about 700 mg / day, about 1 to about 600 mg / day, about 1 to about 500 mg / day, about 1 to about 400 mg / day, about 1 to about 300 mg / day, about 1 to about 200 mg / day, about 1 to about 100 mg / day of the compound of Formula (I). Preferably, the treatment includes administering from about 100-600 mg / day, from about 100-500 mg / day, from about 150-500 mg / day, from about 100-400 mg / day, from about 150-400 mg / day, in particular from about 200 to about 400 mg / day of the compound of Formula (I) or valproic acid. In other more specific embodiments, one of more of the compounds of the present invention are administered at a daily dose of about about 10 mg to about 2000 mg, from about 50 mg to about 1300 mg, e.g., about 100 mg to about 1200 mg, or from about 50 mg to about 1000 mg, e.g., about 100 mg to about 800 mg, about 100 mg to about 600 mg, or about 200 mg to about 600 mg, e.g., about 100 mg to about 800 mg, or about 200 mg to about 600 mg. The daily doses may be administered as a single bolus dose or the total dose may be divided over multiple doses, e.g., 2, 3, 4, 5, 6, 7 or 8 doses, per day. As used herein and unless otherwise indicated, the phrase "therapeutically effective amount" of a composition of the invention is measured by the therapeutic effectiveness of a compound of the invention, wherein at least one adverse effect of a disorder is ameliorated or alleviated. The terms "preventing" or "prevention" is intended to include reducing the frequency or likelihood of (e.g. reducing the risk of) a subject experiencing an undesired physiological activity or symptom associated with an abnormal condition or disorder. The term "prevent" or "prevention" as use herein does not require absolute prevention of the abnormal condition. In one embodiment, "treatment" or "treating" refers to reducing or amelioration of a disease, disorder, abnormal condition or at least one discernible symptom thereof. In another embodiment, "treatment" or "treating" refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease, disorder or abnormal condition. As used herein, the skilled person will understand that references to "prevent" or "prevention" of a particular condition may also be referred to as "prophylaxis" of said condition, and vice versa. Thus, each reference herein to "preventing" a condition may be replaced with a reference to "prophylaxis" of said condition. The term "about" as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, at each instance, such terms may be replaced with the notation "±10%", or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted. In certain embodiments, the compositions of the invention are administered to a patient, for example a human. The terms subject and patient are used interchangeably herein. The subject can be a non-human mammal as well, e.g., for veterinary use for companion pets or for farming or livestock animals. Examples of non-human subject include but are not limited to non-human primates, dogs, cats, cows, pigs, oxen, horses, etc. The compounds of the invention may be administered by any convenient or conventional route, for example, oral, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings, e.g., oral mucosa, rectal and intestinal mucosa, etc., and may be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer a compound or composition of the invention. Methods of administration include but are not limited to inhalation, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally or topically, for example to the ears, nose, eyes, or skin. In a specific embodiment, the compounds of the invention are administered orally. In specific embodiments, it may be desirable to administer one or more compounds of the invention locally to the area in need of treatment. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In one embodiment, administration can be by direct injection at the site (or former site) of an atherosclerotic plaque tissue. In another embodiment, the compounds of the invention can be delivered in a vesicle, for example a liposome. See Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989). In yet another embodiment, the compounds of the invention can be delivered in a controlled release system. In one embodiment, a pump may be used. See Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N. Engl. J. Med. 321:574. In another embodiment, polymeric materials can be used. See Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chern. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, ]. Neurosurg. 71:105). All formulations known in the art and described for valproic acid, and pharmaceutically acceptable salts thereof, may be used when administering the compounds of the present invention. For example, in known pharmaceutical formulation comprising valproic acid in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, the compositions and methods of the present invention contemplate substituting VPA in these known formulations with one or more of the compounds of the present invention. The present compositions will contain a therapeutically effective amount of a compound of the invention, together with a suitable amount of a pharmaceutically acceptable vehicle so as to provide the form for proper administration to the patient. Thus, in particular embodiments, the compound of Formula (I) or valproic acid is provided in the form of pharmaceutical composition comprising at least one pharmaceutical vehicle. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Water can be a vehicle when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Other examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by A. R. Gennaro. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In another embodiment, the compounds of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compounds of the invention for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the compound of the invention is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound of the invention is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. Formulations for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions may contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds of the invention. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains. For the avoidance of doubt, the skilled person will understand that references herein to particular aspects of the invention (such as the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention. The skilled person will understand that compounds of formula (I) (including compounds of formula (la) and (lb)) and valproic acid may be prepared using techniques known to those skilled in the art. Examples The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention. In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context). Example 1 - Synthetic Routes Synthesis of compound la and compound lb Step 1. Dimethyl 2-(2,2,3,3-tetradeuteriopropyl)propanedioate Dimethyl propargylmalonate (10.0 g, 58.8 mmol) and tris(triphenylphosphine)rhodium(I) chloride (1.6 g, 1.8 mmol, 3%) were mixed in 100 ml of toluene. The reaction flask was evacuated and flushed with nitrogen repeatedly. The reaction flask was connected to the hydrogenation manifold and the reaction flask evacuated and flushed with deuterium. The mixture was stirred under deuterium. After complete reduction the reaction mixture was filtered through celite and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by kugelrohr distillation (10 mbar@ 130 °C). A clear, colourless oil was obtained (7.2 g, 69%), XH NMR (400 MHz, Chloroform-d) 3 3.73 (s, 6H), 3.37 (t, 1 = 7.6 Hz, 1H), 1.87 (d, 1 = 7.6 Hz, 2H), 0.88 (s, 1H). Step 2. Dimethyl 2-prop-2-ynyl-2-(2,2,3,3-tetradeuteriopropyl)propanedioate Sodium hydride (60% in mineral oil, 5.55 g, 139 mmol) was slurried in 200 ml of THF cooled on ice under nitrogen. Dimethyl 2-(2,2,3,3-tetradeuteriopropyl)propanedioate (16.5 g, 92.6 mmol) in 50 ml of THF was added dropwise. After 30 minutes propargyl bromide (14.3 g, 120 mmol) in 50 ml of THF was added dropwise. The reaction mixture was stirred for 2 hours at 0 °C and quenched by the addition of 100 ml of sat. NH4CI. Heptane (200 ml) was added, and the phases separated. The organic phase was washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated. A light brown oil was obtained (18 g). Crude, contains mineral oil, used as such, !H NMR (400 MHz, Chloroform-d) 6 3.74 (s, 6H), 2.82 (d, J = 2.7 Hz, 2H), 2.05 - 1.96 (m, 3H), 0.89 (s, 1H). Step 3. Dimethyl 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioate Dimethyl 2-prop-2-ynyl-2-(2,2,3,3-tetradeuteriopropyl)propanedioate (18 g, 83 mmol) and tris(triphenylphosphine)rhodium(I) chloride (1.54 g, 1.66 mmol, 2%) were mixed in 300 ml of toluene. The reaction flask was evacuated and flushed with nitrogen repeatedly. The reaction flask was connected to the hydrogenation manifold and the reaction flask evacuated and flushed with deuterium. The mixture was stirred under deuterium. After 1, 2 and 3 days, 0.5 g more of rhodium catalyst was added and the reaction restarted. After complete reduction the solvent was removed under reduced pressure. Heptane (200 ml) was added. After stirring for 30 minutes the precipitate was removed by filtration through celite. The mother liquor was concentrated, and the residue purified by kugelrohr distillation (30 mbar@ 160 °C). A clear, colourless oil was obtained (13 g, 70%), XH NMR (400 MHz, Chloroform-d) 5 3.70 (s, 6H), 1.83 (s, 4H), 0.86 (s, 2H). Step 4. 2,2-Bis(2,2,3,3-tetradeuteriopropyl)propanedioic acid Sodium hydroxide (13.9 g, 348 mmol) was dissolved in 100 ml of water. Dimethyl 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioate (13 g, 58 mmol) in 50 ml of methanol was added. The reaction mixture was stirred at reflux for 5 hours and at room temperature overnight. The reaction mixture was washed with 2*50 ml of DCM. The aqueous phase was concentrated under vacuum to remove traces of DCM. The solution was cooled on ice and 80 ml of 5 M HCI was added. A white precipitate formed. The mixture was stirred on ice for 1 hour and the precipitate collected by filtration and washed with a small amount of water. White solid (11 g, 97%), NMR (500 MHz, Chloroform-d) 6 1.92 (s, 4H), 0.88 (s, 2H). Step 5. "Compound la", 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid 2,2-Bis(2,2,3,3-tetradeuteriopropyl)propanedioic acid (11 g, 56 mmol) was mixed with 100 ml of water in a glass insert to a steel bomb. The bomb was heated to 160 °C over night. After cooling to room temperature, the water / oil mixture was transferred to a separation flask with heptane. The aqueous phase was extracted three times with heptane. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to a light brown oil (8.0 g, 94%). Contains traces of heptane, XH NMR (400 MHz, Chloroform-d) 6 2.42 - 2.30 (m, 1H), 1.60 (dd, J = 13.4, 8.9 Hz, 2H), 1.43 (dd, J = 13.4, 5.3 Hz, 2H), 0.86 (s, 2H). Step 6. "Compound la, sodium hemi salt", 2 [(2,2,3,3 2H4)propyl](4,4,5,5 2H4)pentanoic acid and sodium 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoate Compound la (8.00 g, 52.5 mmol) and finely ground sodium hydroxide (1.05 g, 26.3 mmol) were mixed in 20 ml of MTBE. The mixture was stirred at 50 °C for 30 minutes. A Clear, light brown solution was obtained. After cooling on ice, 80 ml of acetonitrile was added. A massive precipitate formed. After stirring for one hour on ice bath the precipitate was collected by filtration and washed with acetonitrile. The solid was dried under vacuum overnight. White solid (6.79 g, 79%, assumed hemi salt), XH NMR (400 MHz, DMSO-d6) 3 2.06 (ddd, J = 14.1, 9.0, 5.2 Hz, 1H), 1.41 (dd, J = 12.9, 9.0 Hz, 2H), 1.19 (dd, J = 13.0, 5.2 Hz, 2H), 0.77 (s, 2H), LCMS (ESI-): m / z [M-H]- calcd.: 151, found: 151 Compound lb was prepared as described above but with the addition of performing the final decarboxylation in D2O. Example 2 -SUGEN / hypoxia-induced pulmonary arterial hypertension model in rat The study detailed below (and referred to as Example 2) was conducted to test the potential effect of PO administrations of Compound la, administered at 5 doses in a rat model of SUGEN / hypoxia-induced PAH. Materials and methods The experimental procedures were carried out in accordance to European guidelines for the care and use of laboratory animals (Directive 2010 / 63 / UE). The protocol that was used to induce PAH in rats was approved by an Animal Ethical Committee (French National Committee N°71) and by the Higher Education and Research Ministry (APAFIS#6068-2016062722115986 v5) on December 6th 2018. Candidate compound Compound la (MW 163.3, batch number 81169, manufactured by NCK Denmark in accordance with the process described herein) was stored at +4°C until preparation of the oral formulation. Details regarding the candidate compound tested within the scope of the present study are presented in Table 1. The vehicle solution for the 2 vehicle groups was 0.5% Methylcellulose 400 cP and 0.5% Tween 80 in sterile water. Candidate compound Nature Dose (mg / kg) / schedule Vehicle Route of administration Compound la 1 / once daily from D22 to D42 inclusive 0.5% Methyl cellulose 400 cP and 0.5% Tween 80 PO D, day; kg, kilogram; mg, milligram; PO, per os Table 1. Candidate compound Preparation of candidate compound for oral administration Vehicle preparation A 1% Methocel 400cP solution (e.g. 1 g Methocel 400cP made up to a volume of 100 ml in sterile QSP water) was prepared and added to a equal volume of a 1% Tween 80 solution (e.g. 1 ml Tween 80 solution made up to a volume of 100 ml in sterile QSP water). The pH of the final vehicle solution (0.5% Methocel 400cP and 0.5% Tween 80 in sterile water) was adjusted to 9 with NaOH IM or 5M for large preparations. The vehicle solution was prepared once a week and aliquoted for seven days. Aliquots were stored at +4°C until the day of treatment. Compound la preparation Briefly, the required amount of test item was accurately weighed and solubilized with the 80% of the total vehicle solution under magnetic stirring. A milky solution was obtained. Then, pH was controlled and adjusted to 9 with NaOH IM or 5M for large preparations. Magnetic stirring was applied to obtain a clear solution, and vehicle solution was added to reach the final volume. The pH of the final formulation was controlled and adjusted to 9. Animal housing and identification Acclimatisation of animals lasted at least 5 days (Figure 1). At receipt, animals were collectively housed in cages. During the study, animals had free access to food (RM1, SDS Dietex) and drinking water ad libitum. 5 Experimental groups As detailed in Table 2, the experiments were conducted on 67 rats distributed in 10 groups of rats. Groups 1 to 7 for the efficacy study (n=6-10 per group); Group 8 to 10 for the PK study (n=3 per group). Group N / group Disease induction Treatment Treatment Dose / route / administration volume / dosing schedule Concent ration of the final preparat ion Echocardiography (D2J 1 6 No induction -Normoxia from Do to D42 Vehicle n.a. / PO / 5 ml / kg / once daily from D22 to D42 included n.a. Plasma D42-> storage -80°C Lungs NBF 10% / Eth 70% Echocardiography (D21) 2 10 SUGEN + 3W Hypoxia 10%* + 3W Normoxia Vehicle n.a. / PO / 5 ml / kg / once daily from D22 to D42 included n.a. Plasma D42-> storage -80°C Lungs NBF 10% / Eth 70% 3 8 SUGEN + 3W Hypoxia 10%* + 3W Normoxia Compound la 20 mg / kg / PO / 5 ml / kg / once daily from D22 to D42 included 4 mg / ml Echocardiography (D21) Plasma D42-> storage -80°C Lungs NBF 10% / Eth 70% 4 8 SUGEN + 3W Hypoxia 10%* + 3W Normoxia Compound la 40 mg / kg / PO / 5 ml / kg / once daily from D22 to D42 included 8 mg / ml Echocardiography (D21) Plasma D42^ storage -80°C Lungs -» NBF 10% / Eth 70% Echocardiography (D2i) 5 8 SUGEN + 3W Hypoxia 10%* + 3W Normoxia Compound la 75 mg / kg / PO / 5 ml / kg / once daily from D22 to D42 included 15 mg / ml Plasma D42^ storage -80°C Lungs NBF 10% / Eth 70% SUGEN + 3W 150 mg / kg / PO / 5 ml / kg / Echocardiography (D21) 6 8 Hypoxia 10%* Compound la once daily 30 mg / ml + 3W Normoxia from D22 to D42 included Plasma D42^ storage -80°C Lungs NBF 10% / Eth 70% SUGEN + 3W 7 10 Hypoxia 10%* + 3W Normoxia Echocardiography (D21) 300 mg / kg / PO / 5 ml / kg / Plasma D42^ storage Compound la once daily 60 mg / ml ’80°C from D22 to D42 included Lungs -> NBF 10% / Eth 70% SUGEN + 3W 8 3 Hypoxia 10%* + 3W Normoxia Plasma D22and D4i: ,. , , _ ,,, , Tlh, T2h, T4h. T6h. da Iv 7 9 7 ™ Compound la once aa"y 4 mg / ml -80°C from D22 to D42 included SUGEN + 3W 9 3 Hypoxia 10%* + 3W Normoxia Plasma D22 and D4i: 75 mg / kg / PO / 5 ml / kg / T24h storage at Compound la 1 15 mg / ml -80°C from D22 to D42 included 10 3 SUGEN + 3W Hypoxia 10%* _ , T 300 mg / kg / PO / 5 ml / kg / rn , . Compound la h -i 60 mg / ml Plasma D2? and D4i: once daily Tlh, T2h, T4h, T6h, + 3W Normoxia from D22 to D42 included T24h -» storage at -80°C Total number of tests: 67 D, day; kg, kilogram; mg, milligram; ml, milliliter; nle; NBF, neutral buffered formalin; PBS, phosphate buffered saline; PO, per os; W, week Table 2. Experimental groups PAH induction protocol As depicted in Figure 1, PAH was induced by injecting animals from groups 2 to 10 (Table 2) once with SUGEN (SU5416) on DO (20 mg / kg, SC) and exposing them to normobaric hypoxia for three consecutive weeks before returning to normoxia for three additional weeks (from D21 to D42). Animals from group 1 were injected once with the SUGEN vehicle (0.5% carboxymethylcellulose sodium, 0.9% sodium chloride, 0.4% polysorbate 80 and 0.9% benzyl alcohol in deionized water), maintained in normoxic condition from DO to D42 and were not exposed to hypoxia. To achieve hypoxia, rats from groups 2 to 10 were placed in a hypoxic chamber (A-Chamber, BioSpherix, or equivalent) and exposed to low oxygen (02) levels (around 10±l%) from DO to D21, 24 hours a day. The 02 level inside the chamber was continuously monitored and maintained close to the target value by infusing nitrogen into the chamber. A CO2 absorbent (Soda lime, TEM SEGA France, or equivalent) was placed in the hypoxic chamber. Relative humidity and NH3 was also kept at suitable levels using a humidity absorber and Boric acid (Sigma, France, or equivalent), respectively. PO administrations The PO administrations were performed in animals from groups 1 to 10 (Table 2) in accordance with standard operating procedures. The PO administrations were performed on un-anaesthetized animals using an oral gavage probe. The final volume of administration was set at 5 ml / kg. The volume of administration was adjusted every week (Figure 1) on the basis of the mean body weight of the animals of the corresponding group. If an animal had a weight standing more than 20% compared to the mean body weight of its group, the volume of administration was adjusted especially for this animal on the basis of its own body weight. On the day of terminal recordings, the animals received the administration volume corresponding to their own body weight. Animals returned to normoxia on D21 and PO treatments started on D22. Rats from groups 1 to 10 were treated orally once daily, 7 days a week, from D22 to D42 inclusive (Figure 1). Histopathological evaluation of small pulmonary arteries For each animal from groups 1, 2, 3, 4 and 7, an appropriate number (n = 50) of small pulmonary arteries (diameter smaller than 100 pm) were observed and scored according to Heath-Edward's grading system as a first analysis. In a second time, vessels were clarified as « opened » or « partially or completely occluded » as a second analysis. In details, histological examination of the individual sections from each animal were performed on the whole slide digital scans produced by the Hamamatsu Nanozoomer at 20x magnification. Arteriolar changes were evaluated on hematoxylin-eosin, CD31 and Verhoeff-Van Gieson (V-vG) stained sections. First analysis: Arteriolar changes were evaluated using a semi quantitative scoring system as described by Abe (Abe et al., 2010), which is based on Heath and Edwards (1958). Five-Grade system describing structural changes in the pulmonary arteries was used. In brief, the degree of arteriolar changes will be assessed in 50 arterioles of less than 100 pm diameter per lung section. Degree of injury in individual arteriole was graded using a scale from 0 to 4, based on the extent of lesions: • Grade 0 (GO): normal, • Grade 1 (Gl): medial hypertrophy without intimal changes, • Grade 2 (G2): medial hypertrophy with intimal proliferation, • Grade 3 (G3): medial hypertrophy, intimal proliferation, and fibrosis / fibro-elastosis, • Grade 4 (G4): medial hypertrophy, intimal proliferation, and plexiform lesions (stalk-like branches, angiomatoid lesions, and aneurysm-like lesions). A global arterial score (GAS) was calculated for each individual animal using the formula below: GAS = ((number of Grade 0x0) + (number of Grade lxl) + (number of Grade 2x2) + (number of Grade 3x3) + (number of Grade 4x4)) / 50. Second analysis: Diameter and degree of occlusion were recorded for each graded arteriole. The degree of occlusion was established with the following scoring system: occlusion of individual arterioles were graded as open (no apparent occlusion), partial (<50% lumen decrease), or closed (>50% decrease). Statistical analysis Statistical analysis was performed with the Graphpad 9 software. Values were expressed as mean±SEM. If values were normally distributed, a parametric analysis was performed. If samples were drawn from non-normal populations, a non parametric analysis was performed. First, differences were assessed between Normoxia / Vehicle and SuHxNx / Vehicle using a Mann-Whitney test. Then, the treated SuHxNx groups were compared to SuHxNx / Vehicle using a one-way ANOVA followed by the appropriate post-hoc test. Histopathology on lung arterioles with diameter <100 urn Based on gravimetric results, a histopathological assessment of pulmonary vascular remodelling has been performed on rat lungs from Group 1 (Sham / Vehicle), 2 (SuHxNx / Vehicle), 3 (SuHxNx / Compound la 20mg / kg), 4 (SuHxNx / Compound la 40mg / kg) and 7 (SuHxNx / Compound la 300mg / kg). Arteriolar changes Figure 2 presents the degree of injury in arterioles using a scale from 0 to 4, based on the extent of lesions measured in groups 1, 2, 3, 4 and 7. Figure 2. Arteriolar changes based on the Heath-Edward's grading system (grade 0 to grade 4) on lung arterioles with diameter <100 pm. Global arterial score (GAS) was increased in SuHxNx / Vehicle group compared to Normoxia / Vehicle group (p<0.01; Figure 2A). This elevation in GAS was associated with a significant decrease in the number of normal vessels (grade 0, p<0.01; Figure 2B), a significant increase in the proportion of small pulmonary arteries showing medial hypertrophy (grade 1, p<0.05; Figure 2C), a significant increase in intimal proliferation (grade 2, p<0.01; Figure 2D) and a significant increase in complex lesions such as plexiform lesions (grade 4, p<0.01; Figure 2F). Concerning the groups treated with Compound la: - The lowest dose (20 mg / kg) was associated with a trend to decrease GAS scoring (Figure 2A). It was associated with a slight decrease of grade 4 arterioles in favour of a slight increase of grade 0 and grade 1 (Figure 2F, 2B and 2C, respectively). - The intermediate dose (40 mg / kg) showed a significant decrease of GAS scoring compared to SuHxNx / Vehicle (p<0.01; Figure 2A). It was associated with a significant decrease of grade 3 and grade 4 arterioles (p<0.05 and p<0.01, respectively; Figure 2E and 2F) in favour of grade 0 (p<0.05; Figure 2B). - The highest dose (300 mg / kg) was associated with a significant decrease of GAS scoring compared to SuHxNx / Vehicle (p<0.001; Figure 2A). It was associated with a significant decrease of grade 2 (p<0.05; Figure 2D) and grade 4 arterioles (p<0.05 and p<0.0001, respectively; Figure 2F) in favour of grade 0 (p<0.01; Figure 2B). A panel depicting the proportion of Grade 0, Grade 1, Grade 2, Grade 3 and Grade 4 (A ,B, C) in each experimental group is presented in Figure 3. Arteriolar occlusion The total number of partially or totally occluded vessels was increased in SuHxNx / Vehicle group compared to Normoxia / Vehicle group (p<0.01; Figure 4B) and was associated with a decrease of the numbers of open vessels (p<0.01; Figure 4A). Concerning rats treated with Compound la, the intermediate (40 mg / kg) and the highest dose (300 mg / kg) significantly decreased the proportion of partially to closed vessels (Figure 4B) in favour of open vessels (Figure 4A). The lowest dose had no significant effects on arteriolar occlusion, but the values were lower, as compared with SuHxNx / Vehicle. Individual values for arteriolar remodeling and occlusion on arterioles <100 pm are presented in Table 3. Group (Induction / Treatment) Rat N° GO %G1 %G2 WG3 9tG4 Hope-' % <5C% %>5C% % parts occ usic- * closed GAS 1 32 98 2 0 0 0 10C 0 0 0 0.02 (No induction. 46 94 6 0 0 0 IOC 0 0 0 U.Ot- normoxia from DO 87 96 4 0 0 0 10C 0 0 0 L'.tU 2 1 16 22 48 2 12 24 24 ¢2 76 (Sugen + 3W 2 -- 22 43 4 22 56 • 2 52 64 ■-^-2 hypoxia 10% + 3W 27 - 6 63 4 26 4 6 93 96 2.i2 normoxia / Vehicle 37 24 8 54 0 14 24 -•k 64 76 ..- . 39 IB 5B 0 .2 24 * ■- 64 76 '. A 2 47 10 3 62 2 IB 14 6 83 36 2.11) 50 14 22 44 0 20 26 ID 54 74 1 .ML' 78 4 6 53 2 2B 6 4 9D 94 2.44 95 12 16 52 0 ID 23 ID 73 SC LiO 96 ID ID 48 0 = 2 12 8 BD S3 234 3 18 24 2D 42 0 14 52 16 «12 63 : (Sugen + 3W 33 14 3 ~3 - 6 14 3 78 36 1,76 hypoxia 10% + 3W 52 - 28 43 0 23 16 26 58 34 normoxia / CmR la 80 44 4 23 0 4 ■' — 14 14 23 69 6 4 B2 0 8 6 4 93 94 2 .00 20 mg / kg ) 72 14 4 0 10 14 4 82 36 : 56 16 20 45 0 3 28 — 2 53 77 :.r.4 51 3 ID 73 0 12 1^ 8 83 33 L'Jb 4 6 18 2D 56 0 6 28 14 58 72 :. '.b (Sugen + 3W IS 3 62 0 8 26 4 70 74 1,-..4 hypoxia 10% + 3W 40 42 24 -- 0 73 ID 23 3C L'.iC normoxia / Cmp la 58 28 26 43 0 6 46 ID 44 54 40mg / kg) 6S 70 54 48 24 24 24 0 0 ID 4 56 64 6 ID 28 26 54 36 1 .OLt O.xF 90 40 24 23 0 6 X2 12 26 43 :,06 7 7 54 14 = 2 0 0 64 ID 26 36 9. 7 k (Sugen ♦ 3W 21 66 26 3 0 D 88 4 3 12 L'.42 hypoxia 10% * 3W 22 ZB 20 28 0 4 63 02 28 4C LUI normoxia / Coin la 26 -- 18 55 0 4 26 14 53 .- u :.4t 300mg / kg) 45 59 16 10 24 16 48 0 0 83 56 25 18 28 2C 64 ^.4^ 1. jh 89 24 28 26 0 12 2-0 22 48 7C :.4F 92 q? 24 22 0 70 6 24 SC U..'L 93 52 8 24 0 6 58 2 43 42 1.00 Table 3. The pharmacokinetic-pharmacodynamic (PK / PD) relationship for the arteriolar 5 occlusion effect of Compound la To reveal the PK / PD relationship for Compound la induced reversal of pulmonary arteriolar remodelling in the Sugen / hypoxia model, GAS was plotted against the total and estimated unbound exposures (based on day 41 data) in Figure 5a and b. 10 Unbound exposures are important due to the large interspecies differences in protein binding for Compound la. Unbound exposures were estimated from the total AUC values, as well as, the protein binding fraction previously found in the rat to be 72.5% (at a total concentration of 15226 ng / mL). The AUC value at 40 mg / kg was not explicitly measured in this study and was therefore estimated by linear 15 interpolation from the measured 20 and 75 mg / kg dose AUCs. A clear exposure dependent reversal of GAS is seen in Figure 5a and b. A 4 parameter logistic function was fitted to the mean data using least squares regression. Efficacy was estimated to be 1 GAS unit ie resulting in reversal of approximately 50% of the disease condition. The exposure at which 50% of the maximal Compound la effect was reached (EAUC50) was estimated to be 122 hr.pg / mL. The corresponding unbound exposure (EfAUC50) was estimated to be 33.3 5 hr.pg / mL. According to the relationships depicted in Figure 5, an exposure of approximately 250 hr.pg / mL would deliver full efficacy corresponding to an unbound exposure of 68 pg / mL.hr. Mean GAS values for the 4 groups of Sugen / hypoxia animals (Vehicle Control and 3 10 groups of Compound la treated animals, 20, 40 and 300 mg / kg, n=7-10 / group) are plotted against corresponding estimated plasma total and unbound Compound la AUCs (blue circles) in the upper and lower panels, respectively. A logistic function curve fit (blue line) was used to estimate the effective total and unbound AUCs at which 50% of the maximal Compound la was reached (EAUC50 and EfAUC50). Note 15 that the AUCs for the Vehicle group are arbitrarily set at a low level of 0.1 hr.pg / mL to allow visualization on the logarithmic scale. In conclusion, treatment with Compound la for 3 weeks dose dependently ameliorated pulmonary vascular remodelling in the Sugen / hypoxia rat model of PAH.

Claims

1. A compound of Formula (I)wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof.

2. A method of treating and / or reducing the likelihood of occurrence of an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject in need of treatment thereof, said method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof,wherein Ri is either H or D and wherein D is deuterium, or valproic acid, or a pharmaceutically acceptable salt thereof, wherein the abnormal condition associated with PAH is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof.

3. Use of a compound of Formula (I)wherein Ri is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing an abnormal condition associated with pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF), wherein the abnormal condition is selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof.

4. The compound for use of claim 1, the method of claim 2 or the use of claim 3, wherein Ri is H.

5. The compound for use of claim 1, the method of claim 2 or the use of claim 3, wherein Ri is D.

6. The compound for use of claim 1, the method of claim 2 or the use of claim 3, wherein the compound is valproic acid, or a pharmaceutically acceptable salt thereof.

7. The compound for use, the method, or the use of any one of claims 1-6, wherein the pharmaceutically acceptable salt is a sodium salt.

8. The compound for use, the method, or the use of any one of claims 1-7, wherein the abnormal condition is plexiform lesions.

9. The compound for use, the method, or the use of any one of claims 1-8, wherein the treatment is in a subject suffering from grade 4 pulmonary arteries.

10. The compound for use, the method, or the use of any one of claims 1-7, wherein the abnormal condition is small artery vessel occlusion.

11. The compound for use, the method, or the use of any one of claims 1-7, wherein the abnormal condition is small vessel related fibrosis.

12. The compound for use, the method, or the use of any of claims 1-10, wherein the compound of Formula (I) or valproic acid is provided in the form of pharmaceutical composition comprising at least one pharmaceutical vehicle.

13. The compound for use, the method, or the use of any one of claims 1-12, wherein the compound for use or the pharmaceutical composition is administered to the subject through a route of administration selected from the group consisting of oral, inhalation, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, sublingual, intracerebral, transdermal, rectal and topical administration.

14. The compound for use of any one of claims 1-13, wherein the treatment and / or prevention comprising administering from about 100-600 mg / day, from about 100-500 mg / day, from about 150-500 mg / day, from about 100-400 mg / day, from about 150-400 mg / day, or from about 200 to about 400 mg / day of the compound of Formula (I) or valproic acid.

15. The method of any one of claims 1-13, wherein the method comprises administering from about 100-600 mg / day, from about 100-500 mg / day, from about 150-500 mg / day, from about 100-400 mg / day, from about 150-400 mg / day, or from about 200 to about 400 mg / day of the compound of Formula (I) or valproic acid to the subject.

