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ENDEAVOR, gene therapy for DMD

Sarepta Therapeutics’ investigational gene therapy for the treatment of Duchenne muscular dystrophy, SRP-9001, demonstrates robust expression and consistent safety profile using Sarepta’s commercial process material.

 

  • The first 11 participants enrolled in Study 9001-103 ENDEAVOR showed robust transduction, delivering mean vector genome copies of 3.87 per nucleus.
  • Treated patients achieved mean micro-dystrophin expression levels of 55.4% of normal as measured by western blot.
  • Micro-dystrophin was properly localized to the muscle sarcolemma, with patients achieving a mean percentage of dystrophin positive fibres of 70.5% and intensity of micro-dystrophin expression of 116.9% of normal control measured by immunofluorescence (IF).
  • Safety profile consistent with prior studies and no new safety signals identified.

 

Original press release > CAMBRIDGE, Mass., May 18, 2021 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc. announced positive 12-week expression and safety results from the first 11 participants enrolled in Study SRP-9001-103, an open-label study known as ENDEAVOR conducted in partnership with Roche. In results from the first clinical study using commercially representative material, SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin) demonstrated robust expression of micro-dystrophin and no new safety signals from prior studies, supporting its potentially differentiated profile for the treatment of Duchenne muscular dystrophy. SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein.

 

Doug Ingram, president and chief executive officer, Sarepta – “We are delighted by these seminal results from the ENDEAVOR Study, our first trial results with SRP-9001 made by our commercial-scale manufacturing process. These data show strong transduction of the micro-dystrophin gene, resulting in robust expression of the properly localized micro-dystrophin protein, and did so with no new or unexpected safety signals. In addition to characterizing and differentiating SRP-9001, these results confirm the extraordinary work done over the last two and a half years to build an at-scale gene therapy manufacturing process and corresponding analytics sufficient to meet the needs of the Duchenne population with what we believe will be a potentially life-changing therapy. Armed with these data, we will seek a meeting with the FDA with the goal of rapidly starting our registrational study.”

 

Observed results

In the open-label study, 20 participants between the ages of four and seven were treated with a single infusion of SRP-9001 at a dose of 1.33×1014 VG/kg. In muscle biopsies from the first 11 patients taken 12 weeks after treatment, the following results were observed:

  • All patients demonstrated robust transduction, with a mean micro-dystrophin expression of 55.4% normal, as measured by western blot.
  • Muscle dystrophin levels demonstrated a mean of 70.5% (baseline 12.8%) muscle fibres expressing micro-dystrophin at 12 weeks with a mean intensity at the sarcolemma of 116.9% (baseline 41.0%) compared to normal biopsies, as measured by immunofluorescence. Comparisons between baseline and post-treatment measures were statistically significant (p=0.001 for positive fibres and p=0.002 for intensity).
  • Mean vector genome copies per nucleus reached 3.87.

The safety profile of SRP-9001 observed in the first 11 participants in ENDEAVOR is consistent with the safety seen in earlier studies using clinical manufacturing process material. In line with previously reported clinical data, no clinically relevant complement activation was observed in these 11 patients. Two patients experienced serious adverse events (transaminase elevation in one patient and nausea and vomiting in a second patient) that fully resolved.

About SRP-9001-103 (ENDEAVOR)

Study SRP-9001-103 (Study 103) is an open-label clinical trial of SRP-9001 that has enrolled 20 participants with Duchenne muscular dystrophy between the ages of 4-7. Study 103 uses commercially representative SRP-9001, and the primary endpoint is the change from baseline in the quantity of micro-dystrophin protein expression measured by western blot at 12 weeks. Secondary outcome measures include change from baseline in micro-dystrophin expression fibre intensity measured by immunofluorescence (IF) and micro-dystrophin expression measured by IF percent dystrophin positive fibres at 12 weeks. Exploratory endpoints include the change in vector genome copies per nucleus, North Star Ambulatory Assessment (NSAA) and certain timed functional tests. Including the initial 12-week period, patients will be followed for a total of five years.

About SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin)

SRP-9001 is an investigational gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. Sarepta is responsible for global development and manufacturing for SRP-9001 and plans to commercialize SRP-9001 in the United States upon receiving FDA approval. In December 2019, Roche partnered with Sarepta to combine Roche’s global reach, commercial presence and regulatory expertise with Sarepta’s gene therapy candidate for Duchenne to accelerate access to SRP-9001 for patients outside the United States. Sarepta has exclusive rights to the micro-dystrophin gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital.

About Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, fatal neuromuscular genetic disease in approximately one in every 3,500-5,000 males worldwide. DMD is caused by a change or mutation in the gene that encodes instructions for dystrophin. Symptoms of DMD usually appear in infants and toddlers. Affected children may experience developmental delays such as walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms and other areas. Most patients require full-time use of a wheelchair in their early teens and then progressively lose the ability to independently perform activities of daily living such as using the restroom, bathing and feeding. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and patients usually succumb to the disease in their twenties.

About Sarepta Therapeutics

Sarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. They hold leadership positions in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), and they currently have more than 40 programs in various stages of development. Their multi-platform Precision Genetic Medicine Engine drives our vast pipeline in gene therapy, RNA and gene editing. For more information, please visit www.sarepta.com or follow them on TwitterLinkedInInstagram and Facebook.

More interesting links

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Positive clinical results from phase 2 MOMENTUM study

Sarepta Therapeutics reports positive clinical results from phase 2 MOMENTUM study of SRP-5051 in patients with Duchenne muscular dystrophy amenable to skipping exon 51

  • Results suggest a highly potent next-generation treatment that could offer greater efficacy with less frequent dosing.
  • SRP-5051 dosed monthly at 30 mg/kg delivered mean exon skipping of 10.79% and mean dystrophin expression of 6.55%, consistently higher than the other SRP-5051 dosing cohorts at 12 weeks and weekly eteplirsen at 24 weeks
  • Sarepta’s predictive model indicates that SRP-5051 at 30 mg/kg will achieve greater than 10% dystrophin with monthly chronic dosing.

Original press release > CAMBRIDGE, Mass., May 03, 2021 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc. announced positive results from Part A of the MOMENTUM study (Study 5051-201), a global, Phase 2, multi-ascending dose clinical trial of SRP-5051, its next-generation peptide phosphorodiamidate morpholino oligomer (PPMO) treatment for patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping. In biopsies taken at a median of 12 weeks and after only three doses, results from Part A of the MOMENTUM study found that the 30 mg/kg of SRP-5051 dosed monthly resulted in 18 times the exon skipping and eight times the dystrophin production as eteplirsen, dosed weekly for 24 weeks. Exon-skipping and dystrophin production in the 30 mg/kg cohort were also consistently higher than the 20 mg/kg cohort of MOMENTUM. Hypomagnesemia was identified in patients taking SRP-5051. Cases have resolved with magnesium supplementation, and analysis of all available data indicates that the hypomagnesemia is monitorable and manageable. 

 

Doug Ingram, president and chief executive officer, Sarepta – “We are pleased to report strong, dose-dependent exon-skipping and dystrophin expression results with monthly dosing of SRP-5051 – in ambulant and non-ambulant patients. Even at an early time point of 12 weeks and after as few as only three doses, these data confirm the potential of Sarepta’s next-generation PPMO platform to be a step order improvement over our current PMO platform and to profoundly impact the course of Duchenne. While we saw exceptional expression after only a few initial doses, our models predict that we will exceed dystrophin expression levels of 10% of normal or greater over time with SRP-5051.We are excited to have chosen our target dose for further development. Part A of MOMENTUM is now complete and Sarepta will work with great urgency to discuss the results with regulatory agencies and gain their insights, including the development path to support accelerated approval of SRP-5051 in the United States.”

 

Adverse events

There were three serious, treatment-emergent adverse events in two patients in the 30 mg/kg cohort, including two cases of hypomagnesemia. The events were asymptomatic and have resolved with magnesium supplementation. Markers of kidney function have generally been normal and not shown any consistent relationship to hypomagnesemia. Predictive modelling for dystrophin accumulation that includes assumptions of known turnover of dystrophin in the muscle and analysis of data generated with the PPMO platform indicates that SRP-5051 at 30 mg/kg is likely to deliver greater than 10% dystrophin over time with monthly dosing. Full results will be presented at a future medical meeting.

About MOMENTUM (Study SRP-5051-201)

MOMENTUM is a multi-arm, ascending dose study designed to identify the maximum tolerated dose of SRP-5051, infused monthly. The study will enroll up to 24 patients, both ambulant and non-ambulant, between the ages of 7 to 21 at sites in the U.S., Canada, Australia and the European Union. The primary endpoint is safety, and secondary and exploratory endpoints include exon-skipping, dystrophin expression and tissue concentration. More information can be found on www.clinicaltrials.gov. Read “Positive clinical results from MOMENTUM” here.

About SRP-5051

SRP-5051 uses Sarepta’s PPMO chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. SRP-5051 is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in the exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for the production of an internally truncated dystrophin protein. PPMO is Sarepta’s next-generation chemistry platform designed around a proprietary cell-penetrating peptide conjugated to the PMO backbone, intending to increase tissue penetration, increasing exon skipping and significantly increasing dystrophin production. Around 13% of DMD patients have mutations that make them amenable to skipping exon 51. If successful, the PPMO offers the potential for improved efficacy and less frequent dosing for patients.

About Duchenne Muscular Dystrophy

DMD is an X-linked rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500 – 5,000 male births worldwide. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fibre function. Progressive muscle weakness in the lower limbs spreads to the arms, neck, and other body areas. The condition is universally fatal, and death usually occurs before 30 due to respiratory or cardiac failure.

About EXONDYS 51

EXONDYS 51 (eteplirsen) uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 51 of dystrophin pre-mRNA, resulting in “skipping” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for the production of an internally truncated dystrophin protein.EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in some patients treated with EXONDYS 51. Continued approval may be contingent upon verification of a clinical benefit in confirmatory trials. EXONDYS 51 has met the full statutory standards for safety and effectiveness and is not considered investigational or experimental.

