Gene therapy being conducted by a US-based life science company to treat Duchenne’s muscular dystrophy (DMD) will not offer a cure but may stop the disease in its tracks, according to experts.

Solid Biosciences’ (NASDAQ: SLBD) gene therapy for DMD, SGT-001, is unlikely to be curative as the dystrophin produced as a result of the gene transfer will not replace or correct damage to muscles, experts explained.

While an analyst report noted the company aims to provide curative treatments for DMD, experts say on this occasion the gene therapy is not expected to reverse the effects of the disease.

However, experts said they were impressed with animal model results, adding that the ongoing IGNITE DMD Phase I/II trial (NCT03368742) is likely to produce data to support SGT-001’s ability to halt the progress of the disease.

The mice data can be translated to humans, said two experts, while the third noted the canine results are more transferable.

Clinical trial put on hold, now lifted, says Solid Bio

In March 2018, an IGNITE DMD trail was put on clinical hold after the first patient dosed was hospitalised due to laboratory findings of a decrease in platelet and red blood cell count as well as complement activation. Experts said this issue has since been addressed and is no longer a concern.

The platelet count decreases proved to be transient and the patient showed no abnormal clinical outcomes, experts said. While that patient received 5E13 vg/kg dose of SGT-001, experts said that the optimal dose will likely be 2E14 vg/kg.

In June, Solid Bio announced the lifting of IGNITE DMD’s clinical hold.

Pre-clinical data reassuring for Phase I/II success of SGT-001

Preliminary data, including microdystrophin expression results from the Phase I/II trial are due in the first quarter of 2019, according to Solid Bio’s third quarter 2018 business update.

The trial’s start date was 6 December 2017 and its primary completion date is in March 2020, according to, an online resource. Solid Biosciences did not respond to request for comment.

SGT-001 is an adeno-associated virus (AAV) microdystrophin gene transfer candidate that delivers a synthetic, functional version of the dystrophin gene. While the restoration of dystrophin is better than nothing, the dystrophin will be highly modified and will not be full length or fully functional, according to Steve Wilton, Foundation Chair in Molecular Therapy at the Neuromuscular Research Institute at Murdoch University, Australia.

Fully functional dystrophin is not completely restored, because AAV vectors will remain in muscles as episomal DNA elements, but will be gradually lost over many years due to normal muscle turnover, said Jeffrey Chamberlain, Professor of Neurology, Biochemistry and Medicine of the Division of Medical Genetics at the University of Washington, Seattle.

In addition, a gene therapy approach will not repair already damaged muscle, said Mr Wilton. Patients older over seven will have some muscle damage, which will not be repaired via a gene therapy approach, he said. The Phase I/II is enrolling patients from age 4–17, according to the website.

Reversal of existing DMD damage not likely, say experts

Once the muscle is stabilised, there may be some functional improvements, but a major reversal of existing damage is not likely, said Dominic Wells, Professor in Translational Medicine, Comparative Biomedical Science at the Royal Veterinary College, University of London.

While restoration of dystrophin in muscle fibres is likely to prevent further damage, lost muscle fibres are unlikely to be replaced and fibrotic muscle is unlikely to be repaired by endogenous remodelling, Mr Wells said.

However, SGT-001 is expected to stop the progress of the disease, experts agreed. The MDX mouse data were impressive, they said, pointing to the reduction in creatinine kinase as well as improvements in functional measures like treadmill distance and forelimb grip strength.

Also, the mass spectrometry data showed an above 50% increase in microdystrophin in the heart and quadriceps, which is more than the 15–20% that an MDX mice study showed is needed to halt disease progression, said both Mr Wells and Mr Chamberlain.

The only primary efficacy endpoint in Phase I/II, according to, is a change from baseline in microdystrophin protein in muscle biopsies among the three patients in the active group. The three patients in the untreated control arm will receive SGT-001 after one year on the study if they meet treatment criteria.

The mouse data leads to expectations that there will likely be a halt in disease progression in patients, Mr Chamberlain and Mr Wells said.

Pre-clinical data offers encouragement to Solid Biosciences

Sarepta Therapeutics’ (NASDAQ: SRPT) preclinical data are translating into clinical trials, which is also encouraging and supportive that pre-clinical success can signal efficacious results in humans, Mr Chamberlain said.

Sarepta’s Phase I/II AAVrh74.MHCK7 trial (NCT03375164) demonstrated 76.2% microdystrophin gene expression, a 38.2% mean level of microdystrophin and a more than 87% decrease in creatinine kinase, according to a company press release of June 2018.

Yet, Mr Wilton said, mice data cannot be extrapolated to humans, as mice are still highly mobile despite having muscle dystrophy. Canine models are better, as their mobility is far more affected by the disease, he explained.

The canine model showed strong improvements in functional measurements with respect to extension torque and flexion torque after 90 days and increases in dystrophin biodistribution across a range of muscle areas, said Mr Wilton.

Also providing optimism for Phase I/II success is the canine data, showing above the clinical benchmark of 15–20% microdystrophin in all areas (the biceps, heart and diaphragm), Mr Chamberlain and Mr Wilton said.

However, Mr Wells pointed out the lack of wild-type canine data makes the dystrophin increases difficult to interpret.

Optimal clinical dose likely to be 2E14

While the platelet increases in the first dosed patient — a nonambulatory adolescent — is no longer a concern, Mr Wells said monitoring must be continued and complement activation would pose a serious safety issue.

In lifting the clinical hold, IGNITE DMD patients will receive IV glucocorticoids in the initial weeks post-administration of SGT-001 and there will be enhanced monitoring measures that include a panel for complement activation, the company announced in June.

The amended protocol also specifies that Alexion Pharmaceuticals‘ (NASDAQ: ALXN) Soliris (eculizumab) will be available as a treatment option if complement activation is observed. Additionally, children aged 4–11 will be offered a dose before additional adolescents (aged 12–17), according to an analyst report.

Post-clinical safety concerns not long lasting

IGNITE DMD is assessing several safety endpoints as primary measures. It is a single-ascending dose study testing 5×10^13, or 5E13 vg/kg, then 2E14 vg/kg and finally 4.5E14 vg/kg.

The 2E14 vg/kg dose has been used in other human trials, most notably for children with spinal muscular atrophy type 1, and has proven to be safe, said Mr Chamberlain and Mr Wells.

However, the higher dose of 4.5E14 vg/kg has not yet been tested in humans and based on preclinical data, 2E14 vg/kg shows most of the clinical benefit while doubling the dose did not see a proportional increase in clinical benefit, said Mr Wells and Mr Chamberlain. It is not necessary to increase the dose beyond 2E14 vg/kg, Mr Wilton added.

by Mina Moawad in London

Mina Moawad is a reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.