Why Rare Disease Trial Design Requires the “Right Patients at the Right Time”

Alex Yang
CEO
Polaryx Therapeutics

For ultra-rare pediatric lysosomal storage disorders, clinical trial design is often as challenging as the biology itself. Small patient populations, heterogeneous symptoms and long disease trajectories can make it difficult to show whether an investigational therapy is truly altering the course of disease.

That is the challenge Polaryx Therapeutics is trying to address as it advances a pipeline of disease-modifying small molecule therapies for rare pediatric lysosomal storage disorders. The company’s lead program, PLX-200, is being developed with a trial strategy that relies on objective clinical domains, natural history comparators, biomarker support and careful patient selection.

Xtalks spoke with Alex Yang, CEO of Polaryx Therapeutics, about how the company is approaching trial design in a field where conventional randomized studies are often difficult or impractical.

Moving Beyond Biomarkers Alone

For Yang, one of the central questions in pediatric lysosomal storage disorder trials is simple: how do investigators know whether a drug is working?

Biomarkers can offer important signals, particularly in diseases where neurological decline or cellular dysfunction may be reflected in blood or other measurable biological samples.

Yang said Polaryx is evaluating biomarkers such as neurofilament light chain (NfL), among others. However, he emphasized that on their own, biomarkers are not yet sufficient to demonstrate meaningful clinical benefit in these conditions.

While blood-based biomarkers can be easily assessed with a simple blood draw, they alone cannot show whether the disease is slowing down or reversing, he explained.

This limitation means trial designs must capture clinical domains that matter to patients and families. In pediatric lysosomal storage disorders, those domains can vary widely. Some children may experience seizures, while others may show declines in motor function, speech, vision, sleep or other neurological and functional measures. The heterogeneity of disease presentation makes it difficult to rely on a single endpoint across all patients.

Yang said Polaryx is therefore focusing on domains that can be measured as objectively as possible, including visual acuity, motor function and speech. The goal is to identify signs of disease progression that are clinically meaningful while minimizing subjective interpretation.

Patient Enrollment and Placebos in Rare Disease Pediatric Clinical Trials

Another important part of Polaryx’s approach is timing. Yang said simply enrolling children after diagnosis may not be enough, because some patients can remain asymptomatic for years before showing measurable deterioration. Including patients at different stages of disease could make it difficult to determine whether a therapy is having an effect.

Polaryx’s strategy is to enroll patients who have already begun to show decline in specific domains, then compare their trajectory with natural history data from untreated patients at a similar stage of disease. Yang said this approach is intended to better capture whether treatment slows or reverses deterioration once progression has become measurable.

“What we’re trying to do is not to just enroll any patients, but patients who have started to show some deterioration,” Yang explained.

This type of design reflects a broader challenge in rare pediatric diseases, which is the need to create a comparison framework when placebo-controlled trials may be difficult to conduct.

For progressive childhood disorders, asking families to enroll in long-term placebo arms can be ethically and practically challenging, particularly when there are few or no approved treatment options.

The Growing Role of Natural History Data

Natural history data are central to Polaryx’s development strategy. In rare diseases, these datasets can help define how a condition progresses without treatment and provide context for interpreting outcomes in small, open-label studies.

Yang said Polaryx is using natural history data from patients who have lived with these disorders over the past two decades. The company is also working to ensure that endpoint assessments can be interpreted consistently across patients and across time.

“We try not to be biased and objective,” Yang said. “We’ve done a lot of that work to measure the right domains for all parts of the design work in terms of patient enrollment, enrolling the right patient at the right time, using the right domains and using some of the biomarkers.”

Inter-rater reliability is another key consideration. Yang said Polaryx has worked to create simplified rating scales so independent evaluators assessing historical patients and current trial participants can reach comparable conclusions.

“It can’t be like 20 different scales,” he said. “We have a four-point scale for each of these, so it’s simple.”

The aim is to reduce bias and make comparisons between treated patients and natural history controls more credible. This is particularly important when trials may include only 10 to 20 patients, rather than the hundreds typically seen in more common diseases.

Why Patient and Endpoint Selection Must Be Holistic

Although primary endpoints remain central to regulatory decision-making, Yang said rare disease trials need to be interpreted through a broader lens. Safety, ease of administration, clinical benefit, quality of life and biomarker changes all contribute to the overall evidence package.

For PLX-200, Yang pointed to the potential advantage of an oral solution that could be administered more easily than more invasive approaches used in some rare neurologic diseases. He contrasted the quality-of-life implications of a treatment taken at home with therapies that may require frequent hospital visits or invasive delivery procedures.

“If you have to spend a whole day going to a hospital versus our drug oral solution that is just taken in the morning and evening, that gives a tremendous quality of life for patients,” Yang said.

This helps shape how the therapy’s overall value may be assessed. For pediatric rare diseases, a treatment that is safer, easier to administer and broadly applicable could have meaningful clinical and practical advantages.

Patient identification is another major challenge in ultra-rare pediatric disorders. However, Yang said established patient communities and centers of excellence have made it easier to locate families and clinicians with expertise in specific lysosomal storage disorders.

Although these diseases are rare, many patient advocacy networks have existed for decades. Yang said some communities were formed long before the underlying genetics were fully understood, based on observed clinical symptoms and shared family experiences.

“Although it’s a small number, it’s not that difficult to find where they are because they usually go to the centers of excellence,” Yang explained.

Polaryx plans to conduct trials in both the US and Europe, including countries such as Germany, the UK and Spain. A global strategy is often necessary in ultra-rare diseases because no single country may have enough eligible patients to support a registrational trial. Conducting studies in Europe may also help support future regulatory submissions and market access in that region.

Real-World Data in Rare Disease Trials

Real-world data are becoming increasingly important in rare disease development, particularly where small trials cannot capture every aspect of patient experience. Yang said real-world evidence can help show how a therapy affects patients beyond a narrow clinical endpoint.

“What it comes down to is the holistic approach,” he said. “Real-world data shows how a treatment is actually helping kids, and not just its effect on a small biomarker or certain symptoms. It’s the whole quality of life that really matters.”

For pediatric lysosomal storage disorders, that could include functional changes, daily burden on families, ease of administration, treatment adherence and comparisons with available therapies. In Yang’s view, these considerations are especially important for children, where the burden of treatment can be substantial.

At the same time, he acknowledged that regulators still need objective evidence. In a registrational trial, the FDA will still focus on statistical significance in primary endpoints. The challenge is to combine those endpoints with a broader evidence package that captures the full impact of treatment.

The Need for Evolving Rare Disease Trials

Yang said rare disease trials will need more flexible, scientifically grounded approaches moving into the future. He cautioned that traditional trial designs do not always translate well to ultra-rare, progressive pediatric conditions, especially when symptoms vary and disease progression unfolds over years.

“If we continue to assert very rigorous design as if these ultra-rare and rare indications have some kind of statistical significance, that’s wrong,” Yang said. “You only have 20 to 30 patients max.”

He said the field needs better biomarkers, surrogate endpoints, gene expression measures and disease progression models that can help shorten trial timelines and make outcomes easier to interpret. More robust natural history datasets, stronger consensus among regulators and clinicians and improved use of real-world data could also help trial designs become more efficient.

Technologies like AI may eventually play a role in analyzing complex datasets, improving diagnosis and identifying patterns in disease progression, though Yang said its impact will depend on the quality of the data available.

For companies developing therapies in pediatric lysosomal storage disorders, flexibility will be essential with newer models and approaches in rare disease trials. In conditions where patient numbers are small, disease progression is variable and treatment options remain limited, the success of a clinical program may depend as much on trial design as on the therapeutic mechanism itself.

“I think rare disease especially shows that it’s not a one-size-fits-all when it comes to trials,” Yang said. “You definitely have to really customize, tailor and have a holistic approach.”

Polaryx’s approach reflects that evolving mindset: identify the right patients, measure the right domains, use natural history data carefully and build an evidence package that captures both clinical benefit and real-world impact.

For children and families facing progressive rare diseases, those design choices could determine whether promising therapies are able to reach patients sooner and with evidence that reflects the realities of their disease.