What TK2d Shows About Rethinking Rare Disease Trial Design

Thymidine kinase 2 deficiency, or TK2d, is so rare that only about 120 patients have been described in medical literature. The ultra-rare inherited disease affects the body’s ability to maintain mitochondrial DNA, which cells need to produce energy. Its symptoms can also resemble other neuromuscular diseases, making early diagnosis difficult.

In November 2025, UCB’s Kygevvi (doxecitine and doxribtimine) became the first FDA-approved drug for TK2d, offering a treatment option for adults and children whose symptoms began at age 12 or younger. The approval was supported by one Phase II clinical study, two retrospective chart review studies and an expanded access program.

Xtalks sat down with Sarah Chang, PhD, Medical Strategy Lead at UCB, where she works on the TK2d program and focuses on earlier disease recognition and diagnosis. 

Dr. Chang discussed what ultra-rare disease development can look like in practice, from delayed diagnosis and trial design to regulatory flexibility, real-world evidence and AI.

Delayed Diagnosis Still Shapes Rare Disease Research

For patients with rare and ultra-rare mitochondrial or neuromuscular diseases, the biggest barriers begin at diagnosis.

“I would say that despite recent advances, the biggest unmet needs remain very fundamental,” Dr. Chang said. “So patients are still being diagnosed too late or in some cases not at all.”

TK2d can look like spinal muscular atrophy, Pompe disease or Duchenne muscular dystrophy, which means it may not be top of mind when physicians first evaluate a patient.

The problem extends beyond a single missed test. Families may have to navigate fragmented healthcare systems, repeated appointments and uncertainty while symptoms progress.

“TK2d, it doesn’t get better over time,” she noted. “So missing an early diagnosis has a really big impact on patient outcomes.”

Patients may first present in general care or primary care settings, where rare disease expertise can be limited. The condition can also present with nonspecific symptoms such as fatigue, muscle weakness and neurologic changes, making it harder to know when to order the right genetic tests.

Ultra-Rare Disease Trials Need Different Evidence Models

Traditional large trials are often not realistic in ultra-rare diseases.

The known living patient population is extremely small, which changes what evidence generation can look like in practice.

“For TK2d, at this point in time in 2026, we only know of just over 100 living patients with this disease,” Dr. Chang said. “So it’s simply not possible to run, say, a 300-patient, two-year placebo-controlled trial, as you might see in some of the more common disease states.”

In more common diseases, randomized, placebo-controlled trials may be large enough to compare treatment and control groups over long follow-up periods. In ultra-rare diseases, small patient numbers, limited natural history data and variable disease progression can make those models difficult or unrealistic.

Evidence generation may need to draw from multiple sources, including prospective studies, retrospective chart reviews, real-world data and external controls.

For Kygevvi, UCB used an evidence package that combined several types of data.

“The way we established that efficacy was by applying that innovative study design that I just alluded to previously, where we combined data from one Phase II clinical trial, two retrospective chart reviews and an expanded access program,” Dr. Chang said.

The program also had survival as its primary endpoint.

“We saw that the improvement in survival was significant in treated patients compared with that untreated control group,” Dr. Chang said. “An 86% reduction in the risk of death.”

Precision Medicine Is Changing Who Gets Found

Precision medicine is also changing how rare disease patients are identified, diagnosed and considered for clinical studies.

“I would say that advances in precision medicine are really allowing us to move from more of that symptom-based approach to more of a precise biology-driven model,” Dr. Chang said.

This includes the use of genomic sequencing, such as whole-exome sequencing and whole-genome sequencing. These tools can help identify rare genetic conditions earlier, especially when symptoms overlap with other diseases.

Electronic health records and AI-based pattern recognition may also help flag patients who could have been missed. 

But precision medicine still depends on access to testing and the healthcare systems around it.

“However, I will say that a genetic disease diagnosis does require an HCP to order a genetic test,” Dr. Chang said. “And there can often be a number of barriers to this, whether it be a lack of awareness of the correct genetic test to order, insufficient access to genetic counseling services or genetic testing services.”

Insurance barriers can also affect access to genetic testing. UCB spends time on education related to genetic testing and its role in diagnosing TK2d.

Regulatory Flexibility When Traditional Trials Are Not Feasible

Ultra-rare disease research also raises regulatory questions, particularly when a traditional Phase III trial is not possible.

UCB worked with regulators throughout the Kygevvi clinical development program. The company did not conduct a Phase III study, but the program had survival as a primary outcome and used a dataset that brought together prospective, retrospective and expanded access data.

“We did not have to do a Phase III study. So I think the proof is in the pudding.”

Dr. Chang observed that she has seen more flexibility over time in the regulatory acceptance of innovative trial designs, particularly when randomized trials are not feasible.

Flexibility could mean adapting the evidence model to the disease, available population and feasibility of different study designs.

“If it were 20 years ago, I don’t know that we would have been able to achieve regulatory approval with the current dataset,” she said.

The Biggest Accelerators: Real-World Evidence, AI and Patient Communities

Dr. Chang described the future as a convergence of changes in evidence design, data generation, real-world evidence and AI-driven targeting.

“Real-world evidence is really becoming core,” she said. “It is not supplemental to understanding diseases or therapies in the context of rare diseases.”

In rare and ultra-rare diseases, Dr. Chang said natural history studies and registries are increasingly being used as external control arms.

AI may also become part of that infrastructure, especially for patient identification.

“And then in the artificial intelligence world, the AI technology, it’s really moving from, I would say, hype over to infrastructure,” she said.

Patient identification is central in rare and ultra-rare diseases.

“We can’t generate the data if we don’t have the patients,” Dr. Chang said. “Finding patients earlier means faster trial enrollment, higher probability of success, more data and more opportunities in general.”

Patient advocacy groups also play a role in connecting rare disease programs with patients, families and specialist communities.

“We meet regularly with patient advocacy groups,” Dr. Chang said. “Some of our important partners include the UMDF [the United Mitochondrial Disease Foundation] and MitoAction.”

Both organizations support the mitochondrial disease community. UCB also works in close partnership with the Muscular Dystrophy Association.

In speaking with Dr. Chang, we hope that more flexible evidence generation and stronger patient-community connections are becoming part of how rare disease programs move forward.

“We at UCB are really excited about this approval and what it means for the patient community. We have a lot of interactions with advocacy groups, and we are here to help and support that community, and we’re proud to be part of this program.”