Methods and formulations for prenatal treatment of Alan Handon Dudley syndrome

Abstract

The present disclosure relates to a method for treating Alan Haindon Dudley syndrome, which includes administering 3,5-diiodothyropropionic acid (DITPA) to a pregnant mother during pregnancy who is a prenatal subject in need of treatment for Alan Haindon Dudley syndrome, and a pharmaceutical DIPTA preparation for administration to a pregnant mother during pregnancy who is a prenatal subject in need of treatment for Alan Haindon Dudley syndrome.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 388,239, filed on July 11, 2022, the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to a method for prenatal treatment of Allan - Herndon - Dudley syndrome, which includes administering 3,5 - diiodothyropropionic acid (DITPA) to a pregnant mother of a subject in need of prenatal treatment of Allan - Herndon - Dudley syndrome during a specific gestational period.

Background Art

[0003] Allan - Herndon - Dudley syndrome ("AHDS") is an X - linked recessive developmental disorder that causes intellectual and motor disabilities in males. Specifically, AHDS patients have a mutated SLC16A2 gene, as a result of which the monocarboxylate transporter 8 ("MCT8") protein is abnormal. The symptoms of AHDS are usually caused by the lack of uptake of triiodothyronine ("T3"), a thyroid hormone that is normally transported across the cell membrane by MCT8, into cells. Due to this MCT8 deficiency, T3 is insufficient in the tissues necessary for it to function properly, and T3 accumulates in the serum. Another thyroid hormone, thyroxine ("T4"), usually remains at normal serum levels in AHDS patients, although it may decrease slightly from normal levels in some cases. In AHDS patients, thyroid - stimulating hormone ("TSH") is slightly elevated from normal.

[0004] Currently, there is no treatment for AHDS approved by the US Food and Drug Administration. Clinical trials of triiodothyroacetic acid ("TRIAC"), a drug used for the treatment of AHDS, have been completed. However, since TRIAC is structurally similar to T3, it becomes difficult to accurately evaluate T3 serum levels. Furthermore, TRIAC has been shown to significantly reduce T4 serum levels. See Groeneweg et al. Lancet Diabetes Endocrinol. 2019 Sep;7(9);695-706.

[0005] 3,5-Diiodothyropropionic acid ("DITPA") is another thyroid hormone analog that has been studied for the treatment of AHDS. However, as mentioned above, DITPA is still not approved for use in the treatment of AHDS. The reason for this lack of approval may be due to the absence of an effective dosing regimen, a stable and effective composition, and extensive pharmacological evaluation. International Publication No. WO 2012 / 171065, published on December 20, 2012, attempts to establish a DITPA dosing regimen for AHDS patients, but only theoretical examples are provided in this publication.

[0006] Therefore, there is a need for a prenatal composition of DITPA that is specific, stable, and effective for the prenatal treatment of AHDS and for the symptoms of AHDS, as well as an appropriate dosing regimen. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] DISCLOSURE The present subject matter relates to a pharmaceutical composition comprising 3,5-diiodothyropropionic acid ("DITPA") and a method of administering such a pharmaceutical composition for the prenatal treatment of Alan Heredon Dudley syndrome. The method comprises administering the DITPA pharmaceutical composition to the pregnant mother of a subject in need thereof, and the administration is initiated within 10 weeks after conception of the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1

Mode for Carrying Out the Invention

[0009] The applicant has discovered the timing of administration of 3,5 - diiodothyropropionic acid ( "DITPA" ), which is surprisingly effective in the treatment of Alan Houghton Dudley syndrome ( "AHDS" ).

[0010] In one embodiment, the present technology relates to a method for treating AHDS, which includes daily administering DITPA to a pregnant mother of a subject in need of treatment for AHDS, and the administration is started within 10 weeks after conception of the subject. The administration may be, for example, oral. Oral administration can be carried out, for example, by tablets or by dispersible tablets for oral suspension. The dosage can be up to 2.5 mg / kg, for example, based on the T3 titration level.

[0011] In another embodiment, the administration to a pregnant mother of a subject in need of treatment for AHDS is preferably started within 9 weeks after conception, more preferably within 8 weeks after conception, even more preferably within 7 weeks after conception, even more preferably within 6 weeks after conception, even more preferably within 5 weeks after conception, and most preferably within 4 weeks after conception.

[0012] In another embodiment, the present technology relates to a method for treating Alan Houghton Dudley syndrome, and this method includes a) daily administering DITPA to a subject in need thereof at a first dosage for 2 weeks; b) daily administering DITPA to the subject at a second dosage greater than the first dosage for 2 weeks; c) measuring the serum level of triiodothyronine ( "T3" ) in the subject, and when the T3 serum level is normal, the second dosage is administered daily. d) Optionally, a step of adjusting the daily dosage of DITPA administered to the subject based on the T3 serum level of the subject measured in step c), wherein when the T3 serum level is too high, a third dosage is administered daily, the third dosage being more than the second dosage, and when the T3 serum level is too low, a fourth dosage is administered daily, the fourth dosage being less than the second dosage; e) Optionally, a step of measuring the T3 serum level of the subject on or about the 28th day after the first administration of the third or fourth dosage, wherein when the T3 serum level is normal, the third or fourth dosage is administered daily; f) Optionally, a step of adjusting the daily dosage of DITPA administered to the subject based on the T3 serum level of the subject measured in step e), wherein when the serum T3 level is too low after the daily administration of the third dosage, the second dosage is administered to the subject, when the serum T3 level is too low after the daily administration of the fourth dosage, the first dosage is administered to the subject daily, and when the serum T3 level is too high after the daily administration of the fourth dosage, the second dosage is administered to the subject daily, including.

[0013] In a preferred embodiment, the first dosage is about 1 milligram per kilogram of the subject's body weight per day ("mg / kg / day").

[0014] In another preferred embodiment, the second dosage is about 2 mg / kg / day.

[0015] In another preferred embodiment, the third dosage is about 2.5 mg / kg / day.

[0016] In another preferred embodiment, the fourth dosage is about 1.5 mg / kg / day.

[0017] As used herein, the term "too high" refers to a T3 serum level that exceeds by about 15% or more the T3 serum level considered normal for the subject's age.

[0018] As used herein, the term "too low" refers to a T3 serum level that is at least 15% lower than the T3 serum level considered normal for the age of the subject.

[0019] As used herein, the "normal" T3 serum levels by age of the subject are disclosed in Lem et al., Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age, J Clin Endocrinol Metab, 2012 Sep, 97(9), 3170 - 8, doi:10.1210 / jc.2012 - 1759, Epub 2012 Jun 26.

[0020] In a preferred embodiment, the daily dosage of DITPA is administered once daily to a subject in need thereof. More preferably, the daily dosage of DITPA is divided into two parts, each part being administered every 12 hours. Most preferably, the daily dosage of DITPA is divided into three parts, each part being administered every 8 hours.

[0021] In a preferred embodiment, the administration of DITPA is via an oral route.

[0022] In one embodiment, DITPA can be formulated in a composition comprising DITPA or a salt thereof and one or more pharmaceutically acceptable excipients.

[0023] In a preferred embodiment, DITPA or a salt thereof can be present in the pharmaceutical composition of the present subject matter at a concentration of about 0.001% to about 10% w / w or w / v.

[0024] In a preferred embodiment, one or more pharmaceutically acceptable excipients can be present in the pharmaceutical composition of the present disclosure at a concentration of about 90% to about 99.999% w / w or w / v.

[0025] Pharmaceutically acceptable excipients suitable for use in the subject of the present invention include, but are not limited to, disintegrants, binders, fillers, plasticizers, lubricants, penetration enhancers, surfactants, sweeteners, sweetening enhancers, flavoring agents, and pH adjusters.

[0026] As used herein, the term "disintegrant" refers to a pharmaceutically acceptable excipient that promotes the disintegration of a tablet when the tablet comes into contact with water or other liquids. Disintegrants suitable for use in the present technology include, but are not limited to, natural starches such as corn starch and potato starch, directly compressible starches such as starch 1500, modified starches such as carboxymethyl starch, sodium hydroxymethyl starch, and sodium starch glycolate, as well as starch derivatives such as amylose, crosslinked polyvinylpyrrolidones such as crospovidone, crosslinked sodium carboxymethyl cellulose, sodium hydroxymethyl cellulose, calcium hydroxymethyl cellulose, modified celluloses such as croscarmellose sodium and low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, methacrylic acid divinylbenzene copolymer salts, and combinations thereof.

[0027] Binders suitable for use in the present technology include, but are not limited to, polyethylene glycol, soluble hydroxyalkyl cellulose, polyvinylpyrrolidone, gelatin, natural rubber, and combinations thereof.

[0028] Fillers suitable for use in the present technology include, but are not limited to, dibasic calcium phosphate, tribasic calcium phosphate, calcium hydrogen phosphate anhydrous, calcium sulfate and calcium bisulfate, lactose, sucrose, amylose, dextrose, mannitol, inositol, and combinations thereof.

[0029] Plasticizers suitable for use in the present subject include, but are not limited to, microcrystalline cellulose, triethyl citrate, polyhexanediol, acetylated monoglyceride, glyceryl triacetate, castor oil, and combinations thereof.

[0030] Lubricants suitable for use in the present technology include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, micronized polyethylene glycol, talc, anhydrous colloidal silica, and combinations thereof.

[0031] Penetration enhancers suitable for use in the present subject include, but are not limited to, precipitated silica, maltodextrin, β-cyclodextrin, menthol, limonene, carvone, methyl chitosan, polysorbate, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, cetylpyridinium chloride, disodium edetate dihydrate, sodium deoxycholate, sodium deoxyglycolate, sodium glycolate, sodium caprate, sodium taurocholate, sodium hydroxybenzoyl aminocaprylate, dodecyldimethylaminopropionate, L-lysine, glyceryl oleate, glyceryl monostearate, citric acid, peppermint oil, and combinations thereof.

[0032] Surfactants suitable for use in the present subject include, but are not limited to, sorbitan esters, sodium docusate, sodium lauryl sulfate, cetrimide, and combinations thereof.

[0033] Sweeteners suitable for use in the present technology include, but are not limited to, aspartame, saccharin, acesulfame potassium, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, dextrose, mannitol, glycerin, xylitol, and combinations thereof.

[0034] Sweetening agents suitable for use in the present technology include, but are not limited to, the ammonium salt forms of crude and purified glycyrrhizic acid.

[0035] Flavoring agents suitable for use in the present subject include, but are not limited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, tutti frutti flavor, and combinations thereof.

[0036] pH adjusters suitable for use in the present formulation include, but are not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate, sodium acetate, and combinations thereof.

[0037] In another preferred embodiment, the pharmaceutical composition of the present technology does not contain a preservative.

[0038] The pharmaceutical composition of the present technology can be formulated in any dosage form including, but not limited to, a measured aerosol containing powder and spray, chewable bar, bead, coated, film-coated, gel-coated capsule, liquid-filled and coated pellet, cell sheet, chewable gel, concentrate, elixir, emulsion, film containing solubility, film for solution and film for suspension, gel containing measured gel, beadlet, granule containing granule for solution, granule for suspension, chewing gum, inhalant, injection containing foam, liposome, emulsion, lipid complex, powder, lyophilized powder and liposome suspension, liquid, medicinal drop, ointment, patch, electrically controlled patch, pellet, implantable pellet, pill, powder, powder, measured powder, solution, measured solution, solution concentrate, gel-forming solution / solution drop, spray, measured spray, suspension, suspension, syrup, tablet, chewable tablet, coated tablet, coated particle in tablet, film-coated tablet, tablet for solution, tablet for suspension, orally disintegrating tablet, soluble tablet, sugar-coated tablet, dispersible tablet, tablet with sensor, tape, troche and wafer, and their sustained-release and delayed-release forms.

[0039] In a preferred embodiment, the pharmaceutical composition of the present technology is in the form of a tablet. In a more preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a dispersible tablet. In an even more preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a water-dispersible tablet. In the most preferred embodiment, the pharmaceutical composition of the present formulation is in the form of a water-dispersible tablet, and the tablet is scored so that it can be divided into four equal parts.

[0040] In a preferred embodiment, when the pharmaceutical composition of the present technology is in the form of a water-dispersible tablet, the dispersion time of the tablet is about 70 seconds or less, more preferably about 60 seconds or less, even more preferably about 40 seconds or less, even more preferably about 30 seconds or less, even more preferably about 20 seconds or less, even more preferably about 10 seconds or less, and even more preferably about 5 seconds or less.

[0041] As used herein, the term "pharmaceutically acceptable" refers to components that are not biologically or otherwise undesirable in oral applications.

[0042] As used herein, all numerical values regarding amounts, weights, etc. are defined as each specific value "about", i.e., plus or minus 10%. For example, the phrase "10% w / w" should be understood as "9% - 11% w / w". Accordingly, amounts within 10% of the claimed value are included within the scope of the claim.

[0043] As used herein, "% w / w" refers to the weight percentage of the entire formulation.

[0044] As used herein, "% w / v" refers to the weight percentage by volume of the entire formulation.

[0045] As used herein, the term "effective amount" refers to the amount necessary to treat a subject in need of treatment.

[0046] As used herein, the term "treatment" or "treating" refers to alleviating or improving AHDS or the symptoms of AHDS.

[0047] As used herein, the term "stable" includes, but is not limited to, physical and chemical stability.

[0048] Pharmaceutically acceptable salts that can be used in accordance with the present subject matter include, but are not limited to, hydrochloride, hydrochloride dihydrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, mesylate, maleate, gentisinate, fumarate, tannate, sulfate, tosylate, esylate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts.

[0049] Throughout this application, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" include plural references.

[0050] The disclosed embodiments are merely exemplary embodiments of the inventive concepts disclosed herein and should not be regarded as limiting unless expressly stated otherwise in the claims.

[0051] The following examples are intended to illustrate the technology and teach those skilled in the art how to use the formulations of this new technology. These are not intended to be limiting in any way.

Example

[0052] Example 1 - Administration Schedule (Predictive) for Prenatal Subjects Method DITPA was administered to the pregnant mother of a prenatal male subject who had previously been positive in a test for the SLC16A2 allele correlated with Alan Heredon Dudley syndrome, starting at 4 weeks after conception and ending at the subject's delivery, at a daily dose of 1 mg / kg / day in three divided doses at 8-hour intervals.

[0053] Results This dosing plan was successful in reducing the symptoms of AHDS in neonates compared to affected neonates whose mothers did not receive treatment with DITPA.

[0054] Example 2 - Dosing Plan for Prenatal Subjects (Predictive) Method 3,5-Diiodothyropropionic acid ("DITPA") was administered to pediatric patients suffering from Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, for an additional 2 weeks, the daily dose was increased to 2 mg / kg / day. After an additional 2 weeks, the T3 serum level was evaluated. The patient's T3 serum level was found to be 15% lower than normal. Thereafter, the patient was administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, and at that point the T3 serum level was re-evaluated. As a result of the re-evaluation, the T3 serum level was normal.

[0055] Results This dosing plan enables the appropriate dose for pediatric patients to maintain normal T3 serum levels to be successfully identified.

[0056] Example 3 - Dosing Plan for Pediatric Subjects (Predictive) Method DITPA was administered to pediatric patients suffering from Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, for an additional 2 weeks, the daily dose was increased to 2 mg / kg / day. After an additional 2 weeks, the T3 serum level was evaluated. The patient's T3 serum level was found to be 15% higher than normal. Thereafter, the patient was administered DITPA at a daily dose of 2.5 mg / kg / day for 28 days, and at that point the T3 serum level was re-evaluated. As a result of the re-evaluation, the T3 serum level was normal.

[0057] Results This dosing plan enables the appropriate dose for pediatric patients to maintain normal T3 serum levels to be successfully identified.

[0058] Example 4 - Dosage Plan for Pediatric Patients (Predictive) Method DITPA was administered to pediatric patients with Allan-Herndon-Dudley syndrome at a daily dose of 1 mg / kg / day divided into three administrations at 8-hour intervals for 2 weeks. After the first 2 weeks, the daily dose was further increased to 2 mg / kg / day for another 2 weeks. After another 2 weeks, the T3 serum level was evaluated. It was found that the patient's T3 serum level was 15% lower than normal. Subsequently, the patient was administered DITPA at a daily dose of 1.5 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, it was again found that the T3 serum level was 15% lower than normal. Subsequently, the patient was administered DITPA at a daily dose of 1.0 mg / kg / day for 28 days, and the T3 serum level was re-evaluated at that time. As a result of the re-evaluation, it was found that the T3 serum level was normal.

[0059] Results This dosage plan enables the appropriate dosage for pediatric patients to maintain normal T3 serum levels to be successfully identified.

[0060] Example 5 - In Vitro Evidence of the Direct Effect of SRW-101 (DITPA) on the Decrease in T3 Generated from T4: SRW101 (DITPA) that inhibits liver D1 enzyme activity in vitro DITPA reduces the activity of deiodinase 1 in the liver in vivo and in vitro (see Figure 1). Figure 1 reflects the dose-response of DITPA added to the liver in vitro and the measurement of D1 enzyme activity (i.e., the conversion from T4 to T3). This decrease in activity is the main mechanism by which the T3 concentration is decreased and the T4 concentration is increased by reducing the consumption of T4 and the conversion from T4 to T3. This has been shown to occur in humans with MCT8 deficiency.

[0061] These are the results of the normalization of serum T3 levels, which are important endocrine biomarkers and parameters of treatment effects, to measure the expected metabolic changes resulting from the normalization of thyroid tests.

[0062] More specifically, it is expected that by reducing T3, which acts on peripheral tissues to promote metabolism, the ability to improve nutrition and increase body weight will be enhanced.

[0063] Important measurements such as weight gain (age-corrected) and metabolic parameters (cholesterol, creatine kinase, SHBG) are secondary evaluation items.

[0064] Observations with annotations by parents, such as sleep, dietary records, and exercise activities, are very valuable.

[0065] This provided in vitro evidence of the direct effect of DITPA, which reduces T3 generated from T4, rather than reducing T3 by reducing T4 through TSH suppression as in the case of TRIAC. T4 is important for the brain even in the presence of reduced uptake due to MCT8 deficiency.

[0066] Effect of DITPA on removal of gastrostomy tube (G-tube) A certain child who started DITPA while wearing a G-tube gained weight, so the G-tube was removed.

[0067] Additional information The inventors are planning a clinical trial aimed at obtaining confirmatory evidence to support the NDA approval of a single study. The inventors designed the proposed Phase 3 trial to be a strong one with evaluation items aimed at demonstrating the clinical advantages of DITPA compared to surrogate evaluation items.

[0068] The following are the specific evaluation items and related justifications for the planned Phase 3 trial:

