PERTH, Australia – On the heels of a $1.15 billion deal between Roche Holding AG and Sarepta Therapeutics Inc. for Sarepta’s gene therapy to treat Duchenne muscular dystrophy (DMD), another therapy to treat DMD is emerging from Down Under.

Melbourne-based Antisense Therapeutics Ltd. reported positive results from a phase II trial that showed its immunomodulatory therapy, ATL-1102, met the primary disease progression endpoints at the low dose tested, and it plans to advance the compound into a phase IIb trial that it hopes will be a pivotal trial. 

Conducted at Melbourne Royal Children’s Hospital, the primary objective was to assess the safety and tolerability of 25 mg of ATL-1102 administered once weekly (subcutaneous injection) for 24 weeks in nine non-ambulatory DMD patients. The trial also assessed drug activity and efficacy, including measuring the effects on immune cell numbers in the blood and measuring functional capacity in participants.

The company reported that ATL-1102 was safe and well-tolerated. No serious adverse events were reported, and no patients withdrew from the study. The most common adverse events were related to the subcutaneous administration of the drug, mainly injection site erythema and skin discoloration. 

ATL-1102 is an inhibitor of CD49d expression on T lymphocytes. Studies have shown that DMD patients who have a greater number of T cells with high levels of CD49d have more severe and rapid disease progression. ATL-1102 is the only DMD drug in clinical development that targets CD49d and one of a very limited number of treatments being tested in wheelchair-bound boys with DMD who are at a more advanced stage of the disease. 

The study showed mean reductions in the number of lymphocytes and types of lymphocytes (CD3, CD4, CD8 and those expressing CD49d) measured from baseline to the 24-week treatment period, with a return to around starting levels after week 28. The mean number of CD3+CD49d+ T cells at week 24 was significantly lower compared to week 28 (p=0.030 paired T test).

Bioshares analysts reported that the results were “particularly encouraging,” with a median drop of 9.78% in CD3+CD49d+ T cells at 24 weeks.

“Importantly, just four weeks after treatment had stopped, this level increased to a net increase of 9.93% from baseline, which confirms the mechanism of action of this drug candidate,” the analysts said.

“We had high expectations for ATL-1102 in DMD, and this first study has certainly exceeded them with respect to its efficacy signal at the lower dose tested,” said Antisense Therapeutics CEO Mark Diamond.

The trial also assessed drug activity and efficacy, including measuring functional capacity as evaluated via Performance of Upper Limb Test (PUL2.0) and upper limb strength via Myogrip and Myopinch assessments.

Seven of the nine participants demonstrated either increases or no change in their PUL2.0 scores from baseline, suggesting an overall improvement with a positive mean change of 0.9. Three patients saw a clinically meaningful amount on both PUL and grip strength. Another patient had a similar clinical improvement on PUL2.0 alone and three patients stabilized on that parameter. 

Myogrip and Myopinch assessments using the Myoset system showed a distinct improvement in muscle strength based on the observed mean changes from baseline compared to the loss of muscle strength.

DMD occurs as a result of mutations in the dystrophin gene that causes a reduction in or absence of the dystrophin protein that makes muscles susceptible to injury and triggers the immune system, which exacerbates muscle damage. Ongoing deterioration in muscle strength affects lower limbs, leading to impaired mobility, as well as further loss of function to upper limbs.

The need for wheelchair use can occur in early teenage years for patients on corticosteroids with a mean age of 13, with respiratory, cardiac and cognitive dysfunction also emerging. Patients with a greater number of immune T cells expressing high levels of CD49d have more severe and progressive disease and are wheelchair-bound by the age of 10, despite being on corticosteroid treatment, according to the Pinto-Mariz study published in 2015. 

“Disease stabilization or indeed improvement in functional scores in non-ambulant DMD boys is almost unheard of and a very encouraging result,” said Thomas Voit, director of the National Institute for Health Research for Great Ormond Street Hospital Biomedical Research Centre in the U.K.

“This is even more meaningful as these results have been obtained using different independent measures and over a relatively short trial time of 24 weeks. These results also advise on endpoint choice for a fully powered placebo-controlled registration-enabling study,” said Voit, who is also a study author on the Pinto-Mariz study.

The phase II follow-up period is continuing with the last two patients in the monitoring phase. The last participant last visit for the study will be in the beginning of January, with the final study report to be prepared following trial database lock in the first quarter of 2020.

“The next stage of development will be in translating what we have learned into optimizing clinical benefit for the non-ambulatory boys who comprise about 50 percent of the total DMD population and who have no effective treatment options,” said Diamond.

Moving forward with phase IIb registration study

To that end, the company is moving forward to advance ATL-1102 to a blinded controlled phase IIb study in the EU that may lead directly to early approval, he said.

Over the recent months, Antisense Therapeutics has held scientific advice meetings with three European regulatory authorities with a focus on the phase IIb trial design, dose-escalation plans, applicability of the study endpoints and the study duration.

There was general acceptance by the agencies on the proposed trial efficacy endpoints (PUL2.0, Myoset), safety monitoring plan, dosing duration (12 months) and the use of higher doses. Regulators indicated the study could be a path to an early approval on positive phase IIb results.

The next step will be to follow up the development plan with the EMA and, subsequent to the finalization of the results from the current phase II trial, engage with the FDA on development plans for the U.S.

Antisense Therapeutics in-licensed its antisense therapies from Ionis Pharmaceuticals Inc.

ATL-1102 also completed a phase II efficacy and safety trial that saw significant reductions in the number of brain lesions in patients with relapsing-remitting multiple sclerosis. That study used a higher dose of 400 mg per week.

Bioshares analysts said the stock would be “responsive to the company’s confirming the design of the phase IIb study, receiving regulatory and ethics clearance for the trial, completing manufacture of drug material for the study, and results of discussions with regulatory agencies.”

With a market cap of AU$42 million (US$29.4 million), Antisense Therapeutic shares were trading on Australia’s Securities Exchange (ASX:ANP) at AU9 cents per share on market close Tuesday.

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