Pyridoxal Phosphate for Pyridoxine 5'-Phosphate Oxidase Deficiency

(MEND-PNPO Trial)

Recruiting at 5 trial locations

Overseen By Pat Follows

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Medicure

Must be taking: P5P

Disqualifiers: Allergy to trial drug, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

15 Participants Needed

Trial Summary

What is the purpose of this trial?

The proposed clinical study is intended to evaluate oral P5P for the treatment of patients confirmed to have Pyridox(am)ine 5'-Phosphate Oxidase (PNPO) deficiency via genetic analysis. There is an unmet clinical need for pharmaceutical grade P5P, as to date none has been made commercially available. Patients will receive pharmaceutical grade P5P according to their normal oral P5P dosing regimen, as previously established by their physicians.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be off pyridoxine for at least 24 hours before joining. You will continue taking P5P as prescribed by your doctor.

What data supports the effectiveness of the drug Pyridoxal Phosphate for treating Pyridoxine 5'-Phosphate Oxidase Deficiency?

Research indicates that Pyridoxal Phosphate can be effective in treating Pyridoxine 5'-Phosphate Oxidase Deficiency, as it is known to help manage neonatal seizures associated with this condition. However, there are cases where the treatment did not prevent fatal outcomes, suggesting that while it can be beneficial, it may not be universally effective for all patients. ^{1 2 3 4 5}

Is Pyridoxal Phosphate generally safe for humans?

Pyridoxal Phosphate, the active form of vitamin B6, is generally safe for humans, but high doses can cause side effects. In some cases, it has led to increased liver enzymes, which is a sign of liver stress, and should be monitored, especially in people with existing health conditions. ^{6 7 8 9 10}

What makes the drug Pyridoxal Phosphate unique for treating Pyridoxine 5'-Phosphate Oxidase Deficiency?

Pyridoxal Phosphate (PLP) is unique because it directly provides the active form of vitamin B6, which is essential for patients with Pyridoxine 5'-Phosphate Oxidase Deficiency who cannot produce enough PLP on their own. This drug is crucial as it bypasses the need for the deficient enzyme, offering a direct source of the necessary coenzyme for neurotransmitter synthesis. ^{1 2 11 12 13}

Eligibility Criteria

This trial is for patients with a confirmed genetic diagnosis of PNPO deficiency, who have their seizures typically controlled by taking oral P5P regularly. Both male and female patients can join if they've been on P5P for at least 30 days. Those previously treated unsuccessfully with pyridoxine may also participate but must not have taken it in the last 24 hours. Consent is required.

Inclusion Criteria

I am either male or female.

Written informed consent (by parent or guardian if under the age of 18)

I tried pyridoxine treatment before and it didn't work for me. I haven't taken it in the last 24 hours.

Exclusion Criteria

I am allergic to the trial drug or similar medications.

I do not have any health issues that could make the study unsafe for me or affect my participation.

Involvement in a clinical research study within 4 weeks prior to screening and/or prior enrollment in the study. Participation in observational registry studies is permitted.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pharmaceutical grade P5P according to their normal oral P5P dosing regimen

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pyridoxal Phosphate

Trial Overview The study tests pharmaceutical grade Pyridoxal Phosphate (P5P) given orally to treat PNPO deficiency. Patients will continue their usual dose of P5P as prescribed by their doctors, but now using a pharmaceutical grade version that hasn't been commercially available before.

Participant Groups

Group I: Single Arm Active Experimental Treatment 1 Intervention

Pyridoxal 5'-Phosphate

Pyridoxal Phosphate is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Pyridoxal 5'-Phosphate for:

• PNPO deficiency
• Seizures responsive to pyridoxal 5'-phosphate

Approved in European Union as Pyridoxal 5'-Phosphate for:

• PNPO deficiency
• Seizures responsive to pyridoxal 5'-phosphate

Approved in Canada as Pyridoxal 5'-Phosphate for:

• PNPO deficiency
• Seizures responsive to pyridoxal 5'-phosphate

Who Is Running the Clinical Trial?

Medicure

Lead Sponsor

Trials

8

Recruited

4,700+

Findings from Research

PNPO deficiency is a treatable genetic condition that can cause severe neonatal seizures and epileptic encephalopathy, as demonstrated in a case study of a girl who developed seizures shortly after birth and had a confirmed mutation in the PNPO gene.

Importantly, a normal cerebrospinal fluid (CSF) level of pyridoxal 5'-phosphate does not exclude the possibility of PNPO deficiency, highlighting the need for genetic testing in suspected cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy. Levtova, A., Camuzeaux, S., Laberge, AM., et al.[2020]

The c.347G>A (p.Arg116Gln) mutation in the PNPO gene affects the thermal stability and cofactor binding of the PNPO enzyme, leading to impaired function, which supports its pathogenic role in PNPO deficiency.

Three new patients with this mutation exhibited varying seizure types and responded dramatically to pyridoxine treatment, highlighting the potential for effective therapy in managing symptoms associated with this genetic condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyridoxine-5'-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g>A (P.·Arg116gln) mutation. di Salvo, ML., Mastrangelo, M., Nogués, I., et al.[2018]

A patient with pyridox(am)ine-5-phosphate oxidase deficiency, which causes neonatal seizures and requires lifelong vitamin B6 therapy, also had mild hemophilia A, leading to worsened bleeding symptoms due to the vitamin B6 treatment.

This case highlights the potential toxicity of vitamin B6 supplementation and emphasizes the importance of closely monitoring bleeding symptoms in patients receiving pyridoxine or pyridoxal-5-phosphate therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B6 and Bleeding: A Case Report of a Novel Vitamin Toxicity. Borst, AJ., Tchapyjnikov, D.[2019]

A patient with severe pyridox(am)ine 5'-phosphate oxidase deficiency, caused by a novel mutation in the PNPO gene, died despite receiving pyridoxal phosphate (PLP) treatment, highlighting the potential limitations of this therapy.

The case suggests that PLP treatment should be initiated promptly upon clinical suspicion of the deficiency, rather than waiting for complete biochemical confirmation, as early intervention may be critical for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new fatal case of pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency. Ruiz, A., García-Villoria, J., Ormazabal, A., et al.[2013]

A study established age-stratified reference values for cerebrospinal fluid (CSF) pyridoxal 5'-phosphate (PLP) in a pediatric population, analyzing samples from 113 controls aged 1 day to 18 years, which is crucial for diagnosing pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency.

In patients with PNPO deficiency, CSF PLP levels were significantly lower than the established reference values, indicating that low PLP levels can be a marker for this deficiency in neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyridoxal 5'-phosphate values in cerebrospinal fluid: reference values and diagnosis of PNPO deficiency in paediatric patients. Ormazabal, A., Oppenheim, M., Serrano, M., et al.[2016]

Mild inadequacy of vitamin B6 (plasma PLP <20 nmol/L) is common in 19-27% of the US population and is linked to increased inflammation, particularly in conditions like inflammatory bowel disease (IBD).

In a mouse study, both low and high levels of plasma PLP were associated with reduced markers of colonic inflammation, suggesting that vitamin B6 supplementation could be beneficial in managing IBD by influencing the breakdown of sphingosine 1-phosphate, a lipid involved in inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary vitamin B6 intake modulates colonic inflammation in the IL10-/- model of inflammatory bowel disease. Selhub, J., Byun, A., Liu, Z., et al.[2021]

In a study of 39 patients with chronic renal failure undergoing hemodialysis, levels of vitamin B6 forms (PL-5'-P, PL, PN) were found to be significantly elevated, with mean concentrations of PL-5'-P and PN being 20 times higher than those in healthy controls.

Due to the potential neurotoxicity associated with high levels of pyridoxine (PN), it is recommended that vitamin B6 supplements be closely monitored in patients with chronic renal failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated plasma vitamers of vitamin B6 in patients with chronic renal failure on regular haemodialysis. Allman, MA., Pang, E., Yau, DF., et al.[2015]

A 2-week supplementation of 27 mg/d pyridoxine (PN)-HCl significantly increased plasma levels of pyridoxal 5'-phosphate (PLP) from 45 nmol/L to 377 nmol/L, indicating effective absorption and transport of this coenzyme.

The supplementation altered plasma amino acid profiles, decreasing glutamic acid and increasing levels of several amino acids, suggesting enhanced protein metabolism and amino acid utilization in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relation of short-term pyridoxine-HCl supplementation to plasma vitamin B-6 vitamers and amino acid concentrations in young women. Kang-Yoon, SA., Kirksey, A.[2018]

Pyridoxal phosphate (PLP), the active form of vitamin B6, is important for neurotransmitter metabolism and its deficiency can lead to refractory seizures, particularly in pediatric patients.

In a review of cases with low-normal cerebrospinal fluid PLP values, while some patients initially responded positively to PLP supplementation, adverse reactions occurred in 4 out of 5 cases, including asymptomatic liver enzyme increases, leading to discontinuation of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyridoxal Phosphate Supplementation in Neuropediatric Disorders. Cortès-Saladelafont, E., Molero-Luis, M., Hsjd Working Group, ., et al.[2018]

A new HPLC method for measuring plasma pyridoxal-5-phosphate (PLP) and 4-pyridoxic acid (4-PA) requires only a small sample volume and avoids toxic reagents, making it suitable for large clinical studies.

In a study of 168 healthy subjects, plasma PLP levels were significantly associated with plasma 4-PA, BMI, and sex, indicating that these factors are important in determining PLP concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple high-performance liquid chromatography (HPLC) method for the measurement of pyridoxal-5-phosphate and 4-pyridoxic acid in human plasma. Cabo, R., Kozik, K., Milanowski, M., et al.[2014]

The study provides evidence for the presence of a previously unrecognized enzyme, pyridoxal reductase, in humans that may play a role in converting pyridoxal (PL) to pyridoxine (PN), suggesting a new aspect of the vitamin B6 salvage pathway.

In vitro experiments with various mammalian cell lines demonstrated that they can reduce PL to PN in a time- and dose-dependent manner, indicating that this enzymatic activity is present across different cell types, although the specific protein responsible remains to be identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of pyridoxal reductase activity as part of human vitamin B6 metabolism. Ramos, RJ., Albersen, M., Vringer, E., et al.[2020]

The biosynthesis of pyridoxal 5'-phosphate (PLP), an essential coenzyme, relies on two specific enzymes: pyridoxal kinase and pyridoxine phosphate oxidase, highlighting their critical roles in vitamin B-6 metabolism.

Recent studies have revealed conserved regions in these enzymes across different species, suggesting their evolutionary importance and potential as targets for new pharmacological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on interconversions of vitamin B-6 with its coenzyme. McCormick, DB., Chen, H.[2018]

Mutations in the PNPO enzyme, specifically R95C and R229W, significantly impair its function, leading to a drastic reduction in the production of pyridoxal 5'-phosphate (PLP), which is crucial for neurotransmitter synthesis and can cause neonatal epileptic encephalopathy (NEE).

The study reveals that both wild-type and mutated PNPO enzymes can tightly bind PLP and transfer it to activate other vitamin B6 enzymes, suggesting a protective role for PLP in the body and highlighting the importance of PNPO in maintaining PLP levels for neurological health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inactive mutants of human pyridoxine 5'-phosphate oxidase: a possible role for a noncatalytic pyridoxal 5'-phosphate tight binding site. Ghatge, MS., Karve, SS., David, TM., et al.[2019]

References

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

Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy. [2020]

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

Pyridoxine-5'-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g>A (P.·Arg116gln) mutation. [2018]

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

B6 and Bleeding: A Case Report of a Novel Vitamin Toxicity. [2019]

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

A new fatal case of pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency. [2013]

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

Pyridoxal 5'-phosphate values in cerebrospinal fluid: reference values and diagnosis of PNPO deficiency in paediatric patients. [2016]

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

Dietary vitamin B6 intake modulates colonic inflammation in the IL10-/- model of inflammatory bowel disease. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Elevated plasma vitamers of vitamin B6 in patients with chronic renal failure on regular haemodialysis. [2015]

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

Relation of short-term pyridoxine-HCl supplementation to plasma vitamin B-6 vitamers and amino acid concentrations in young women. [2018]

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

Pyridoxal Phosphate Supplementation in Neuropediatric Disorders. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A simple high-performance liquid chromatography (HPLC) method for the measurement of pyridoxal-5-phosphate and 4-pyridoxic acid in human plasma. [2014]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Discovery of pyridoxal reductase activity as part of human vitamin B6 metabolism. [2020]

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

Update on interconversions of vitamin B-6 with its coenzyme. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Inactive mutants of human pyridoxine 5'-phosphate oxidase: a possible role for a noncatalytic pyridoxal 5'-phosphate tight binding site. [2019]