Table 1-1

Table 1-2

[0069] The main evaluation items of the present inventors were selected based on the following factors to ensure a high probability of NDA success: · The estimated PTRS to reach the main evaluation item based on the difference in T3 levels at the end of the randomized withdrawal period is such that it has a power of detecting a change of at least 100 ng / dL in serum T3 levels from baseline (start of randomized withdrawal) to week 8 (week 34 of the trial) exceeding 99% compared to placebo. The present inventors know from previous studies (such as LT3 treatment in primary hyperthyroidism) that since LT3 levels increase within a few hours after treatment, the T3 levels of MCT8-deficient patients who discontinued SRW101 should increase rapidly within 8 weeks and there should be sufficient time to return to the high baseline value within a few days. · The main secondary evaluation item is to evaluate the complete total T3, free T4, and TSH response rates at the end of dose escalation and maintenance therapy with SRW-101 in the first single-group, open-label part (week 24) of the study in the mITT population. The main secondary null hypothesis is that the proportion of patients who are total T3, free T4, and TSH complete responders at the visit at week 24 is 0.2 or less. The alternative hypothesis is that the proportion of patients who are total T3, free T4, and TSH complete responders at the visit at week 24 is greater than 0.2. An exact test for one proportion is used. The efficacy of SRW-101 is declared when the proportion of responders at the visit at week 24 is statistically significantly greater than 0.2 at a one-sided alpha level of 0.025. With a sample size of 40 patients aged 0 to 17 years, when using a one-sided exact test for one proportion at the target significance level of 0.025, the power of detecting a difference of 100 ng / dL is almost 100%. For secondary results, assume that the proportion in the null hypothesis population is 0.2 and the alternative hypothesis is 0.80. · The number and percentage (expressed as a percentage) of responders for total T3, free T4, and TSH are calculated at each scheduled time point during the OLDT period and the OLDM period (including the 24th visit). These percentages are summarized for each scheduled time point, along with the exact (Clopper-Pearson) 95% CI. Enrolled patients who lacked thyroid function test evaluation at the 24th week are counted as non-responders for the primary secondary evaluation item. Other secondary evaluation item analyses are specified in the statistical analysis plan (SAP), and then the approximate power is calculated.

[0070] The subject matter of this specification is not limited to the specific embodiments described above, but should be understood to include any embodiments within the scope of the general terms of the following claims enabled by the embodiments described herein, or any embodiments described in terms sufficient for one of ordinary skill in the art to make and use the claimed subject matter.

Claims

1. A method for treating Alan Houghton Dudley syndrome, the method comprising: determining that a prenatal subject requires treatment for Alan Houghton Dudley syndrome; administering 3,5-diiodothyropropionic acid (DITPA) or a salt thereof to the mother of the prenatal subject during pregnancy; and the administration is initiated within 10 weeks after conception of the subject.

2. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 9 weeks after conception.

3. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 8 weeks after conception.

4. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 7 weeks after conception.

5. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 6 weeks after conception.

6. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 5 weeks after conception.

7. The method according to claim 1, wherein the administration to the mother during pregnancy is initiated within 4 weeks after conception.

8. The method according to any one of claims 1 to 7, wherein the administration comprises administering a daily dose to the mother during pregnancy.

9. The method according to claim 8, wherein the daily dose is administered in a single dose once a day.

10. The method according to claim 8, wherein the daily dose is divided into two parts and administered twice a day or every 12 hours.

11. The method according to claim 8, wherein the daily dose is divided into three parts and administered three times a day or every 8 hours.

12. The method according to any one of claims 1 to 11, wherein the administration comprises oral administration.

13. A pharmaceutical composition for treating Alan Houghton Dudley syndrome in a prenatal subject in need thereof, the composition comprising 3,5-diiodothyropropionic acid (DITPA) or a salt thereof.

14. The pharmaceutical composition according to claim 13, wherein the composition is formulated for oral administration.

15. The pharmaceutical composition according to claim 13 or 14, wherein the composition is formulated for daily administration.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein the composition further comprises one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition according to any one of claims 13 to 16, wherein the DITPA or a salt thereof is present at a concentration of about 0.001% to about 10% w / w or w / v. **Claim 18** The pharmaceutical composition according to claim 16 or 17, wherein the one or more pharmaceutically acceptable excipients are present at a concentration of about 90% to about 99.999% w / w or w / v. **Claim 19** The pharmaceutical composition according to any one of claims 16 to 18, wherein the one or more pharmaceutically acceptable excipients include at least one of a disintegrant, a binder, a filler, a plasticizer, a lubricant, a penetration enhancer, a surfactant, a sweetener, a sweetener enhancer, a flavoring agent, and a pH adjuster.

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