Conducting rigorous clinical trials in ultra-rare diseases presents unique scientific and ethical challenges that often require investigators to rethink traditional study designs. For thymidine kinase 2 deficiency, where disease prevalence is exceptionally low and untreated early-onset disease is associated with rapid progression and high mortality, conventional randomized placebo-controlled trials were not a practical or ethical option.
According to the report, Michio Hirano, MD, professor of neurology at Columbia University Irving Medical Center, discusses the integrated clinical evidence that supported the approvals of doxecitine and doxribtimine.
The development of this therapy, now called Kygevvii, was unconventional. Patients were initially treated on a compassionate use basis at academic centers, predominantly in Spain and the United States, but also in several other countries.
Many patients were treated under different protocols at their individual academic sites. Fortunately, a biotechnology incubator company became involved and was able to establish a unified protocol that transitioned most of these patients from compassionate use into a single phase 2 open label study.
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This allowed investigators to collect data according to industry standards that could ultimately support regulatory review by the FDA. After those initial patients entered the phase 2 trial, there were two additional open label compassionate use programs sponsored by the pharmaceutical companies.
The overall development program combined data from compassionate use studies and the phase 2 trial to evaluate efficacy and safety. Because there was no placebo arm, comparisons had to be made using historical controls.
Investigators believed that conducting a placebo-controlled trial would not have been ethical, particularly after observing such dramatic improvements in survival among patients with early-onset disease. Instead, the company used several sources of historical controls, including patients’ natural history before treatment, previously published cases in the literature, and patients identified through a rigorous international survey of clinicians.
Those analyses demonstrated that the therapy clearly improved survival and also led to recovery of motor milestones in many patients. The company identified 257 patients with TK2 deficiency, which is remarkable considering the disease has an estimated incidence of approximately 1.6 cases per million people.
Of those patients, 104 participated in the phase 2 study or one of the open label compassionate use programs, while the remaining untreated patients served as comparators. This development program generated compelling evidence that the therapy produced meaningful clinical benefit.
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In practice, this development means that patients with TK2 deficiency now have a therapeutic option that can significantly improve their survival and motor function. This is particularly important for patients with early-onset disease, who previously had limited treatment options and a poor prognosis.
The therapy was successful in obtaining approval from both the FDA and the European Medicines Agency.
It is an achievement that will have a lasting impact on the lives of patients with TK2 deficiency.
Regulatory bodies played a key role in this process.