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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a medical research study to test a medication in patients 10 years of age and older with a disease called medium-chain acyl-CoA dehydrogenase deficiency (MCADD) caused by the common ACADM c.985 A\>G (K304E) mutation. The medication is sodium phenylbutyrate (ACER-001), which is currently FDA approved for the treatment of Urea Cyle Disorders. Previous research suggests that sodium phenylbutyrate may also be effective in the treatment MCADD. This study will investigate the safety and efficacy (how well it works) of sodium phenylbutyrate in patients with MCADD.

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.

What data supports the effectiveness of the drug sodium phenylbutyrate for MCADD?

Sodium phenylbutyrate is used to treat urea cycle disorders by helping the body get rid of excess nitrogen, and it has shown effectiveness in managing metabolic issues in conditions like maple syrup urine disease. While not directly studied for MCADD, its role in managing similar metabolic disorders suggests potential benefits. ^{1 2 3 4 5}

Is sodium phenylbutyrate safe for human use?

Sodium phenylbutyrate has been used safely in humans for conditions like urea cycle disorders, with studies showing it helps manage waste nitrogen in the body. However, it can cause some side effects, especially in younger patients, due to higher exposure to a byproduct called phenylacetic acid. ^{1 2 4 6 7}

How is the drug sodium phenylbutyrate unique for treating MCADD?

Sodium phenylbutyrate (NaPBA) is unique because it is a nitrogen-scavenging agent that provides an alternative pathway for nitrogen disposal, which is not a standard treatment approach for MCADD. Additionally, the ACER-001 formulation of NaPBA is designed to mask its unpleasant taste, potentially improving patient compliance. ^{1 2 4 6 8}

Research Team

Gerard Vockley, MD, PhD

Principal Investigator

UPMC Children's Hospital of Pittsburgh

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Developing a new formulation of sodium phenylbutyrate. [2012]

2. England 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. [2022]

3. United States 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. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Impact of sodium phenylbutyrate treatment in acute management of maple syrup urine disease attacks: a single-center experience. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Study of Antitumor Activity of Sodium Phenylbutyrate, Histon Deacetylase Inhibitor, on Ehrlich Carcinoma Model. [2016]