Sabizabulin for use in the treatment of polycystic kidney disease

Abstract

The present invention relates to a composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of polycystic kidney disease (PKD).

Description

[0001] SABIZABULIN FOR USE IN THE TREATMENT OF POLYCYSTIC KIDNEY DISEASE

[0002] Field of the invention

[0003] This invention relates to new uses of sabizabulin.

[0004] Background of the invention

[0005] Polycystic kidney disease (PKD) is an inherited disorder in which clusters of cysts develop primarily within your kidneys, causing your kidneys to enlarge and lose function over time. Cysts are noncancerous round sacs containing fluid. The cysts vary in size, and they can grow very large. Having many cysts or large cysts can damage the kidneys. Polycystic kidney disease can also cause cysts to develop in your liver and elsewhere in the body. The disease can cause serious complications, including high blood pressure and kidney failure.

[0006] Abnormal genes cause polycystic kidney disease. The two main types of polycystic kidney disease, caused by different genetic flaws and modes of inheritance, are Autosomal dominant polycystic kidney disease (ADPKD) and Autosomal recessive polycystic kidney disease (ARPKD). Both ADPKD and ARPKD are rare genetic forms of chronic kidney disease, with an estimated prevalence of 30-50 / 100,000 and 1.2 / 100,000, respectively. Pathophysiologically, ADPKD is characterised by the formation and growth of numerous fluid-filled cysts in the kidney, and often extra renal organs including the liver and pancreas. The progressive expansion of kidney cysts eventually impacts upon normal renal function, leading commonly to hypertension and ultimately end stage renal disease (ESRD) in most patients before the age of 60. Despite its classification as a rare disease, it is the most common genetic cause of ESRD. The disease course of ARPKD is more severe, with progression to ESRD commonly occurring in childhood or early adulthood, and extrarenal manifestations including lung hypoplasia and hepatic fibrosis occurring with variable frequency and severity.

[0007] Mutations in the PKD1 gene encoding polycystin 1 (PCI) account for approximately 80% of all ADPKD cases, while mutations in the PKD2 gene encoding polycystin 2 (PC2) account for approximately 15% of all ADPKD cases, with remaining ADPKD cases either genetically unresolved or caused by rare mutations in other genes. PCI and PC2 are primarily localised to the cilia of epithelial cells, where individually, and as a heteromeric complex, they mediate numerous cellular signalling pathways, primarily via calcium and cAMP regulation. Upon mutation of either gene, these signalling pathways are perturbed, and culminate in loss of cellular polarity, increased cellular proliferation, and increased fluid secretion which all drive the formation and expansion of renal cysts. Mutations in the PKHD1 gene encoding the protein fibrocystin account for almost all cases of ARPKD. While the function of fibrocystin is incompletely understood, like the polycystins it is also localised to the primary cilia of epithelial cells, and disease-causing mutations are believed to result in similar perturbations in intracellular signalling.

[0008] Most available treatments for PKD are limited to addressing its symptoms, which commonly include hypertension, kidney stones and pain. The vasopressin 2 receptor antagonist tolvaptan represents the only disease-modifying therapy approved for the treatment of ADPKD, and is moderately efficacious in the slowing of kidney volume expansion and functional decline. Notwithstanding, tolvaptan is only approved for a subset of ADPKD patients, namely adults with rapidly progressing disease, and is also associated with common aquaretic side effects, and rare but potentially serious hepatic injury. There remains a significant unmet need for new therapeutics to address the causative mechanisms of ADPKD. There are currently no disease-modifying therapies approved for ARPKD.

[0009] Despite various efforts to identify a more effective therapy for treating PKD, no such successful therapies have been reported to date. Especially given the prevalence of the disease, there is clearly a need for new and effective therapies to treat or prevent PKD.

[0010] Sabizabulin (IUPAC name [2-(lH-Indol-3-yl)-lH-imidazol-5-yl]-(3,4,5- trimethoxyphenyl)methanone) is a microtubule inhibitor in clinical development for the treatment of prostate cancer and SARS-CoV-2 infection. Its primary mechanism of action is via binding to the colchicine site of 0-tubulin, thus inhibiting microtubule polymerisation. The downstream consequences of this molecular event are cell cycle inhibition as well as the impairment of the trafficking of viral particles and inflammatory mediators, which are hypothesised to underly the efficacy of sabizabulin in cancer and viral inflammatory conditions, respectively. While clinical development is still ongoing and the molecule has not yet been approved for either indication (prostate cancer and SARS-CoV-2 infection), reported data thus far suggests that sabizabulin has a favourable safety profile when compared with existing approved microtubule inhibitors.

[0011] Summary of the invention

[0012] The present invention is a composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of PKD. As will be evident from the data presented below, sabizabulin is effective in treating and preventing PKD.

[0013] A first aspect of the invention is a composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of PKD.

[0014] A second aspect of the invention is use of sabizabulin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of PKD. A third aspect of the invention provides a method of treating or preventing PKD, wherein the method comprises administering the patient with a composition comprising sabizabulin or a pharmaceutically acceptable salt thereof.

[0015] Description of the figures

[0016] Figure 1 shows the results of sabizabulin on cyst growth in the presence of a ddAVP stimulus in a primary human cell model of ADPKD.

[0017] Figure 2 shows the results of sabizabulin on kidney volume in mice with polycystic kidney disease.

[0018] Detailed description

[0019] In the present invention, and as demonstrated by the below in vitro data, sabizabulin inhibits the growth of cysts, and is therefore effective at treating and preventing PKD.

[0020] The term "comprises" or "comprising" will take its usual meaning in the art, namely indicating that the component includes but is not limited to the relevant features (i.e. including, among other things). As such, the term "comprises" will include references to the component consisting essentially of (such as consisting of) the relevant features. The term "consists of" or "consisting of" will take its usual meaning in the art, namely indicating that the component includes and is limited to the relevant features.

[0021] By the term "treatment" or "treating" as used herein, we refer to therapeutic (curative) treatment. Treatment also includes stopping the disease from developing or slowing further progression of the disease. For example, treatment may include preventing a cyst from growing bigger or slowing a cyst's growth rate.

[0022] By the term "prevention" or "preventing" as used herein, we refer to "prophylactic" treatment, which includes administering sabizabulin to a patient that has mutations in the PKD1 and / or PKD2 and / or PKHD1 gene, preferably the PKD1 and / or PKD2 gene.

[0023] In one embodiment, sabizabulin is used for the treatment or prevention of PKD, such as ADPKD or ARPKD, preferably ADPKD.

[0024] "Patient" and "subject" are used interchangeably and refer to the subject that is to be administered the sabizabulin. Preferably the subject is a human. ADPKD and ARPKD are highly allelically heterogeneous diseases. The Mayo Clinic PKD database currently lists 1225 pathogenic or likely pathogenic PKD1 germline mutations and 196 pathogenic or likely pathogenic PKD2 germline mutations, many of which are unique to individual families. As such there are no prototypical common mutations that represent the diseases. In one embodiment the patient has a mutation in the PKD1 gene and / or the PKD2 gene, preferably the mutation is pathogenic. In one embodiment, the patient has a mutation in the PKHD1 gene, preferably the mutation is pathogenic. In one embodiment, sabizabulin is used for the treatment or prevention of PKD (such as ADPKD or ARPKD, preferably ADPKD), wherein the patient has had or is going to have surgery to remove some or all of cysts caused by the PKD. This may be particularly advantageous if the cysts are large and / or expands across tissue boundaries, and / or large in number, so it is difficult to remove them all by surgery and / or a quick removal of at least some of it is desired / beneficial.

[0025] The term "surgery" has its normal meaning in the art. Surgery is an invasive technique with the fundamental principle of physical intervention on organs / organ systems / tissues for diagnostic or therapeutic reasons.

[0026] As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.

[0027] The present invention is directed to a composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of PKD, preferably ADPKD or ARPKD. In a preferred embodiment the composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, is for use in the treatment or prevention of ADPKD. In another embodiment the composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, is for use in the treatment or prevention of ARPKD.

