Applying Doxecitine and Doxribtimine in Real-World Clinical Practice

Body text: The approval of doxecitine and doxribtimine represents an important milestone for patients with thymidine kinase 2 deficiency, but regulatory approval is only the beginning of integrating a new therapy into routine clinical practice. As awareness of the disease grows, neurologists and neuromuscular specialists will play a central role in identifying appropriate patients, initiating treatment, and coordinating long-term care.

In this final installment of the 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, reflects on the practical lessons learned from decades of studying TK2 deficiency. He discusses the challenges clinicians are likely to encounter as the therapy becomes more widely adopted and outlines the principles that will help maximize patient outcomes.

This episode explores what comes next for the field, from improving recognition of TK2 deficiency and streamlining treatment initiation to emphasizing multidisciplinary management throughout the disease course. Hirano also shares his perspective on future research, including the promise of gene therapy and combination treatment strategies that could further improve outcomes for patients with this ultra-rare mitochondrial disease.

As this therapy becomes incorporated into clinical practice, most neurologists are still unlikely to see many patients with TK2 deficiency. Even so, what challenges and unanswered questions do you think we'll need to address over the next several years as this therapy becomes more widely adopted?

Okay. It's great that Kyevbi is now commercially available in both the United States and Europe. I think the first challenge is identifying patients. This disease is still underdiagnosed because many physicians, including neuromuscular specialists, are not yet familiar with TK2 deficiency. When evaluating patients who appear to have spinal muscular atrophy or Pompe disease, clinicians should also consider TK2 deficiency in the differential diagnosis because it can present very similarly, with weakness beginning anywhere from infancy through adulthood and early respiratory involvement. Like those other neuromuscular disorders, TK2 deficiency is now a treatable disease, so recognizing it is the critical first step.

Diagnosis can be established through genetic testing using many commercially available neuromuscular gene panels, but it is important to ensure that TK2 is included on the panel. Whole exome sequencing is another option. Once the diagnosis is confirmed, clinicians must also become familiar with initiating therapy. UCB has established the Onward program to help patients and providers complete the necessary enrollment forms, obtain payer authorization, and begin treatment.

The medication itself requires some education because it is supplied as a powder in sachets rather than as tablets. It must be mixed with water daily and administered orally three times each day. Treatment also requires gradual dose escalation, beginning at 260 mg/kg/day for the first 2 weeks, increasing to 520 mg/kg/day for another 2 weeks, and then advancing to the full dose of 800 mg/kg/day if tolerated. As we discussed earlier, diarrhea is the most common adverse event, so learning how to manage that side effect is an important part of treatment.

TK2 deficiency should be viewed as a chronic disease, and clinicians need to recognize it across all stages of illness, preferably as early as possible so treatment can begin before significant muscle destruction and fibrofatty replacement occur. Early diagnosis and early initiation of therapy are critical because outcomes are much better when treatment begins before irreversible muscle damage has developed.

Management also requires a multidisciplinary approach. Neurologists play an important role in monitoring treatment response, but patients also benefit from physical therapy, which can help maximize functional improvements. Those with dysphagia should receive evaluation from speech and swallow specialists, including swallow studies and feeding tube placement when appropriate. Early pulmonary assessment is also essential because respiratory muscle involvement is common, making pulmonologists important members of the care team. Clinicians should continue to monitor treatment response while also following liver enzymes and managing diarrhea, the most common adverse effect of therapy.

Looking ahead, we now have patients who have remained on this therapy for as long as 15 years, and it continues to appear safe. However, because this is still a relatively new treatment, long-term monitoring remains important. It is also important to remember that this therapy is not a cure. It can stabilize disease and produce meaningful improvements, but patients still require ongoing multidisciplinary care and long-term treatment.

There is also reason to be optimistic about the future. We have demonstrated in a mouse model that gene therapy is effective for TK2 deficiency, and even more encouraging, combining gene therapy with nucleoside therapy produced substantially greater benefit than either approach alone. While pharmacologic therapy alone doubled or tripled survival in the mouse model, combining it with gene therapy extended survival by more than 30-fold. We hope to pursue this strategy in the future, but for now, we are very pleased with the meaningful impact that pharmacologic therapy is already having for patients.