Clinical deep dive 

DMD is a severe, X-linked condition characterized by progressive muscle degeneration and weakness. It is caused by variants in the DMD gene, which result in the absence of dystrophin protein and lead to degeneration of muscle fibers. Approximately 2:3 of DMD cases result from inheritance from carrier mothers, while 1:3 develop the condition due to de novo mutations. The condition affects both skeletal and cardiac muscle. As such, life-threatening cardiac and respiratory complications may arise as the disease progresses. Patients with DMD develop muscle weakness and atrophy in muscles close to the trunk such as those in the upper legs, pelvic area, upper arms and shoulder area. Muscle weakness and atrophy spread to the lower legs, forearms, neck and trunk as the condition advances. Most patients progress to require a wheelchair by their teenage years. 

Cardiovascular complications are a leading cause of disease-related morbidity and mortality in patients with DMD. In the heart, dystrophin deficiency manifests clinically as a cardiomyopathy. As the condition advances, the myocardium is unable to meet physiological demands. As a result, heart failure onsets. In this state, patients are also at risk of life-threatening rhythm abnormalities.

DMD is the most common childhood onset muscular dystrophy, and it is nearly exclusive to male patients. The typical age of onset is between 3 and 5 years of age. DMD is estimated to occur in approximately 1: 3,500 live male births. In North America, the prevalence is approximately 6:100,000 people. According to the manufacturer, the affected population is estimated at approximately 15,000 to 20,000 patients in the United States. Moreover, approximately 25% of patients with DMD will develop cardiomyopathy by the age of 6 and 59% by the age of 10. 

There is currently no curative treatment for DMD. Corticosteroids are standard of care for DMD treatment to slow the progression of musle weakness (e.g., prednisone, deflazacort [Emflaza], vamorolone [Agamree]). Additionally, exon skipping therapies (eteplirsen [Exondys 51], golodirsen [Vyondys 53], viltolarsen [Viltepso], casimersen [Amondys 45]), the gene therapy delandistrogene moxeparvovec-rokl (Elevidys) and the histone deacetylase inhibitor givinostat (Duvyzat) are FDA approved for the treatment of DMD in select patients.  

In terms of cardiac management, the DMD Care Considerations Working Group recommendeds traditional treatment strategies for heart failure due to the lack of dystrophin-specific targeted cardiac treatments. The National Heart, Lung, and Blood Institute (NHLBI) Working Group recommends that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are initiated by 10 years of age. Because ACE inhibitors and ARBs have relatively low risk, earlier therapy should not be discouraged. Regardless of age, pharmacologic therapy is recommended once heart failure symptoms develop or when cardiovascular abnormalities are observed on imaging studies (e.g., depressed left ventricular ejection fraction [LVEF], abnormal chamber dimensions, or the presence of myocardial fibrosis). β-adrenergic blockade therapy is often initiated with evidence of ventricular dysfunction. Additionally, eplerenone has shown an attenuation of the decline in cardiac function, but the use of mineralocorticoid receptor antagonists varies in clinical practice. 

Drug and clinical trial overview 

The safety and efficacy of deramiocel was evaluated in a randomized, multicenter, double-blind, placebo-controlled Phase 2 trial. The HOPE-2 trial enrolled late ambulatory and non-ambulatory male patients with genetically confirmed DMD who were 10 years of age or older. Patients were eligible for enrollment if they had a Performance of Upper Limb (PUL) entry item score between 2 and 5, which corresponds to loss of full overhead reach but preserved hand-to-mouth function. Additionally, patients were required to be receiving treatment with a glucocorticoid for at least 12 months. Patients with a LVEF < 35% were excluded. Eligible patients were randomly assigned in a 1:1 fashion to receive either deramiocel at a dose of 1.5x10⁸ CDCs or placebo IV every three months for a total of four infusions. Twenty patients were randomized; eight were assigned to deramiocel, and 12 were assigned to placebo. The primary efficacy endpoint was the change from baseline to 12 months in the mid-level elbow dimension of the PUL 1.2 instrument. At the primary endpoint, the mean change from baseline in mid-level PUL 1.2 favored deramiocel (-0.8 points for deramiocel vs. -3.4 points for placebo; p = 0.014). Additionally, the secondary endpoint of regional systolic left ventricular wall thickening was assessed by cardiac magnetic resonance imaging (cMRI) at months six and 12. This endpoint did not statistically favor deramiocel over placebo. In the HOPE-2 trial, cMRI assessments demonstrated improvements in heart function and structure for deramiocel-treated patients, which were exploratory endpoints. LVEF decreased over time in the placebo group while patients treated with deramiocel improved marginally; at month 12, patients treated with deramiocel had a mean increase in LVEF of 0.1 percentage points, while patients in the placebo group experienced a mean decrease in LVEF by 3.9 percentage points. The exploratory outcomes of left ventricular end systolic and end diastolic indexed volumes favored treatment with deramiocel (least square mean difference in percentile ranked change of 53.1 mL/m² and 47.8 mL/m², respectively) as compared to placebo. Creatine kinase (CK)-MB, another exploratory endpoint, decreased in patients receiving deramiocel, which was indicative of decreased cardiac muscle damage. Treatment was generally well-tolerated, and no deaths were reported during the trial. There were no cases of acute respiratory decompensation or immune sensitization syndrome. Seven treatment-emergent adverse events (TEAEs) were deemed related to the investigational product or the administration procedure. In three patients receiving deramiocel, five hypersensitivity reactions were reported. 

Additionally, the manufacturer has reported three-year data from the ongoing HOPE-2-OLE trial. After the one-year HOPE-2 trial, patients entered an off-treatment gap phase, which averaged approximately 392 days. Subsequently, patients could enter the HOPE-2-OLE trial. In the HOPE-2-OLE trial, 12 non-ambulant patients from the HOPE-2 trial received treatment with deramiocel (five in the original deramiocel arm and seven in original the placebo arm). Over 36 months, patients treated with deramiocel had a modeled yearly decline in the PUL v2.0 total score of 3.46 points, while the external comparator (EC) group showed a mean decline of 7.19 points. Median changes in LVEF in all patients undergoing cMRI (n = 10) demonstrated an improvement of 1.9 percentage points in patients treated with deramiocel after 24 months. This improvement was maintained after 36 months of therapy, as demonstrated by a median 1.2 percetage point improvement. A subgroup analysis was performed in patients with an initial LVEF > 45%. In this patient population, a median improvement of 3.1 and 3.0 percentage points was seen at 24 and 36 months, respectively. In comparison, an EC displayed a median decline in LVEF of 5.0 percentage points over 24 months. In patients with LVEF > 45%, this correlates to a difference of 8.1 percentage points in LVEF at 24 months. Additionally, improvement or stabilization was seen in end systolic and end diastolic indexed volumes in patients treated with deramiocel as compared to EC. No new safety signals were reported.