Advancing antiviral therapeutics for immunocompromised populations

As viral infections continue to present serious health risks to immunocompromised individuals, particularly organ and stem cell transplant recipients, the development of safe, targeted antiviral therapies remains an urgent medical need. These patients are often excluded from conventional trials and have limited treatment options, especially for viral pathogens that can reactivate under immunosuppression. One such pathogen is BK virus (BKV), a common but often overlooked threat that can cause severe complications such as kidney damage and graft loss.

In this Q&A, we speak with the Chief Scientific Officer Jacques Dumas of AiCuris, to explore the scientific and clinical complexities of developing antiviral therapies for immunocompromised populations. At the centre of the conversation is AIC468, a first-in-class antisense drug targeting BK virus (BKV).

Developing drugs for immunocompromised patients presents unique challenges. Could you explain the key scientific and clinical considerations Aicuris prioritises when designing therapies for this vulnerable population?

The primary driver for selecting a development programme in immunocompromised populations is the medical need. Aicuris prioritises viral infections that are difficult to treat or lack approved standard-of-care therapies, such as BK virus (BKV) and adenovirus. Once an indication is identified, we focus on programmes with a strong potential to demonstrate safety and efficacy in animal models, thereby supporting the prediction of clinical outcomes.

How does Aicuris integrate insights from immunology and infectious disease research to enhance the efficacy and safety profiles of its drug candidates for immunocompromised patients?

Our drug candidates undergo rigorous preclinical testing to ensure solid predictions of both safety and efficacy before initiating the first human trials. Safety assessments are conducted through a comprehensive series of in vitro and animal studies across multiple species, in full compliance with regulatory guidance for clinical trial initiation. In parallel, we strive to anticipate efficacy in humans, using relevant cell assays or in vivo models.

Could you walk us through the strategic rationale behind Aicuris’ second clinical programme, AIC468, and how it addresses unmet medical needs in immunocompromised populations?

AIC468 is an antisense nucleotide specifically designed to suppress BKV, a pathogen that remains latent after initial infection but can reactivate under immune suppression. Reactivation is particularly problematic in transplant patients, where it can lead to kidney damage and even graft loss.

BKV is an attractive target due to its clear tissue tropism and well-characterised viral genome, making it amenable to sequence-specific antisense strategies. Preclinical data demonstrate potent viral inhibition in kidney-derived cell systems and animal models that mimic immunosuppressive conditions. These models allowed us to validate target engagement and assess off-target effects early in development.

Given the lack of approved therapies, a new, well-tolerated drug targeting BKV could be a game changer for kidney transplant patients with BKV infection globally and we look forward to further evaluating AIC468 in our ongoing clinical development. The safety data we have seen to date in the single ascending dose part of our Phase I trial are already very encouraging.

In the clinical development of AIC468, what innovative approaches or biomarkers are being utilised to monitor patient response and optimise treatment outcomes?

The AIC468 clinical development builds on the experience and expertise we have gained through the successful clinical development of letermovir and pritelivir. Following successful completion of our currently ongoing Phase I development later in 2025, our clinical development plan will employ a seamless operational approach and adaptive design, where we will merge Phase II and Phase III trials into a single, continuous protocol. This design, while grounded in regulatory precedent, eliminates the usual pause or gap between phases, thereby reducing development timelines and enrolment gaps and allowing us to modify our clinical trial design based upon emerging data. The Phase II part is intended to indicate proof of mechanism and is planned to start in 1H2026.

We will further leverage PK/PD modelling and simulation to inform the selection of extended dosing regimens based on the observed exposure–response relationships. These advances allow us to pursue an accelerated development path while maintaining high standards of evidence, ultimately aiming to bring treatment options to immunocompromised patients facing BKV infection.

How does the clinical data generated from AIC468 influence Aicuris’ broader approach to drug development for immunocompromised patients, and what implications could it have for future therapies?

Aicuris has already demonstrated its ability to deliver novel antiviral therapies to patients with weakened immune systems with two products: letermovir, which is marketed in more than 60 countries worldwide, and pritelivir, which is currently in pivotal stage development.

• Letermovir, a cytomegalovirus (CMV) drug we developed in collaboration with Merck/MSD, has now become the standard of care for the prophylaxis of CMV infections in haematopoietic stem cell transplantation (HSCT) and kidney transplant patients. Since 2017 thousands of patients worldwide have benefitted from reduced risk for severe consequences, including increased mortality after active CMV infection.
• Pritelivir is a novel compound designed to treat herpes simplex virus (HSV) infections in immunocompromised patients. Our Phase III trial just completed recruitment and we look forward to delivering top line data for this compound before year end.

AIC468 comes next in our clinical development pipeline and further strengthens our position as a leader in the antiviral space. If proof-of-concept for AIC468 can be successfully demonstrated in kidney transplant patients with BKV infection, Aicuris has the potential to expand its development to HSCT patients, where BKV reactivation is linked to severe haemorrhagic cystitis, a condition currently also lacking effective treatment options.

We are on our way to offering new antivirals for patients at risk after transplantation and associated immune suppression, making a positive impact on the lives of those who currently have no or limited treatment options.

Looking ahead, what do you see as the biggest opportunities and challenges for the development of next-generation drugs targeting infections in immunocompromised patients, and how is Aicuris positioning itself to lead in this space?

Despite its small size, Aicuris is already a major player in delivering therapies for viral infections in immunocompromised populations. Over the years, our group has built a track record of clinical success in this space as well as a solid pipeline. While our company is still headquartered in Wuppertal, Germany, we have expanded our expertise in late-stage clinical development and will be growing the commercial group with our US subsidiary which opened in 2023.

Looking ahead, we aim to continue exploring indications in the immunocompromised space, where there are still numerous opportunities to make a meaningful difference for patients. Importantly, these markets, including stem cell and solid organ transplants, as well as advanced HIV disease, are highly specialised and can be accessed efficiently with a targeted commercial effort, particularly in the US and Europe. This makes them well suited to a focused company like Aicuris. From both an R&D and commercial perspective, we believe the future is bright.