# P-113. Interim Results of the First-in-human Phase 1 Trial of AIC468: A Novel Antisense Oligonucleotide that Targets BK-Virus Transcripts

## TL;DR

A new antisense drug called AIC468 shows promising safety and pharmacokinetics in early human trials for treating BK virus in transplant patients.

## Contribution

AIC468 is a novel antisense oligonucleotide targeting BK virus transcripts, with first-in-human safety and PK data reported.

## Key findings

- AIC468 was safe and well-tolerated at SC doses up to 600 mg and IV 200 mg in healthy volunteers.
- Plasma exposure increased supra-proportionally with ascending subcutaneous doses of AIC468.
- Most adverse events were mild and not dose-related, with no severe safety concerns observed.

## Abstract

Reactivation of BKV in immunosuppressed patients, kidney transplant recipients, is associated with BKV-associated nephropathy, renal failure & graft loss with no effective or approved antiviral treatments. AIC468 is a splice-modulating antisense oligonucleotide (ASO) that targets BKV pre-mRNA and prevents large T-Ag formation, which is essential for viral replication. Potent antiviral activity was demonstrated in BKV-infected primary human kidney epithelial cells and the mechanism of action was confirmed in a BKV-Tat mouse model.Table 1:Plasma pharmacokinetic parameters after single doses of AIC468 in healthy volunteersFigure 1:Mean (+SD) plasma concentration profiles after single doses of AIC468 in healthy volunteers (0-48 hours)

Plasma pharmacokinetic parameters after single doses of AIC468 in healthy volunteers

Mean (+SD) plasma concentration profiles after single doses of AIC468 in healthy volunteers (0-48 hours)

This single-center, randomized, double-blind, placebo-controlled, FIH trial (EUCT 2023-510074-13-00) consists of two parts. Part A is a single ascending dose study in healthy volunteers (HVs), which includes 6 subcutaneous (SC) and 1 intravenous (IV) administration cohorts. Part B is a multiple dose ascending dose study in HVs which includes 3 SC administration cohorts with once weekly dosing over one month. Within each cohort in Part A and B, 6 HVs received AIC468 and 2 received a matching placebo. Here we report interim pharmacokinetics (PK) and blinded safety results from Part A of the ongoing trial.

Fifty-six HVs were dosed across 7 cohorts. A total of 93 AEs were reported in 41 (73%) HVs, of which 31 (33%) were considered related to study treatment. Majority of AEs 78 (84%) were mild in intensity, including 9 (10%) Injection Site Reactions. One unrelated SAE (hospitalization due to cut wound) was reported. There were no severe AEs, or dose-related trends in the nature, incidence or severity of AEs. Vital signs, ECG, and safety laboratory parameters were unremarkable.

Plasma exposure (AUC0-24h, Cmax) increased with dose from 25 to 600 mg in a mild supra-proportional manner. AIC468 showed typical ASO plasma concentration profiles with rapid absorption after SC administration (Tmax between 2–5 hours) and rapid distribution to peripheral tissues. The absolute bioavailability at 200 mg SC is 82%.

AIC468 single SC doses between 25 mg and 600 mg and IV dose of 200 mg were safe and well tolerated in HVs. Plasma exposure increased supra-proportionally with ascending SC doses, most likely due to saturation of tissue uptake mechanisms. Additional data from this ongoing Phase 1 trial will be presented.

Susanne Bonsmann, Diploma in Chemistry Engineering, AiCuris Anti-infective Cures AG: Employee Vedran Pavlovic, MD, VP Pharma Consultancy Ltd: Director|VP Pharma Consultancy Ltd: Ownership Interest|VP Pharma Consultancy Ltd: Stocks/Bonds (Private Company) Bernadette Surujbally, MSc, AiCuris Anti-Infectives Cures AG: Stocks/Bonds (Private Company)|Roche: Stocks/Bonds (Private Company) Gnana Oli Rajaraman, B.Pharm, PhD, AiCuris Anti-infective Cures AG: Employee Cynthia Wat, MBBS MRCP MFPM, Aicuris Anti-infective Cures AG: Employee|Aicuris Anti-infective Cures AG: Stocks/Bonds (Private Company)|ID Pharma Consultancy Ltd: Director|ID Pharma Consultancy Ltd: Ownership Interest|ID Pharma Consultancy Ltd: Stocks/Bonds (Public Company) Dirk Kropeit, n/a, AiCuris Anti-infective Cures AG: employee