RARE Daily

Dyne Reports Positive Phase 1/2 Data, Commences $300 Million Offering

May 21, 2024

Rare Daily Staff

Dyne Therapeutics commenced a $300 million offering as it reported positive clinical data from its ongoing phase 1/2 ACHIEVE trial of DYNE-101 its experimental therapy for myotonic dystrophy type 1 and phase 1/2 DELIVER trial of DYNE-251, its experimental therapy for Duchenne muscular dystrophy who are amenable to exon 51 skipping.

New data from both trials demonstrated impact on key disease biomarkers as well as improvement in multiple functional endpoints and favorable safety profiles.

DM1 is a rare, progressive, genetic disease that affects skeletal, cardiac and smooth muscle. It is a monogenic, autosomal dominant disease caused by an abnormal trinucleotide expansion in a region of the DMPK gene. This expansion of CTG repeats causes toxic RNA to cluster in the nucleus, forming nuclear foci and altering the splicing of multiple proteins essential for normal cellular function. This altered splicing results in a wide range of symptoms. People living with DM1 typically experience myotonia and progressive weakness of major muscle groups, which can affect mobility, breathing, heart function, speech, digestion, and vision, as well as cognition.

DYNE-101 is an experimental therapeutic being evaluated in the phase 1/2 global ACHIEVE clinical trial for people living with DM1. DYNE-101 consists of an antisense oligonucleotide conjugated to a fragment antibody that binds to the transferrin receptor 1, which is highly expressed on muscle. It is designed to enable targeted muscle tissue delivery with the goal of reducing toxic DMPK RNA in the nucleus, releasing splicing proteins, allowing normal mRNA processing and translation of normal proteins, and potentially stopping or reversing the disease progression.

DYNE-101 has been granted orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of DM1.

ACHIEVE is a Phase 1/2 global clinical trial evaluating DYNE-101, consisting of a 24-week multiple ascending dose randomized placebo-controlled period, a 24-week open-label extension and a 96-week long-term extension. The trial, which is designed to be registrational, is enrolling adult patients with DM1 who are 18 to 49 years of age. The primary endpoints are safety and tolerability, with secondary endpoints of pharmacokinetics and pharmacodynamics, including change from baseline in splicing, as well as measures of muscle strength and function.

Dyne reported efficacy data from 40 adult DM1 patients enrolled in the randomized, placebo-controlled multiple ascending dose portion of the DYNE-101 ACHIEVE trial, including 12-month data of 16 patients in the lowest dose cohort, six-month data from the mid-size dose cohort of 16 patients, and three-month data from the highest dose cohort of eight patients.

In the ACHIEVE trial, DYNE-101 demonstrated robust muscle delivery and dose-dependent, consistent splicing correction while also showing improvement in multiple functional endpoints and patient reported outcomes.

DYNE-101 continued to show dose dependent splicing correction as seen in earlier cohorts. Patients in the highest dose cohort had a 27 percent mean splicing correction from baseline across a broad, 22-gene panel at three months, with all participants demonstrating splicing correction.

DYNE-101 demonstrated an improvement in myotonia as measured by video hand opening time in all reported cohorts. It also demonstrated an improvement in muscle strength as measured by Quantitative Myometry Testing, a test of muscle strength and fatigue, and early and sustained potential benefit in 10-Meter Walk/Run Test and 5 Times Sit to Stand Test.

The therapy also demonstrated improvements in patient reported outcomes including an overall improvement in scores for the Myotonic Dystrophy Health Index and in all 17 subscales, as well as in the Myotonic Dystrophy Type 1 Activity and Participation Scale’s assessment of various activities of daily living.

No related serious treatment emergent adverse events have been identified.

Duchenne muscular dystrophy (DMD) is a rare disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. These mutations, the majority of which are deletions, result in the lack of dystrophin protein and progressive loss of muscle function. Loss of strength and function typically first appears in pre-school age boys and worsens as they age. As the disease progresses, the severity of damage to skeletal and cardiac muscle often results in patients experiencing total loss of ambulation by their early teenage years and includes worsening cardiac and respiratory symptoms and loss of upper body function by the later teens. There is no cure for DMD and currently approved therapies provide limited benefit.

DYNE-251 is an investigational therapeutic being evaluated in the phase 1/2 global DELIVER clinical trial for people living with DMD who are amenable to exon 51 skipping. DYNE-251 consists of a phosphorodiamidate morpholino oligomer conjugated to a fragment antibody  that binds to the transferrin receptor 1, which is highly expressed on muscle. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create a truncated, functional dystrophin protein, with the goal of stopping or reversing disease progression. DYNE-251 has been granted fast track, orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration for the treatment of DMD mutations amenable to exon 51 skipping.

DELIVER is a phase 1/2 global clinical trial evaluating DYNE-251, consisting of a 24-week multiple ascending dose randomized placebo-controlled period, a 24-week open-label extension and a 96-week long-term extension. The trial, which is designed to be registrational, is enrolling ambulant and non-ambulant males with DMD who are ages 4 to 16 and have mutations amenable to exon 51 skipping. The primary endpoints are safety, tolerability and change from baseline in dystrophin levels as measured by Western blot. Secondary endpoints include measures of muscle function, exon skipping and pharmacokinetics.

Patients treated with 10 mg/kg of DYNE-251 Q4W had a mean absolute dystrophin level of 3.22 percent of normal and a 2.97 percent change (unadjusted for muscle content) from baseline at 6 months. Eteplirsen reached a mean absolute unadjusted dystrophin level of 0.30 percent of normal and a 0.06 percent change from baseline at six months. When adjusting for muscle content, the DYNE-251 treated group reached 7.64 percent mean absolute dystrophin, which is greater than levels reported by peptide conjugate in clinical development.

Trends in improvement were observed in multiple functional endpoints in the 10 mg/kg DYNE-251 Q4W group at six months, including North Star Ambulatory Assessment, Stride Velocity 95th Centile, 10-Meter Walk/Run Time, and Time to Rise from Floor.

DYNE-251 demonstrated a favorable safety profile. The majority of treatment emergent adverse events were mild or moderate and no related serious treatment emergent adverse events have been identified.

“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,” said John Cox, Dyne’s president and CEO.

Photo: John Cox, Dyne’s president and CEO

 

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