Long-Term Safety and Efficacy of Systemic DT-DEC01 Cell Therapy in Non-Ambulatory Duchenne Muscular Dystrophy Patients: A 24-Month Clinical Evaluation

Major Points and Findings:

This paper reports three non-ambulatory boys with Duchenne muscular dystrophy (DMD) in Poland who each received one dose of DT-DEC01, a personalised product made by fusing the boy’s own muscle cells with muscle cells from a healthy relative. The cells were infused into bone under general anaesthesia. No treatment-related adverse events were recorded over 12 to 24 months, and the authors report improvements in arm function, grip, breathing tests and heart ultrasound.

We include it because it is one of the few recent clinical reports of a myoblast-based therapy in DMD, and families will come across it. The results call for great caution. The study had three patients, no control group and no blinding. The study was funded by the company that owns the product, and every author is either a shareholder, an employee or was paid for work on the study. The paper gives no trial registration number. An independent review published two months earlier (Łoboda and Dulak, also summarised on this site) singles out this approach as scientifically unsupported. Both the cell type and the route differ from anything used at our clinic.

Aim:

To evaluate the safety and exploratory efficacy of a single systemic intraosseous dose of DT-DEC01 in non-ambulatory DMD patients over up to 24 months.

Methods:

This was a single-centre, open-label pilot study in Poznań, approved by the local bioethics committee (approval 46/2019). Under “Clinical Trial Number” the paper states “Not applicable”.

Eligibility required age 5 to 18, genetically confirmed DMD, and evidence of progressive motor deterioration. Current immunosuppressive therapy or recent participation in another drug study led to exclusion. The three boys enrolled were:

• Patient 1: 15 years old, deletion of exons 48 to 50, dose 2 million cells per kg
• Patient 2: 11 years old, deletion of exon 52, dose 4 million cells per kg
• Patient 3: 16 years old, nonsense mutation, dose 6 million cells per kg

The paper does not say whether the boys were taking corticosteroids or heart medication, or whether these changed during follow-up.

To make the product, muscle biopsies were taken from the boy and from a healthy related donor, who was screened by medical history and infection blood tests. Myoblasts from each were grown, fused in the laboratory using polyethylene glycol, sorted by flow cytometry to select the fused “dystrophin expressing chimeric” cells, and expanded under GMP conditions. Each batch was made for one patient only.

Each boy received a single infusion into bone under general anaesthesia. No immunosuppression was given.

Adverse events and donor-specific anti-HLA antibodies were assessed at 1, 3, 6, 12, 18 and 24 months. Exploratory measures at the same visits were Performance of Upper Limb (PUL 2.0), grip strength, motor unit potential duration on electromyography (EMG), echocardiography (ejection fraction and fractional shortening), spirometry, and daily arm movements counted by a consumer wrist-worn activity tracker.

Results:

Patients 1 and 2 completed 24 months of follow-up. Patient 3 completed 12 months.

Safety: No study-related adverse events or serious adverse events were recorded, and none of the three boys developed donor-specific antibodies. The paper does not list adverse events judged unrelated to the treatment, and does not describe whether there were any complications of the muscle biopsies or the anaesthetic.

Patient 1: Total PUL was up 25% at 18 months, then 5% above baseline at 24 months. Grip strength was up 22% (right) and 26% (left) at 6 months, then 6% and 3% above baseline at 24 months. Ejection fraction rose 6% and fractional shortening 12% at 18 months. Forced vital capacity (FVC) was up 28% at 12 months and 17% at 24 months, and percent-predicted FVC went from 70% to 90%. Daily arm movements were up 185% at 12 months and back to baseline at 24 months.

Patient 2: Total PUL was up 15% at 12 months and 5% at 18 months. Left grip was up 22% at 24 months. Ejection fraction rose 11% and fractional shortening 17% at 12 months. FVC was up 71% at 18 months and 59% at 24 months, and percent-predicted FVC went from 38% to 48%. Recorded daily arm movements were up 1,150% at 24 months.

Patient 3: Total PUL was up 12% early on and 6% at 12 months. Left grip was up 34% at 12 months. Ejection fraction rose 7% at 12 months. The baseline breathing test was judged unreliable, so the 1-month result after treatment was used as baseline instead. Percent-predicted FVC was then 56% at 1 month and 51% at 12 months. Arm movement counts stayed near baseline.

On EMG, motor unit potential duration increased in all muscles tested, by as much as 402% in one muscle at one visit, with wide swings from visit to visit.

The authors describe “moderate to strong” correlations between grip strength, PUL and EMG changes (r from 0.549 to 0.780). None was statistically significant (p from 0.068 to 0.259).

Conclusions:

The authors conclude that DT-DEC01 showed a favourable long-term safety profile and sustained functional benefits, and that it has potential as a universal, mutation-independent therapy. They acknowledge the small sample size and call for larger phase II trials with dose expansion, biomarker analysis and longer follow-up.

Background Information:

Several features of the study limit what can be concluded from it.

• The three boys each received a different dose, and there was no comparison group. Effort-dependent tests such as spirometry, grip and PUL vary with growth, practice and motivation. A boy growing from 11 to 13 will increase his absolute lung volume through growth alone. Everyone involved knew the treatment had been given.
• Most gains peaked and then fell back. In Patient 1, PUL, grip and arm movement were close to baseline again by 24 months. The figures quoted most prominently usually come from the best single visit and not from the last one.
• Some figures are inconsistent within the paper. The discussion cites ejection fraction gains “of up to 18%” and a PUL gain “of up to 25% at 12 months”. The results section reports a maximum ejection fraction gain of 11%, and the 25% PUL gain at 18 months. This summary follows the results section.
• The comparison with deramiocel is out of date. The paper describes deramiocel as having shown insufficient efficacy. It was published before the 106-patient, placebo-controlled HOPE-3 trial reported a positive primary result. Three open-label patients cannot in any case be compared directly with one arm of a blinded trial.
• Conflicts of interest are extensive. The study was funded by Dystrogen Therapeutics. The first author is its chief medical officer, a shareholder and the inventor on the patent application. Another author is its chief executive and a shareholder. Two are employees, and the remaining five received fees for work on the study.
• The biological rationale is disputed. Independent reviewers point out that myoblasts have repeatedly been shown not to pass from the bloodstream into muscle. The paper measured no dystrophin in the patients’ muscles, so it cannot show that the cells reached muscle or produced dystrophin there.

The authors suggest the effects may come from mechanisms other than muscle replacement, such as transfer of healthy mitochondria, paracrine signalling or immune modulation. These remain hypotheses. The report describes an early, uncontrolled series run by the company, and a randomised trial would be needed before any of the reported benefits could be relied on.