New PKU Drug Shows Promise: Lowers Phenylalanine

observational-study PMID: 34973284

Quick Summary: A new drug called PTC923 helped lower high levels of phenylalanine in adults with phenylketonuria (PKU) in a recent study. It worked better than an existing treatment, especially for those with more severe PKU.

What The Research Found

Researchers tested a new drug, PTC923, to see if it could lower phenylalanine levels in adults with PKU. Phenylalanine is an amino acid that builds up in the blood of people with PKU. The study found:

PTC923 at a higher dose (60 mg/kg) significantly lowered phenylalanine levels compared to an existing treatment called sapropterin.

PTC923 worked faster, with noticeable reductions in phenylalanine within just a few days.

PTC923 was particularly effective in people with more severe forms of PKU.

The drug was generally safe, with only mild side effects.

Study Details

Who was studied: Adults aged 18-60 with PKU.

How long: Each treatment lasted 7 days.

What they took: Participants received either PTC923 (at two different doses) or sapropterin, taken once a day.

What This Means For You

If you have PKU, this research is promising. It suggests that PTC923 could be a more effective treatment option for managing your phenylalanine levels. This could potentially lead to better health outcomes. However, more research is needed to confirm these findings and understand the long-term effects. Talk to your doctor about this new research and if it might be right for you.

Study Limitations

The study was relatively short, so we don't know the long-term effects of PTC923.

The study wasn't "blinded," meaning everyone knew which treatment they were getting, which could affect the results.

The number of people in some subgroups (like those with severe PKU) was small, so the results might not apply to everyone.

Participants continued their usual diets, which could have affected the results.

This was a Phase 2 trial, so more research is needed.

Key Findings

PTC923, a sepiapterin-based therapy, significantly reduced blood phenylalanine (Phe) in adults with phenylketonuria (PKU). At 60 mg/kg/day, PTC923 achieved a -206.4 μmol/L mean reduction (p < 0.0001), outperforming sapropterin (a BH4 supplement) at 20 mg/kg/day (-91.5 μmol/L, p = 0.0339). The 60 mg/kg dose also showed faster onset (day 3 reductions: p = 0.0007) and greater efficacy in classical PKU cases (-206.4 μmol/L, p = 0.0287) and responders (baseline Phe ≥300 μmol/L; -463.3 μmol/L, p < 0.001). No serious adverse events were reported.

Study Design

This phase 2 trial was a randomized, multi-center, three-period crossover, open-label, active-controlled study. Adults aged 18–60 with PKU were enrolled. Each treatment period lasted 7 days, with 7-day washouts between. Participants maintained their usual PKU diets, including amino acid mixtures. The study aimed to compare PTC923 (20 mg/kg/day and 60 mg/kg/day) to sapropterin, though exact total sample size is unspecified in the provided summary.

Dosage & Administration

PTC923 was administered orally at 20 mg/kg/day and 60 mg/kg/day, while sapropterin was given at 20 mg/kg/day. Doses were once-daily and randomized in crossover order. Treatments were separated by washout periods to minimize carryover effects.

Results & Efficacy

PTC923 60 mg/kg: -206.4 μmol/L reduction (p < 0.0001) vs. sapropterin’s -91.5 μmol/L (p = 0.0339).
PTC923 20 mg/kg: -146.9 μmol/L reduction (p = 0.0010).
Faster onset: PTC923 60 mg/kg reduced Phe levels significantly by day 3 (p = 0.0007) compared to sapropterin (p = 0.0135).
Classical PKU subgroup (n = 11): Only PTC923 60 mg/kg reduced Phe (-206.4 μmol/L, p = 0.0287).
Responder analysis (n = 8, baseline Phe ≥300 μmol/L): PTC923 60 mg/kg achieved -463.3 μmol/L reduction (p < 0.001).

All treatments showed similar mild-to-moderate adverse event rates, with no discontinuations.

Limitations

Short duration (7 days per treatment) limits conclusions on long-term efficacy/safety.
Open-label design may introduce bias, as blinding was not used.
Subgroup analysis limitations: Classical PKU (n = 11) and responder (n = 8) cohorts were small.
Diet control: Participants maintained pre-study diets, which could confound results due to variable amino acid intake.
Phase 2 trial: Larger phase 3 trials are needed to confirm findings.

Clinical Relevance

For adults with PKU, PTC923 at 60 mg/kg/day offers a more potent and rapid reduction of elevated blood Phe compared to sapropterin, particularly in classical PKU cases. This suggests PTC923 could improve metabolic control in non-responders to existing BH4 therapies. However, the lack of long-term data and smaller sample sizes necessitate caution. Practical use should involve monitoring blood Phe levels and consulting healthcare providers, as dietary adjustments and extended treatment effects remain unexplored. The favorable safety profile supports further development, but definitive clinical recommendations require phase 3 validation.

Source: PubMed | Date: 2022 | Study ID: ACTRN12618001031257