A phase 2/3 study to evaluate efficacy and clinical benefit of AT-007 with Sorbitol Dehydrogenase (SORD) Deficiency

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Applied Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

20 Oct 2022 → 4 May 2026

Decision date (initial)

2025-01-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-518250-16-00

EudraCT number

2022-000491-18

ClinicalTrials.gov

NCT05397665

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Safety, Efficacy

Clinical Outcome Objective:
• To evaluate the effect of long-term (24 months) administration of AT-007 on the 10 m walk/run test (10MWRT) in patients with SORD Deficiency 16 to 55 years of age

Pharmacodynamic/Biomarker Objective:
• To evaluate the effect of long-term (12 months) administration of AT-007 on the levels of blood sorbitol in patients with SORD Deficiency

Secondary objectives 11

1. To evaluate the effect of long-term (12 months) administration of AT-007 on the 10MWRT in patients with SORD Deficiency
2. To evaluate the effect of long-term (12 months) administration of AT 007 on the Charcot Marie Tooth Functional Outcome Measure (CMT-FOM) total and subdomain scores in patients with SORD Deficiency
3. To evaluate the effect of long-term (12 months) administration of AT-007 on the Charcot Marie Tooth Health Index (CMTHI) score in patients with SORD Deficiency
4. To evaluate the effect of long-term (24 months) administration of AT-007 on the CMTHI score in patients with SORD Deficiency
5. To evaluate the effect of long-term (24 months) administration of AT 007 on the CMT-FOM total and subdomain scores in patients with SORD Deficiency
6. To assess the patients’ perspective on the impact of disease on their lives and the benefit or perceived harm during the study with an “exit interview”
7. To evaluate the safety of long-term administration of AT 007 in patients with SORD Deficiency
8. To evaluate the pharmacokinetic (PK) parameters of AT-007 in patients with SORD Deficiency
9. To evaluate the effect of long-term (12 months) administration of AT-007 on the percentage of fat in lower extremity muscle as assessed by magnetic resonance imaging (MRI) in patients with SORD Deficiency
10. To evaluate the effect of long-term administration (24 months only if Month 12 between-group difference [AT-007 minus placebo] is not statistically significant) of AT-007 on the percentage of fat in lower extremity muscle as assessed by MRI in patients with SORD Deficiency
11. To evaluate the correlation of changes in blood sorbitol with all clinical outcomes

Conditions and MedDRA coding

Sorbitol Dehydrogenase (SORD) Deficiency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures.
2. Male and non-pregnant, non-lactating female patients between the ages of 16 and 55 years, inclusive.
3. Females must be of non-childbearing potential (defined as surgically sterile [i.e., had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy ≥6 months prior to the first dose of study drug] or postmenopausal for ≥1 year [confirmatory follicle stimulating hormone or FSH test results required] prior to the first dose of study drug) or agree to use a highly effective form of birth control from Screening until 30 days after the last dose of study drug.
4. Males must be unable to procreate (defined as surgically sterile [i.e., had a vasectomy ≥6 months prior to Screening]) or must agree to use a highly effective form of birth control from Screening through 105 days (sum of 5 half-lives and 90 days interval as per CTFG guidelines) after the last dose of study drug.
5. Clinical diagnosis of CMT2 or dHMN due to SORD Deficiency confirmed by medical record or written communication by health care professional, elevated sorbitol level (>10,000 ng/mL), and gene analysis report indicating a biallelic mutation in SORD.
6. Patient may be on concomitant medications and dietary supplements; however, they must be on stable doses for at least 1 month prior to Screening and throughout the study. In addition, all over-the-counter (OTC) and/or prescription medications must be reviewed and approved by the Investigator.
7. Willing and able to be confined to the clinical research unit (CRU) as required by the protocol.

Exclusion criteria 33

1. 10MWRT classified as very severe disease (e.g. 10MWRT >15 seconds to complete OR unable to complete 10MWRT without the use of an assistive device such as a cane/walker/wheelchair).
2. History or presence of clinically significant hematopoietic, renal, hepatic, endocrine (e.g. diabetes), metabolic, pulmonary, neurological (e.g. other neuropathy, myopathy or neuromuscular disorder), psychiatric, cardiovascular, immunological, dermatological, or gastrointestinal diseases that are - a priori - altering the proper evaluation of the safety and efficacy of AT-007; conditions capable of altering the absorption, metabolism, or elimination of drugs; or conditions that constitute a risk factor when taking the study drug and/or impact the conduct or results of the study.
3. Body Mass Index (BMI) >35 kg/m2.
4. Clinically relevant underweight, weight loss suggestive of a pathology unrelated to SORD deficiency, or BMI < 17.5 kg/m2.
5. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at Screening or previous treatment for hepatitis B, hepatitis C, or HIV infection.
6. Individuals who smoke or use tobacco or nicotine-containing products.
7. Pregnant, lactating, or not using/not willing to use appropriate means of contraception.
8. Any prior history of substance abuse (including alcohol) or treatment for such.
9. Positive urine drug screen (UDS) for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates) or cotinine.
10. Non-ambulatory disability.
11. Prior bilateral ankle stabilization surgery.
12. Impaired renal function or estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2. Note: The eGFR is an estimation of renal function, and the ultimate decision of whether a patient has normal renal function (and can be included in the study) is at the discretion of the Investigator, assuming there are no safety concerns. Also, because eGFR can vary from day to day based on outside factors, patients can be re screened for eGFR multiple times to understand the renal function of the patient.
13. Hemoglobin (Hgb) < 10.0 g/dL at Screening.
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin (except in case of Gilbert’s syndrome) > 1.5 x upper limit of normal (ULN) at Screening.
15. Urinary albumin-to-creatinine ratio (UACR) > 30 mg/g at Screening in the presence of elevated creatinine (>2X ULN).
16. History or presence of cardiovascular disorders including myocardial infarction, stroke, uncontrolled hypertension (sitting blood pressure ≥140/90 mmHg), left ventricular (LV) hypertrophy, atrial fibrillation, or valvular heart disease considered clinically significant by the Principal Investigator (PI) and/or Sponsor medical representative.
17. Abnormal findings on the Screening 12-lead ECG, such as ST/T wave changes, pathological Q wave changes, or any rhythm other than normal sinus rhythm considered clinically significant by the PI and/or Sponsor medical representative.
18. Evidence of significant active hematological disease and/or cumulative blood donation of 1 unit (500 mL) or more including blood drawn during clinical studies in the last 3 months.
19. History of significant drug allergy or drug hypersensitivity.
20. Investigators, site personnel directly affiliated with this study, and their immediate families (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
21. Any other condition that, in the opinion of the Investigator, precludes the patient from following and completing the protocol.
22. A clinically significant abnormal finding on the physical exam/visual health assessment, medical history, ECG, or clinical laboratory results at Screening.
23. A significantly abnormal diet (per Investigator judgment) during the 4 weeks preceding the first dose of study drug.
24. Participation in another clinical study of a different investigational product within 30 days prior to the first dose of study drug.
25. Use of any OTC medication (including nutritional or dietary supplements, herbal preparations, or vitamins) ≤7 days prior to the first dose of study drug until the last dose of study drug without evaluation and approval by the Investigator.
26. Use of any prescription medication, except those allowed per protocol (Section 5.2.2), from 30 days prior to the first dose of study drug until the last dose of study drug without evaluation and approval by the Investigator.
27. Treatment with any sensitive substrates of Breast Cancer Resistance Protein (BCRP) or potent inhibitors of BCRP. This includes, but is not limited to the following: BCRP substrates: rosuvastatin, sulfasalazine; BCRP inhibitor: cyclosporine A. For additional information, consult the US Food and Drug Administration (FDA) Drug-drug Interaction (DDI) website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Upon review/approval by the PI, a wash-out period of 7 days may be allowed if the medication’s half-life is < 12 hours.
28. Treatment with sensitive substrates of cytochrome P450 3A4 (CYP3A4), CYP2B6, CYP2C19, or CYP1A2. This includes, but is not limited to the following: midazolam, triazolam, buspirone, alfentanil, dronedarone, eletriptan, conivaptan, lovastatin, simvastatin, bupropion, omeprazole, alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, tizanidine. For additional information, consult the FDA DDI website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Upon review/approval by the PI, a wash-out period of 7 days may be allowed if the medication half-life is < 12 hours.
29. Treatment with any substrates of organic anion transporter (OAT) 3 (OAT3) or inhibitors of OAT1 or OAT3. This includes, but is not limited to the following: OAT3 substrates: adefovir, cefaclor, ceftizoxime, famotidine, furosemide, ganciclovir, oseltamivir carboxylate, penicillin G; and OAT inhibitor: probenecid. For additional information, consult the FDA DDI website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Upon review/approval by the PI, a wash-out period of 7 days may be allowed if the medication’s half-life is < 12 hours.
30. Treatment with any inhibitors of organic anion transporting polypeptide B1 or B3 (OATP1B1 or OATP1B3). This includes, but is not limited to the following: clarithromycin, erythromycin, gemfibrozil, rifampin, simeprevir. For additional information, consult the FDA DDI website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Upon review/approval by the PI, a wash-out period of 7 days may be allowed if the medication’s half-life is < 12 hours.
31. Treatment with drugs potentially associated with transaminase elevations, such as mirtazapine.
32. Treatment with potentially nephrotoxic drugs (e.g., amitriptyline, aspirin, doxepin, lithium, amphotericin B, foscarnet, ganciclovir, pentamidine, rifampin, antiretrovirals [e.g., adefovir, tenofovir], calcineurin inhibitors [e.g., cyclosporine, tacrolimus], angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, clopidogrel, ticlopidine, pamidronate, zoledronate, statins, chemotherapeutics, contrast dye, loop diuretics, thiazides, triamterene, allopurinol, gold therapy, haloperidol, quinine, ranitidine).
33. Consumption of beverages or foods that contain alcohol, high levels of sorbitol, grapefruit, poppy seeds, broccoli, brussels sprouts, pomegranate, star fruit, char-grilled meat, or caffeine/xanthine from 48 hours prior to the first dose of study drug through the last dose of study drug. Patients will be instructed not to consume any of the above products; however, allowance for sporadic consumption may be evaluated and approved by the Investigator based on the potential for interaction with the study drug. Not more than half cup of coffee per day should be consumed.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from baseline to Month 12 in the level of blood sorbitol
2. Change from baseline to Month 24 on the 10MWRT

Secondary endpoints 10

1. Change from baseline to Month 12 on the 10MWRT
2. Change from baseline to Month 12 on CMT-FOM total and subdomain scores
3. Change from baseline to Month 12 on CMTHI score
4. Correlation between change in sorbitol and changes in all clinical outcomes
5. Change from baseline to Month 12 in the percentage of fat in lower extremity muscle as assessed by MRI
6. Change from baseline to Month 24 on CMTHI score
7. Change from baseline to Month 24 on the CMT-FOM total and subdomain scores
8. Change from baseline to Month 24 in the level of blood sorbitol and correlation with all clinical outcomes
9. Change from baseline to Month 24 in the percentage of fat in lower extremity muscle as assessed by MRI (only if Month 12 between-group difference [AT-007 minus placebo] is not statistically significant)
10. Assessment of the patients’ perspective on the impact of disease on their lives and the benefit or perceived harm during the study with an “exit interview”

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Applied Therapeutics Inc.

Sponsor organisation

Applied Therapeutics Inc.

Address

545 5th Avenue

City

New York

Postcode

10017-3609

Country

United States

Scientific contact point

Organisation

Applied Therapeutics Inc.

Contact name

Management

Public contact point

Organisation

Applied Therapeutics Inc.

Contact name

Management

Third parties 9

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications