A dose-finding study to evaluate mRNA-3210 in participants with phenylketonuria

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Moderna Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

completed 12 Sep 2024

Decision date (initial)

2024-07-16

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

ModernaTX, Inc.

External identifiers

EU CT number

2023-506963-32-00

ClinicalTrials.gov

NCT06147856

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Pharmacokinetic, Pharmacogenetic, Efficacy, Others

Evaluate the safety and tolerability of multiple doses at escalating dose levels of IV administered mRNA-3210.

Secondary objectives 1

1. • Characterize the PD response as determined by changes in blood Phe levels following IV infusion of mRNA-3210. • Characterize the blood PK of mRNA3210 (mRNA and SM86) following IV infusion. • Assess the presence and development of anti-PEG antibodies.

Conditions and MedDRA coding

Participants with Phenylketonuria

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Participants are eligible to be included in the study if they meet all the following criteria: 1. Signed written informed consent obtained prior to performing any study procedure, including Screening procedures.
2. 2. Age ≥18 to ≤70 years at the time of informed consent.
3. 3. Confirmed diagnosis of PKU due to PAH deficiency by molecular genetic testing from a central lab. Note: Genetic confirmation of PKU due to PAH deficiency can be obtained during the Limited Screening Period as described in Section 4.1.1 of the protocol.
4. 4. At least 3 blood Phe levels ≥600 μmol/L regardless of adherence to a Phe-restricted diet: 2 obtained during the Screening Period (at least 72 hours apart) and at least one historical value 6 to 24 months prior to start of Screening. Note: Blood samples collected to evaluate participants’ Phe levels to determine eligibility should be drawn in the absence of acute illness.
5. 5. Have received documented approval from: a. Study dietitian confirming that participant is willing and able to maintain dietary protein intake consistent with baseline intake during study participation (as described in Section 8.9), AND b. Investigator’s clinical review confirming that diet alone will be sufficient to control the disease during study participation.
6. 6. If applicable, maintained stable dose of neuropsychiatric medication (ie, for ADHD, depression, anxiety, or other psychiatric disorders) prior to enrollment (as described in Section 6.6.1 of the protocol) and willing to maintain stable dose throughout study participation unless, per Investigator assessment, a change is clinically indicated.
7. 7. Sexually active females of childbearing potential and sexually active males of reproductive potential must agree to use a highly effective method of contraception during the study, and for 3 months following the last administration of the study intervention (Section 10.4.2 of the protocol).

Exclusion criteria 20

1. Participants are excluded from the study if any of the following criteria apply: 1. Receipt of sapropterin or large-neutral amino acids within 14 days or 5 half-lives (whichever is longer) of the start of Screening.
2. 2. Participants with BH4 deficiency or DNAJC12 deficiency confirmed by genetic testing from a central lab. Note: Genetic testing for BH4 and DNAJC12 deficiency can be obtained during the Limited Screening Period as described in Section 4.1.1.
3. 3. Receipt of pegvaliase within 2 months of start of Screening (see Section 6.6 of the protocol).
4. 4. For patients previously on pegvaliase: use or planned use of any injectable drugs containing PEG, including medroxyprogesterone injection, within 3 months prior to the start of Screening and during study participation with the exception of COVID-19 vaccinations (as described in Section 5.2 and Section 6.6.2 of the protocol).
5. 5. Receipt of any investigational drug within 30 days or 5-half-lives (whichever is longer) of Screening.
6. 6. Intake of medications known to interfere with folate metabolism (eg, aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim, triamterene, etc.) within 14 days or 5 half-lives (whichever is longer) of start of Screening.
7. 7. Having received gene therapy with PAH at any time previously.
8. 8. Median QTcF of triplicate standard 12-lead ECGs >450 msec at Screening.
9. 9. For female participants of reproductive potential, positive pregnancy test at Screening or Day 1 or currently breastfeeding.
10. 10. Positive HBsAg, positive PCR for HCV RNA, or HIV (positive HIV1/HIV-2 antibodies). Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible for study participation. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA (Section 8.2.3.3).
11. 11. History of hypersensitivity to any component/excipient used in this study.
12. 12. History of hypersensitivity or contraindication to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers.
13. 13. Participant has a history of anaphylaxis or severe hypersensitivity reactions to PEG (including, but not limited to, PEGylated LNP COVID-19 vaccines and other PEG-containing medications or products) or polysorbates.
14. 14. Laboratory abnormality within an exclusionary threshold at Screening (Table 10) and/or any clinically relevant abnormal laboratory values at Screening per Investigator criteria.
15. 15. Glomerular filtration rate <30 mL/min/1.73 m2 as estimated by the 2021 CKD-EPI creatinine equation.
16. 16. Participants who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures.
17. 17. Participants who, in the Investigator’s opinion, are cognitively impaired and unable to complete study procedures such as the PRO assessments or providing consent.
18. 18. Any other clinically significant medical condition (including but not limited to unstable cardiovascular disease, acute kidney, or liver failure) that, in the Investigator’s opinion, could interfere with the interpretation of study results or limit the participant’s participation in the study, or could potentiate the risk while participating in the study.
19. 19. Participant plans to receive a COVID vaccine any time after 28 days before the first dose of study intervention and before 7 days after the third dose of study intervention.
20. 20. History of substance or alcohol abuse that in the Investigator’s assessment would impair the participant’s ability to comply with the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Number of participants with TEAEs.

Secondary endpoints 3

1. • Changes from baseline in blood Phe levels. • Characterization of PD parameters, including Emax, AUEC, and duration of response.
2. • Characterization of blood PK parameters of mRNA and SM 86, including, but not limited to, Cmax, Tmax, AUC, t½, CL, and Vz.
3. • Presence and titers of anti-PEG antibodies.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Moderna Therapeutics Inc.

Sponsor organisation

Moderna Therapeutics Inc.

Address

200 Technology Square

City

Cambridge

Postcode

02139-3578

Country

United States

Scientific contact point

Organisation

Moderna Therapeutics Inc.

Contact name

Moderna Clinical Trials

Public contact point

Organisation

Moderna Therapeutics Inc.

Contact name

Moderna Clinical Trials

Third parties 21

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Documents 1 file

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications