Express Use probiotics to "eat" this disease-causing amino acid! Innovative therapies are about to enter Phase 3 trials

Recently, Synlogic announced that the Phase 2 clinical trial of its phenylketonuria treatment drug has achieved positive top-line results
.
Based on these results, the company determined that SYNB1934 will enter the pivotal Phase 3 clinical study and subsequent commercialization process
as a drug candidate.

Phenylketonuria (PKU) is a congenital abnormality
in amino acid metabolism caused by phenylalanine hydroxylase deficiency.
If left untreated, PKU can lead to high levels of phenylalanine (Phe) in the blood, which can lead to severe intellectual disability and behavioral problems
.
Therefore, controlling phenylalanine intake by severely limiting the amount of natural protein in the diet is critical to remission, supplemented by amino acid supplements to maintain the patient's daily needs, this lifelong treatment can effectively prevent most complications
associated with PKU.
However, treatment of PKU can be a heavy burden on the patient's family and is difficult to maintain
for a long time.
In addition, treatment outcomes for some PKU patients remain suboptimal, highlighting the enormous unmet medical needs
in this area.
In response to this stubborn disease, Synlogic uses the genetically engineered probiotic E.
coli Nissle has successfully developed 2 biopharmaceutical product candidates, SYNB1934 and SYNB1618, which reduce phenylalanine levels
in a patient's blood by depleting phenylalanine from the gastrointestinal tract.

Synlogic has released the latest positive top-line results from the Synpheny-1 study, an open-label, 28-day Phase 2 clinical study to evaluate the safety, tolerability and efficacy
of SYNB1618 and SYNB1934 in PKU patients.
The study enrolled a total of 20 adult PKU patients who had undergone dietary control and/or sapropterin prior to enrollment and had blood Phe concentrations of more than 600 μmol/L
.
Eleven of these patients were enrolled in the SYNB1618 treatment group and 9 patients were included in the SYNB1934 treatment group, and 10 patients have completed the SYNB1618 group and 5 patients have completed the treatment
of the SYNB1934 group.

The primary endpoint of the Synpheny-1 trial was the change in the area under the curve (AUC) of the labeled phenylalanine tracer (D5-Phe) level curve in the blood after dietary testing before and after the treatment period, which is a specific indicator
of the ability of each drug candidate to consume phenylalanine as expected.
The study also included a 15-day dose-escalation protocol in which the constant dose on days 7 to 14 was 1x10^{for 12} viable cells
.
Other endpoints included change in plasma phenylalanine levels from baseline in fasting state, incidence of therapeutic sudden adverse events (TEAEs), and plasma levels (D5-TCA) and urine levels (D5-HA)
of other strain-specific metabolites.
During the study, the subjects' dietary intake of phenylalanine was strictly managed to match the patient's usual protein and phenylalanine intake
.

Image source: 123RF

According to the published results, the plasma D5-Phe levels and fasting state of plasma Phe in the two treatment groups were significantly reduced
compared with baseline.
In patients who completed dosing, the mean change in fasting plasma Phe levels from baseline in members of the SYNB1618 group at day 14 was -20% compared to -34%
in the SYNB1934 group.
In addition, the results included data
from patients who had taken sapropterin (Kuvan) before the trial began.
The outcomes of these patients were consistent with overall efficacy, showing the potential
of SYNB1934 and SYNB1618 as adjuncts.

Among patients who completed dosing, 60% of patients had Phe levels reduced by more than 20% on day 7 or 14 (6 members of SYNB1618 and 3 members of SYNB1934), with plasma Phe levels reduced by an average of -42%
in both groups.
Specifically, plasma Phe reduction in the SYNB1618 and SYNB1934 treatment groups ranged from -20% to -61% and -29% to -80%,
respectively.
The safety profile of both therapies was good, adverse events reported during treatment were mild to moderate, and no serious adverse events (SAEs) occurred
.
Throughout the study, 3 patients discontinued due to gastrointestinal-related adverse events, 1 patient withdrew informed consent, and 1 patient withdrew from the study after the adverse event of facial flushing, which was considered to be a possible anaphylaxis
.