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

Phase 2/3

Active, not recruiting

Conditions: Sorbitol Dehydrogenase (SORD) Deficiency

Registration Number: 2024-518250-16-00

Lead Sponsor: Applied Therapeutics Inc.

Brief Summary: 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

Detailed Description: This international, multi-center, randomized, double-blinded, placebo-controlled, phase 2-3 study is designed to assess the pharmacodynamic (PD) efficacy and clinical benefit of long term administration of AT 007 versus placebo in male and non-pregnant female subjects with genetically confirmed SORD Deficiency aged 18-55 and able to ambulate with a 10MWRT time of \<10 seconds.

The study will be conducted at up to 12 sites worldwide. Genetically confirmed SORD Deficiency patients with blood sorbitol levels \>10,000 ng/ml will be screened and randomized in a 2:1 ratio to receive either AT-007 daily or a matching placebo for 24 months. A total of up to 72 subjects will be enrolled.

The primary clinical outcome measure, 10-meter walk-run test (10MWRT), will be assessed at 24 months and compared to baseline.

Recruitment & Eligibility

Status: Ongoing, recruitment ended

Sex: Not specified

Target Recruitment: 45

Inclusion Criteria

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.

Male and non-pregnant, non-lactating female patients between the ages of 16 and 55 years, inclusive.

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 an acceptable form of birth control from Screening until 30 days after the last dose of study drug.

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 an acceptable form of birth control from Screening through 30 days after the last dose of study drug.

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.

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.

Willing and able to be confined to the clinical research unit (CRU) as required by the protocol.

Exclusion Criteria

10MWRT classified as severe disease, as described in the operating manual (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).

Non-ambulatory disability.

Prior bilateral ankle stabilization surgery.

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.

Hemoglobin (Hgb) < 10.0 g/dL at Screening.

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.

Urinary albumin-to-creatinine ratio (UACR) > 30 mg/g at Screening in the presence of elevated creatinine (>2X ULN).

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.

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.

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.

History of significant drug allergy or drug hypersensitivity.

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.

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).

Any other condition that, in the opinion of the Investigator, precludes the patient from following and completing the protocol.

A clinically significant abnormal finding on the physical exam/visual health assessment, medical history, ECG, or clinical laboratory results at Screening.

A significantly abnormal diet (per Investigator judgment) during the 4 weeks preceding the first dose of study drug.

Participation in another clinical study of a different investigational product within 30 days prior to the first dose of study drug.

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.

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.

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.

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.

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.

Body Mass Index (BMI) >35 kg/m2.

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.

Treatment with drugs potentially associated with transaminase elevations, such as mirtazapine.

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).

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.

Clinically relevant underweight, weight loss suggestive of a pathology unrelated to SORD deficiency, or BMI < 17.5 kg/m2.

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.

Individuals who smoke or use tobacco or nicotine-containing products.

Pregnant, lactating, or not using/not willing to use appropriate means of contraception.

Any prior history of substance abuse (including alcohol) or treatment for such.

Positive urine drug screen (UDS) for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates) or cotinine.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change from baseline to Month 12 in the level of blood sorbitol		Change from baseline to Month 12 in the level of blood sorbitol
Change from baseline to Month 24 on the 10MWRT		Change from baseline to Month 24 on the 10MWRT

Secondary Outcome Measures

Name	Time	Method
Change from baseline to Month 12 in the percentage of fat in lower extremity muscle as assessed by MRI		Change from baseline to Month 12 in the percentage of fat in lower extremity muscle as assessed by MRI
Change from baseline to Month 24 on CMTHI score		Change from baseline to Month 24 on CMTHI score
Change from baseline to Month 24 on the CMT-FOM total and subdomain scores		Change from baseline to Month 24 on the CMT-FOM total and subdomain scores
Change from baseline to Month 12 on the 10MWRT		Change from baseline to Month 12 on the 10MWRT
Change from baseline to Month 12 on CMT-FOM total and subdomain scores		Change from baseline to Month 12 on CMT-FOM total and subdomain scores
Change from baseline to Month 12 on CMTHI score		Change from baseline to Month 12 on CMTHI score
Correlation between change in sorbitol and changes in all clinical outcomes		Correlation between change in sorbitol and changes in all clinical outcomes
Change from baseline to Month 24 in the level of blood sorbitol and correlation with all clinical outcomes		Change from baseline to Month 24 in the level of blood sorbitol and correlation with all clinical outcomes
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)		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)
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”		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”

Trial Locations

Locations (2): Axon Clinical s.r.o.
🇨🇿
Prague 5, Czechia
IRCCS Foundation Istituto Neurologico Carlo Besta
🇮🇹
Milan, Italy
Axon Clinical s.r.o.
🇨🇿Prague 5, Czechia
Pavel Seeman
Site contact
+420224436789
pavel.seeman@lfmotol.cuni.cz