Tadalafil Improves Microvascular Function in Duchenne Leg Muscles, Study Suggests

Sean Forbes, PhD

In a small-scale study of boys with Duchenne muscular dystrophy (DMD) treated with tadalafil, an FDA-approved vasodilator, results indicated that the therapy can rescue activity-dependent microvascular impairment in leg muscles. In addition, according to the study authors, the data support the use of post-contractile MRI blood oxygenation level dependent (BOLD) response to be used as a screening method for vascular responsiveness.¹

Led by Sean Forbes, PhD, a research assistant professor at the University of Florida Department of Physical Therapy, post-contractile BOLD response was quantified in the tibialis anterior following dorsiflexion contractions before and after 1 tadalafil dose (0.6 mg/kg) in 6 boys with DMD aged 8 to 13 years old. Results showed an increase in BOLD response after treatment, from 1.9% (SD, 1.6%) to 3.2% (SD, 0.8%) in DMD (P = .09), while the BOLD-response was 4.4% (SD, 1.7%) in unaffected controls.

Coming into the study, tadalafil had been previously assessed in a phase 3 study of DMD; however, results showed that the agent failed to improve patients’ 6-minute walk distance. Tadalafil also had no effect on secondary outcomes of North Star Ambulatory Assessment and timed function tests.2 Forbes and colleagues postulated that the lack of accounting for variable disease severity and/or a lack of sufficient daily muscle activity may have accounted for the negative findings.

In the latest analysis, presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, 4 of the 6 boys with DMD demonstrated tadalafil responsiveness. Among responders, the difference between pre and post-dosing was greater (Pre: 1.0% [SD, 0.4]; Post: 3.0% [SD, 0.9]; P <.05). Of the nonresponders, 1 patient had the highest pre-dosing BOLD response, suggesting muscle oxygenation was not limiting.

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In preclinical models, tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to boost defective NO-cGMP signaling in skeletal muscle microvessels, as well as prevent exercise-induced ischemia, injury, and fatigue in mdx mice. Short-term dosing of the therapy also ameliorates forearm muscle ischemia during handgrip exercise in boys with DMD and men with Becker muscular dystrophy, a milder form of dystrophinopathy.

In the previously published phase 3 study, a subgroup of boys aged older than 10 years declined less on total PUL score and shoulder subscore while on low-dose tadalafil than placebo. After 48 weeks, total PUL score declined by 4% with placebo vs 1% with low-dose tadalafil (P = .02) and shoulder subscore by 14% with placebo vs 4% with low-dose tadalafil (P = .004). This data raised 2 potential explanations for the negative primary outcome of the trial, investigators noted.

"Because DMD progresses faster in lower than in upper extremities, the boys in this trial may not have engaged in enough daily ambulation and fatiguing leg exercise for the drug to prevent use-dependent leg muscle injury," lead author Ronald G. Victor, MD, and colleagues, wrote. "In DMD, the therapeutic target of tadalafil, defective NO-cGMP signaling in skeletal muscle microvessels, regulates muscle blood flow only when the muscles are active.15–17 Because PDE5 levels were found in 1 study to be lower than normal in leg muscle biopsy tissue of 4 adult men with Becker muscular dystrophy,38 another possibility is that the cellular target of the drug (PDE5) was lacking in DMD leg muscle microvessels."

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REFERENCES
1. Forbes S, Taivassalo T. Assessing leg vascular responsiveness to tadalafil using MRI in boys with DMD: implications for adjuvant vasodilator therapy. Presented at: MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. POSTER S70.
2. Victor RG, Sweeney HL, Finkel R, et al. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Neurology. 2017;89(17):1811-1820. doi:10.1212/WNL.000000000004570.