Understanding the Clinical Development Strategy Behind Doxecitine and Doxribtimine

Body text: 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 (TK2d), 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.

In this NeurologyLive® Special Report, Michio Hirano, MD, professor of neurology at Columbia University Irving Medical Center and a lead author of the pivotal Brain Communications publication, discusses the integrated clinical evidence that supported the approvals of doxecitine and doxribtimine. Throughout the series, Hirano provides insight into how years of collaborative research and clinical investigation ultimately established the first approved therapy for patients with TK2 deficiency.

In this episode, Hirano explains why the clinical development program relied on compassionate use programs, an open label phase 2 study, and carefully assembled historical controls rather than a placebo-controlled trial. He discusses how investigators were able to collect meaningful efficacy and safety data across multiple international sites and why the strength of the observed survival and functional outcomes ultimately supported regulatory approval despite the unconventional study design.

Edited transcript: The development of this therapy, now called Kygevvii, was unconventional, to say the least. As I mentioned earlier, 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, as I mentioned earlier, 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. This allowed us 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. As a result, 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. We 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.

Overall, 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.

Those analyses demonstrated that the therapy clearly improved survival and also led to recovery of motor milestones in many patients. So it was certainly an unconventional development program, but it generated compelling evidence that the therapy produced meaningful clinical benefit. I believe that is ultimately why it was successful in obtaining approval from both the FDA and the European Medicines Agency.