Abiraterone for the treatment of spontaneous hyperadrenocorticism in dogs

Abstract

Disclosed is abiraterone or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use in the treatment of Cushing's disease in dogs, wherein the pharmaceutically acceptable salt is preferably abiraterone acetate.

Description

[0001]ABIRATERONE FOR THE TREATMENT OF SPONTANEOUS HYPERADRENOCORTICISMIN DOGS FIELD OF THE INVENTION The invention relates to the use of abiraterone for use in the treatment of Cushing’s diseasein dogs, and to the preparation of a medication for the treatment of Cushing’s disease in dogs.BACKGROUND OF THE INVENTION Spontaneous hyperadrenocorticism (HAC) is one of the most common endocrine disorders in dogs and is caused by excessive production and secretion of glucocorticoid hormones by theadrenal glands (Bennaim et al., 2019, Vet. J.252, 105342).In the canine adrenal cortex, 3 functional and morphological layers can be distinguished: the zona glomerulosa, responsible for the production of the mineralocorticoid aldosterone, thezona fasciculata and the zona reticularis (Rijnberk and Kooistra (eds.), 2010 ClinicalEndocrinology of Dogs and Cats: An Illustrated Text, Schlütersche). The zona fasciculata andthe zona reticularis are the main sources of glucocorticoid secretion. Additionally, the zona reticulata also produces androgens such as androstenedione. Glucocorticoid secretion is strictly regulated by the hypothalamic-pituitary-adrenocortical axis, while aldosterone secretion isregulated by plasma potassium, angiotensin II, and adrenocorticotropic hormone (ACTH)secretion. In dogs, the pituitary gland is divided into three functional units: the anterior pituitary (formed by the pars infundibularis and pars distalis), the pars intermedia and the posterior pituitary (neurohypophysis). In healthy individuals, corticotropin-releasing hormone (CRH), produced by the hypothalamus, is the principal stimulant of episodic secretion of ACTH by the pars distalis which stimulates glucocorticoid production and secretion from the adrenal glands. In turn, glucocorticoids suppress the secretion of both ACTH by the pars distalis and CRH by the hypothalamus. ACTH is also produced by the B cells of the pars intermedia where itssecretion is regulated by tonic dopaminergic inhibition (Rijnberk and Kooistra, supra).Using cholesterol as the precursor molecule, zone-dependent enzyme expression in the adrenal cortex is essential for distinct steroid production. In humans, the production of aldosterone or cortisol depends on the zone-specific expression of aldosterone synthase (CYP11B2) and 11β-hydroxylase cytochrome P450 (CYP11B1), respectively. Sanders et al. (2016, J. Vet. Int. Med.30, 741–750) found that the canine adrenal cortex expresses only one CYP11B gene coding for an enzyme which has both aldosterone synthase activity but is alsoefficient in cortisol production. Therefore, zone-dependent steroid synthesis must thereforedepend on a different zone-specific enzyme. The authors found that in dogs CYP17 expression was significantly higher in the zona fasciculata compared with the zona glomerulosa, explaining the zone specific production of aldosterone and cortisol. HAC is classified as ACTH-dependent and ACTH-independent. ACTH-dependent causes described in dogs include pituitary-dependent HAC (PDH; also known as Cushing’s disease, after Harvey Cushing, the neurosurgeon who in 1932 first described the syndrome in humans(Feldman et al., 2014, Can. Fel. Endocrin., Elsevier Saunders; Rijnberk and Kooistra, supra)and ectopic ACTH production (Galac et al., 2005, Dom. Anim. Endocr.28, 338–348). PDHaccounts for approximately 80-85% of cases of spontaneous HAC in dogs and is the result of excessive secretion of ACTH by a pituitary corticotrophic adenoma. ACTH-independent causes described in dogs include hypersecretion of cortisol by a functional adrenocortical tumour (AT, 15-20% of the cases) and ACTH-independentmacronodular adrenal hyperplasia (e.g. food-dependent HAC) (Galac et al., 2008 Vet. J.177,141–143). As mentioned, functional pituitary tumours are the most frequent cause of spontaneous HAC, resulting in autonomous secretion of ACTH, bilateral adrenocortical hyperplasia and chronic excessive secretion of glucocorticoids. It is suggested that approximately 70% of ACTH- secreting pituitary tumours arise from the pars distalis, while the remainder originate from the pars intermedia. The vast majority of ACTH-secreting pituitary tumours are adenomas, whileinvasive adenomas and carcinomas are rare (Bennaim et al., 2019, supra).Functional ATs with excessive production of cortisol results in negative feedback on the hypothalamus and pituitary gland, suppressed ACTH secretion and resultant atrophy of the cortisol-secreting cells within the contralateral adrenal gland and the non-neoplastic cortisol- secreting cells of the affected adrenal gland. The majority of functional ATs are carcinomas andthe remainder adenomas. Functional ATs occur unilaterally in most cases (Bennaim et al.,2019, supra). The exact prevalence of spontaneous HAC is largely unknown, but has been estimated tobe around 0.17-0.28% (Carotenuto et al., 2019, Open Vet. J.9, 27–32; O’Neill et al., 2016, J.Small Anim. Pract.57, 365–373; Schofield et al., 2022, J. Small Anim. Pract.63, 265–274). Thelarge majority of affected dogs is older than 6 years of age but spontaneous HAC has been documented in dogs as young as 1 year. There is no apparent sex-related predisposition, although AT appears to be diagnosed more commonly in female dogs. A predisposition for spontaneous HAC (independent of cause) has been shown for several breeds. Poodles, Dachshunds, Bichon Frisés, standard Schnauzers, various Terrier breeds, German Shepherd dogs, Beagles, Labrador Retrievers, Boxers and Boston Terriers appear to be at increased risk for HAC. The proportion of dogs weighing >20 kg is significantly higher in dogs with functional ATs compared to those with PDH. PDH tends to occur more frequently