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Toxicology Written Summary · 2.6.6.1

Brief summary

The nonclinical safety of NVT-317 was evaluated in a program spanning single- and repeat-dose toxicity, genotoxicity, safety pharmacology, and toxicokinetics in Sprague-Dawley rats and cynomolgus monkeys, with reproductive and carcinogenicity assessments staged to support later phases. The program was designed under ICH M3(R2) and S6(R1) and conducted under GLP unless otherwise noted, using the oral and intravenous routes selected to bracket the intended clinical exposure.

Across pivotal studies the candidate was well tolerated at clinically relevant multiples of exposure, with the liver identified as the primary target organ and hepatocellular hypertrophy as the principal monitorable finding. No adverse effects on the cardiovascular, respiratory, or central-nervous systems were identified at exposures bracketing the projected therapeutic margin, and exposure was approximately dose-proportional with no meaningful accumulation across the dosing period.

This summary integrates findings across the individual study reports filed in Module 4 and carries the resulting no-observed-adverse-effect levels forward into the integrated risk assessment in 2.6.7. Each conclusion below is stated against the assertions the uploaded study reports actually support; where a statement is not yet traceable to a source, it is flagged in the panel to the right.

Toxicology Written Summary · 2.6.6.2

Single-dose toxicity

Single-dose toxicity was characterized as part of the dose-range-finding program in both species. In the rat, single oral doses up to 2000 mg/kg produced no mortality and no treatment-related macroscopic findings at necropsy; transient, dose-related reductions in food intake and body-weight gain were observed over the first 48 hours and resolved without intervention. The maximum non-lethal dose was established at or above the highest dose tested.

In the cynomolgus monkey, single ascending intravenous doses were tolerated without adverse clinical observations, and no effects were seen on the limited safety-pharmacology endpoints collected during the acute phase. Toxicokinetic sampling confirmed systemic exposure increased with dose across the range evaluated, supporting the dose selection for the subsequent repeat-dose studies.

Acute findings were limited to the transient, self-limiting gastrointestinal effects expected for the class and did not define a target organ. These data support the starting doses used in the pivotal repeat-dose program and are not, on their own, intended to establish a clinical safety margin.

Toxicology Written Summary · 2.6.6.3

Repeat-dose toxicity

The repeat-dose toxicity of NVT-317 was characterized in pivotal 13-week oral studies in Sprague-Dawley rats and cynomolgus monkeys, each conducted under GLP with an integrated toxicokinetic component. In the rat, daily oral administration at 30, 100, and 300 mg/kg/day was generally well tolerated, and a no-observed-adverse-effect level (NOAEL) of 100 mg/kg/day was identified in both sexes. The principal treatment-related finding was dose-dependent hepatocellular hypertrophy at 300 mg/kg/day, accompanied by modest increases in absolute and relative liver weights and a mild, non-progressive elevation in ALT; these changes were considered adaptive rather than degenerative, with no associated necrosis or biliary involvement.

Findings at the high dose resolved over a 4-week recovery period, with no microscopic correlates at terminal sacrifice and liver weights returning toward control values, supporting reversibility of the hepatic response. The 13-week monkey study was consistent with the rodent profile and established a comparable NOAEL, with no adverse cardiovascular signals observed on telemetry and no target-organ toxicity at exposures exceeding the anticipated clinical range.

Safety pharmacology endpoints were integrated into the repeat-dose program in accordance with ICH S7A, encompassing the cardiovascular, respiratory, and central-nervous systems. No functional effects were identified at exposures bracketing the projected therapeutic margin. Collectively, the repeat-dose findings support the proposed clinical starting dose and define hepatocellular hypertrophy as the primary monitorable effect, reversible on cessation of dosing.

Toxicology Written Summary · 2.6.6.4

Genotoxicity

The genotoxic potential of NVT-317 was assessed in a standard battery consistent with ICH S2(R1), comprising a bacterial reverse-mutation assay, an in vitro assay for chromosomal damage in mammalian cells, and an in vivo rodent micronucleus assay. The compound was non-mutagenic in the bacterial reverse-mutation assay across all tester strains, both with and without metabolic activation.

In the in vitro mammalian assay, no biologically relevant increase in structural or numerical chromosomal aberrations was observed up to the limit of cytotoxicity. The in vivo micronucleus assay was negative at exposures confirmed by satellite toxicokinetic sampling to substantially exceed the projected clinical exposure, and bone-marrow exposure was demonstrated. On the weight of evidence, NVT-317 is considered to lack genotoxic potential under the conditions tested.

Toxicology Written Summary · 2.6.6.5

Carcinogenicity

Dedicated carcinogenicity studies have not been conducted, consistent with the intended clinical duration at the time of this submission and the staging anticipated under ICH S1. A weight-of-evidence assessment of carcinogenic risk is presented in lieu of completed bioassays, drawing on the negative genotoxicity battery, the absence of preneoplastic findings in the 13-week studies, and the pharmacological class.

The adaptive hepatocellular hypertrophy observed at the high dose in the rat was not accompanied by hypertrophy-associated proliferative change, and no test-article-related neoplastic or preneoplastic lesions were identified in any tissue at terminal or recovery sacrifice. A 2-year rat bioassay and a 26-week transgenic mouse study are planned to read out ahead of the filings supporting chronic clinical use.