16. The use of any one of claims 1-13, wherein the medicament comprises about 100-600 mg, from about 100-500 mg, from about 150-500 mg, from about 100-400 mg, from about 150-400 mg, or from about 200 to about 400 mg of the compound of Formula (I) or valproic acid for daily administration.

17. A method of treating pulmonary arterial hypertension (PAH) and / or idiopathic pulmonary fibrosis (IPF) in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein Ri is either H or D and wherein D is deuterium, or valproic acid, or a pharmaceutically acceptable salt thereof, wherein the subject is refractory to treatment for PAH and / or IPF with a previously ceased or ongoing treatment regimen.

18. The method of claim 17, wherein said previously ceased or ongoing treatment failed to sufficiently lower blood pressure in the subject's pulmonary arteries.

19. The method of claim 17 or claim 18, wherein the subject's pulmonary artery pressure is greater than about 20 mmHg at rest after said previously ceased or ongoing treatment but prior to said administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof.

20. The method of any one of claims 17 to 19, wherein the previously ceased or ongoing treatment is treatment with one or more therapeutic agent selected from the group consisting of PDE5 inhibitors (such as sildenafil and tadalafil), soluble guanylate cyclase stimulators (such as riociguat), endothelin receptor antagonists (such as aprocitentan, bosentan, macitentan, tezosentansitaxentan, ambrisentan, atrasentan, BQ-123, sparsentan, zibotentan, avosentan, edonentan, and clazosentan), prostacyclins and prostacyclin agonists (such as selexipag, epoprostenol, treprostinil, and iloprost), and long acting calcium channel blockers (such as nifedipine, diltiazem, and amlodipine.

21. The method of any one of claims 17 to 20, wherein the previously ceased or ongoing treatment is an ongoing treatment, wherein treatment with the compound of Formula I, or a pharmaceutically acceptable salt thereof, or valproic acid, or a pharmaceutically acceptable salt thereof, is in addition to (i.e. co-administered with) the ongoing treatment.Application No: GB2414126.9Claims searched: 1-15 in partExaminer: Dr Kerri StenningDate of search: 10 February 2025Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X 1-3, 6, 10, 12-16 PLoS ONE, vol. 10, no. 1, 2015, B. Lan et al.. Therapeutic Efficacy of Valproic Acid in a Combined Monocrotaline and Chronic Hypoxia Rat Model of Severe Pulmonary Hypertension, pages 1-14. See particularly the Methods section and Fig 31 X 1-5, 7-16 GB 2613900 A (CERENO SCIENTIFIC AB) See particularly paragraphs [0028], [0039], [0040], the Markush structure (I) on page 2 and the Examples. X,Y X:l-3, 6- 12;Y: 13- 16 BioStock, 6th February 2024, Cereno s CEO on being granted Compassionate Use, biostock.se, [online], Available via: https: / / www.biostock.se / en / 2024 / 02 / cerenos-ceo-on-being-granted-compassionate-use / , [Accessed 4th February 2025] See particularly the video interview X,Y X:l-3, 6-12;Y: 13-16 Cereno Scientific, 30th August 2024, First patient dosed in Cereno Scientific s Expanded Access Program with CS1 in rare disease Pulmonary Arterial Hypertension, cerenoscientific.com, [online], https: / / cerenoscientific.com / press-single / ?releaseIdentifier=4F9329BB5D5C0FF6, [Accessed 4 February 2025] See whole document Y 13-16 Cereno Scientific, 4th February 2022, Effect of CS1 in Subjects With Pulmonary Arterial Hypertension, ClinicalTrials.gov, [online], Available via: https: / / clinicaltrials.gov / study / NCT05224531, [Accessed 4th February 2025] See whole documentX Document indicating lack of novelty or inventive step A Document indicating technological background and / or state of the art. Y Document indicating lack of inventive step if P Document published on or after the declared priority date but combined with one or more other documents of same category. before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.Field of Search:Search of GB. EP, WO &US patent documents classified in the following areas of the UKCX :Worldwide search of patent documents classified in the following areas of the IPC____________A61K; C07B; C07C______________________________________________The following online and other databases have been used in the preparation of this search report SEARCH-PATENT, SEARCH-NPL, INTERNETInternational Classification:Subclass Subgroup Valid From A61K 0031 / 19 01 / 01 / 2006 A61P 0009 / 00 01 / 01 / 2006 A61P 0009 / 12 01 / 01 / 2006 C07B 0059 / 00 01 / 01 / 2006 C07C 0053 / 128 01 / 01 / 2006

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