Review of new pharmacotherapies for Duchenne muscular dystrophy
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Approximately 16 of every 100,000 children are diagnosed with Duchenne muscular dystrophy. Diagnosis typically occurs in boys aged 2 to 3 years.
Duchenne muscular dystrophy (DMD) is a genetic alteration in the X chromosome of dystrophin, a vital protein of muscle fibers, manifesting as progressive muscle weakness and degeneration. DMD has no cure, and therefore, pharmacotherapy is focused on slowing disease progression and symptom management.
Cardiac complications of DMD
Due to medical advances, the maximum survival age has increased into patients’ 30s. Manifestations of DMD are now seen in adult patients and across various medical specialties. Complications of the cardiac system are one of the most common causes of morbidity and mortality in this population. Patients with DMD can develop cardiomyopathy resulting in left ventricular enlargement with LV wall thinning and reduced LV ejection fraction. Right ventricular function is most often preserved. Patients have increased risk for cardiac arrhythmias, most commonly sinus tachycardia, but atrial fibrillation and atrial flutter may also be seen. This often occurs with dilated cardiomyopathy or cor pulmonale due to the respiratory distress that can progressively occur in the underlying disease. Ventricular arrhythmias are found in 30% of patients, most often as premature ventricular beats. Once the heart and lungs are affected, the condition typically is life-threatening.
Management strategies
Management of DMD is complex and requires a multidisciplinary team for lifestyle modifications, physical aids and medication therapy. The most recent guidance documents from the DMD Care Considerations Working Group were published in 2018. There are many cardiac considerations for a patient with DMD, but usually the first cardiac medication initiated is for HF. The ideal time to initiate first-line HF therapy is still currently debated in the literature, but the most recent recommendation is to have initiated an ACE inhibitor or angiotensin receptor blocker once HF signs and symptoms manifest or no later than age 10 years. Beta-blockers can also be considered at this point if there is a demonstrated decrease in LV function. These medications can slow the cardiac disease course and should be titrated as tolerated.
The role of eplerenone combined with an ACE inhibitor in DMD HF is promising based on two studies demonstrating a slowing of LV function decline; however, the DMD Care Considerations Working Group recommends more studies be completed before a formal recommendation is made. If mineralocorticoid receptor antagonists like eplerenone are used, serum creatinine and potassium levels should be closely monitored. Some experts recommend using diuretics and digoxin as additional management of HF symptoms because a patient’s BP often does not allow titration of ACE inhibitors/angiotensin receptor blockers and beta-blockade. However, clinicians should bear in mind that intravascular volume and BP are potentially complicated by the corticosteroids commonly used to slow disease progression. Additionally, novel agents for the treatment of adult HF like sacubitril/valsartan (Entresto, Novartis) and ivabradine (Corlanor, Amgen) have potential benefits in DMD. However, they have not been studied in this patient population, and clinicians may find barriers with insurance coverage and affordability. Although outside the scope of this article, cardiology practitioners should also be aware of the risk for cardiomyopathy in female DMD gene carriers.
New medical therapies
Several new medications for DMD have been approved since 2016 due to advances in technology. One such focus in treating DMD is to use exon skipping to restore disrupted DNA for dystrophin protein production. Antisense oligonucleotides are used to mask these exons and allow the gene to be pieced together correctly. Not all patients with DMD are candidates for exon-skipping therapies, and they are not curative. However, they can improve muscle-related symptoms. Most of these have received accelerated approval by the FDA; however, robust clinical trials are ongoing to confirm clinical benefit in DMD.
Ataluren (Translarna, PTC Therapeutics), eteplirsen (Exondys 51, Sarepta Therapeutics), viltolarsen (Viltepso, NS Pharma), casimersen (Amondys 45, Sarepta Therapeutics) and golodirsen (Vyondys 53, Sarepta Therapeutics) are antisense oligonucleotides that have come to market or are being studied for future use. All these medications are dosed based on weight and require weekly injections. Their adverse event profiles vary but are typically self-limiting, such as headache, nausea and cough. These agents are renally cleared, yet dose-adjustment parameters are not currently known based on lack of studies or variation in serum creatinine measurements in patients with DMD. Patients with DMD have reduced skeletal muscle mass, therefore serum creatinine may not be a reliable measure of kidney function. This adds complexity to creating thresholds for dose adjustments. It is prudent to consider referral of these patients to a pediatric nephrologist for further evaluation. Additional monitoring parameters may apply depending on each specific medication (Table). All of these drugs are based on phosphorodiamidate morpholino oligomer chemistry, which results in their ability to affect gene correction and dystrophin expression in skeletal muscle and not cardiac tissue; therefore, impact on HF is limited.
Deflazacort (Emflaza, PTC Therapeutics) is a corticosteroid that was approved for DMD in 2017. This medication is also dosed by weight and comes in tablets or a suspension. It is a prodrug and a derivative of prednisone; therefore, the adverse event and monitoring profile are consistent with other corticosteroids. This includes effects on the patient’s intravascular volume and BP (Table). The standard of care is equivalent to 0.75 mg/kg per day of prednisone. The potency of prednisone to deflazacort is estimated to be approximately 1:1.3; 8 mg of deflazacort is similar to 6 mg of prednisone. There is some evidence that potency may be dependent on the disease state.
Finally, vamorolone (VBP15, ReveraGen Biopharma) is a first-in-class drug candidate that binds to the same receptors as corticosteroids but modifies the downstream activity of the receptors. It is currently undergoing phase 3 trials with the intention of stabilizing membranes, having eplerenone-like activity (in animal models) and reducing inflammation in patients with DMD without the harsh adverse events of corticosteroids. In an extension of the phase 2b open-label trial, vamorolone showed less growth retardation and other corticosteroid adverse events compared with published incidences of prednisone-treated patients. More evidence and clinical trial experience is needed before the full benefit of this drug is understood. Vamorolone is currently being reviewed by the FDA.
Close collaboration required
The disease course of DMD affects multiple organs and systems in the body. A close collaboration across a DMD patient’s treatment team, including cardiology, is imperative to the success of the treatment plan. Cardiac manifestations tend to happen later in the disease progression, but early screening and continued monitoring can ensure pharmacologic and nonpharmacologic modalities, which affect the disease course, are started in a timely fashion.
- References:
- Amondys 45 [package insert]. Cambridge, MA: Sarepta Therapeutics Inc.; 2021.
- Birnkrant DJ, et al. Lancet Neurol. 2018;doi:10.1016/S1474-4422(18)30024-3.
- Birnkrant DJ, et al. Lancet Neurol. 2018;doi:10.1016/S1474-4422(18)30025-5.
- Buddhe S, et al. Pediatrics. 2018;doi:10.1542/peds.2018-0333I.
- Conklin LS, et al. Pharmacol Res. 2018;doi:10.1016/j.phrs.2018.09.007.
- Emflaza [package insert]. Northbrook, IL: Marathon Pharmaceuticals, LLC.; 2017.
- Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics Inc.; 2016.
- Nayak S, et al. Indian J Dermatol. 2008;doi:10.4103/0019-5154.44786.
- Rajdev A, et al. Card Electrophysiol Clin. 2015;doi:10.1016/j.ccep.2015.03.011.
- Ryder S, et al. Orphanet J Rare Dis. 2017;doi:10.1186/s13023-017-0631-3.
- Smith EC, et al. PLoS Med. 2020;doi:10.1371/journal.pmed.1003222.
- Translarna [summary of product characteristics]. Dublin, Ireland: PTC Therapeutics International Limited; 2017.
- Vila MC, et al. Skelet Muscle. 2015;doi:10.1186/s13395-015-0070-6.
- Viltepso [package insert]. Paramus, NJ: NS Pharma, Inc.; 2020.
- Vyondys 53 [package insert]. Cambridge, MA: Sarepta Therapeutics Inc.; 2019.
- For more information:
- Brittany Florczykowski, BCPS, is a senior medical science liaison with Janssen Pharmaceuticals.
- Mark Huffmyer, PharmD, BCGP, BCACP, CACP, is on the Clinical Pharmacist Neurology Service Line at University of Kentucky Specialty Pharmacy Services and Infusion Services and assistant adjunct professor at University of Kentucky College of Pharmacy; Huffmyer can be reached at mark.huffmyer@uky.edu.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
Editor’s Note: This article was updated on Feb. 22, 2022 to correct the name of PTC Therapeutics, the manufacturer of deflazacort (Emflaza). The Editors regret the error.
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