Gene Therapy for Phenylketonuria

Not currently recruiting at 3 trial locations

Overseen By Trial Specialist

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BioMarin Pharmaceutical

Disqualifiers: Bh4 deficiency, Liver dysfunction, Malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Single administration

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of a new gene therapy, BMN 307, for individuals with phenylketonuria (PKU). PKU is a condition where the body cannot break down a specific amino acid due to a PAH deficiency, leading to harmful build-ups. Participants will receive one dose of BMN 307 and undergo close monitoring. The study seeks adults with PKU who can maintain their current protein diet and have high phenylalanine levels in their blood. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new gene therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you must avoid substances that can harm the liver after receiving the treatment.

Is there any evidence suggesting that BMN 307 is likely to be safe for humans?

Research has shown that BMN 307, a gene therapy for phenylketonuria (PKU), raises some safety concerns. Earlier studies found that BMN 307 was generally well tolerated, with the most common side effect being a temporary increase in liver enzymes, indicating possible liver irritation. However, the FDA paused the trial due to potential safety issues found in lab animals, specifically involving liver tumors. As a result, the treatment's safety remains under close examination. Prospective participants should carefully weigh both the potential benefits and risks when considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PKU?

Unlike the standard treatments for phenylketonuria (PKU), which typically involve a strict diet low in phenylalanine combined with medications like sapropterin or pegvaliase, BMN 307 offers a novel approach through gene therapy. This therapy aims to address the root cause of PKU by delivering a correct copy of the PAH gene directly to the liver, potentially enabling the body to naturally break down phenylalanine. Researchers are excited about BMN 307 because it could provide a long-term solution with fewer dietary restrictions, significantly improving quality of life for those with PKU.

What evidence suggests that BMN 307 might be an effective treatment for PKU?

Research shows that BMN 307 is a promising gene therapy for treating phenylketonuria (PKU). This treatment uses a special virus to deliver a healthy version of the gene that helps break down phenylalanine, an amino acid that builds up in people with PKU. Studies have shown that BMN 307 could potentially restore the body's natural ability to process phenylalanine, leading to lower levels in the blood. While early data mainly focuses on safety, signs indicate that this therapy might help manage PKU effectively. Some reports suggest that just one dose might be enough to see changes in phenylalanine levels. Overall, BMN 307 is being closely watched as a new way to address PKU by fixing the genetic problem at its source. Participants in this trial will receive one of three different doses of BMN 307 to evaluate its effectiveness and safety. ^{6 7 8 9 10}

Who Is on the Research Team?

Medical Director, MD

Principal Investigator

BioMarin Pharmaceutical

Are You a Good Fit for This Trial?

This trial is for adults with Phenylketonuria (PKU), a condition where the body can't break down an amino acid called phenylalanine due to PAH deficiency. Participants must have high levels of phenylalanine in their blood and be willing to maintain their current diet, avoid liver-damaging substances, use contraception, and follow study rules.

Inclusion Criteria

Ability and willingness to maintain dietary protein intake consistent with baseline intake

I am willing and able to follow the study's procedures and requirements.

I am willing to avoid liver-damaging substances after treatment.

Exclusion Criteria

I have previously undergone gene therapy.

Any condition that, in the opinion of the investigator or Sponsor, would prevent the subject from fully complying with the requirements of the study

I have had cancer before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single administration of BMN 307

Single administration

Follow-up

Participants are monitored for safety and efficacy after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• BMN 307

Trial Overview The trial tests BMN 307, a gene therapy intended to correct the genetic defect causing PKU. It's given once to see if it's safe and effective at lowering phenylalanine levels. The study gradually increases doses among participants who are closely monitored over time.

How Is the Trial Designed?

Group I: Dose 3 of BMN 307 Experimental Treatment 1 Intervention

Group II: Dose 2 of BMN 307 Experimental Treatment 1 Intervention

Group III: Dose 1 of BMN 307 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

BioMarin Pharmaceutical

Lead Sponsor

Trials

162

Recruited

115,000+

Alexander Hardy

BioMarin Pharmaceutical

Chief Executive Officer since 2023

MBA from INSEAD

Greg Friberg

BioMarin Pharmaceutical

Chief Medical Officer

MD from New York Medical College

Published Research Related to This Trial

The study demonstrated that using a synthetic AAV vector (Anc80) to deliver a functional copy of the PAH gene in a mouse model of PKU resulted in a significant and lasting reduction of phenylalanine levels, indicating effective restoration of metabolic function.

Administration of the AAV vector was safe, with no serious adverse effects observed even at the highest tested dose, and only minor, transient changes in liver enzymes, suggesting a promising approach for gene therapy in PKU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model. Kaiser, RA., Weber, ND., Trigueros-Motos, L., et al.[2022]

In female PKU mice, the administration of mPAH cDNA using a phiBT1 bacteriophage integration system completely corrected the hyperphenylalaninemic and hypopigmentation phenotypes after 10 weekly treatments, demonstrating the efficacy of this gene therapy approach.

The study found no liver pathology in the mice even after multiple administrations, indicating that this method is safe for repeated use in gene therapy for metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. Chen, L., Woo, SL.[2017]

Gene therapy using adeno-associated viruses (AAVs) to deliver the phenylalanine hydroxylase (PAH) enzyme has shown effective and sustained clearance of phenylalanine (Phe) in mice for over a year, indicating a potential long-term treatment for phenylketonuria (PKU).

Combining PAH gene therapy with supplementation or gene therapy for tetrahydrobiopterin (BH(4)) in skeletal muscle resulted in significant and lasting reductions in blood Phe levels, suggesting a dual approach could be a viable alternative to the strict dietary restrictions currently required for PKU patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. Thöny, B.[2021]

Infusing a recombinant adenoviral vector that expresses the human PAH gene into the portal circulation of PAH-deficient mice can restore 10-80% of normal liver PAH activity and normalize serum phenylalanine levels, indicating a promising approach for treating classical phenylketonuria (PKU).

While the effects of this gene therapy are currently temporary and re-administration does not enhance the outcome, the results suggest that with the development of more persistent gene delivery systems, PKU could potentially be fully corrected through somatic gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for phenylketonuria. Eisensmith, RC., Woo, SL.[2019]

Long-term enzyme substitution therapy in adults with phenylketonuria (PKU) has shown unexpected improvements in neuropsychiatric outcomes, suggesting a potential shift in treatment perspectives for this condition.

Various gene therapy approaches, including rAAV vectors and genome editing, have successfully targeted the liver in mouse models of PKU, indicating promising avenues for future human gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Grisch-Chan, HM., Schwank, G., Harding, CO., et al.[2023]

AAV8-PAL gene therapy effectively corrected high phenylalanine levels in both male and female PKU mice, demonstrating long-term efficacy after a single intravenous treatment.

The therapy showed no significant liver injury, indicating a safe approach for potential treatment of phenylketonuria (PKU) in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase. Tao, R., Xiao, L., Zhou, L., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04480567

AAV Gene Therapy Study for Subjects with PKU This is a Phase 1/2, open-label, dose escalation study to evaluate the safety, efficacy and tolerability of BMN 307 in adult PKU subjects with PAH deficiency.

2. medical.biomarin.com medical.biomarin.com/en-us/wp-content/uploads/sites/2/2023/06/ACMG-2021-Phenom-Interim-Data-Final.pdf?v=1.1

Phenom - BioMarin Medical Prospective clinical study on the clinical impact of phenylketonuria in adolescents and adults: Phenom study design. Presented at the ACMG Annual Clinical ...

3. prnewswire.com prnewswire.com/news-releases/us-fda-placed-a-clinical-hold-on-bmn-307-phearless-phase-12-gene-therapy-study-in-adults-with-pku-based-on-interim-pre-clinical-study-findings-301369619.html

U.S. FDA Placed a Clinical Hold on BMN 307 Phearless ... The Phearless study is evaluating BMN 307, an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy, in adults with phenylketonuria (PKU).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12428815/

Advancing Gene Therapy for Phenylketonuria ... PKU, and the primary outcomes studied are safety and reduction in plasma Phe. For the most part, data have suggested BMN 307 is generally ...

5. biomarin.com biomarin.com/news/press-releases/biomarin-pioneer-in-phenylketonuria-pku-and-gene-therapy-receives-fda-fast-track-designation-for-pku-investigational-gene-therapy-bmn-307/

BioMarin, Pioneer in Phenylketonuria (PKU) and Gene ... BMN 307 will be evaluated to determine safety and whether a single dose of treatment can restore natural Phe metabolism, increase plasma Phe levels, and enable ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04480567

AAV Gene Therapy Study for Subjects with PKU This is a Phase 1/2, open-label, dose escalation study to evaluate the safety, efficacy and tolerability of BMN 307 in adult PKU subjects with PAH deficiency.

7. biomarin.com biomarin.com/news/press-releases/u-s-fda-placed-a-clinical-hold-on-bmn-307-phearless-phase-1-2-gene-therapy-study-in-adults-with-pku-based-on-interim-pre-clinical-study-findings/

U.S. FDA Placed a Clinical Hold on BMN 307 Phearless ... The Phearless study is evaluating BMN 307, an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy, in adults with phenylketonuria (PKU).

8. patientworthy.com patientworthy.com/2021/09/28/bmn-307-trial-pku-stopped-safety-concerns/

BMN 307 Trial for PKU Stopped Over Safety Issues The FDA stopped the trial, which was evaluating the therapy for patients with phenylketonuria (PKU), due to potential safety issues discovered during ...

9. mdpi.com mdpi.com/1422-0067/26/17/8722

Advancing Gene Therapy for Phenylketonuria For the most part, data have suggested BMN 307 is generally well tolerated, with transient liver enzyme elevations representing the commonest adverse events. A ...

10. biospace.com biospace.com/biomarin-s-pku-gene-therapy-study-still-on-hold

BioMarin PKU Study Still On Hold After FDA Requests ... The hold was based on interim safety data from a preclinical, non-GLP pharmacology study that identified liver tumors in lab animals on the ...