in smaller dogs; 75% of dogs with PDH weigh less than 20 kg. Approximately 50% of dogs with functional AT weigh more than 20 kg (Bennaim et al., 2019, supra; Feldman et al., 2014, supra). In dogs with HAC, the clinical signs observed reflect the gluconeogenic, lipolytic, protein catabolic, anti-inflammatory and immunosuppressive effects of excess glucocorticoid hormones(see Table 1, taken from Behrend et al., 2013, J. Vet. Int. Med.27, 1292–1304). Clinical signsrelating to the underlying cause of HAC (e.g. neurological signs arising from a pituitary tumour)are possible (Bennaim et al., 2019, supra).Table 1 Clinical manifestations of canine hyperadrenocorticism Once a many factors including client financial constraints, the level of commitment involved in treatment, and a consideration of the risk / benefit ratio of the treatment compared with the consequences associated with the disease. Treatment options and protocols and prognosis also vary depending on the form of HAC present. Therefore, differentiation between PDH and AT should be obtained before choosing a therapy. Without treatment, dogs with PDH have a median survival time of 359 days (95%confidence interval (CI), 271–829) to 506 days (95% CI, 292–564) (Nagata et al., 2017, J. Vet.Int. Med. 31, 22–28). There are no data on the survival of dogs with an AT without treatment.The treatment of PDH should ideally be directed at eliminating the stimulus for cortisol production, i.e., the pituitary lesion causing excessive ACTH secretion. Experience has been gained with microsurgical transsphenoidal hypophysectomy (i.e., complete pituitary removal) in dogs with PDH. However, this technique can only be performed in specialized institutions withintensive peri- and post-operative care, and where imaging techniques such as CT and MRI canbe used to define the location and size of the pituitary prior to surgery. Afterwards, since thewhole pituitary including normal tissue is resected, in dogs, life-long substitution therapy withthyroxine and glucocorticoids is required. Also, central diabetes insipidus (CDI) may complicatethe postoperative course necessitating temporary or permanent desmopressin supplementationas well (van Rijn et al., 2016, J. Vet. Int. Med. 30, 989–995). The main complications ofhypophysectomy are perioperative death, transient mild postoperative hypernatremia, transientreduction or cessation of tear production, prolonged or permanent diabetes insipidus, and in27% of dogs with PDH that were in remission after hypophysectomy, recurrence of HAC wasobserved (Sanders et al., 2018, Vet. J.241, 42–51).For ATs, the treatment of choice is adrenalectomy. Surgery is however not always possible, for numerous reasons: the presence of metastases, it is a technically difficult surgicalprocedure, and serious intra- and postoperative complications may occur; the reported mortalityis variable but can exceed 25%. The main complications that can occur during surgery include minor to severe haemorrhage, hypotension, and tachycardia. The tumour capsule can rupture, possibly more often in laparoscopic than in open adrenalectomies, but does not commonly lead to tumour regrowth. The main complications that can occur postoperatively include pancreatitisand thromboembolism. The reported HAC recurrence rate varies between 12% and 30%, whichcan be either because of regrowth of the AT or metastases (Lemetayer et al, 2018, Can. Vet. J.59, 397–407; Sanders et al., supra).Radiotherapy can also be useful to decrease tumour size and reduce neurological signs in dogs with large pituitary tumours. Information on the use of radiotherapy in canine ATs is limited. Evidently, this type of therapy will only be possible in specialized institutions (Sanders et al., supra). Consequently, in most cases of spontaneous HAC, medical therapy is preferred. The goal of medical therapy is not to eliminate the source of autonomous ACTH or cortisol production, but rather to achieve normocortisolism, eliminate the clinical signs, avoid long term complications and mortality and improve the quality of life. Nowadays, spontaneous HAC is primarily treated with trilostane, authorised in Europe since 2005 for the treatment of pituitary-dependent and adrenal-dependent HAC (Cushing’ssyndrome) in dogs. Trilostane is e.g. marketed by Dechra under the trade name Vetoryl©.Trilostane is a synthetic steroid analogue that competitively inhibits the steroidogenicenzyme 3β-hydroxysteroid dehydrogenase (3βHSD) in the adrenal cortex, which is required for the production of all classes of adrenocortical hormones (Potts et al., 1978, Steroids 32, 257–267). Trilostane therefore inhibits both cortisol and aldosterone production.Additionally, trilostane possibly also inhibits other enzymes in the steroidogenesis cascade, such as 11β-hydroxysteroid dehydrogenase (11βHSD), which catalyses the conversion of physiologically active cortisol to inactive cortisone, and 11β-hydroxylase (CYP11B1)(Lemetayer, supra ; Ramsey, 2010, North Am. Small Anim. Pract. 40, 269–283; Sieber-Ruckstuhl et al., 2006, Dom. Anim. Endocr.31, 63–75). The effect of trilostane on CYP11B1might contribute to further inhibition of aldosterone production. In EP1385527B2 it is stated that only lowering the elevated serum cortisol concentrationsfor a short period of time by giving intermittent doses of trilostane, usually only once per day, is capable of relieving symptoms of HAC. However, it is currently established that because theduration of cortisol suppression is less than 12 h in most dogs, administrating trilostane twicedaily can improve the clinical response while keeping the total daily dose relatively low, and significantly reducing the adverse effects (Arenas et al., 2013, J. Vet. Int. Med.27, 1478–1485;Augusto et al., 2012 Tierarztl. Prax. Ausg. K Kleintiere Heimtiere 40, 415–424; Feldman, 2011,J. Am. Vet. Med. Ass.238, 1441–1451). The advantages of using trilostane are a high efficacy and the ability to monitor therapyobjectively by use of an ACTH stimulation test. However, the main downsides of treatment with trilostane are related to the low selectivity for the glucocorticoid pathway and occurrence of disruptive changes in the adrenal cortex, which necessitate careful dosing schemes and regularcheck-ups. Consequently, treatment with trilostane can result in a relatively high rate of adverseeffects. Transient hypocortisolism (shortage of glucocorticoids) is the most important side effect of trilostane therapy, possibly combined with or followed by complete hypoadrenocorticism (shortage of both glucocorticoids and mineralocorticoids), and even adrenal haemorrhage, necrosis and apoptosis can occur with resultant prolonged or permanent cortisol deficiency with or without aldosterone deficiency. Decreased aldosterone secretory reserve can occur commonly regardless of the level of control of HAC and cannot be predicted by measurement of electrolyte concentrations. Aldosterone deficiency has potentially dangerous consequences, such as hyperkalaemia, hyponatraemia, severe volume depletion, hypotension, and death. As such, the Vetoryl product literature (FDA pack insert Vetoryl) contains specific warnings that angiotensin converting enzyme (ACE) inhibitors should be used with caution with trilostane, as both drugs have aldosterone-lowering effects which may be additive, impairing the patient's ability to maintain normal electrolytes, blood volume and renal perfusion. There have been a few reports of deaths (including sudden death) in dogs when treated concurrently with trilostane and an ACE inhibitor (Vetoryl SPC). Likewise, potassium sparing diuretics (e.g. spironolactone) should not be used with trilostane as both drugs have the potential to inhibit aldosterone effects, increasing the likelihood of hyperkalaemia. Adrenal enlargement due to hyperplasia, adrenal haemorrhage, necrosis and apoptosis have been observed in PDH dogs treated with trilostane. Several publications suggest that it is not trilostane itself but rather the increased ACTH production, resulting from a loss of negative feedback caused by low blood cortisol concentrations, that causes these adverse effects in theadrenal glands, potentially leading to hypoadrenocorticism (Burkhardt et al., 2011, J. Vet. Int.Med. 27, 919–923; Galac et al., 2010 Vet. J. 183, 75–80; Reusch et al., 2007 Vet. Rec.160,219–224). It has been known for over 15 years that trilostane therapy causes a significant increase of endogenous ACTH concentrations in dogs (Galac et al., 2010, supra; Griebsch etal., 2014, J. Vet. Int. Med. 28, 160–165; Sieber-Ruckstuhl et al., supra; Witt and Neiger, 2004Vet. Rec.154, 399–400). Other reported adverse effects may vary from 25-40% and include lethargy, weakness, decreased appetite, vomiting, and diarrhoea. Fatality and sudden death has also occurred. Finally, pharmacokinetic data in dogs have demonstrated large inter-individual variability in trilostane absorption (Vetoryl SPC). Another medical option to treat HAC is mitotane. Mitotane is an adrenocorticolytic agentthat leads to progressive adrenocortical necrosis and atrophy. It also inhibits the steroidogenic enzymes CYP11A1 and CYP11B1, which contributes to inhibition of cortisol synthesis, and induces other cytochrome P450 enzymes such as CYP3A4, which leads to increased metabolic clearance of glucocorticoids. In addition, mitotane has the added advantage that it can destroyadrenocortical tumour cells (den Hertog et al., 1999, Vet. Rec. 144, 12-17).However, as this is a cytotoxic drug, additional safety measures are warranted. Afterwards, substitution therapy with glucocorticoids, mineralocorticoids and salt is required. A relatively high rate of adverse effects, more pronounced than that of trilostane, is observed. Therefore, the use of mitotane for the treatment of canine HAC has been largely replaced by trilostane (Sanders et al., supra). Other medications, such as cabergoline, retinoic acid, ketoconazole and selegiline hydrochloride are used less frequently, mostly due to limited efficacy and / or tolerance. Selegiline hydrochloride is approved by the American FDA for the treatment of PDH and cognitive dysfunction syndrome in dogs, but its use in dogs with Cushing's disease has met withlimited success (Reusch et al.1999, J. Vet. Int. Med. 13, 291-301).Thus, despite the progress made in the treatment of spontaneous HAC in dogs, there remains a need for new and safe therapeutic approaches for treatment of dogs suffering from asystemic disease, in particular from hyperadrenocorticism (HAC), such as spontaneous HAC.The present invention now provides a CYP17A1 inhibitor for use in the treatment of systemic disease in dogs, in particular hyperadrenocorticism. ACYP17A1 inhibitor is a type of drug which inhibits the enzyme CYP17A1 (Malikova et al.,2017, J. Ster. Biochem. Mol. Biol. 174, 192-200). It may inhibit both of the functions of theenzyme, 17α-hydroxylase and 17,20-lyase, or may be selective for inhibition of one of these twofunctions, generally 17,20-lyase (Küçükemre-Aydın et al., 2015, Turk. J. Ped. 57, 277-281).CYP17A1 inhibitors are well-known for use in treatment of humans, and have mainly beenused in the treatment of prostate cancer. CYP17A1 inhibitors that are not selective for inhibition of 17,20-lyase must be combined with a glucocorticoid such as prednisone in order to avoid adrenal insufficiency and mineralocorticoid excess caused by prevention of cortisol production (Gomez et al., 2014, Steroids 95, 80-87). Abiraterone acetate (AA) is a potent inhibitor of steroidogenic enzyme 17α-hydroxylase / 17,20-lyase (CYP17A1) and is approved for the treatment of metastatic castration- resistant prostate cancer (mCRPC) in humans to reach maximal androgen suppression(Zytiga®; EP 2478907 B1; EP 2061561 B1). Although generally well tolerated, AA induceshypocortisolism with a concomitant rise in circulating ACTH concentration in patients with mCRPC, which necessitates coadministration of glucocorticoids to reduce the associated sideeffects (Attard et al., 2012, J. Clin. Endocrin. Metab.97, 507–516). As such, it could also beused to treat human patients with Cushing syndrome, but evidence so far is limited to a fewcase reports and preliminary clinical data (Chacko et al., 2022, J. Gastrointest. Oncol.13,2626–2632; Claps et al., 2016, AACE Clin. Case Rep.2, e337–e341; Abate et al., 2022, J. End. Soc., 6, S_1, A82–A83). Abiraterone (3β)-17-(pyridyn-3-yl)-androsta-5,16-dien-3-ol (CAS #: 154229-19-3) has thefollowing structure: Abiraterone acetate (AA) is a pro-drug of abiraterone, developed for the treatment of cancer in humans as disclosed in EP 2061561B1 and EP 2478907B1. Its chemical name is 17-(3-pyridyl)androsta-5, acetate (CAS #: 154229-18-2) and has the following structure:Abiraterone acetate is already of metastatic prostate cancer in humans in combination with prednisone or prednisolone (to prevent side effects of theinduced glucocorticoid deficiency). Apart from the acetate salt, abiraterone citrate has beendescribed in WO2014 / 075583. Δ4-abiraterone (D4A) is the active metabolite of abiraterone. Its chemical name is 17-(3- Pyridinyl)-androsta-4,16-dien-3-one (CAS #: 154229-21-7) having the following structure: During the development of Zytiga® as treatment of metastatic castration-resistant prostate cancer (in combination with prednisone) in humans, it was found that there was a distinctdifference between humans and dogs in metabolism of AA (FDA NDA 202379). In humans, the two major circulating metabolites are abiraterone sulphate and N-oxide abiraterone sulphate, accounting for about 43% of exposure each. Comparative in vitro metabolism studiesdemonstrated that in most animal and human hepatocytes, abiraterone sulphate was clearly themajor metabolite, but this was not the case in dogs. The in vitro metabolic profiles in human and monkey were qualitatively as well as quantitatively comparable. Therefore, non-clinical (toxicology) studies were conducted in rats and cynomolgus monkeys instead of dogs. As such, there is currently no information about the safety of AA in dogs. In humans, adverse events of AA of concern include hepatotoxicity, heart failure, mineralocorticoid excess and adrenal insufficiency. Of the 21 patients enrolled in a phase Iclinical trial, hypertension, hypokalaemia and lower-limb oedema were observed in 6, 10 and 1patient, respectively (Attard et al., 2008, J. Clin. Oncol.26, 4563–4571). Administration ofeplerenone, a mineralocorticoid receptor antagonist, was required to control these side effects. In another trial, only 4 of 42 patients received AA with no clinical evidence of mineralocorticoid excess (Attard et al., 2012, supra). Of the other 38 patients, 36 patients were treated with eplerenone and in 2 patients dexamethasone was added before an attempt with eplerenone. This syndrome of secondary mineralocorticoid excess is caused by increased levels of steroids upstream of CYP17. Indeed, treatment with AA resulted in an up to 6-fold increase in ACTHlevels and a 4-fold to 50-fold increase in 11-deoxycortisone and 10-fold to 95-fold increase incorticosterone (Attard et al., 2008, supra), both mineralocorticoid precursor metabolites that are able to exert mineralocorticoid activity. The combination of corticosteroids (dexamethasone) with AA prevented the syndrome of secondary mineralocorticoid excess. The European product information of Zytiga indeed specifically states that Zytiga may cause hypertension,hypokalaemia and fluid retention as a consequence of increased mineralocorticoid levelsresulting from CYP17 inhibition. Co-administration of a corticosteroid suppresses the ACTH drive, resulting in a reduction in incidence and severity of these adverse reactions (EPAR Zytiga product information). However, co-administration of glucocorticoids is obviously not an option when administering AA for treatment of hypercortisolism. The requirement for additionaltreatment with a mineralocorticoid receptor blocker such as eplerenone or spironolactone wouldconstitute a clear disadvantage compared with trilostane for treatment of hypercortisolism indogs. In human patients with advanced castration-resistant prostate cancer, treated with AA,plasma ACTH concentrations increased from a median of 17 pg / ml before treatment to124 pg / ml on treatment (Attard et al., 2012, supra). An increase of endogenous ACTH is alsooften seen in dogs during trilostane therapy. A severe increase in ACTH might be associated with side effects such as microscopic bleeding and adrenocortical necrosis (Burkhardt et al.,2011, supra; Galac et al., 2010, supra ; Teshima et al., 2009, Domest. Anim. Endocrinol.36,32–44). Teshima et al. (2009) found that trilostane administered to healthy Beagle dogs at5 mg / kg twice daily caused a remarkable increase of circulating endogenous ACTHconcentrations: from 23.4 (14.9-45.5) pg / ml before treatment to 621.9 (103.1-2506.5) pg / ml and918.9 (191.3-7303.5) pg / ml after respectively 4 and 8 weeks of trilostane treatment. These dogsdeveloped hypocortisolism, evidenced by very low circulating cortisol concentrations, lack of response to ACTH stimulation and bilateral adrenal cortical hyperplasia. Also in dogs with PDH, circulating endogenous ACTH concentrations increased significantly following trilostane treatment. In the study by Witt and Neiger (2004, supra) median endogenous ACTHconcentrations before and after treatment with trilostane were 102 pg / ml (range 18-312 pg / ml)and 246 pg / ml (range 18-600 pg / ml), respectively. Sieber-Ruckstuhl et al. (2006, supra)reported circulating ACTH concentrations of 79.5 (16-260) pg / ml before treatment whichincreased to 182 (62-495) pg / ml after 3-7 weeks of trilostane treatment. Burkhardt et al.(2013, J.Vet. Int. Med.27, 919–923) reported that circulating endogenous ACTH concentrations in dogswith PDH treated with trilostane ranged from 10 to 1250 pg / ml. Finally, in another study, plasmaACTH concentrations in well-controlled dogs with PDH were 58.5 (9-459) pg / ml beforetreatment and 175.5 (31.5-594) pg / ml during treatment (Galac et al., 2010, supra). PlasmaACTH concentrations exceeding 600 pg / ml are considered to be associated with adrenalnecrosis and hypocortisolism. Indeed, endogenous ACTH concentrations of dogs thatdeveloped hypocortisolism during trilostane treatment ranged from 954-1381 pg / ml. Similar totrilostane in dogs, treatment with AA in humans also results in an increase of ACTH plasma concentrations. As such AA provides no benefit over trilostane for the treatment of hypercortisolism in dogs, as similar side effects caused by increased endogenous ACTH concentrations are to be expected. Considering the above, i.e., the difference in metabolism of AA in dogs, need for preventive and / or curative co-medication, increased ACTH-levels in humans after treatment with AA, the use of CYP17A1 inhibitors, in particular abiraterone has not been considered as an alternativeto trilostane for the treatment of HAC in dogs. Accordingly, there are no safety data for dogs inthis respect. It was now surprisingly found that circulating endogenous ACTH concentrations in dogs are unaffected by AA treatment. Even after 4 weeks of AA administration, there was no biologically relevant increase in endogenous ACTH levels (Example 1). Moreover, no abnormal clinical findings or clinically significant changes in haematology or serum biochemistry that could be attributed to the AA administration were observed during the study, providing the first evidence that AA can be safely used in dogs as well. It was also unexpectedly found that the increase in 11-deoxycorticosterone and corticosterone levels was far less pronounced in dogs than in humans after treatment with AA (Example 1). In dogs, treatment with AA resulted in a 2-fold to 13-fold increase in 11- deoxycorticosterone levels and 2-fold to 20-fold increase in corticosterone levels on Day 28, whereas in humans, treatment with AA resulted in a 4-fold to 50-fold increase in 11-deoxycortisone and 10-fold to 95-fold increase in corticosterone (Attard et al., 2008, supra). A possible explanation might be a higher degree of metabolization of AA to the active metabolite Δ4-abiraterone (D4A) in dogs compared to humans, resulting in a more pronounced inhibition of CYP21. Abiraterone can be converted to the D4A metabolite by 3β-hydroxysteroiddehydrogenase (3βHSD) isoforms (Li et al., 2015, Nature 523, 347–351), which is highlyexpressed in canine adrenocortical cells (Sanders et al., 2018, Endocrinology 159, 3689-3698; de Wit et al., 27thECVIM-CA Congress 2017, https: / / www.vin.com / doc / ?id=8172822)). The unexpected findings that AA therapy in dogs does not affect circulating endogenous ACTH levels and results in a lower increase of 11-deoxycorticosterone and corticosterone levelscompared to humans has specific advantages for the canine patient in that it provides a saferway to treat spontaneous HAC in dogs. Based on these new findings, it can be concluded that CYP17A1 inhibitors, preferablyabiraterone, more preferably abiraterone acetate, can be used to treat dogs with systemic diseases, preferably HAC, such as for example ACTH-dependent HAC, including PDH (Cushing’s disease) and ectopic ACTH secretion, and ACTH-independent HAC, including HAC caused by a functional adrenocortical tumour and ACTH-independent macronodular adrenal hyperplasia (e.g. food-dependent HAC). Also herein a method for the treatment of systemic disease in dogs, comprisingadministration of a therapeutically effective amount of 17α-hydroxylase / 17,20-lyase (CYP17A1)inhibitor to a dog in need of such a treatment is disclosed. The term “systemic disease” as usedherein includes HAC, for example ACTH-dependent HAC, including pituitary dependent HAC (Cushing’s disease) and ectopic ACTH secretion, and ACTH-independent HAC, including HAC caused by functional adrenocortical tumours and ACTH-independent macronodular adrenal hyperplasia (e.g. food-dependent HAC). Pharmacological treatment of HAC preferably acts by lowering production cortisol to the appropriate level that gives partial or total relief, preferably total relief, from the clinical signs associated with HAC. A person skilled in the art will be able to define an appropriate level and devise a dosage regimen accordingly. In particular, it is possible to look up or measure levels in normal individuals and devise a dosage regimen to reduce levels to or towards the normal range. The Examples of the present application can be used as guidance. Adrenal hormone levels may be measured by any suitable means. For cortisol, ACTH stimulation tests are preferred in dogs. The ACTH stimulation test can be performed by collection of serum or plasma samples before and one hour after intravenous or intramuscular injection of syntheticACTH at a dose of 5 μg / kg. Cortisol concentrations can be measured by radioimmunoassay.Post-ACTH cortisol levels may be reduced to e.g. less than 250 nmol / l or less than 150 nmol / l.The invention relates toabiraterone or a pharmaceutical acceptable salt thereof, in atherapeutically effective amount for use in the treatment of Cushing’s disease in dogs. Actualdosage regimens will be chosen to lower circulating cortisol levels to the desired level and to provide relief from clinical signs associated with HAC. Thus as used herein “therapeutically effective amount” will refer to an amount required to reach a therapeutic response in dogs. The skilled person will be able to choose a therapeutically effective amount depending on, for example, the route of administration, the weight of the subject and the severity of the conditionbeing treated. Administration may be once, twice or three times a day, preferably with food.Compounds of the invention may be administered in any pharmaceutically acceptable manner, such as orally, rectally, locally, transdermal, parenteral, sublingual or as buccal or nasal spray. Oral administration of abiraterone acetate is preferred, e.g. of a tablet, capsule orsuspension formulation. Injection is also a preferred route of administration, e.g. intravenous,intramuscular or subcutaneous injection. The abiraterone is preferably in the form of abiraterone acetate. Since hypercortisolism is one of the symptoms of Cushing’s disease in dogs, the treatment is preferably without concurrent administration of glucocorticoids, since such administration wouldexacerbate the hypercortisolism.In an attractive embodiment, the therapeutically effective amount is about 0.1 - 30 mg / kgbody weight, preferably 0.1 – 25 mg / kg.Abiraterone is preferably administered orally, in particular in the form of a tablet, capsule orsuspension formulation. For oral administration, doses of 1 - 5000 mg are preferred, more preferably 1 to 1000 mg,more particularly 2 to 500 mg. Due regard shall however be had to the weight of the subject tobe treated. Dosages may therefore be measured in mg per kg body weight, for example 0.1 to2 mg / kg, or up to 5, 10, 25 or 30 mg / kg.The invention will now be further illustrated by way of the following figures and examples, whereinFigure 1 shows individual and mean plasma cortisol concentrations in 4 dogs after oraladministration of 25 mg / kg AA suspension during 5 days.Figure 2 shows mean plasma cortisol concentrations in dogs at Day 1 (Figure 2A) and Day 5(Figure 2B) after oral administration of vehicle control (G1, n=4), 10 mg / kg AA (G2, n=4) or 25 mg / kg AA (G3, n=4) orally once daily during 6 days.Figure 3 shows mean plasma cortisol concentrations before and after ACTH stimulation indogs at before (Day -7) and after (Day 6) oral administration of vehicle control (G1, n=4), 10 mg / kg AA (G2, n=4) or 25 mg / kg AA (G3, n=4) orally once daily during 6 days.Figure 4 shows mean plasma ACTH concentrations in dogs at Day 1 (Figure 4A) and Day 5(Figure 4B) after oral administration of vehicle control (G1, n=4), 10 mg / kg AA (G2, n=4) or 25 mg / kg AA (G3, n=4) orally once daily during 6 days.Figure 5 shows mean plasma ACTH concentrations in 8 dogs before (Day -6), during (Day 14)and after (Day 28) oral administration of 10 mg / kg AA once daily during 4 weeks.Figure 6 shows plasma concentrations of abiraterone (Figure 6A) and the metabolite D4A(Figure 6B) in dogs after a single dose of 10 mg / kg (n=4) or 25 mg / kg (n=4)abiraterone acetate suspension.Figure 7 shows mean abiraterone plasma concentrations in 8 dogs after oral administration of10 mg / kg AA once daily during 4 weeks.Figure 8 shows mean abiraterone plasma concentrations in 9 dogs after a single oral dose of20 mg AA administered as a suspension or tablet formulation in fed or fastedconditions.Figure 9 shows plasma ACTH concentrations in 6 dogs with PDH following treatment with AA.Figure 10 shows serum aldosterone concentrations before ACTH stimulation in 6 dogs withPDH following treatment with AA. EXAMPLES Example 1 Ability of abiraterone acetate to selectively block adrenal steroidogenesis in healthy dogs The ability of abiraterone acetate (AA) to selectively block adrenal steroidogenesis was assessed in healthy male Beagle dogs. In a first study, 4 dogs were orally administered 25 mg / kg AA, formulated as a methylcellulose suspension, once daily during 5 days. Dogs received a high fat pellet diet approximately 30 minutes before dosing. Blood samples for cortisol measurements were collected at Day 1 and Day 5 at regular intervals prior to and up to 24 h after dosing. Plasma cortisol levels were reduced at 2 to 8 hours post daily dosing with AA and gradually returned to normal levels thereafter. Individual and mean plasma cortisol concentrations at day 5 are shown in Figure 1. Based on the results from this first study, the effect of AA on the pituitary-adrenocorticalaxis was examined in more detail in 12 healthy male Beagle dogs (11.6 – 14.2 kg). Dogs wereallocated to one of three treatment groups and received either vehicle control (G1, n=4), 10 mg / kg AA (G2, n=4) or 25 mg / kg AA (G3, n=4) orally once daily during 6 days (Days 1-6). Blood samples were collected at Day 1 and Day 5 at regular intervals (pre-dose, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h after dosing). Plasma cortisol and endogenous ACTH (eACTH) concentrations were measured by routine immunoassay testing (Immulite). In addition, ACTH-stimulation tests were performed on Day -7 (baseline) and on Day 6. The ACTH stimulation test was performed by collection of plasma samples for cortisol measurement before and one hour after intramuscular injection of 0.25 mg ACTH (Synacthen). On Day 6, the ACTH stimulation test was performed 3.5 hours after dosing. Compared to the vehicle control group (G1), AA administration reduced plasma cortisollevels at 2-8 hours post daily dosing with a slow return to normal levels by 24 hours post dose. Mean plasma cortisol concentrations at Day 1 are shown in Figure 2A; mean plasma cortisol concentrations at Day 5 are shown in Figure 2B. On Day 6, cortisol response to ACTH stimulation was markedly reduced in both treatment groups (G2 and G3) compared to the vehicle-control (G1). Mean plasma cortisol concentrations before and after ACTH stimulation are shown in Figure 3. However, remarkably plasma endogenous ACTH concentrations were unaffected by abiraterone acetate treatment. Mean plasma ACTH concentrations at Day 1 are shown in Figure 4A; mean plasma ACTH concentrations at Day 5 are shown in Figure 4B. In a subsequent study, eight healthy male Beagle dogs received 10 mg AA / kg orally (by gavage) once daily during 4 weeks. A physical exam was performed during acclimation (Day -7) and at study end (Day 29). Clinical observations were performed once daily during acclimation and twice daily during the administration period. Body weight was recorded weekly. Blood samples for routine haematology and serum chemistry were collected from all animals onDay -7, Day 15 and Day 29.On Day -6, Day 14 and Day 28, ACTH stimulation tests were performed. Blood samples for pharmacodynamic profiling were collected immediately prior to, 30 min and 1h after ACTH stimulation for the determination of corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, cortisol, progesterone, 17-OH progesterone, androstenedione, and aldosterone. Plasma endogenous ACTH concentrations were determined in the samples collected before ACTH stimulation. Oral administration of AA at 10 mg / kg / day for 28 days was well tolerated. No abnormalclinical observations were recorded throughout the acclimation and treatment period. No changes in haematology or serum biochemistry that could be attributed to the AA administration were observed during the study. Treatment with AA resulted in selective and continuous inhibition of CYP17, evidenced by decreased steroid levels downstream of CYP17 (androstenedione, 11-deoxycortisol, cortisol) and an increase in steroid precursor levels upstream of CYP17 (progesterone, 11- deoxycorticosterone and corticosterone). Table 2 shows mean adrenal hormone concentrationspre- and post-ACTH-stimulation before (Day -6) and during treatment with AA (Day 14 and Day28). Although the %stimulation in cortisol decreased after AA treatment (1153% on Day -6,777% on Day 14 and 851% on Day 28), these differences were not statistically significant,indicating there was still sufficient adrenocortical reserve. After ACTH stimulation, the ratio 11- deoxycorticosterone / progesterone decreased significantly on both Day 14 (0.25±0.08,p=0.005) and Day 28 (0.17±0.06, p=0.004) compared to Day -6 (0.58±0.25), suggestingconcurrent inhibition of CYP21 by AA. Treatment with AA resulted in a median 9-fold (range 2- fold to 13-fold) increase in basal 11-deoxycorticosterone levels and median 10-fold (range 2-fold to 20-fold) increase in basal corticosterone levels on Day 28. Aldosterone concentrations were lower on Day 14 and Day 28 compared to Day -6, but remained in the normal physiological range and response to ACTH stimulation was still present, indicating that there was still sufficient adrenocortical reserve capacity. Table 2: The mean±SD adrenal hormone levels (nmol / l; aldosterone in pmol / l) before (pre-stim) and after (post-stim) ACTH-stimulation in 8 healthy male Beagle dogs before (Day -6) and during (Day 14 and Day 28) treatment with 10 mg / kg abiraterone acetate given orally. Day -6 Day 14 Day 28Pre-stim Post-stim Pre-stim Post-stim Pre-stim Post-stimAndrostenedione 7.20±2.52 8.68±2.90 2.27±0.61* 2.37±0.44* 2.20±0.61* 2.30±0.61*17-OH1.63±0.21 5.95±1.48 3.03±1.01* 6.63±1.16 3.54±1.38* 5.86±1.55progesterone11-deoxycortisol 3.09±3.43 34.53±18.49 0.40±0.19 5.41±1.99* 0.36±0.11 3.39±1.23*Cortisol 73.38±31.65 792.25±503.47 18.00±9.12* 116.00±20.24* 16.00±8.64* 106.38±35.70*Progesterone 3.76±1.79 9.73±1.61 15.96±6.81* 72.88±34.35* 24.44±6.04* 104.25±45.00*11-deoxycortico-sterone 0.38±0.45 5.54±.2.44 1.54±0.36* 17.52±8.35* 2.09±0.58* 15.84±5.19*Corticosterone 3.62±3.43 50.41±9.84 14.53±5.18* 157.06±23.41* 25.26±15.18* 162.79±24.32*Aldosterone 196±132 687±240 52±22* 365±119* 87±52 432±164** denotes a significant difference from Day -6 Individual ACTH plasma levels ranged from <5.0-12.6 pg / ml before treatment to 5.5-28 pg / ml on Day 14 and <5.0-36 pg / ml on Day 28. Mean plasma ACTH concentrationsincreased from Day -6 (6.5±3.7 pg / ml) to Day 14 (15.1±7.3 pg / ml, p=0.002), but remainedrelatively low. The increase from Day -6 to Day 28 (15.4±10.9 pg / ml) was not statisticallysignificant at all (Figure 5). So, unexpectedly, even after 4 weeks of AA administration, there was no biologically relevant increase in endogenous ACTH levels. Example 2 Abiraterone plasma concentrations in healthy Beagle dogs Plasma concentrations of abiraterone and the metabolite D4A after single dose of 10 mg / kgor 25 mg / kg abiraterone acetate (methyl cellulose suspension), showing peak at 0.5-1h hourswith rapid elimination thereafter, are shown in Figure 6A (abiraterone) and 6B (D4A). Treatment was administered 30 minutes after feeding of a high fat pellet diet. In another study, eight healthy male Beagle dogs received 10 mg AA / kg orally (by gavage)once daily during 4 weeks. Blood samples were collected on Days 1, 14 and 28 pre-dose andup to 8h after treatment for the determination of plasma abiraterone concentrations. Mean abiraterone plasma concentrations are shown in Figure 7. Following oral administration of AAsuspension, rapid absorption was observed with Tmax values at 0.5-1 h. Mean elimination half-lives were in the range of 1.2-1.4 h. There were no differences in AUCt, Cmax, AUCinf, kel and t1 / 2 between the study days, indicating that there was no accumulation of abiraterone plasma concentrations following repeated dosing. Next, relative bioavailability of AA tablet formulation and AA suspension and the effect offeeding was investigated in nine healthy Beagle dogs (body weight range 10.0-13.1 kg). Asingle oral dose of 20 mg AA was administered, corresponding to a dosage of 1.5-2 mg / kg.Mean abiraterone plasma concentrations are shown in Figure 8. Example 3 Abiraterone acetate for treatment of spontaneous hyperadrenocorticism in dogs The use of abiraterone acetate (AA) for the treatment of spontaneous HAC (also referred to as hypercortisolism) was evaluated in dogs with PDH. Six dogs (3 females and 3 males), weighing from 9.7 to 27 kg (mean ± SD: 16.6±6.6 kg)were identified with clinical signs and biochemical abnormalities indicative of PDH. Age rangedfrom 5.3 to 10.0 years (mean ± SD: 8.1±1.8) years. Clinical findings consistent with PDH at thebeginning of the study included polyuria / polydipsia (all dogs, n=6), urinary incontinence (n=4), polyphagia (n=4), potbelly (n=3), panting (n=4), dermatological problems (n=5), decreased activity (n=5) and muscle atrophy (n=4). In all dogs, the diagnosis was confirmed by a urinary corticoid to creatinine ratio (UCCR)combined with the high-dose dexamethasone suppression test. In addition, dynamic contrast- enhanced CT was performed to confirm the presence of a pituitary tumour and to exclude the presence of an adrenal tumour. At enrolment, all dogs showed an exaggerated cortisolresponse in the ACTH stimulation test with post ACTH plasma cortisol concentration rangingfrom 610 to 1101 nmol / L (mean ± SD: 790±188). Basal plasma endogenous ACTH (eACTH)ranged from 10 to 50 pg / ml (mean ± SD: 30.8±15.9) and serum aldosterone concentrationranged from 42 to 322 nmol / L (mean ± SD: 105.2±107.4).Dogs were treated with AA tablets twice daily, administered orally with food. The initial dailydose was based upon the body weight of the dog and ranged between 2.0 and 2.2 mg / kg / day.Dosages were subsequently adjusted based upon the response to therapy (clinical signs and an ACTH stimulation test). Follow-up re-examinations consisted of biweekly hospital visits starting after 7 days. At these points, owners completed a health-related quality-of-life questionnaire consisting of 19questions for dogs with Cushing’s syndrome (Schofield et al., 2019, J. Vet. Int. Med. 33, 2595–2604; Schofield et al., 2020, J. Vet. Int. Med.34, 2306–2318) and were questioned aboutpotential side effects. In addition, a physical examination was performed as well as laboratory testing consisting of haematology, serum biochemistry, eACTH concentration, and the ACTHstimulation test which included cortisol and aldosterone measurements. In between the hospitalvisits, telephone follow-ups were scheduled with the owners.In 3 dogs, clinical signs quickly improved and were well controlled within 38-49 days after starting abiraterone treatment. In 2 other dogs, clinical signs were clearly improved but not completely resolved. In three dogs concomitant antidiuretic therapy was added in order to control severe polyuria and urinary incontinence. Based on the owner’s assessment, the quality of life improved for 5 out of 6 dogs (with 3 dogs scored as “greatly improved”). At the first re-examination, post-ACTH cortisol decreased in all dogs to 29.3%-77.1% of theoriginal value (mean ± SD 52 ± 16%). By the third follow-up visit, post-ACTH cortisol decreasedin all dogs to less than 55% of the original value, and remained decreased throughout the entire treatment period, while still maintaining sufficient adrenal reserve (see Table 3). Table 3: Post ACTH stimulation test plasma cortisol values of dogs with PDH after various periods of abiraterone acetate treatment Pre-8.3 ± 23.0 ± 36.7 ± 52.5 ± 70.5 ± 78.0 ±Time (days) 125 treatment 1.5 2.3 2.1 3.8 13.7 1.4 790.0 ± 427.7 ± 353.5 ± 252.2 ± 185.2 ± 212.3 ± 222.5 ±Cortisol (nmol / L) 105 187.7 196.7 177.6 140.6 113.0 136.3 20.5 % of pre-treatment52 ± 31 ± 24 ± 24 ± 27 ±100%43 ± 18%11% cortisol 16% 14% 12% 14% 6% Number of dogs 6 6 6 6 6 4 2 1Based on both improvement of clinical signs and post-ACTH cortisol concentrations, 5 out of 6 dogs were considered stabilized. The final daily dosage of AA upon which the dogs wereconsidered stabilised ranged from 5.5 mg / kg to 26.1 mg / kg.One dog (dog no.5) experienced a possible treatment-related adverse event (shortepisode of vomiting, diarrhoea and reduced appetite) that required cessation of AA therapy for 3days. After treatment with maropitant the dog recovered and treatment with AA was continueduneventfully. Endogenous ACTH concentrations remained within reference range in all dogs. At studyexit, plasma eACTH concentration ranged from 33 to 55 pg / ml (mean ± SD: 43.2 ± 9.4). Therewas no increase in eACTH following treatment with AA with overall levels ranging from 9 to96 pg / ml (mean ± SD 38.6 ± 17.9) (see Figure 9). As expected, no decrease in pre-ACTHserum aldosterone was seen during treatment with AA (see Figure 10). At study exit, pre-ACTHaldosterone serum concentrations ranged from 58 to 556 pmol / L (mean ± SD: 257.0±176.8). In4 dogs, aldosterone levels remained below the upper reference limit of 393 pmol / L throughoutthe whole study. In dog no.5, pre-ACTH aldosterone levels exceeded the upper reference limitat 21 and 35 days after start of treatment, but returned to normal thereafter. In dog no.1, serum aldosterone concentrations already reached the upper limit at start and exceeded this upper limit from the first visit onwards. Despite high aldosterone levels, blood potassium levels remained normal in this dog. At enrolment, liver enzymes alkaline phosphatase (AF) and alanine amino-transferase(ALAT), were elevated in 6 dogs, and cholesterol and glucose 5 and 4 dogs, respectively. Plasma creatinine and urea were below normal in 6 and 5 dogs, respectively. At study exit, liver enzymes were decreased in all dogs and urea and creatinine were normalized in 6, respectively 5 dogs. With the exception of 1 episode of hypokalaemia in dog no.5, other biochemistry abnormalities noted during the course of therapy were all without clinical consequence. In 5 out of 6 dogs, urine specific gravity (SG) at enrolment was < 1.020, which is consistentwith PDH. In 4 out of those 5 dogs, the SG increased to > 1.020 during the study period. In dogno 6. SG increased to 1.017. Overall, AA was well tolerated. The following adverse events were reported: vomiting,diarrhoea, reduced appetite and mild hypokalaemia.

Claims

CLAIMS1. Abiraterone or a pharmaceutical acceptable salt thereof in a therapeutically effectiveamount for use in the treatment of Cushing’s disease in dogs.

2. Abiraterone for use of claim 1, wherein the abiraterone is in the form of abiraterone acetate.

3. Abiraterone for use of claim 1 or 2, wherein the treatment is without concurrentadministration of glucocorticoids.

4. Abiraterone for use of any of the preceding claims, wherein the therapeutically effectiveamount is about 0.1 - 30 mg / kg body weight.

5. Abiraterone for use of any of the preceding claims, wherein abiraterone is administeredorally, preferably in the form of a tablet, capsule or suspension formulation.

6. Abiraterone for use of any of the preceding claims, wherein abiraterone is administered ina dosage of 1 – 5000 mg, preferably 1 – 1000 mg, more preferably 2 – 500 mg.

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