Safety Considerations for the First Approved Therapy in TK2 Deficiency

Body text: With the efficacy of doxecitine and doxribtimine now established, understanding how to safely administer the therapy is equally important as clinicians begin incorporating it into routine practice. Although the treatment has demonstrated meaningful improvements in survival and functional outcomes, appropriate monitoring and dose adjustments remain essential to maximizing long-term benefit.

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 efficacy and safety findings that supported regulatory approval of the first disease-modifying therapy for thymidine kinase 2 deficiency. Throughout the series, Hirano offers practical guidance to help clinicians translate these findings into real-world patient care.

In this episode, Hirano reviews the therapy's safety profile, including the most commonly reported adverse events and how they can be managed in clinical practice. He also emphasizes an important clinical perspective on efficacy, noting that for many patients with this relentlessly progressive disease, stabilization itself represents a meaningful therapeutic success, particularly among adults with more slowly progressive disease.

Edited transcript: Before we move to safety, I'd like to go back to one efficacy point. While many patients experienced improvements in motor milestones, some, especially older adults, experienced stabilization of their disease. That is also a significant clinical victory because TK2 deficiency is naturally a progressive disease. Preventing further decline is an important outcome for these patients, so I wanted to emphasize that point.

Now, regarding safety, this therapy is generally well tolerated. The most common adverse event is diarrhea, which was reported in more than 80% of patients. In most cases, it is self-limited and can be managed with antidiarrheal medications such as loperamide. Taking the medication with meals can also help lessen the diarrhea.

Occasionally, if the diarrhea becomes severe, we pause treatment and then restart the medication at a lower dose. This is more commonly necessary in larger adult patients because they require higher doses of the therapy. Even at reduced doses, however, patients can still experience meaningful clinical benefit, so we often titrate the dose according to what each individual can tolerate.

A smaller number of patients develop elevations in liver enzymes, particularly transaminases. Interpreting these laboratory findings can be challenging in patients with myopathy because both creatine kinase and transaminases may be elevated. For that reason, we also measure gamma-glutamyl transferase, or GGT, to help determine whether the elevated transaminases are truly originating from the liver.

If transaminase levels increase to more than three to five times the upper limit of normal, we may temporarily stop treatment to allow the liver to recover before restarting the medication at a lower dose. Permanent discontinuation has been very uncommon. At least two patients treated in Spain ultimately stopped therapy because of recurrent elevations in transaminases, but overall, these cases have been rare.