Phase 1/2 Study of KRRO-121 in Healthy Volunteers and Patients With UCD

KRRO-121 is a GalNAc-conjugated RNA editing oligonucleotide in development for the potential treatment of hyperammonemia in patients with UCDs. Utilizing Korro's proprietary OPERA® platform, KRRO-121 is designed to generate a stabilized, de novo glutamine synthetase (GS) protein, a critical enzyme involved in ammonia clearance. This synthetic rescue approach is designed to augment ammonia clearance in hyperammonemia-driven diseases such as UCDs. Korro's preclinical data support the potential for KRRO-121 to be a UCD treatment that may control ammonia levels independent of any mutational background (pan-UCD).

The purpose of this first-in-human (FIH) study is to determine the safety and tolerability of escalating doses of KRRO-121, to evaluate the pharmacokinetics of KRRO-121, and to assess the effect of KRRO-121 in healthy volunteers and in study participants with UCD. The study name is ANCHOR: AssessmeNt of Control of Hyperammonemia through Oligonucleotide-based RNA editing

• KRRO-121 (Drug): KRRO-121, subcutaneous injection
• Placebo (Drug): Placebo, subcutaneous injection

Primary outcomes

• Incidence of dose limiting toxicities (DLT) (Safety and Tolerability) [Day 1 through 14 days post-dose]: General toxicity: Any Grade 3 or higher adverse event (AE) per Common Terminology Criteria for Adverse Events (CTCAE); Serious adverse events: Any serious adverse event (SAE) assessed as related or possibly related to KRRO-121.
• Frequency and severity of treatment-emergent adverse events (TEAEs; per Common Terminology Criteria for Adverse Events [CTCAE]) (Safety and Tolerability) [Day 1 through Day 50]: Any adverse event (AE) per Common Terminology Criteria for Adverse Events (CTCAE),

Secondary outcomes

• Maximum blood concentration (Cmax) [Day 1 to Day 50]: Maximum blood concentration (Cmax) of KRRO-121

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

* Adult male or female participants, 18 to 65 years of age
* Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and screening laboratory assessments, in the opinion of the Investigator.
* Female participant of childbearing potential or male participant that is willing to use an approved, reliable means of contraception
* Willing and able to provide signed written informed consent and to comply with all study requirements

Exclusion Criteria:

* Any medical history that is clinically significant in the opinion of the Principal Investigator and Sponsor Medical Monitor
* Any laboratory value at screening or predose on Day -1 outside the local laboratory reference range that is clinically significant in the opinion of the Principal Investigator and Sponsor Medical Monitor
* Evidence of active systemic infection at Screening or Day 1 requiring antimicrobial, antiviral, or antifungal therapy
* Use of any investigational drug or device within 3 months or 5 half-lives (whichever is longer) prior to Day 1
* Concurrent participation in any other interventional clinical study