Sodium Phenylbutyrate for MCADD

Overseen By Elizabeth McCracken, MS, CGC

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Jerry Vockley, MD, PhD

Must not be taking: Probenecid, Corticosteroids, Valproic acid, others

Disqualifiers: Active infection, Renal insufficiency, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 5 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of sodium phenylbutyrate, a medication already used for certain metabolic disorders, in individuals with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). MCADD is a genetic condition that affects fat metabolism, and the trial will assess the treatment's safety and effectiveness. Participants will be divided into groups to receive different doses of the medication to determine the most effective dose. Suitable candidates have MCADD with a specific genetic mutation (c.985A>G) and can participate in study activities like blood tests. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as those affecting kidney function, increasing protein breakdown, or raising ammonia levels, within 48 hours before starting and throughout the study. Additionally, sodium benzoate must be stopped one week before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the FDA has approved sodium phenylbutyrate for treating Urea Cycle Disorders, indicating its safety for individuals with these conditions. In past studies, most patients tolerated sodium phenylbutyrate well.

While specific studies on sodium phenylbutyrate for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) are ongoing, its approval for other conditions suggests general safety. However, this trial is in the early stages, and researchers are still gathering detailed safety information for individuals with MCADD.

As with any medication, participants might experience side effects. Consulting healthcare providers about potential risks is advisable before deciding to join a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about sodium phenylbutyrate for MCADD (Medium-Chain Acyl-CoA Dehydrogenase Deficiency) because it offers a novel approach by potentially modifying metabolism, which differs from the typical dietary management and carnitine supplements currently in use. MCADD is usually managed by avoiding fasting and maintaining a low-fat, high-carbohydrate diet, but sodium phenylbutyrate might enhance the body's ability to handle metabolic stress by acting on different metabolic pathways. This treatment introduces an innovative method by using a drug with a unique mechanism, potentially providing new hope for better management of MCADD symptoms and complications.

What evidence suggests that sodium phenylbutyrate might be an effective treatment for MCADD?

Research has shown that sodium phenylbutyrate treats Urea Cycle Disorders by helping the body eliminate excess ammonia. This has led to its investigation for medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a condition affecting energy production. In this trial, participants will receive varying dosages of sodium phenylbutyrate to assess its potential in managing MCADD by providing an alternative energy processing method. Although approved for other conditions, its use for MCADD remains under study. Early research suggests potential benefits, but further studies are necessary to confirm its effectiveness for this condition. ^{1 2 3 6 7}

Who Is on the Research Team?

Gerard Vockley, MD, PhD

Principal Investigator

UPMC Children's Hospital of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for people aged 10 and older with MCADD, a genetic disorder affecting fat metabolism. Participants must have the ACADM c.985 A>G mutation, be able to undergo study procedures like IV placement, and use contraception if of childbearing age. Those under certain medications or with conditions that increase risk are excluded.

Inclusion Criteria

I have MCADD with at least one common mutation confirmed.

I am 16 years or older for cohort 1, or between 10-15 years for cohort 2.

I can stay overnight for the study, have an IV placed, and get blood drawn.

Exclusion Criteria

I do not have any active infections or other ongoing health issues.

I do not have severe health issues or very high liver enzyme levels.

My kidney function is normal, with an eGFR of 60 mL/min/1.73m2 or higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive sodium phenylbutyrate with two overnight admissions and fasting procedures

5 weeks

2 overnight visits, 1 outpatient visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 outpatient visit

What Are the Treatments Tested in This Trial?

Interventions

• Sodium Phenylbutyrate

Trial Overview

The study tests Sodium Phenylbutyrate (ACER-001), an FDA-approved drug for Urea Cycle Disorders, now being investigated for treating MCADD in patients with a specific genetic mutation. The focus is on its safety and effectiveness in this new application.

How Is the Trial Designed?

Group I: 4.0 g/m2/day BID sodium phenylbutyrate Experimental Treatment 1 Intervention

Up to 8 subjects (4 - ages 10-15 years old and 4 - 16 years of age and older) will be randomized to take 4.0 g/m2/day divided into two daily doses taken 12 hours apart

Group II: 3.0 g/m2/day QD sodium phenylbutyrate Experimental Treatment 1 Intervention

Up to 8 subjects (4 - ages 10-15 years old and 4 - 16 years of age and older) will be randomized to take 3.0 g/m2/day in one daily dose

Group III: 3.0 g/m2/day BID sodium phenylbutyrate Experimental Treatment 1 Intervention

Up to 8 subjects (4 - ages 10-15 years old and 4 - 16 years of age and older) will be randomized to take 3.0 g/m2/day divided into two daily doses taken 12 hours apart

Sodium Phenylbutyrate is already approved in United States for the following indications:

Approved in United States as ACER-001 for:

• Urea Cycle Disorders

Who Is Running the Clinical Trial?

Jerry Vockley, MD, PhD

Lead Sponsor

Trials

6

Recruited

460+

Acer Therapeutics Inc.

Industry Sponsor

Trials

3

Recruited

220+

Published Research Related to This Trial

Phenylbutyrate (PB) and its metabolite phenylacetate (PA) show good penetration into cerebrospinal fluid (CSF) after intravenous administration, suggesting potential effectiveness in treating central nervous system tumors.

The study indicates that administering PB may provide greater exposure to both PB and PA compared to PA alone, which could enhance their anticancer effects in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. Berg, S., Serabe, B., Aleksic, A., et al.[2019]

Sodium phenylbutyrate demonstrated significant antitumor activity in a study involving 120 female mice with Ehrlich ascites carcinoma, particularly at a dose of 800 mg/kg, where it inhibited tumor growth by 71%.

The treatment not only effectively reduced tumor size but also prolonged the lifespan of the mice by 28 days, indicating its potential as a low-toxicity cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of Antitumor Activity of Sodium Phenylbutyrate, Histon Deacetylase Inhibitor, on Ehrlich Carcinoma Model. Fadeev, NP., Kharisov, RI., Kovan'ko, EG., et al.[2016]

ACER-001, a new formulation of sodium phenylbutyrate, has been shown to be bioequivalent to the traditional NaPBA powder in four Phase 1 studies, indicating it can effectively serve as a treatment for urea cycle disorders (UCDs).

The formulation is designed to mask the unpleasant taste of NaPBA and demonstrated lower systemic exposure to potentially harmful metabolites when taken in a fasting state, suggesting it may reduce adverse effects while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders. Cederbaum, SD., Edwards, J., Kellmeyer, T., et al.[2023]

The combination of 5-azacytidine (5-AC) and sodium phenylbutyrate was generally safe and well tolerated in a phase I trial involving 27 patients with advanced solid tumors, with minor toxicities primarily related to bone marrow suppression.

Despite the safety of the treatment, the clinical response was disappointing, with only one patient achieving stable disease for 5 months, while the majority experienced progressive disease, indicating a lack of significant therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Lin, J., Gilbert, J., Rudek, MA., et al.[2021]

In a randomized trial involving 137 participants with ALS, the combination of sodium phenylbutyrate and taurursodiol slowed the decline in functional ability compared to placebo, with a significant difference in the ALS Functional Rating Scale score over 24 weeks.

While the primary outcome showed a beneficial effect, secondary outcomes did not differ significantly between the treatment and placebo groups, and the main side effects of the treatment were gastrointestinal in nature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. Paganoni, S., Macklin, EA., Hendrix, S., et al.[2022]

Sodium phenylbutyrate and glycerol phenylbutyrate effectively help patients with urea cycle disorders excrete waste nitrogen as urinary phenylacetylglutamine, with sodium phenylbutyrate already approved for treatment.

A population pharmacokinetic model developed from data of four Phase II/III trials (involving patients aged 2 months to 72 years) revealed that both drugs have similar systemic effects, but glycerol phenylbutyrate has slower absorption and greater presystemic conversion, which may influence dosing strategies, especially in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders. Monteleone, JP., Mokhtarani, M., Diaz, GA., et al.[2022]

The new taste-masked formulation of sodium phenylbutyrate (Luc 01) significantly improves acceptability compared to the licensed granules, as it masks the bitter taste and is preferred by healthy volunteers, which is crucial for patient compliance.

Luc 01 is bioequivalent to the licensed product, showing no significant differences in pharmacokinetics, meaning it delivers the same therapeutic effect while being easier to tolerate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing a new formulation of sodium phenylbutyrate. Guffon, N., Kibleur, Y., Copalu, W., et al.[2012]

Sodium phenylbutyrate (NaPBA) effectively reduced plasma leucine levels in patients experiencing acute attacks of maple syrup urine disease (MSUD), with a mean reduction rate of approximately 530 µmoL/L/day within the first 24 hours of treatment.

In a study involving 10 patients and 19 episodes of MSUD attacks, NaPBA treatment improved clinical and biochemical outcomes without the need for extracorporeal toxin removal, making it a viable option for smaller medical centers and patients with hemodynamic instability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience. Zubarioglu, T., Dede, E., Cigdem, H., et al.[2021]

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Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2020;129:13-9. [PubMed: 31836396].

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This study will investigate the safety and efficacy (how well it works) of sodium phenylbutyrate in patients with MCADD. Detailed Description. Participation in ...

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Study of Sodium Phenylbutyrate (ACER-001) for the Treatment of Pediatric and Adults Patients With Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD).