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Myotonic Dystrophy Agent DYNE-101 Performs in Phase 1/2 ACHIEVE Trial
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Overall, investigators observed DMPK knockdown, consistent splicing correction, and meaningful function improvement in myotonia while on DYNE-101.
Wildon Farwell, MD, MPH
Dyne Therapeutics has announced positive initial data from its phase 1/2 ACHIEVE trial (NCT05481879) assessing its investigational antisense oligonucleotide (ASO) agent DYNE-101 in myotonic dystrophy type 1. All told, the agent achieved dose-dependent muscle delivery with a safety profile that was similar to previous observations. The next clinical data update is expected in the second half of 2024.1
ACHIEVE consists of a 24-week multiple ascending dose (MAD) randomized placebo-controlled period, a 24-week open-label extension, and a 96-week long-term extension. The data, which included those in the MAD portion of the trial (n = 32), showed a 40% mean DMPK knockdown after 3 months in the 3.4 mg/kg Q4W group of DYNE-101. In comparison, the 1.8 mg/kg Q4W group achieved 25% knockdown. This is noteworthy as DM1 is caused by an abnormal trinucleotide expansion in a region of the DMPK gene.
"These compelling initial data from our ACHIEVE and DELIVER trials highlight the exciting opportunity we have to advance our investigational therapeutics for devastating diseases with no or limited treatment options. DYNE-101 demonstrated early dose-dependent results, including in correction of splicing, the key biomarker for DM1, as well as meaningful improvement in myotonia at the lowest dose," Wildon Farwell, MD, MPH, chief medical officer, Dyne, said in a statement.1
DYNE-101, designed to enable targeted muscle tissue delivery, consists of an antisense oligonucleotide (ASO) conjugated to a fragment antibody that bindsto the transferrin receptor 1. ACHIEVE was split between a 1.8 mg/kg cohort (n = 16), the approximate AOS dose, and a 3.4 mg/kg Q4W cohort (n = 16), both of which randomized patients to either DYNE-101 (n = 6) or placebo (n = 4) once every 4 weeks. A small group also participated in a recovery arm (n = 6) where they received 2 doses of DYNE-101 followed by placebo for the remainder of the MAD.
Additional 3-month findings showed a 19% and 13% mean splicing correction in the DYNE-101 3.4 mg/kg Q4W and 1.8 mg/kg Q4W groups, respectively. All evaluable participants in the 3.4 mg/kg Q4W group demonstrated splicing correction across the 22-gene panel. Data from the recovery group supported the notion that less frequent dosing regimen may lead to better response. Patients in the DYNE-101 3.4 mg/kg recovery group demonstrated a 22% mean splicing correction compared with 19% for those in the standard 3.4 mg/kg QW4 group.
Treatment with DYNE-101 resulted in robust delivery after 3 months as well. Administration of 3.4 mg/kg of DYNE-101 Q4W demonstrated a mean ASO muscle concentration of 21.5 ng/g at 3 months, while administration of 1.8 mg/kg Q4W showed a mean ASO muscle concentration of 10.0 ng/g at 3 months.
READ MORE: First Patient Dosed With PGN-EDODM1 in Phase 1 FREEDOM-DM1 Trial for Myotonic Dystrophy Type 1
Myotonia, a common issue for patients with DM1, was also improved with treatment. Overall, patients treated with 1.8 mg/kg of DYNE-101 Q4W had a mean 3.8 second benefit in functional myotonia at 6 months as measured by video hand opening time. In addition, patient reported outcomes began to show effect for the lowest dose group, with improvements in Myotonic Dystrophy Health Index total and fatigue subscale, suggesting potential benefit in the central nervous system.
Safety and tolerability data from this initial assessment included 45 patients enrolled through the 5.4 mg/kg Q8W cohort of the MAD portion. All told, most treatment-emergent adverse events were mild or moderate in intensity, with nasopharyngitis (11%), fatigue (9%), and infusion site rash (9%) as the most commonly observed. There were 2 serious TEAEs of atrioventricular block first degree and pneumonia that were unrelated to the study drug.
Investigators found that 18% of participants had elevated liver enzymes; however, this had no impact on liver function. In the results, the study authors noted that interpreting this finding was complicated by underling disease and elevated baseline values up to around 2.5 times greater than the upper limit of normal. Recurrence of worsening of atrioventricular block, a severe, non-serious TEAE, was reported in the participant with atrioventricular block of first degree.
