Clinical trial NCT05972629: A Phase 1/Phase 2 Open-label Study to Evaluate the Safety, Tolerability, and Efficacy of a Single Intravenous Administration of SAR444836 in Adult Participants With Phenylketonuria
Official title: A Phase 1/Phase 2, Open-label, Dose-escalation, and Dose Expansion Study to Evaluate the Safety, Tolerability, and Efficacy of SAR444836, an Adeno-associated Viral Vector-mediated Gene Transfer of Human Phenylalanine Hydroxylase, in Adult Participants With Phenylketonuria
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Phenylketonuria
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2023-08-02
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single group Phase 1/Phase 2, 1-arm, open-label study with SAR444836, an adeno-associated virus (AAV) vector-mediated gene transfer of human phenylalanine hydroxylase (PAH), for the treatment of adult participants with phenylketonuria (PKU) on a chronic, stable diet. The purpose of the study is to evaluate the safety and efficacy of SAR444836 in reducing phenylalanine (Phe) levels and in the elimination of a Phe restricted diet.

Participants will receive a one-time intravenous (IV) administration of SAR444836.

The study is constituted of 2 separate parts: a dose escalation part, and a dose expansion part where subsequent participants will be administered a safe and effective dose level identified during the dose escalation part. In both study parts, clinical and laboratory assessments will be collected to: a) assess the incidence of adverse events, and b) evaluate the effect of SAR444836 on reductions in blood Phe levels and maintenance of these Phe levels after elimination of a Phe restricted diet.

The study duration will be for a minimum duration of 5 years following SAR444836 administration, for each participant and includes a 6-week screening phase, a 96-week treatment follow-up period after SAR444836 administration, followed by an additional 3 years of long-term safety (and efficacy) monitoring.

There will be a total of 47 study visits. Many study visits may occur as remote visits and be performed by a qualified in-home service provider.

Actual study duration for an individual participant may be longer than 5 years due to the administration of SAR444836 to participants in Stage 1A in a serial fashion, the duration of the screening period, and/or other factors such as delays in scheduling study visits.


Eligibility criteria: Inclusion Criteria:

* Adult males, and females of non-childbearing potential, 18-65 years of age at the time of informed consent.
* Participants must have uncontrolled classical PKU due to PAH deficiency (despite Phe-restricted dietary management or Palynziq) in the judgement of the Investigator.
* Two historical plasma Phe values ≥ 600 μmol/L in the preceding 12 months while on Phe restricted diet therapy. Two plasma Phe values ≥ 600 μmol/L drawn at least 72 hours apart during the screening period while on Phe restricted diet therapy in the absence of an acute illness.
* Participant has the ability and willingness to maintain their present diet for the duration of the Post-treatment Follow-up Phase (through Week 96), unless otherwise directed as per protocol
* Body mass index (BMI) ≤ 35 kg/m2
* Willingness to use effective methods of contraception.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

* Presence of neutralizing antibodies against the AAV SNY001 capsid
* Abnormal liver function laboratory testing evidenced by alanine aminotransferase (ALT)\>1.5X upper limit normal (ULN), aspartate transaminase (AST)\>1.5X ULN, alkaline phosphatase \>1.5X ULN, Total and direct bilirubin \>1.5X ULN (bilirubin levels above the laboratory's normal range are acceptable in individuals with a documented history or laboratory evidence of Gilbert's Disease)
* Any significant underlying liver disease or any of the following documented diagnoses, indicative of significant underlying liver disease:

  * Portal hypertension; or
  * Splenomegaly; or
  * Hepatic encephalopathy
* Serum albumin measurement below the lower limit of normal of the laboratory OR AST-to-Platelet Ratio Index \> 1.0
* Serum creatinine \>1.5X ULN
* Hemoglobin A1c \>6.5% or fasting glucose \>126 mg/dL
* Screening laboratory testing demonstrating any of the following:

  * HIV; or
  * active or prior hepatitis B virus (HBV) infection defined as positive test for hepatitis B surface antigen (HBsAg) or positive test for hepatitis B core antibody (total HBcAb) or detectable HBV DNA; or
  * active hepatitis C virus (HCV) infection defined as positive test for hepatitis C antibody followed by detectable HCV RNA or if a participant is presently receiving (or has received within 6 months prior to screening) anti-viral therapy for hepatitis C
* Clinically significant, active bacterial, viral, fungal, or parasitic infection (based on Investigator's judgement)

The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: From Baseline to Week 260
Secondary outcomes:
measure: Proportion of participants with sustained plasma level of Phe<360 μmol/L for ≥4 weeks without dietary Phe restriction at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Change from baseline in plasma level of Phe at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Change from baseline in dietary protein intake at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Proportion of participants with sustained plasma level of Phe <600 μmol/L for ≥ 4 weeks without dietary Phe restriction at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Proportion of participants with sustained plasma level of Phe <120 μmol/L for ≥ 4 weeks without dietary Phe restriction at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Change from baseline in plasma Phe: Tyr ratio at Week 24, 48, and Week 96 or Early Termination Visit following SAR444836 administration
timeFrame: From Baseline to Week 96
measure: Number of participants with abnormal laboratory chemistry values
timeFrame: From Baseline to Week 96
measure: Assessment of the duration of viral vector shedding of SAR444836 in sampling of urine, saliva, and semen at 4-week intervals following SAR444836 administration
timeFrame: From Baseline to Week 96
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco - Parnassus Heights- Site Number : 8400007
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado - Aurora- Site Number : 8400015
state: Colorado
city: Gainesville
country: United States
facility: University of Florida College of Medicine- Site Number : 8400010
state: Florida
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center- Site Number : 8400014
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh- Site Number : 8400018
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - Charleston - Jonathan Lucas Street- Site Number : 8400004
state: South Carolina
Study officials:
affiliation: Sanofi
name: Clinical Sciences &amp; Operations
role: STUDY_DIRECTOR
References: