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DYNE-101 Continues to Show Success in Early-Stage ACHIEVE Trial of Myotonic Dystrophy
DYNE-101 demonstrated dose-dependent splicing correction, with the 5.4 mg/kg cohort showing a 27% mean correction at 3 months.
John Cox
Newly announced topline data from the ongoing phase 1/2 ACHIEVE trial (NCT05481879) showed that treatment with DYNE-101, an investigational antisense oligonucleotide (ASO), resulted in robust muscle delivery and dose-dependent, consistent splicing correction while also showing improvement in multiple functional end points and patient-reported outcomes among those with myotonic dystrophy type 1 (DM1).1 The company also reported positive data from its phase 1/2 DELIVER trial (NCT05524883) of DYNE-251, which NeurologyLive® covered in a separate post.
The newly announce efficacy data, which includes 40 adults with DM1 enrolled in the randomized, placebo-controlled multiple ascending dose (MAD) portion of ACHIEVE, builds on positive findings announced in January. Similar to previous observations, the therapy continued to demonstrate a dose-dependent splicing correction. Specifically, patients in the 5.4-mg/kg–Q8W cohort had a 27% mean splicing correction from baseline across a broad, 22-gene panel at 3 months, with all participants showing splicing correction.
More specifically, the efficacy analysis comprised of 16 patients in the 1.8 mg/kg Q4W cohort who had 12-month data, 16 patients in the 3.4 mg/kg Q4W cohort with 6-month data, and 8 participants from the 5.4 mg/kg Q8W cohort. Results showed that DYNE-101-treated patients showed improvement in muscle strength as measured by Quantitative Myometry Testing, and early sustained potential benefit in 10-Meter Walk/Run test and 5 Times Sit to Stand Test. Those on the therapy also saw improvements in patient-reported outcomes, specifically the Myotonic Dystrophy Type 1 Activity and Participation Scale.
"We are excited to report new clinical data from both our ACHIEVE and DELIVER trials demonstrating meaningful impact on key biomarkers and functional improvement in multiple clinical endpoints that matter to patients," John Cox, president and chief executive officer at Dyne, said in a statement.1 "We believe these data reflect the best-in-class potential for these product candidates and reinforce the opportunity to transform the treatment of DM1 and DMD as well as the potential of the FORCE platform to address other rare muscle diseases."
Myotonia, a common complication of DM1, was also improved through DYNE-101. All told, those in the 1.8 mg/kg Q4W group had a mean 3.1-second benefit in myotonia at 3 months that increased to 4.4 seconds at 12 months. Additionally, the 5.4-mg/kg–Q8W cohort had a mean 4.5-second improvement in myotonia at 3 months. During the treatment period, patients on the agent also saw improvement in Myotonic Dystrophy Health Index (MDHI), a patient-reported outcome, and the 17 subscales within it, which include peripheral muscles, central nervous system, and gastrointestinal measures.
Safety and tolerability data, which included 56 patients enrolled through the 6.8-mg/kg–Q8W cohort of the MAD portion of the trial, continued to highlight DYNE-101’s safety profile. Overall, there were no serious treatment-emergent adverse events reported, and most treatment-emergent adverse events were considered mild or moderate in nature. In its previous update, Dyne noted that nasopharyngitis, fatigue, and infusion site rash were the most common treatment-emergent adverse events.
In its announcement, the company also wrote that enrollment through the 6.8-mg/kg–Q8W cohort is complete, with approximately 500 total doses of DYNE-101 administered to date. Based on dialogue with the Center for Drug Evaluation and Research division of the FDA, Dyne continues to pursue an accelerated approval pathway for the therapy, including leveraging splicing as a potential surrogate biomarker.
"We believe the breadth and depth of these data are truly differentiating. Our robust preclinical work is translating into clinical benefit along with favorable safety profiles for both DYNE-101 and DYNE-251," Wildon Farwell, MD, MPH, chief medical officer at Dyne, said in a statement.1 "The DM1 and Duchenne communities have waited too long for new and better therapeutic options. Building on the strength of these encouraging data and recent regulatory interactions, we look forward to continuing to engage with global regulatory authorities throughout this year to pursue expedited approval pathways and address the urgent unmet medical needs in these communities. We are thankful to the participants and clinicians in these trials and the communities for their continued partnership."
DYNE-101, designed to enable targeted muscle tissue delivery, consists of an antisense oligonucleotide (ASO) conjugated to a fragment antibody that binds to the transferrin receptor 1. In the previously announced data, investigators found that 18% of participants had elevated liver enzymes; however, this had no impact on liver function. The study authors noted that interpreting this finding was complicated by underling disease and elevated baseline values up to 2.5 times greater than the upper limit of normal.2
