New methods

Abstract

A compound of formula (I) is disclosed: [Refer to original abstract doc for image] where R1 is either H or D, and D is deuterium; or valproic acid, or a pharmaceutically acceptable salt thereof, for u

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 ah, 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. BHef Description of the Drawings FIGURE 1 depicts a work plan for a PAH induction protocoi wherein D, day; IV, intravenous administration; PO, peros 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, milligram 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). FIGURE 6 depicts pulmonary vascular resistance (Woods units) scores, from right heart catheterization procedures before and after treatment, for subjects administered with a total daily dose of 480 mg, 960 mg or 1920 mg of sodium valproate (equivalent to approximately 420 mg, 840 mg, 1680 mg of valproic acid). DetaBed 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-2,2,3,3-d4)pentanoic-4,4,5,5-di 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-tetradeuteropropyi)valeric acid (compound la) and compound lb may be referred to herein as 2-(Propyl-2,2,.3,.3-d4)pentanoic-2,4,4z5z5-d5 acid or 2,4,4,5,5-Pentadeutero-2-(2,2,3,3-tetradeuteropropy!)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 biood 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 aiso 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 specificaliy, 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 p h a rm a ce u t ica I com pos i t i o n. 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 miidest 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 II / III / IV, suffering from Class III / IV or suffering from 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, piexiform iesions 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 piexiform 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 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, 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, 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 sait 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. Improvement in blood pressure (e.g., lowering of blood pressure in a subject suffering from hypertension) in a subject's pulmonary arteries may be demonstrated by measuring the blood pressure in the subject's pulmonary arteries after administration of a compound of the invention, or pharmaceutically acceptable salt thereof, compared to the blood pressure in the subject's pulmonary arteries after administration of a said compound. The lowering of blood pressure in a subject's pulmonary arteries following administration of a compound of the invention, or pharmaceutically acceptable salt thereof, as compared to prior to administration of said compound may be at least about 10%, (at least) about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%. The improvement in blood pressure in a subject's pulmonary arteries at a given dose of the compound of the invention, or pharmaceutically acceptable salt thereof, may be demonstrated using suitable methods known in the art. For example, changes in the blood pressure in a subject's pulmonary arteries may be observed by comparing the pulmonary arterial blood pressure for a subject who has been administered a compound of the invention, or pharmaceutically acceptable salt thereof, with the corresponding data for a subject who has not been administered said compound. 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 tadaiafil), soluble guanyiate 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. co-administered 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 tadaiafil), 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 (e.g. third line and / or fourth line 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, orfrom 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, orfrom about 1 milligram to about 70 milligrams per kilogram body weight, or from about 1 milligram to about 60 milligrams per kilogram body weight, orfrom about 1 milligram to about 50 milligrams per kilogram body weight, or from about 1 milligram to about 40 milligrams per kilogram body weight, or from about 1 milligram to about 30 milligrams per kilogram body weight, or from about 1 milligram to about 20 milligrams per kilogram body weight, orfrom about 1 milligram to about 10 milligrams per kilogram body weight, orfrom 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 indicated by Figure 6, it is possible to achieve remarkably large reductions in pulmonary vascular resistance (PVR) through administration of a significantly lower amount (about 420 mg; equivalent to about 480 mg sodium valproate) of valproic acid, or a pharmaceutically acceptable salt thereof. The finding that administration of a reduced dose of valproic acid, or a pharmaceutically acceptable salt thereof, required to achieve a reduction in PVR (as measured in Wood units) is beneficial because a lower dose enables administration of valproic acid over a prolonged period of time to subjects suffering from chronic diseases or disorders. Of particular interest are chronic diseases or disorders associated with arterial remodeling, for example pulmonary arterial hypertension, which is mainly caused by the increase of PVR due to the pathological changes of the pulmonary arterioie itself (which eventually leads to right heart failure and death), and interstitial lung diseases (ILDs). The inventors have surprisingly found that administering a lower dose of valproic acid, or a pharmaceutically acceptable salt thereof, may be particularly advantageous in treating or preventing pulmonary arterial hypertension (PAH) and / or an interstitial lung disease (ILD), such as pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis (1PF). Thus, there is provided valproic acid for use in treating and / or preventing pulmonary arterial hypertension (PAH), wherein the treatment and / or prevention comprises administering to a subject a total daily dose of from about 300 mg to about 900 mg, for example about 300 mg to about 850 mg, such as from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof. According to a third aspect of the invention, there is provided valproic acid for use in treating and / or preventing pulmonary arterial hypertension (PAH), wherein the treatment and / or prevention comprises administering to a subject a total daily dose of from about 300 mg to about 500 mg of valproic acid, ora pharmaceutically acceptable salt thereof. According to an alternative third aspect of the invention, there is provided a method of treating pulmonary arterial hypertension (PAH) in a subject in need thereof, the method comprising administering to the subject a total daily dose of from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof. According to a further alternative third aspect of the invention there is provided the use of from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pulmonary arterial hypertension (PAH) for daily administration. Thus, according to a fourth aspect of the invention, there is provided valproic acid for use in treating and / or preventing an interstitial lung disease (ILD), such as pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis (IPF), wherein the treatment and / or prevention comprises administering to a subject a total daily dose of from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof. According to an alternative fourth aspect of the invention, there is provided a method of treating and / or preventing an interstitial lung disease (ILD), such as pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis (IPF), in a subject in need thereof, the method comprising administering to the subject a total daily dose of from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof. According to a further alternative fourth aspect of the invention there is provided the use of from about 300 mg to about 500 mg of valproic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing an interstitial lung disease (ILD), such as pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis (IPF) for daily administration. As described herein, the skilled person will recognise that the compound of Formula I as described in the first and second aspects of the invention (including all embodiments and features thereof) may be effective in the treatments of the third and / or fourth aspects of the invention (including all embodiments and features thereof) described herein. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 310 mg to about 500 mg, from 320 mg to about 500 mg, from 330 mg to about 500 mg or from 340 mg to about 500 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 350 mg to about 500 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 350 mg to about 490 mg or from 360 mg to about 490 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 370 mg to about 490 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 380 mg to about 490 mg, from 390 mg to about 490 mg, or from 390 mg to about 490 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is from about 400 mg to about 480 mg, from 400 mg to about 470 mg, or from 400 mg to about 450 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 400 to about 450 mg. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg. In particular embodiments, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, or about 500 mg. In particular embodiments, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400, about 410 mg, about 420 mg, about 430 mg, about 440 mg, or about 450 mg. In particular embodiments, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg. In particular embodiments, the total daily dose of valproic acid, or a pharmaceutically acceptable salt thereof, is about 420 mg. As described herein, in the third and / or fourth aspects of the invention valproic acid may be administered in the form of a pharmaceutically acceptable salt, preferably said salt is a sodium salt of valproic add (i.e. sodium valproate). The skilled person will recognise that a dose of about 420 mg valproic acid (i.e. the free base) is equivalent to about 480 mg of the sodium salt of valproic acid (i.e. sodium valproate). The skilled person will understand that the term "total daily dose" of valproic acid, or pharmaceutically acceptable salt thereof, refers to the total amount of valproic acid administered in a single day (00:00 to 23:59) to the subject in need of the treatment or prevention of the third and / or fourth aspects of the invention. Accordingly, in the third and / or fourth aspects of the invention (as all embodiments and particular features thereof) valproic acid, or pharmaceutically acceptable salt thereof, may be administered to the subject (e.g. a human subject) in a single daily dose (e.g. via oral delivery). The skilled person will understand that timings referred to using the 24-hour system may also be referred to as timings using the 12-hour system (i.e. with AM and PM denoting times before and after 12:00 noon, respectively). For example, 20:00 may also be referred to as 8:00 PM, and 06:00 as 6:00 AM. Advantageously, the total dally dosage of valproic acid, or pharmaceutically acceptable salt thereof, may be administered in separate doses two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of about 150 mg, about 200 mg, or about 250 mg twice daily). In a particular embodiment, valproic acid, or pharmaceutically acceptable salt thereof, is administered more than once per day. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or pharmaceutically acceptable salt thereof, is administered as one or more separate doses. The skilled person wouid therefore understand that the total daily dose may be administered to the subject as a single dose once per day, or, more preferably, as more than one (for example, two or three, preferably two) separate (i.e. individual) doses in a single day. In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or pharmaceutically acceptable salt thereof, is administered as two separate doses in a single day. In such embodiments, a first separate dose of valproic acid is administered to the subject during a part of the day (e.g. the morning) and a second separate dose of valproic acid is administered to the subject during another (i.e, different) part of the day (e.g. the afternoon). In particular embodiments of the third and / or fourth aspects of the invention, the total daily dose of valproic acid, or pharmaceutically acceptable salt thereof, is administered as one (i.e. single) separate dose in the morning (00:00 to 11:59, such as 06:00 to 11:59) and one separate dose in the evening (18:00 to 23:59). For example, one separate dose is administered at about 06:00, about 06:30, about 07:00, about 07:30, about 08:00, about 08:30, about 09:00, about 09:30, about 10:00, about 10:30, about 11:00, or about 11:30, and the other one separate dose is administered at about 18:00, about 18:30, about 19:00, about 19:30, about 20:00, about 20:30, about 21:00, about 21:30, about 22:00, about 22:30, about 23:00, or about 23:30. In particular embodiments of the third and / or fourth aspects of the invention, the separate doses of valproic acid, or pharmaceutically acceptable salt thereof, are administered at least 1 hour apart, at least 2 hours apart, at least 3 hours apart, at least 4 hours apart, at least 5 hours apart, at least 6 hours apart, at least 7 hours apart, at least 8 hours apart, at least 9 hours apart, at least 10 hours apart, at least 11 hours apart, at least 12 hours apart. In particular embodiments of the third and / or fourth aspects of the invention, the separate doses are administered at least 8 hours apart, preferably 12 hours apart. The skilled person will recognise that when the total daily dose of valproic, or pharmaceutically acceptable salt thereof, is administered to the subject in need of the third and / or fourth aspects of the invention in more than one (preferably two) separate doses, those separate doses may be the same or different. Advantageously, the more than one (preferably two) separate doses of valproic acid administered to the subject are different. For example, the third and / or fourth aspects of the invention may comprise administration to the subject in need of the treatment of third and / or fourth aspects of the invention of one separate dose of from about 120 mg to about 240 mg (e.g. 140 mg) of valproic acid and administration of another one separate dose of from about 250 mg to about 380 mg (e.g. 280 mg) of vaiproic acid. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is from about 250 mg to about 380 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 120 mg to about 240 mg of valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is from about 250 mg to about 350 mg of vaiproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 120 mg to about 200 mg of valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is from about 250 mg to about 300 mg of vaiproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 120 mg to about 160 mg of valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is from about 270 mg to about 290 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 130 mg to about 150 mg of valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, or about 380 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240 mg of valproic acid, or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, one separate dose is about 280 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is about 140 mg of valproic acid, or a pharmaceutically acceptable salt thereof. It is known, for example in WO 2017 / 175013, to be beneficial to administer valproic acid, or a pharmaceutically acceptable salt thereof, at a time of day (e.g. in the evening) to achieve peak plasma concentration (Cmax) of the valproic acid in a subject in the, preferably early, morning (e.g. at about 06:00). When more than one (preferably two) different separate doses of valproic acid administered to the subject, it has been found advantageous to administer the higher (i.e. larger) separate dose of valproic acid, or a pharmaceutically acceptable salt thereof, in the afternoon (i.e. 12:00 to 23:59), preferably in the evening (18:00 to 23:59) and administer the lower (i.e, smaller) separate dose of valproic acid, or a pharmaceutically acceptable salt thereof, in the morning (00:00 to 11:59, such as 06:00 to 11:59). In particular embodiments of the third and / or fourth aspects of the invention, a dose of about 2.80 mg of valproic acid, or a pharmaceutically acceptable salt thereof, is administered in the evening and a dose of about 140 mg of valproic acid, or a pharmaceutically acceptable salt thereof, is administered in the morning. In particular embodiments of the third and / or fourth aspects of the invention, the PAH is associated with one or more of the conditions selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof. In particular embodiments of the third and / or fourth aspects of the invention, the PAH is associated with plexiform lesions. The treatment of the third and / or fourth aspects of the invention may be useful in providing the refractory to treatment for PAH as required in the second aspect of the invention (including all embodiments and features thereof). Thus, in particular embodiments of the third and / or fourth aspects of the invention, the treatment is administered to a subject refractory to treatment for PAH with a previously ceased or ongoing treatment regimen. In particular embodiments of the third and / or fourth aspects of the invention, said previously ceased or ongoing treatment failed to sufficiently lower blood pressure in the subject's pulmonary arteries. In particular embodiments of the third and / or fourth aspects 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 valproic acid or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects 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. In particular embodiments of the third and / or fourth aspects of the invention, the previously ceased or ongoing treatment is an ongoing treatment, wherein treatment with administering the valproic acid, or a pharmaceutically acceptable salt thereof, is in addition to (i.e. co-administered with) the ongoing treatment. Certain pharmaceutical compositions are able to release valproic acid in a delayed manner, which in turn makes such compositions ideally suited for use in the treatment of PAH (pulmonary arterial hypertension). Said pharmaceutical compositions may be provided through the preparation of formulations wherein valproic acid, or a pharmaceutically acceptable salt thereof, is present in combination with a further (secondary) acid component. Thus, in particuiar embodiments of the third and / or fourth aspects of the invention, the valproic acid is provided in the form of pharmaceutical composition comprising at least one pharmaceutical vehicle, wherein the pharmaceutical composition comprises: a. valproic acid (VPA) and / or a pharmaceutically acceptable salt thereof; and b. one or more secondary acid, and optionally comprising one or more pharmaceutically acceptable excipient. As used herein (particularly in relation to embodiments of the third and / or fourth aspects of the invention), references to a secondary add and / or a pharmaceutically acceptable salt thereof may refer to an acid other than VPA or a pharmaceutically acceptable salt thereof (i.e. a further, additional acid component). The skilled person will understand that references herein to secondary acids will refer to protic (i.e. Bronsted-Lowry) acids. The skilled person will understand that suitable secondary acids and pharmaceutically acceptable salts thereof will be those known in the art as pharmaceutically acceptable acids (such as those described herein as being suitable for the formation of pharmaceutically acceptable salts). In particular embodiments, component (b) in the formulation of the third and / or fourth aspects of the invention is one or more secondary acid, as described herein (i.e. not a salt thereof). Particular secondary acids (i.e. acids forming component (b)) that may be mentioned include organic acids (i.e. pharmaceutically acceptable organic acids). References to organic acids will be readily understood by those skilled in the art as referring to an organic (i.e. carbon-based) compound having one or more (e.g. one or two, such as two) acidic moieties (i.e. moieties comprising an acidic proton). In particular embodiments of the third and / or fourth aspects of the invention, component (b) is an organic acid. For the avoidance of doubt, wherein component (b) is one or more organic acid (i.e. not a salt thereof), the skilled person will understand that suitable components will have at least one carboxylic acid group present in non-salt form (i.e. as the free acid), although additional carboxylic acid groups present in said component may be in salt form, as described herein. In particular embodiments wherein component (b) is one or more organic acid, each carboxylic acid group present in such acids will be in non-salt (i.e, free acid) form (which, for the avoidance of doubt, will refer to such groups being in free acid form upon preparation of the composition). In particular embodiments of the third and / or fourth aspects of the invention, each carboxylic acid group in component (b) is in non-sait form. In particular embodiments of the third and / or fourth aspects of the invention, the secondary acid is selected from the list consisting of adipic acid, citric acid, fumaric acid, glycine, lysine, maleic acid, malic acid, lactic acid, sorbic acid, potassium phosphate monobasic, sodium phosphate monobasic, succinic acid, acetylsalicylic acid and tartaric acid. In particular embodiments of the third and / or fourth aspects of the invention, the suitable secondary acid is selected from the group consisting of sorbic acid, acetylsalicylic acid, fumaric acid, adipic acid and succinic acid. In a particular embodiment of the third and / or fourth aspects of the invention, the suitable secondary acid is selected from the group consisting of sorbic acid, acetylsalicylic acid, fumaric acid and adipic acid. In a particular embodiment of the third and / or fourth aspects of the invention, the suitable secondary acid is selected from the group consisting of sorbic acid, acetylsalicylic acid and fumaric acid. In a particular embodiment of the third and / or fourth aspects of the invention, the suitable secondary acid is selected from the group consisting of acetylsalicylic acid, succinic acid and fumaric acid. In particular embodiments of the third and / or fourth aspects of the invention, the secondary acid is selected from the list consisting of succinic acid and fumaric acid. In particular embodiments of the third and / or fourth aspects of the invention, the secondary acid is fumaric acid. In particular embodiments of the third and / or fourth aspects of the invention, the one or more suitable secondary acid is not (i.e. is other than) acetylsalicylic acid (aspirin). In alternative embodiments of the third and / or fourth aspects of the invention, the one or more suitable secondary acid is acetylsalicylic acid (aspirin). In particular embodiments of the third and / or fourth aspects of the invention, the suitable secondary acid will have a solubility in water (e.g. in distilled water at 25 °C) of below about 60 g / l (e.g, below about 50, about 40, about 30, about 20, about 10, about 8 or about 5 g / l). The skilled person will appreciate that, where the one or more suitable secondary acid is acetylsalicylic acid (aspirin), that component may also provide a therapeutic effect, such as a synergistic effect in treatment when combined with VPA, or a pharmaceutically acceptable salt thereof. In such instances, the skilled person will be able to select an amount of acetylsalicylic acid that will provide the required therapeutic effect and will result in a composition having the required release profile. In such embodiments of the third and / or fourth aspects of the invention, the amount of acetylsalicylic acid is between about 30 mg to about 500 mg in relation to the dose being administered per 24 hours. In another such embodiment, the amount of acetylsalicylic acid is between about 50 mg to about 350 mg in relation to the dose being administered per 24 hours. In further such embodiments of the third and / or fourth aspects of the invention, the amount of acetylsalicylic acid is between about 75 mg to about 325 mg in relation to the dose being administered per 24 hours, such as about 75 mg, about 160 mg or about 320 mg (e.g. about 75 mg or about 160 mg). In particular embodiments of the third and / or fourth aspects of the invention, references to one or more secondary acid may refer to one or two (e.g. one) secondary acid(s). The skilled person will be able to select the amount of secondary acid (either in absolute terms or relative to the amount of VPA and / or pharmaceutically acceptable salt thereof) required in the relevant component (i.e. the component comprising the VPA and / or pharmaceutically acceptable salt thereof and secondary acid) in order to obtain the required release profile. In particular embodiments of the third and / or fourth aspects of the invention, the secondary acid (i.e. component (b), e.g. succinic acid or fumaric acid) may generally be present in an amount from about 1% to about 200% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component (i.e. in the formulation, such as in the core component of the formulation). Alternatively, the secondary acid (i.e. component (b), e.g. succinic acid or fumaric acid) may generally be present In an amount from about 0.1% to about 200% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof. In particular embodiments of the third and / or fourth aspects of the invention, the amount of secondary acid (e.g. succinic acid or fumaric acid) will generally be from about 10% to about 70% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component. In more particular embodiments, the amount of secondary acid (e.g. succinic acid or fumaric acid) will generally be from about 10% to about 50% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% and about 50%. In certain embodiments, the amount of secondary acid (e.g. succinic acid or fumaric acid) will generally be from about 80% to about 120% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 90% to about 110%. For the avoidance of doubt, in particular embodiments of the third and / or fourth aspects of the invention, the secondary acid (e.g. succinic acid or fumaric acid) may be present in an amount from about 1% to about 15% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 1% to about 10%, about 1% to about 5%, about 5% to about 15%, about 5% to about 10% (e.g. about 1% or about 5%, or about 2 to about 5%, about 2 to about 7%, about 3 to about 7%, about 4 to about 8%, about 8 to about 12%, or about 7 to about 13%). In alternative embodiments of the third and / or fourth aspects of the invention, the secondary acid (e.g. succinic acid or fumaric acid) may be present in an amount from about 0.1% to about 15% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 0.5% to about 10% or about 0.5% to about 5% (e.g. about 0.1 to about 3%, about 0.5 to about 3%, about 0.1 to about 5%, or about 0.5 to about 5%). In particular embodiments of the third and / or fourth aspects of the invention, the amount of secondary acid (e.g. succinic acid or fumaric acid) is from about 0.1 % (e.g. about 1 %) to about 15% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 0.1 % (e.g. about 1 %) to about 10%. Preferably, the secondary acid (e.g. succinic acid or fumaric acid) is present in an amount of from about 0.1 to about 3% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof. The skilled person will understand that ratios of various components in the pharmaceutical formulation may also be expressed as molar percentages. Thus, each percentage describing the amount of secondary acid by weight as provided herein may also be expressed as a molar percentage. As described herein, pharmaceutical formulations comprising compounds of the invention may comprise one or more coating. In particular, such a coating may be present on the one or more component comprising VPA and / or a pharmaceutically acceptable salt thereof and the secondary acid, in which cases each such component may be referred to as a core component. As described herein, such core components may form a single (coated) tablet or may be provided in the form of multiparticulates, which multiparticulates may be individually coated, and which multiparticulates may be delivered as a single dose (e.g. compressed into a tablet or delivered in a capsule, such as a hard capsule, e.g. a hard gelatin capsule). As described herein, particular coatings that may be employed in such formulations may include enteric coatings and sustained release coatings, such as those described herein. In particular embodiments of the third and / or fourth aspects of the invention, the one or more coating is: (I) an enteric coating; (ii) a sustained release coating (including a pore forming coating); and / or (ill) a protective film. In particular, one or more (e.g. one) of said coatings may be an enteric coating. Said enteric coatings will be well known to the person skilled in the art. These include but are not limited to shellac, waxes, fatty acids, polymers, plastics and plant fibers. Examples of such polymers include, but are not limited to, hypromellose phthalate (hydroxypropyl methylcellulose phthalate, HPMCP), hypromellose acetate succinate, cellulose acetate trimellitate, acrylic acid / methacrylic acid copolymers (e.g. po!y(methacrylic acid-co-methyl methacrylate), cellulose acetate phthalate (CAT), poly(vinyl acetate phthalate, PVAP) and ethyl acrylate. Other materials for enteric coating include dextrins, amylose starch and starch derivatives, sodium alginate, Zein and Aqua-Zein R, More particular examples of such polymers include, but are not limited to, hypromellose phthalate (hydroxypropyl methylcellulose phthalate, HPMCP HP-50, HP-55, HP-55S), hypromellose acetate succinate (Aqoat AS-HF / HG, Aqoat AS-LF / LG, Aqoat AS-MF / MG), cellulose acetate trimellitate, enteric polymethacrylates (e.g. poly(methacrylic acid-co-methyl methacrylate), 1:1 (Eudragit® L 100, Eudragit® L 12.5), poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit® L 30 D-55, Eudragit® L 100-55, Acryi-EZE® 93A, Acryl-EZE MP, Kollicoat® MAE 30 DP, Kollicoat® MAE 100 P, Eastacryl 30D, ), poly (methacrylic acid-co-methyl methacrylate) 1:2 (Eudragit® S 100, Eudragit® S 12.5), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit® FS 30 D)), cellulose acetate phthalate (CAP, Aquacoat® CPD), and poly(vinyl acetate phthalate, PVAP, Sureteric®) and ethyl acrylate. In particular embodiments, the enteric coating polymers are selected from the group of enteric polymethacrylates (e.g. poly(methacrylic acid-co-methyl methacrylate) 1:1 (Eudragit® L 100, Eudragit® L 12.5), poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit® L 30 D-55, Eudragit® L 100-55, Acryl-EZE® 93A, Acryl-EZE MP, Kollicoat® MAE 30 DP, Kollicoat® MAE 100 P, Eastacryl SOD, ), poly (methacrylic acid-co-methyl methacrylate) 1:2 (Eudragit® S 100, Eudragit ® S 12.5), poly(methyl acryiate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit® FS 30 D)). Particular enteric coatings that may be mentioned include Eudragit® L 30 D-55 and Eudragit® FS 30 D. In one embodiment the enteric coating is Eudragit® L 30 D-55 or Eudragit® FS 30 D. The skilled person will understand that different materials have different properties, such as in relation to the dissolution pH, and can thus be used to control the absorption pattern, such as by delaying release of a drug for a specific time. Further information relating to the use of enteric coatings is provided in, for example, Singh Deep Hussan, et al., IOSR Journal of Pharmacy (2012), and the Handbook of Pharmaceutical Excipients Rowe, Raymond C; Sheskey, Paul J; Cook, Walter G; Fenton, Marian E,, Seventh edition, the disclosures of which are incorporated herein by reference in their entirety. Commercially available systems for enteric coatings and coatings for sustained release include variants of OPADRY® (Colorcon), Surelease® (Colorcon), Nutrateric® (Colorcon), Kollicoat® (BASF), Eudragit® (Evonic), (e.g. Eudragit® RL, Eudragit® RS, Eudragit® S, Eudragit® L, Eudragit FS and Eudragit® E), Sheffcoat EC and Sheffcoat Ent (Kerry). In further embodiments, the core component may be coated with a combination of a sustained release coating (e.g. of a type and in an amount as described herein) and an enteric coating (e.g. of a type and in an amount as described herein). For the avoidance of doubt, such coatings may be applied separately (i.e. in distinct layers), such as by providing a core composition which is coated with an enteric coating (i.e. as a first coating layer) and then a sustained release coating (i.e. as a second coating layer), wherein suitable enteric coatings and sustained release coatings include those as described herein. In a yet further embodiment, the core component may be coated with a sustained release coating (e.g. of a type and in an amount as described herein) and then an enteric coating (e.g. of a type and in an amount as described herein). In a yet further embodiment, the core component may be coated with an enteric coating (e.g. of a type and in amount as described herein) and then a sustained release coating (e.g. of a type and in amount as described herein). For the avoidance of doubt, in particular embodiments, the core component may be coated with a protective film. In particular embodiments, the secondary acid component of pharmaceutical formulations (component (b)) may itself be present as a coating (i.e. a coating layer) on the component comprising VPA or a pharmaceutically acceptable salt thereof (component (a)), which coating iayer may be distinct from other coating layers (e.g. enteric and / or sustained release coatings) or combined with (e.g. mixed with) such coatings. For example, in certain embodiments, the secondary acid component of pharmaceutical formulations of the third and / or fourth aspects of the invention as described herein (component (b)) may itself be present as a coating (i.e. a coating layer) on the component comprising VPA or a pharmaceutically acceptable salt thereof (component (a)), which composition is then further coated (e.g. with enteric and / or sustained release coatings). In such instances, formulations may be described as having a core that is component (a), which is coated by a first coating which is component (b) and an optional second (or further) coating (which may be, for example, one or more enteric and / or sustained release coating(s), or mixtures thereof). In a particular embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients (e.g. a pharmaceutically acceptable adjuvant, diluent or carrier), such as those described herein. It is also been found that formulations (e.g. tablets or multiparticulates) comprising a secondary acid allow for beneficial dissolution profiles with high loading of the active pharmaceutical ingredient (i.e. valproic acid, or a pharmaceutically acceptable salt thereof; referred to herein as component (a)). Thus, in particular embodiments of the third and / or fourth aspects of the invention, the formulation comprises one or more component having a solid core comprising component (a), wherein component (a) is present in an amount that is at least 30% (e.g. at least 35%, such as at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65% or at least 70%) by weight thereof, and optionally wherein said solid core further comprises component (b). In particular embodiments of the third and / or fourth aspects of the invention, the formulation comprises one or more component having a solid core comprising component (a), wherein component (a) is present in an amount that is at least 50% by weight thereof, and optionally wherein said solid core further comprises component (b). In particular embodiments of the third and / or fourth aspects of the invention, component (a) may generally be present in an amount that is at least (e.g. greater than) 30% by weight of the core component of the formulation (i.e. the solid core which optional coating layers may be applied to). In more particular embodiments of the third and / or fourth aspects of the invention, component (a) is present in an amount greater than 35% by weight of the core component of the formulation, such as at least 40%, at least 45% or, particularly, at least 50%. In yet more particular embodiments of the third and / or fourth aspects of the invention, component (a) is present in an amount greater than 55% by weight of the core component of the formulation, such as at least 60%, at least 65% or, particularly, at least 70%, at least 75% or at least 80%, For the avoidance of doubt, the skilled person will understand that references to the core component of the formulation (i.e. in the form of a solid tablet or multiparticulates for oral administration) wiil refer to a soiid portion forming the central component of the formulation, to which coating layers may be applied. For the avoidance of doubt, component (a) forms part of the core component of the formulation. Thus, the core may further comprise, in addition to component (a), excipients as described herein and / or (e.g. and) component (b) as described herein, with the skilled person being able to calculate appropriate amounts of said components in core composition as required. For the avoidance of doubt, the skilled person wiil understand that the total amount (as a % by weight) of components in the formulation (e.g. in the core component of the formulation; such as component (a)) must be calculated taking account of the other components of the formulation or particular component thereof, and by definition cannot exceed 100% by weight of the formulation or particular component thereof. In particular embodiments of the third and / or fourth aspects of the invention, the pharmaceutical composition comprising components (a) and (b) (e.g. in the form of one or more component having a solid core) further comprises one or more coating to, for example, delay release of the active ingredient. In certain embodiments of the third and / or fourth aspects of the invention (particularly those having one or more coating), the core component may contain one or more components designed to promote disintegration in aqueous media. Thus, in a particular embodiment of the third and / or fourth aspects of the invention, the formulation is provided as a tablet (or capsule) for oral administration comprising one or more coated core (e.g. a single coated core, or a plurality of coated multiparticulates (such as mini tablets, pellets or granules) each having such a core), said core(s) containing VPA, or a pharmaceutically acceptable salt thereof, wherein: (i) said coating is formed of material selected and / or formulated in a manner to delay release of the active ingredient for the required time (e.g. for about six hours); and (ii) said core is formulated to in a manner designed promote disintegration in aqueous media (e.g. comprising one or more disintegrants). Thus, in particular embodiments of the third and / or fourth aspects of the invention, the formulation may be provided in a form (e.g. a tablet or multiparticulates, such as minitablets, granules or pellets) having an inner core containing VPA and / or a pharmaceutically acceptable salt thereof that is coated with an enteric coating layer. In such embodiments, the enteric coating layer may delay the release of the VPA and / or a pharmaceutically acceptable salt thereof until the pH in the Gl-tract reaches a pH where the enteric coating dissolves. In such cases, in view of the teachings provided herein, the skilled person will be able to adjust the choice of enteric coating polymers to achive the required release profile. Thus, in