[0028] In an alternative embodiment, the present invention is directed to a composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of PKD, preferably ADPKD or ARPKD, more preferably ADPKD, wherein sabizabulin is the only active agent in the composition. By only active agent it is meant that the composition does not contain other components which may be used in the treatment or prevention of PKD.

[0029] Alternatively, the composition comprising sabizabulin, or a pharmaceutically acceptable salt thereof, may be used in combination with one or more additional active agents.

[0030] The compositions of the invention may contain a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant any diluent or excipient, such as fillers or binders, that is compatible with the other ingredients of the composition, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.

[0031] In the present invention, the composition may be administered in a variety of dosage forms. In one embodiment, the composition may be formulated in a format suitable for oral, rectal, parenteral, intranasal or transdermal administration or administration by inhalation or by suppository. In one embodiment, the composition may be formulated in a format suitable to be administered intraperitoneally, orally or intravenously, preferably intravenously or orally, more preferably orally. In one embodiment, the composition may be formulated in a format suitable to be administered by parenteral, transdermal, sublingual, rectal or inhaled administration.

[0032] The composition may be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferably, the composition is formulated such that it is suitable for oral administration, for example tablets and capsules. Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, celluloses or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents and surfactants such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.

[0033] The composition may also be administered parenterally, whether intraperitoneally, subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.

[0034] The composition may also be administered by inhalation. An advantage of inhaled medications is their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

[0035] The present invention also provides an inhalation device containing the composition of the present invention. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.

[0036] The composition may also be administered by intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. By this method absorption is very rapid and first pass metabolism is usually bypassed, thus reducing inter-patient variability. Further, the present invention also provides an intranasal device containing the composition according to the present invention. The composition may also be administered by transdermal administration. For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions or suspensions may be employed. The present invention therefore also provides a transdermal patch containing the composition.

[0037] The composition may also be administered by sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising the composition.

[0038] The composition may also be formulated with an agent which reduces degradation of the substance by processes other than the normal metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensural or parasite organisms living on or within the patient, and which are capable of degrading the compound.

[0039] Liquid dispersions for oral administration may be syrups, emulsions and suspensions.

[0040] Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

[0041] Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

[0042] In an embodiment of the invention, the composition is administered in an effective amount to treat or prevent PKD, preferably ADPKD or ARPKD, more preferably ADPKD. An effective dose will be apparent to one skilled in the art, and is dependent on a number of factors including age, sex, weigh, which the medical practitioner will be capable of determining.

[0043] In a preferred embodiment, the composition comprises 0.01 mg to 500 mg, preferably 1 mg to 250 mg, more preferably 2 mg to 100 mg, even more preferably 3 mg to 9 mg of sabizabulin. For example, the composition may comprise 0.5 mg to 500 mg, 0.01 mg to 100 mg, 0.5 mg to 80 mg, 0.1 mg to 10 mg, 3mg to 75 mg, 4 mg to 70 mg, 5 mg to 65 mg, 10 mg to 50 mg, 12.5 mg to 40 mg, 20 mg to 30mg, and / or 3 mg to 9 mg of sabizabulin, such as 2.85 mg, 6 mg, 11.4 mg, 14 mg, 28.5 mg, 30 mg, 35 mg, or 57 mg of sabizabulin.

[0044] In one embodiment, a single dose of the composition of the invention comprises between 0.005 mg / kg to 5 mg / kg, preferably 0.01 mg / kg to 1 mg / kg, such as 0.01 mg / kg to 0.1 mg / kg, more preferably 0.05 mg / kg to 0.9 mg / kg, yet more preferably 0.08 mg / kg to 0.8 mg / kg of sabizabulin based on the subject's weight (kg). In an embodiment of the invention, the composition is administered at least once a day. Preferably it is administered as a single daily dose.

[0045] Alternatively, the composition may be administered once a day, twice a day, three times a day or four times a day.

[0046] Preferably the single daily dose is 0.5 mg to 200 mg, preferably 1 mg to 125 mg, more preferably 2 mg to 100 mg, even more preferably 3 mg to 9 mg of sabizabulin. For example, the daily dose may comprise 2.5 mg to 80 mg, 3 mg to 75 mg, 4 mg to 65 mg, 1 mg to 10 mg, 3 mg to 9 mg, and / or 4 mg to 8 mg of sabizabulin.

[0047] In an embodiment of the invention, the composition comprises 0.25 mg to 100 mg of sabizabulin and is administered twice daily. In an embodiment, each dose is 0.25 mg to 50 mg, more preferably 0.5 mg to 25 mg, yet more preferably 1 mg to 10 mg of sabizabulin. In an embodiment, each dose is 2 mg to 70 mg, such as 2.5 mg to 60 mg. In an embodiment, each daily dose is 4 mg to 140 mg, such as 5 mg to 100 mg of sabizabulin, more preferably 3 mg to 9 mg of sabizabulin.

[0048] In another embodiment, each dose of the composition of the invention administered twice daily comprises between 0.0025 mg / kg to 2.5 mg / kg, preferably 0.005 mg / kg to 0.5 mg / kg, more preferably 0.025 mg / kg to 0.45 mg / kg, yet more preferably 0.04 mg / kg to 0.4 mg / kg of sabizabulin based on the subject's weight (kg). For example, each dose of the composition of the invention administered twice daily comprises between 0.01 mg / kg to 1 mg / kg, such as 0.04 mg / kg, 0.08 mg / kg, 0.4 mg / kg, or 0.8 mg / kg of sabizabulin based on the subject's weight (kg).

[0049] In an embodiment of the invention, the composition comprises 0.15 mg to 150 mg and is administered three times daily. Preferably each dose is 0.3 mg to 30 mg, more preferably 0.6 mg to 10 mg, yet more preferably 1 mg to 3 mg of sabizabulin.

[0050] In another embodiment, each dose of the composition of the invention administered thrice daily comprises between 0.0015 mg / kg to 2 mg / kg, preferably 0.003 mg / kg to 0.35 mg / kg, more preferably 0.015 mg / kg to 0.3 mg / kg of sabizabulin based on the subject's weight (kg).

[0051] In an embodiment of the invention, the composition comprises 0.125 mg to 125 mg and is administered four times daily. Preferably, each dose is 0.25 mg to 63 mg, more preferably 0.5 mg to 12.5 mg, yet more preferably 0.75 mg to 2.25 mg of sabizabulin.

[0052] In another embodiment, each dose of the composition of the invention administered four times daily comprises between 0.00125 mg / kg to 1.25 mg / kg, preferably 0.0025 mg / kg to 0.25 mg / kg, more preferably 0.0125 mg / kg to 0.225 mg / kg of sabizabulin based on the subject's weight (kg). Preferably, the dosage regime is such that the total daily dosage of sabizabulin does not exceed 500 mg, more preferably it does not exceed 100 mg, even more preferably it does not exceed 80 mg.

[0053] In order to treat or prevent PKD, preferably ADPKD or ARPKD, more preferably ADPKD, the composition comprising sabizabulin may be used in a chronic dosage regime i.e. chronic, long-term treatment. Suitably the regime lasts for at least one week, such as at least two weeks, at least three weeks, at least one month, suitably at least two months, such as at least three months.

[0054] The present invention also relates to use of sabizabulin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of PKD, preferably ADPKD or ARPKD, more preferably ADPKD. This embodiment of the invention may have any of the preferred features described above.

[0055] The present invention also relates to a method of treating or preventing PKD, preferably ADPKD or ARPKD, more preferably ADPKD comprising administering the patient with a composition comprising sabizabulin or a pharmaceutically acceptable salt thereof. This embodiment of the invention may have any of the preferred features described above. The method of administration may be according to any of the routes described above.

[0056] The invention includes pharmaceutically acceptable prodrugs of sabizabulin. The term "pharmaceutically acceptable prodrug" refers to a biologically inactive compound which can be metabolized in the body to produce a drug. Suitably, a compound of the invention is administered in the form of a prodrug which is converted to the active form during absorption into the body. Suitably, the compound prodrug of the present invention is an ester, carbonate, carbamate, amide, phosphate or oxime prodrug.

[0057] Compositions of the invention also extends to compositions comprising any polymorphic forms of sabizabulin herein defined, including salts thereof. Compositions of the invention also extend to all solvates of the compounds herein defined. Examples of solvates include hydrates.

[0058] Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skills in the art to which this invention pertains.

[0059] Experimental Section

[0060] Example 1 - In vitro drug testing utilizing primary ADPKD patient kidney cells

[0061] Cell models

[0062] Primary human ADPKD kidney cells were derived from a resected patient kidney and cultured in kidney culture medium. Patient genotype was confirmed by sequencing of cystic tissue as PKD1: C.12712OT p.Gln4238*. Culture conditions

[0063] Cells were mixed with PrimCyst-Gel (Crown Bioscience Netherlands BV) and pipetted into 384-well plates to a final cell density of 450 objects per well. Culture medium was added to each well after gel polymerization. Cells were grown in gel for 24 hours, after which the cells were exposed for 48 hours to vehicle, or the cystogenic stimulus l-deamino-8-D- arginine vasopressin (ddAVP) with or without sabizabulin.

[0064] Sample processing

[0065] After 48 hours of treatment, cultures were fixed with 4% formaldehyde, permeabilized with 0.2% Triton X-100 and stained with 0.25pM rhodamine-phalloidin and 0.1% Hoechst 33258 for 2 days at 4°C, protected from light. After fixation and staining, plates were washed with PBS and stored at 4°C prior to imaging.

[0066] Imaging and image analysis

[0067] Imaging was performed using an ImageXpress Micro XLS (Molecular Devices) with a 4x NIKON objective. For each well around 35 images in the Z-direction were made for both channels, capturing the whole z-plane in each image. Image analysis was performed using Ominer™ software (Crown Bioscience Netherlands BV). Cysts were segmented using detection of Hoechst-stained nuclei and Rhodamine-phalloidin-stained cellular f-actin. Cyst area was determined by calculating for the area in px of each object in every in-focus plain. This was averaged per well. Cyst area was normalised to controls and is presented as a percentage normalised value.

[0068] Drugs

[0069] Sabizabulin (Axon Medchem BV) had a purity of > 99.5%. After solubilisation in DMSO, sabizabulin was tested in an 8-point concentration curve, with 6-8 replicate wells per condition.

[0070] Data analysis

[0071] Curve fitting and plot generation was performed with GraphPad Prism 10 (GraphPad Software, La Jolla, CA).

[0072] Results

[0073] Results for sabizabulin can be seen in Figure 1. In a primary human cell model of ADPKD, sabizabulin dose-dependently reduces ddAVP-stimulated cyst growth to levels below those seen in the absence of ddAVP. Error bars represent standard deviation. Conclusions

[0074] Sabizabulin inhibits cyst growth in a primary human cell model of ADPKD. It is therefore expected that sabizabulin will reduce, treat, and prevent PKD, particularly ADPKD.

[0075] Example 2 - in vivo mice model

[0076] Animals

[0077] Ksp-TamCre x PkdlLox mice on a C57 / BL6 background were bred then housed in individually ventilated cages with sterilized corncob bedding and a shelter-like device to stimulate natural patterns of behavior. Male mice only were utilized for this study. Animals were maintained at 21°C ± 2°C with a relative humidity 40 - 70%, on a 12 / 12 light / dark cycle with air renewed 8-20 times / hour. During the in-life period, animals had ad libitum access to standard pelleted food and water. To induce a kidney-specific knockout of Pkdl, mice were dosed by oral gavage on postnatal day (PND) 18, 19 & 20 with tamoxifen at 150 mg / kg / day (Pkdl KO). Non-tamoxifen treated mice were used as Pkdl wildtype controls.

[0078] Compounds

[0079] Sabizabulin was formulated in 0.5% methylcellulose and dosed by oral gavage once daily (QD) at 2.5mg / kg or twice daily (BID) at 0.5mg / kg, Img / kg or 5mg / kg from PND42. After ± 14 days of dosing, some weight loss in the 5mg / kg BID dosing group necessitated a dose reduction to 2.5mg / kg BID, which was maintained for the remainder of the study. As a positive control, tolvaptan was dosed in medicated food (0.1% w / w) and was additionally administered QD by oral gavage at 75mg / kg after formulation in 2% DMSO: 1% methylcellulose. Compound treatment groups were compared with a QD dosed vehicle control group.

[0080] Ultrasound

[0081] Ultrasound measurements were collected at baseline on PND41 prior to the initiation of dosing on PND42, and again at PND75 after 33 days of dosing. Mice were anaesthetized with isoflurane anesthesia, and hair was removed from the right side of the abdomen prior to collection of a 3D ultrasound scan of the right kidney with a Vevo 3100 ultrasound imaging system. Kidney volume measurements taken at PND75 were normalized to measurements taken at baseline on PND41 from the same animal. Statistical analysis

[0082] After log transformation to correct deviation from normal distribution, data was analysed with GraphPad Prism 10.4 using parametric one-way ANOVA and Dunnet's multiple comparisons test. Pkdl wildtype mice were not included in statistical analyses.

[0083] Results

[0084] The results for sabizabulin can be seen in Figure 2. Sabizabulin reduces kidney volume in mice with polycystic kidney disease.

[0085] Daily treatment with 5mg / kg BID sabizabulin then reduced to 2.5mg / kg BID sabizabulin ("5>2mg / kg BID" label in Figure 2) (due to weight loss as described above) or the positive control tolvaptan for 33 days significantly reduces baseline-normalised kidney volume at PND75 in Pkdl knockout mice. Each symbol in Figure 2 represents one animal, and error bars represent standard deviation. In Figure 2, ** = p<0.01, and **** = p<0.0001 compared with vehicle treated control, analysed with one-way ANOVA with Dunnet's multiple comparisons test. In Figure 2, n = 10 for Pkdl wildtype, and n = 20-22 for Pkdl knockout groups.

[0086] According to direct scaling, a similar dose, such as a dose of 2.5 mg / kg sabizabulin twice daily which has been shown to be effective in the mouse model described herein, may exhibit similar therapeutic effectiveness in treating human patients with PKD. Alternatively, according to the principles of allometric scaling, a dose per kg which is the size of the mouse dose divided by 12.3 may be effective in humans, such as a dose of 0.2 mg / kg, may exhibit similar therapeutic effectiveness in treating human patients with PKD.

Claims

Claims1. A composition comprising sabizabulin or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of polycystic kidney disease (PKD).

2. A composition according to claim 1, for use in the treatment or prevention of autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD), preferably ADPKD.

3. The composition for use according to claim 1 or 2 in the treatment of ADPKD or ARPKD, preferably ADPKD.

4. The composition for use according to any preceding claim, wherein the subject of the treatment or prevention is human.

5. The composition for use according to any preceding claim, wherein the composition comprises 0.01 mg to 500 mg, preferably 1 mg to 250 mg, more preferably 2 mg to 100 mg, even more preferably 3 mg to 9 mg of sabizabulin.

6. The composition for use according to any preceding claim, wherein administration is by a dose one, two, three or four times per day, preferably one time per day.

7. The composition for use according to claim 6, wherein the daily dose comprises 0.5 mg to 200 mg, preferably 1 mg to 125 mg, more preferably 2 mg to 100 mg, even more preferably 3 mg to 9 mg of sabizabulin.

8. The composition for use according to any preceding claim, to be administered intraperitoneally, orally or intravenously, preferably intravenously or orally, more preferably orally.

9. The composition for use according to any of claims 1 to 7, to be administered by parenteral, transdermal, sublingual, rectal or inhaled administration.

10. The composition for use according to any preceding claim, wherein sabizabulin is the only active agent in the composition.

11. Use of sabizabulin, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of PKD.

12. Use according to claim 11, having any of the additional features of claims 2 to 10.

13. A method of treating or preventing PKD, wherein the method comprises administering the patient with a composition comprising sabizabulin or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13, having any of the additional features of claims 2

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