The Preclinical Gauntlet: Securing Capital And Designing Regulatory Pathways For Ultra-Rare ASO Drugs (Pt. 2)

A conversation with Dan Williams, Ph.D., CEO, SynaptixBio

Scientific breakthroughs often dominate headlines in RNA therapeutics, but many development programs succeed or fail for reasons that have little to do with molecular biology.

For rare disease companies, challenges such as regulatory strategy, toxicology requirements, clinical trial design, manufacturing, and financing frequently become the true determinants of progress. These realities are particularly pronounced in pediatric indications, where development pathways can be both scientifically and operationally demanding.

In Part 2 of Life Science Connect Acquisition Editor Michael Soloway’s conversation with SynaptixBio CEO Dan Williams, they discuss what it takes to build a lean antisense oligonucleotide (ASO) company, navigate regulatory uncertainty, and secure the resources necessary to advance a rare disease therapy into the clinic.

Miss Part 1? Read it now.

ARNA: Reaching lead selection is as much an organizational milestone as a scientific one. What capabilities were most important to build early?

DW: Reaching lead selection wasn't just about building the right molecule but also about building the right organization. From the beginning, we made a deliberate decision to remain a lean virtual biotech. Rather than investing heavily in internal infrastructure, we've relied on a small experienced core team that manages the science while working closely with consultants, CROs, and CMOs.

Our internal team is intentionally small. It includes myself, our head of preclinical sciences, who also leads preclinical development, our operations lead, and cofounder Michelle Tang, who continues to provide scientific expertise. Together, we've focused on setting the scientific strategy, managing projects, and coordinating our external partners rather than performing every experiment in-house.

For us, the critical capability wasn't building large laboratory operations — it was building strong project management and scientific oversight. Success depended on selecting the right external partners, clearly communicating expectations, and ensuring every activity remained aligned with our development strategy.

This virtual model has allowed us to access specialized expertise when needed while remaining flexible and capital efficient. Increasingly, we're seeing larger biotechnology and pharmaceutical companies adopt similar approaches, relying on strategic outsourcing while maintaining a focused internal team responsible for scientific leadership and decision-making.

ARNA: What lessons have you learned about structuring a small organization around a technically complex ASO program?

DW: One of the biggest lessons has been the importance of building a multidisciplinary team. In a small biotech, people need to be comfortable wearing multiple hats. On any given day, someone might move from project management to scientific discussions, then shift to contracts, finance, or intellectual property. That level of flexibility is essential because you simply don't have the luxury of large specialized departments.

The main exception is clinical development. As we moved toward the clinic, we deliberately brought in a chief medical officer with deep expertise in leukodystrophies. Clinical development requires highly specialized knowledge, from designing protocols and selecting endpoints to understanding the needs of patients and investigators, so that's an area where dedicated expertise is indispensable.

Beyond our core team, we've built strong partnerships with CROs and CMOs that have extensive experience in antisense oligonucleotide development. That allows us to access specialized capabilities while maintaining a lean internal organization.

The challenge isn't just finding talented people; it's finding people who enjoy working across disciplines and can adapt quickly as priorities change. In a small company, flexibility is just as important as technical expertise.

Operating this way has kept our overheads low and allowed us to remain agile, but it also requires careful planning. With a small team, no single person can become the sole repository of critical knowledge. We've worked to ensure that key information, contracts, and operational processes are shared so the organization remains resilient, even if someone is unavailable. Building that level of redundancy is just as important as building the science itself.

ARNA: What do you see as the biggest challenge in advancing an ASO into the clinic?

DW: The answer is probably not what most people would expect, but I believe the biggest challenge is funding.

There are always scientific hurdles in ASO development. You can encounter issues during preclinical testing, discover that a lead candidate isn't suitable, and have to go back and optimize the chemistry. We've experienced that ourselves. Those challenges are part of drug development.

The greater challenge, particularly for rare diseases, is securing enough investment to move a promising therapy into the clinic. We know there's a significant unmet medical need and very little competition for this indication. The difficulty is convincing investors that, despite the small patient population, the commercial opportunity justifies the investment.

There are mechanisms that help support rare disease development, such as orphan drug incentives and priority review vouchers, which can significantly enhance a program's value. Even so, investors ultimately need confidence that the therapy can generate an appropriate return while delivering meaningful benefit to patients.

Pediatric programs also add another layer of complexity. Regulatory expectations for safety are understandably high, which means more extensive toxicology studies and additional development costs before you can begin clinical trials. Taken together, those financial and regulatory demands often become the greatest obstacle, not the science itself.

ARNA: How are you thinking about regulatory engagement and clinical trial design given the patient population size and disease biology?

DW: Regulatory engagement has been a priority from the beginning because developing a therapy for an ultra-rare pediatric disease doesn't follow a conventional path.

One of the biggest challenges is designing an appropriate preclinical program. Traditional regulatory expectations often include toxicology studies in two relevant animal species. For an antisense oligonucleotide, however, that's not always practical because the molecule is designed to bind to a highly specific RNA sequence. If the target sequence doesn't exist in another species, the studies become much less informative and can even introduce misleading safety findings that aren't relevant to humans.

In our case, we're conducting juvenile non-human primate studies using intrathecal administration, the same route we intend to use clinically. Those studies are highly specialized and extremely expensive. For a small biotechnology company, the cost of generating the necessary toxicology package can rival, or even exceed, the cost of an early-stage clinical trial. Securing the funding to complete that work is therefore a significant challenge.

Clinical trial design presents another hurdle because TUBB4A leukodystrophy is a relatively recently characterized disease. Although natural history studies are underway and are providing valuable information, the available data sets are still evolving. Building a sufficiently robust natural history to support endpoint selection, external controls, and regulatory decision-making will require continued investment and collaboration.

That's why we've engaged with regulators early and often. We've held discussions with the FDA, EMA, and the U.K.'s MHRA, obtaining Orphan Drug and Rare Pediatric Disease designations while seeking scientific advice on our preclinical strategy and proposed clinical development plan. Those interactions have helped ensure we're generating the data regulators expect before submitting an IND.

Looking ahead, we'll continue working closely with regulatory agencies on issues such as trial design, the use of external controls versus placebo, biomarker development, and opportunities for accelerated pathways available to rare disease therapies. Regulatory agencies are clearly making progress toward supporting orphan drug development, but the landscape continues to evolve. Maintaining an ongoing dialogue is essential to ensuring our development strategy evolves alongside regulatory expectations.

ARNA: What risks keep you most focused as you prepare for the transition into clinical development?

DW: I wrote down in big capital letters, FUNDING. My absolute top priority is funding. I am acutely aware that SynaptixBio cannot begin a clinical trial without the capital secured to finish it.

Beyond that, our primary operational hurdle is navigating the formal toxicology testing. While our early work on tolerability and safety looks promising, you only get a true understanding of toxicology, molecule stability, and pharmacokinetic (PK) profiles once you enter formal repeated-dose testing across multiple animal models. There is always an inherent scientific risk that a molecule simply won't make it across the finish line.

Finally, designing the studies around placebos and external controls presents a major challenge. These studies are notoriously difficult to execute and highly expensive, so we are actively focused on finding ways to manage and mitigate those specific risks.

ARNA: For other early-stage RNA or ASO companies, what do you think is most often underestimated when moving from discovery to development?

DW: First and foremost is cost; based on my experience, the sheer amount of capital required to transition into development is almost always underestimated.

Funding aside, companies frequently underestimate the regulatory component, specifically the time and effort required to map out a strategy. My strongest advice, especially for teams working on orphan diseases, is to engage with regulatory consultants early to start asking the hard questions. We are likely on the cusp of significant regulatory shifts from the FDA, MHRA, and EMA designed to incentivize and streamline rare disease pathways. Don't wait for those to happen; give yourself ample runway to fully understand the regulatory landscape for your specific molecule.

ARNA: Beyond this lead program, how are you thinking about the broader applicability of your platform?

DW: We originally established SynaptixBio around a single asset, but we are steadily transitioning toward a multi-indication pipeline. The FDA actually catalyzed this shift by defining TUBB4A-related leukodystrophy as four separate diseases. While our primary focus remains on the largest subset — H-ABC — this regulatory guidance allows us to expand our target scope to include the other variations, starting with isolated hypomyelination.

Looking further ahead, recent literature indicates that a (mutated) TUBB4A gene silencer has significant therapeutic potential in other indications, and we are actively evaluating opportunities to expand our platform into those broader clinical areas.

Closing Thoughts

The development of therapies for rare diseases is often described as a scientific challenge. Williams argues that while science remains essential, success increasingly depends on execution across multiple fronts simultaneously.

From regulatory engagement and toxicology planning to fundraising and clinical design, advancing a rare disease ASO requires a level of organizational discipline that extends far beyond target biology. As RNA therapeutics continue to expand into increasingly specialized indications, the lessons learned by companies such as SynaptixBio may prove valuable for a broader generation of emerging developers seeking to transform promising discoveries into approved medicines.

About The Expert

Dan Williams, Ph.D., is chief executive officer, executive director, and cofounder of SynaptixBio. Williams is an accomplished biopharmaceuticals leader with two decades of industrial experience from bench to operational and scientific executive roles. Throughout his career, Wiliams has served as vice president of research operations at Adaptimmune PLC and chief product officer at Meatable B.V.