particular embodiments of the third and / or fourth aspects of the invention, the formulation may be provided in a form (e.g. a tablet or multiparticulates, such as minitablets, granules or pellets) having an inner core containing VPA and / or a pharmaceutically acceptable salt thereof that is coated with a sustained release coating. In such embodiments, the sustained release coating layer may delay the release of the VPA and / or a pharmaceutically acceptable salt thereof in order to reach the desired release profile. In such cases, the skilled person will be able to adjust the choice of sustained coating polymers to achieve the required release profile. In further such embodiments of the third and / or fourth aspects of the invention, the inner core containing the VPA and / or a pharmaceutically acceptable salt thereof is coated by a mixture of one or more enteric coating polymers and one or more sustained release coating polymers. In such embodiments, the sustained release polymer(s) may delay the dissolution and release of the enteric coating polymer(s) when the pH in the Gl-tract reaches a pH where the enteric coating is soluble, thereby further delaying the release of the VPA and / or a pharmaceutically acceptable salt thereof. In more particular embodiments of the third and / or fourth aspects of the invention, the inner core containing the VPA and / or a pharmaceutically acceptable salt thereof is first coated with a sustained release coating and thereafter an enteric coating. In such embodiments, the coatings may delay the release of the VPA and / or a pharmaceutically acceptable salt thereof until the pH in the Gl-tract reaches a pH where the enteric coating dissolves and thereafter further sustain the release due to the sustained release coating. The skilled person will understand that there are several materials that can be used to form a sustained release coating on a pharmaceutical composition (such as a tablet, capsule and / or multiparticulate unit dosage form. For example, the sustained release materials may be selected from the group of sustained release polymers including, but not limited to, ethylcellulose (Aquacoat® ECD, Aquaion® EC, Ethocel™, Surelease®), non-water soluble polymethacrylates (such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (e.g. Eudragit® RL 100, Eudragit® RL PO, Eudragit® RL 30 D, Eudragit RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5), non-water soluble acrylates copolymers (such as poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D), polyvinyl acetate (Kollicoat® SR 30 D). In a particular embodiment, the sustained release polymers are selected from the group of non-water soluble polymethacrylates (such as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylamrnonioethyl methacrylate chloride) (e.g. Eudragit® RL 100, Eudragit® RL PO, Eudragit® R.L 30 D, Eudragit RL 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® RS 12.5), poly(ethyl acryiate-co-methyl methacrylate) 2:1 (Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D). Particular sustained release coatings that may be mentioned include Eudragit® RL 30 D, Eudragit® RS 30 D, Eudragit® NE 30 D and Eudragit® NE 40 D. Commercially available systems for enteric coatings and coatings for sustained release include variants of OPADRY® (Colorcon), Sureiease® (Colorcon), Nutrateric® (Colorcon), Kollicoat® (BASF), Eudragit® (Evonic), (e.g, Eudragit® RL, Eudragit® RS, Eudragit® S, Eudragit® L, Eudragit FS and Eudragit® E), Sheffcoat EC and Sheffcoat Ent (Kerry). The skilled person will understand that some coatings may require the use of one or more plasticizers to obtain the required resuits, and the use of such agents will be known to those skilled in the art. Such plasticizers may include, for example, citrate esters, glycerol, propylene giycol, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributu! citrate, acetylated monoglycerides, triacetin and glycerintriacetate. Pigments, antitacking agents (e.g, talc) and / or plasticizers may be added to, for example, a polymeric coating solution in order to improve the technical properties of, for example, a membrane and / or modify the release characteristics of the formulation. The skilled person will also understand that other substances can also be included in the polymer coatings in order to control and / or modify the release characteristics of the formulation. Such substances can, for example, be pore forming, soluble substances such as salts, sugars and soluble polymers (e.g polyethylene glycol, polyvinyl alcohol and hydroxypropyl methylcellulose). For example, the sustained release coating as described herein may be a coating designed to allow for the formation of pores therein, which may be referred to as pore forming coating. Many polymer combinations to achieve sustained (which may also be referred to as modified) release, using a pore-forming film as described above, are possible. Suitability is based on the compatibility of the chosen polymers in each system and this is known to a person skilled in the art. Suitable polymer combinations include, but are not limited to, blends of ethyl cellulose and hydroxypropyl methyl cellulose, blends of ethyl cellulose and Eudragit® L, blends of Eudragit® NM 30 D and Eudragit® L 30 D-55, blends of Eudragit® NE and Eudragit® L, blends of Kollicoat® SR and Kollicoat® MAE and blends of Kollicoat® SR 30 D and Kollicoat® IR. In one embodiment that may be mentioned, the sustained release coating comprises a blend of Kollicoat® SR 30 D and Kollicoat® IR or Eudragit® NM 30 D and Eudragit® L 30 D-55. In a further embodiment, the sustained release coating comprises a blend of Kollicoat® SR 30 D and Kollicoat® IR.. In a particular embodiment, the sustained release coating comprises a blend of Kollicoat® SR 30 D and Kollicoat® IR and the polymer ratio is from about 75% to about 95% (e.g. about 75% to about 85%, about 85 to about 95, about 75%, about 80%, about 85%, about 90% or about 95%). For the avoidance of doubt, pore forming coatings may be applied as (i.e. in the place of) sustained release coatings in configurations as described herein. For example, the core component of the formulation (as described herein) containing the VPA and / or a pharmaceutically acceptable salt thereof is coated with a blend of two polymers (one water soluble and one non-water soluble, resulting in a pore-forming film for sustained release). As described earlier, such sustained release coatings can be combined with an enteric coating, either before or after the sustained release coating (in particular, before the sustained release coating). In such embodiments, the coatings may modify the release of the VPA and / or a pharmaceutically acceptable salt thereof by altering the ratio of these two polymers. Typically, the polymer ratio (expressed as total percentage of non-water soluble polymer by dry weight in a blend of the two polymers) may be 10-99%. More particularly the polymer ratio may be from 20 to 99%, from 30 to 99%, from 40 to 99%, from 50 to 99%, from 60 to 99%, from 70 to 99%, from 80 to 99% or from 90 to 99%. Yet more particularly, the polymer ratio may be from 60 to 70%, from 70 to 80% or from 80 to 90%. In a particular embodiment, the polymer ratio is from about 75% to about 95% (e.g. about 75% to about 85%, about 85 to about 95, about 75%, about 80%, about 85%, about 90% or about 95%). For the avoidance of doubt, in particular embodiments, the core component may be coated with a protective film. Examples of polymers for protective coatings / films (that may provide moisture protection, oxygen protection and / or taste masking) include, but are not limited to, Kollicoat® Protect (polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol, BASF®), Kollicoat® Smartseal 30 D (methyl methacrylate (MMA) and diethylaminoethyl methacrylate), Opadry® amb II (Colorcon®), Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, Hydroxypropylmethykellulose (e.g. Methocel®, Anycoat®, Pharmacoat®), HydroxypropylceHulose (e.g. Coatcel® and Kiucel®), Hydroxyethylcellulose (e.g. Natroso!®), poly (vinyl pyrrolidone) (e.g. Koliidon®), poly (vinyl pyrrolidone) / poly (vinyl acetate) copolymers, poly (vinyl alcohol) / poly (ethylene glycol) copolymers (e.g. Kollicoat® IR), poly (ethylene glycol), maltodextrines and polyd ext rose. In one embodiment the protective film polymer is selected from the group of Kollicoat® Protect, Kollicoat® Smartseal 30 D, Opadry® amb II, Eudragit® E 100, Eudragit® E 12.5, Eudragit® E PO, Hydroxypropylmethylcellulose (e.g. Methocel®, Anycoat®, Pharmacoat®), Hydroxypropylcellulose (e.g. Coatcel® and Kiucel®), Hydroxyethylcellulose (e.g. Natrosol®), poly (vinyl pyrrolidone) (e.g. Koliidon®), poly (vinyl pyrrolidone) / poly (vinyl acetate) copolymers, poly (vinyl alcohol) / poly (ethylene glycol) copolymers (e.g. Kollicoat® IR) and poly (ethylene glycol). In one embodiment the protective film polymer is Kollicoat® IR. The skilled person will understand that the delay of the release of the active ingredient from the composition (e.g. the tablet) is achieved as a combined effect of these coatings. For example, where a composition (such as a tablet, capsule or multiparticulate (e.g. granule, pellet or minitablet)) is coated so as to delay release for a total of six hours after oral administration, it may comprise two layers of coating, each coating delaying release for three hours (or one coating delaying release for two hours and a further coating delaying release for four hours), i.e. with the first coating being removed to expose the second coating, and so on (in other words, said coatings being exposed in a sequential manner). In such embodiments, the coatings may modify the release of the VPA and / or a pharmaceutically acceptable salt thereof by altering the ratio of the polymers described herein. Typically, the polymer ratio (expressed as total percentage of non-water soluble polymer by dry weight in a blend of the two polymers) may be 10-99%. More particularly the polymer ratio may be from 20 to 99%, from 30 to 99%, from 40 to 99%, from 50 to 99%, from 60 to 99%, from 70 to 99%, from 80 to 99% or from 90 to 99%. Yet more particularly, the polymer ratio may be from 60 to 70%, from 70 to 80% or from 80 to 90%. In a particular embodiment, the polymer ratio is from about 75% to about 95% (e.g. about 75% to about 85%, about 85 to about 95, about 75%, about 80%, about 85%, about 90% or about 95%). For the avoidance of doubt, those skilled in the art will understand that there are several ways to combine one or more coating material in order to achieve the desired release profile. For example, materials can be combined in different coating layers, such as a first sustained release coating covered by a second enteric coating, or together (i.e, mixed) in one or more coating layers, such as a combination of a sustained release polymer and an enteric coating polymer wherein, when the enteric coating polymer dissolves, pores are formed in the sustained release polymer. Such combinations of a sustained release polymer and an enteric coating polymer include, for example, the Nutrateric® system marketed by Colorcon®. In further embodiments of the third and / or fourth aspects of the invention, the core component may be coated with a combination of a sustained release coating (e.g, of a type and in an amount as described herein) and an enteric coating (e.g. of a type and in an amount as described herein). For the avoidance of doubt, such coatings may be applied separately (i.e, in distinct layers), such as by providing a core composition which is coated with an enteric coating (i.e. as a first coating layer) and then a sustained release coating (i.e. as a second coating layer), wherein suitable enteric coatings and sustained release coatings include those as described herein. In a yet further embodiment of the third and / or fourth aspects of the invention, the core component may be coated with a sustained release coating (e.g. of a type and in an amount as described herein) and then an enteric coating (e.g, of a type and in an amount as described herein). In particular embodiments of the third and / or fourth aspects of the invention, pharmaceutical composition comprising components (a) and (b) as is coated with a sustained release coating (e.g. of a type and in an amount as described herein) and then an enteric coating (e.g, of a type and in an amount as described herein). In a yet further embodiment of the third and / or fourth aspects of the invention, the core component may be coated with an enteric coating (e.g. of a type and in amount as described herein) and then a sustained release coating (e.g, of a type and in amount as described herein). As used herein, references to formulations allowing for delayed or controlled released will be understood by those skilled in the art. In this regard, it will be understood that the terms delayed and controlled may be used interchangeably. As used herein (particularly in reference to the third and / or fourth aspects of the invention, including all embodiments thereof), the term "substantially all" will refer to an amount that is at feast 60% of the total amount present (i.e. the total amount included in the composition). In particular, the term may refer to an amount that is at least 70% of the total, such as at least 80% of the total. More particularly, the term may refer to an amount that is at least 90% of the total, such as at least 95% (e.g. at least 99%) of the total. In a particular embodiment of the third and / or fourth aspects of the invention, references to substantially all of the VPA, or a pharmaceutically acceptable salt thereof, being released may refer to substantially all of one dose (i.e. at least one therapeutically effective dose) thereof. The skilled person will understand that the release of the active ingredient may be delayed if the composition is administered with or shortly after food. Thus, references to the time taken for the active ingredient to be released may refer to the time taken for such release when the composition is administered to a patient at least two hours after that patient has consumed food (which may be referred to as administration on an empty stomach, or the like). ft may also be appreciated that it may be beneficial to administer compounds of the invention with food (e.g. to reduce gastrointestinal side-effects). Thus, in a particular embodiment of the first to seventh aspects of the invention, the treatment comprises administering VPA, or a pharmaceutically acceptable salt thereof, with food (e.g. administered to a patient who has consumed food less than two hours prior to administration or who will be directed to consume food within 30 minutes of administration). As used herein (particularly in reference to the third and / or fourth aspects of the invention, including all embodiments thereof), references to an active ingredient being "released" (i.e. from a pharmaceutical formulation) will refer to the active ingredient being in a form that is (or would be) available for absorption (i.e. when administered orally, systemic absorption from the gastro intestinal (GI) tract), such as in a form that is dispersed or dissolved in surrounding media. When used in relation to tablets and / or capsules for oral administration, the term will indicate that the active ingredient is not contained in said tablet or capsule (which may include the active ingredient being no longer contained within multiparticulates (e.g. coated granules, pellets or minitablets) contained within said tablets or capsules) but is instead distributed in the GI tract. In a particular embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, or a pharmaceutically acceptable salt thereof, is released during a period from about six to about eight hours after administration (such as about six to about seven hours after administration, or such as about seven to about eight hours after administration, e.g, about seven hours after administration). In more particular (and alternative) embodiments of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of VPA, or a pharmaceutically acceptable salt thereof, is released during a period that is: (I) from about three to about five hours after administration (from about four to about five hours after administration); (ii) from about four to about six hours after administration; (iii) from about five to about seven hours after administration; (iv) from about six to about eight hours after administration; (v) from about seven to about nine hours after administration; (vi) from about eight to about ten hours after administration (e.g. from about eight to about nine hours after administration); (vii) from about nine to about eleven hours after administration; (viii) from about ten to about twelve hours after administration; (ix) from about eleven to about thirteen hours after administration; (x) from about twelve to about fourteen hours after administration. In yet more particular (and alternative) embodiments of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, ora pharmaceutically acceptable salt thereof, is released during a period that is from about four to about six hours after administration. In another particular (and alternative) embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, ora pharmaceutically acceptable salt thereof, is released during a period that is from about five to about seven hours after administration. In another particular (and alternative) embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, ora pharmaceutically acceptable salt thereof, is released during a period that is from about six to about eight hours after administration. In another particular (and alternative) embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, ora pharmaceutically acceptable salt thereof, is released during a period that is from about severs to about ten hours after administration. In yet another particular (and alternative) embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, or a pharmaceutically acceptable salt thereof, is released during a period that is from about seven to about nine hours (e.g. about 8 to about 9 hours) after administration. In another particular (and alternative) embodiment of the third and / or fourth aspects of the invention, the pharmaceutical composition is formulated such that substantially all of the VPA, or a pharmaceutically acceptable salt thereof, is released during a period that is from about eight to about ten hours after administration. In particular embodiments, the pharmaceutical composition may be formulated such that substantially none (e.g. less than 10%, such as less than 5%, e.g. less than 3%, 2% or 1%) of the VPA, or a pharmaceutically acceptable salt thereof, is released prior to the relevant release window as specified (e.g. prior to about four hours after administration). As described herein, the release profile of the active ingredient (i.e. VPA, or pharmaceutically acceptable salt thereof) may be characterized by delayed release followed by rapid release (i.e. a rate of release as may be expected in an immediate release formulation), rather than the prolonged, gradual release that may be provided by an extended release formulation. In particular embodiments of the third and / or fourth aspects of the invention, the composition is in the form (e.g. as a tablet or capsule for oral administration) that is formulated such that substantially all of the VPA and / or pharmaceutically acceptable salt thereof is released during a period from about four to about eight hours after administration. In particular embodiments of the third and / or fourth aspects of the invention, substantially ail of the VPA and / or pharmaceutically acceptable salt thereof is released during a period from about six to about eight hours after administration. 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 conventions! route, for example, oral, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings, e.g.f 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.f 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, intravaginai, transderma!, 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 a!., 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, J. Neurosurg. 71:105). AH 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 locai anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are suppiied 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, ail 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 rnmol) 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 ceiite 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%), !H NMR (400 MHz, Chloroform-d) 6 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-yny 1-2-(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. NaHCOs and brine, dried over MgSCU, filtered and concentrated. A light brown oil was obtained (18 g). Crude, contains mineral oil, used as such, *H NMR. (400 MHz, Chloroform-d) 5 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)propaned!oate 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 ceiite. 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%), NMR (400 MHz, Chioroform-d) 5 3.70 (s, 6H), 1.83 (s, 4H), 0.86 (s, 2H), Step 4. 2,2-Bis(2,2,3,3-tetradeuteriopropyI)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 NazSCM, filtered and concentrated to a light brown oil (8.0 g, 94%). Contains traces of heptane, 3H NMR (400 MHz, Chloroform-d) 8 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), NMR (400 MHz, DMSO-d6) 6 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 D?O. 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 protoco! that was used to induce PAH in rats was approved by an Anima! 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% Methylceliuiose 400 cP and 0.5% Tween 80 in sterile water. Candidate compound Nature Dose (mg / kg) / schedule Vehicle Route of administration Compound 1 / once daily from D?? to 0.5% Methyl cellulose 400 cP PO Da? inclusive and 0.5% Tween 13 80 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 watered libitum. 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 (D21) 1 6 No induction - Normoxia from Vehicle n.a. / PO / 5 ml / kg / once daily n.a. Plasma D42~> storage ■80°C Do to D42 from D22 to D42 included Lungs -» NBF 10% / Eth 70% Echocardiography (D2i) 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 daHy from D22 to D42 included 8 mg / ml Echocardiography (D21) Plasma D4?-> storage -80°C Lungs -> NBF 10% / Eth 70% Echocardiography (D21) 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% 6 8 SUGEN + 3W Hypoxia 10%* + 3W Normoxia Compound la 150 mg / kg / PO / 5 ml / kg / once daiiy from D22 to D42 included 30 mg / ml Echocardiography (D21) Plasma D42~> storage -80°C Lungs NBF 10% / Eth 70% SUGEN + 3W 7 10 Hypoxia 10%* 3W Normoxia Echocardiography (D2i) 300 mg / kg / PO / 5 ml / kg / Plasma D4?-> storage „ , T once daily , . -80°C Compound la ’ 60 mg / ml from D22 to D42 included Lungs -3»- NBF 10% / Eth 70% SUGEN + 3W 8 3 Hypoxia 10%* + 3W Normoxia Plasma Dz2and Dai: / 1 ; nr\ / c 1 / 1 ■ Tlh, T2h, T4h, T6h, 20 mg / kg / PO / 5 m / kg / x \ y y . .. J T^.4h -»storage at , T once dady „ . . 3 Compound la y 4 mg / ml from D22 to D42 included SUGEN+3W 9 3 Hypoxia 10%* + 3W Normoxia Plasma D22and D41: / 1 , , c .,. , Tlh, T2h; T4h, T6h, / 5 mg / kg / PO / 5 m / kg / a M M T24h -» storage at „ . T once dady .,. . . - Compound la ? 15 mg / ml -80°r from D22 to D42 included SUGEN + 3W 10 3 Hypoxia 10%* + 3W Normoxia Compound la 300 mg / kg / PO / 5 ml / kg / once daily from D22 to D« included 60 mg / ml Plasma D22 and 0«.: Tlh, T2h, T4h, T6h, T24h storage at -80°C Tota^ number of tests; 67 D, day; kg, kilogram; mg f, 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% carboxymethyiceiiulose 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 anima! 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 intima! 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 4 x 4)) / 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 / Vehicie using a Mann-Whitney test. Then, the treated SuHxNx groups were compared to SuHxNx / Vehicie using a one-way ANOVA followed by the appropriate post-hoc test. Histopathology on lung arterioles with diameter <100 um Based on gravimetric results, a histopathological assessment of pulmonary vascular remodelling has been performed on rat lungs from Group 1 (Sham / Vehicle), 2 (SuHxNx / Vehicie), 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 / Vehicie group compared to Normoxia / Vehicle group (pcO.Ol; Figure 2A). This elevation in GAS was associated with a significant decrease in the number of normal vessels (grade 0, pcO.Ol; 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 piexiform 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 / Vehicie (pcO.Ol; Figure 2A). It was associated with a significant decrease of grade 3 and grade 4 arterioles (p<0.05 and pcO.Ol, 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 / Vehicie (pcO.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 pcO.OOOl, 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. 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A,® (Sugen * 3W 33 14 S 70 i & 04 s ,'E £6 hyp.&kia 3.0¼ + 3W S2 ai 58 40 0 IS IS 55 s4 A.SS ■n-ormciKRa / 24 23 3 4 72 54 14 28 2G mg / kg) 72 6 S4 4 4 72 0 a 8 20 14 4 4 :S0 £2 94 86 S4 1B 53 46 0 S 28 22 50 / <4 51 8 30 TO 3 22 13 8 -30 23 4 i S,K 23 55 0 6 58 14 58 77 * 3W is 22 3 53 0 3 26 4 70 / 4 hypmria 1SM+3W 43 2« 22 0 “0 10 '33 50 0,8$ nor tnoxea / Cmp la SB 28 26 40 3 S 46 SO -44 54 -s, X.' 54 24 0 10 66 & 28 54 48 24 34 0 i. 64 2> ‘ 36 46 24 33 o 6 =:- 12 56 Si! 7 r 54 24 S3 3 3 84 SO 75 36 0,"8 tSugert +■ 3W 21 66 26 5 0 Q 83 4 8 12 0,43 hypoxia ISM + 3W 22 33 20 ZS 3 a &0 S3 -18 40 ■normasKa / 28 4S 54 15 S3 20 56 18 48 0 0 OS eO 56 14 •&0 is 34 20 64 f;,4x S3 24 28 BS 3 22 23 23 ■4s TO AAH J?2 53 24 22 0 Li 70 6 24 36 0,76 42 55 •8 34 3 6 58 2 •40 42 1,00 Table 3, The pharmacokinetic-pharmacodynamic (PK / PD) relationshipfor 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. Unbound 10 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 interpolation from the 15 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 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 / mLhr. Mean GAS values for the 4 groups of Sugen / hypoxia animals (Vehicle Control and 3 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 maxima! Compound la was reached (EAUC50 and EfAUC50). Note 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. Example 3 - Sodium valproate phase H a clinical study Study Design Randomized adult PAH patients with WHO Functional class II or III, stable on standard of care therapy for 90 days, to one of three total daily doses of sodium valproate; 480 mg, 960 mg or 1920 mg (equivalent to approximately 420 mg, 840 mg, 1680 mg of valproic acid). Subjects were enrolled for up to 22 weeks including a treatment period of 12 weeks. Right heart catheterization procedures were performed before and after the treatment period (providing data on e.g. pulmonary arterial pressure and pulmonary vascular resistance). The trial was conducted at 10 specialist clinical sites. 25 patients were randomized to sodium valproate treatment out of which 21 patients completed the treatment without protocol deviations. Study Resuits Efficacy data from the three doses were pooled together due to therapeutic drug exposure (i.e. plasma concentration) also in the low dose group. Sodium vaiproate showed compelling positive impact on exploratory clinical parameters already over a 12-week treatment period: * REVEAL risk score: o 43% (9 / 21) of the patients improved risk score o 71% 15 / 21) of the patients improved or had a stable risk score ® Functional Class: o 33% (7 / 21) of the patients improved functional class o 86% (18 / 21) of the patients improved or had a stable functional class ® Mean pulmonary arterial pressure (mPAP, AUG): o 67% (14 / 21) of the patients had sustained pressure reduction The phase H a study clinical data, together with preclinical information, is consistent with reversing pathological remodeling. An in-depth analysis made on a subgroup of patients with a remarkable response showed: ® 25% (5 / 21) of patients responded to sodium valproate with remarkably large reductions in pulmonary vascular resistance (PVR reduced by >30%, range 35-51%, mean 45%) consistent with the proposed reverse vascular-remodeling mechanism of action. ® These large reductions in PVR were strongly associated with robust increases in right ventricular stroke volume, ® Surprisingly, 4 / 5 of the remarkable responders (remarkable responders highlighted with a rectangie in Figure 6) were found in the lowest dose group (480 mg). In fact, even more surprisingly the 4 best responders were all in the lowest dose group (480 mg) and the data point furthest to the left (pretreatment value approximately 5.7 and post-treatment value approximately 3.7) within the rectangle in Figure 6 represents a responder that was in the 1920 mg dose group. The 480 mg dose was lower than the dose used in the Phase I clinical study in this program. It was not expected that this dose would show any significant clinical effects when the study was designed, only expected in the mid and high dose, and this was one of the reasons why a placebo control was not included in this Phase II study. The data from the study directly demonstrating a dose-dependent positive impact on reverse vascular remodeling in small lung arteries, provide rationale that sodium valproate may act with a disease-modifying capacity in 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 ciaim 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 ciaim 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,22. Valproic acid for use in treating and / or preventing pulmonary arterial hypertension (PAH), wherein the treatment and / or prevention comprises administeringto a subject a total daily dose of from about 300 mg to about 500 mg of valproic acid or a pharmaceutically acceptable salt thereof.

23. The valproic acid for use as according to claim 22, wherein the total daily dose is from about 350 mg to about 500 mg.

24. The valproic acid for use as according to claim 22, wherein the total daily dose is from about 370 mg to about 490 mg.

25. The valproic acid for use as according to claim 22, wherein the total daily dose is about 400 to about 450 mg.

26. The valproic acid for use as according to any one of claims 22 to 25, wherein the total daily dose is administered as one or more separate doses.

27. The valproic acid for use as according to claim 26, wherein the total daily dose is administered as two separate doses.

28. The valproic acid for use as according to claim 27, wherein the total daily dose is administered as one dose in the morning and one dose in the evening.

29. The valproic acid for use as according to claim 27 or claim 28, wherein the separate doses are administered at least 8 hours apart, preferably 12 hours apart.

30. The use of valproic acid as according to any one of claims 27 to 29, wherein one separate dose is from about 250 mg to about 380 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 120 mg to about 240 mg of valproic acid, or a pharmaceutically acceptable salt thereof.

31. The use of valproic acid as according to claim 30, wherein one separate dose is from about 250 mg to about 300 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other separate dose is from about 120 mg to about 160 mg of valproic acid, or a pharmaceutically acceptable salt thereof.

32. The use of valproic acid as according to claim 31, wherein one dose is about 280 mg of valproic acid, or a pharmaceutically acceptable salt thereof, and the other dose is about 140 mg of valproic acid, or a pharmaceutically acceptable salt thereof.

33. The use of valproic acid, as according to claim 32, wherein a dose of about 280 mg of vaiproic acid, or a pharmaceutically acceptable salt thereof, is administered in the evening and a dose of about 140 mg of valproic acid, or a pharmaceutically acceptable salt thereof, is administered in the morning.

34. The use of valproic acid, as according to any one of claims 22 to 33, wherein the PAH is associated with one or more of the conditions selected from the group consisting of plexiform lesions, artery vessel occlusion, vessel related fibrosis and a combination thereof.

35. The use of valproic acid, as according to claim 34, wherein the PAH is associated with one or more of the conditions selected from the group consisting of plexiform lesions.

36. The use of valproic acid, as according to any one of claims 22 to 35, wherein the treatment is administered to a subject refractory to treatment for PAH with a previously ceased or ongoing treatment, regimen.

37. The use of valproic acid of claim 36, wherein said previously ceased or ongoing treatment failed to sufficiently lower blood pressure in the subject's pulmonary arteries.

38. The use of valproic acid of claim 36 or claim 37, 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 valproic acid or a pharmaceutically acceptable salt thereof.

39. The use of valproic acid according to any one of claims 36 to 38, 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), endothehn 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.

40. The use of valproic acid according to any one of claims 36 to 39, wherein the previously ceased or ongoing treatment is an ongoing treatment, wherein treatmentwith administering the valproic acid, or a pharmaceutically acceptable sait thereof, is in addition to (i.e. co-administered with) the ongoing treatment.

41. The use of any of claims 22-40, wherein the valproic acid is provided in the form of pharmaceutical composition comprising at least one pharmaceutical vehicle, wherein the pharmaceutical composition comprises:a. valproic acid (VPA) and / or a pharmaceutically acceptable salt thereof; and b. one or more secondary acid,and optionally comprising one or more pharmaceutically acceptable excipient,42. The use of claim 41, wherein component (b) is an organic acid.

43. The use of claim 41 or claim 42, wherein each carboxylic acid group in component (b) is in non-salt form.

44. The use of any one of claims 41 to 43, wherein the secondary acid is selected from the list consisting of adipic acid, citric acid, fumaric acid, glycine, lysine, maleic acid, malic acid, lactic acid, sorbic acid, potassium phosphate monobasic, sodium phosphate monobasic, succinic acid, acetylsalicylic acid and tartaric acid.

45. The use of any one of claims 41 to 44, wherein the secondary acid is selected from the list consisting of succinic acid and fumaric acid.

46. The use of any one of claims 41 to 45, wherein the secondary acid is fumaric acid.

47. The use of any one of claims 41 to 46, wherein the amount of secondary acid is from about 0.1 % (e.g. about 1 %) to about 15% of the weight of the VPA and / or a pharmaceutically acceptable salt thereof in the relevant component, such as about 0.1 % (e.g. about 1 %) to about 10%.

48. The use of any one of claims 41 to 47, wherein the formulation comprises one or more component having a solid core comprising component (a), wherein component (a) is present in an amount that is at least 50% by weight thereof, and optionally wherein said solid core further comprises component (b).

49. The use of any one of claims 41 to 48, wherein the pharmaceutical composition comprising components (a) and (b) (e.g. in the form of one or more component having a solid core) further comprises one or more coating.

50. The use of claim 49, wherein the one or more coating is:(i) an enteric coating;(ii) a sustained release coating (including a pore forming coating); and / or(iii) a protective film,51. The use of claim 50, wherein the pharmaceutical composition comprising components (a) and (b) is coated with an enteric coating (e.g. of a type and in an amount as described herein) and then a sustained release coating (e.g. of a type and in an amount as described herein).

52. The use of any one of claims 41 to 51, wherein the composition is in the form of a tablet or capsule for oral administration and is formulated such that substantially all of the VPA and / or pharmaceutically acceptable salt thereof is released during a period from about four to about eight hours after administration.

53. The use of claim 52., wherein substantially all of the VPA and / or pharmaceutically acceptable salt thereof is released during a period from about six to about eight hours after administration.

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