What is exon skipping?

Mutations in the dystrophin gene are one cause of DMD. Most commonly, one or more exons (a portion of a gene) are missing, and the remaining exons don’t fit together correctly. (Think of a zipper that doesn’t work properly because teeth are missing.) Because of this error, cells cannot make the dystrophin protein that muscles need to work properly. Without it, muscle cells become damaged and, over time, are replaced with scar tissue and fat. Scientists are developing drugs that skip over parts containing missing or defective exons to fix the broken genetic machinery. In this way, the machinery can produce a less imperfect dystrophin protein, improving muscle function in children with exon mutations. > Pipeline exon-skipping

About Sarepta

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FDA Approval of AMONDYS 45 (casimersen)

Sarepta Therapeutics announces FDA approval of AMONDYS 45 (casimersen) injection to treat Duchenne muscular dystrophy (DMD) in patients amenable to skipping exon 45.

Feb. 25, 2021, >Original press release<

Sarepta Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) had approved AMONDYS 45 (casimersen). AMONDYS 45 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for Duchenne muscular treatment dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with AMONDYS 45, which is reasonably likely to predict clinical benefit for those patients who are exon 45 amenable. Consistent with the accelerated approval pathway, the continued approval of AMONDYS 45 may be contingent on confirmation of a clinical benefit in confirmatory trials.

 

Quickly

  • AMONDYS 45 is Sarepta’s third RNA exon-skipping treatment for DMD approved in the U.S.
  • The commercial distribution of AMONDYS 45 in the U.S. will commence immediately.
  • Information for patients and clinicians is available at www.SareptAssist.com.  

The ESSENCE trial

The ESSENCE trial is a placebo-controlled confirmatory trial to support the AMONDYS 45 approval – it is ongoing and expected to conclude in 2024.

This trial is a double-blind, placebo-controlled, multi-center Phase 3 study evaluating the efficacy and safety of casimersen (SRP-4045 as AMONDYS 45™) and golodirsen (SRP-4053, approved as VYONDYS 53™). Eligible patients with out-of-frame deletion mutations amenable to exon 45 or 53 skippings are randomized to receive once-weekly intravenous (IV) infusions of 30 mg/kg of SRP-4045 or 30 mg/kg of SRP-4053, respectively (combined-active group) or placebo for up to 96 weeks. This is followed by an open-label extension period in which all patients will receive open-label active treatment for 48 weeks, up to week 144 of the study.

Clinical efficacy is being assessed at regularly scheduled study visits, including functional tests such as the six-minute walk test (6MWT). All patients undergo a muscle biopsy at baseline and undergo a second muscle biopsy either at week 48 or week 96.

Safety is being assessed by collecting adverse events, laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations throughout the study.

 

Doug Ingram, president and chief executive officer, Sarepta – “This is an important day for Sarepta and, far more importantly, for the patients that we serve. After years of scientific commitment, investment and development, the approval of AMONDYS 45, Sarepta’s third approved RNA therapy, offers treatment to the 8% of the DMD community who have a confirmed exon 45 amenable mutation. Along with our other approved RNA therapies, we can now offer treatment options for nearly 30% of Duchenne patients in the U.S. And our commitment to bring therapies to the greatest percentage of the DMD community as soon as possible continues.”

 

Marissa Penrod, founder of Team Joseph and parent of an 18-year old with Duchenne – “Decades of research and commitment have fueled and now accelerate our progress towards new treatments for Duchenne. “The extraordinary diligence and persistence of the Duchenne community – patients and families, clinicians and researchers – have led us to today’s approval, where we now have exon-skipping treatments for almost a third of those with Duchenne.”

AMONDYS 45 is priced at parity with Sarepta’s other approved exon-skipping treatments. Patients and physicians can access more information at www.SareptAssist.com or by calling 1-888-727-3782.

About AMONDYS 45

AMONDYS 45 (casimersen) is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene amenable to exon 45 skipping. AMONDYS 45 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 45 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon skipping is intended to allow for the production of an internally truncated dystrophin protein.

AMONDYS 45 is approved under accelerated review based on an increase in dystrophin production in skeletal muscle of patients amenable to exon 45 skipping. Continued approval may be contingent upon verification of a clinical benefit in confirmatory trials.

AMONDYS 45 has met the full statutory standards for safety and effectiveness and, as such, is not considered investigational or experimental.

About Casimersen

Casimersen uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to skip exon 45 of the Duchenne gene. Casimersen is designed to bind to exon 45 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon skipping is intended to allow for the production of an internally truncated dystrophin protein. Read more here.

About Sarepta Therapeutics

The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Company’s programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visit www.sarepta.com or follow them on TwitterLinkedInInstagram and Facebook.

More about DMD

DMD is caused by genetic mutations that prevent dystrophin production. Patients with DMD experience progressive and irreversible muscle loss, with symptoms appearing as early as two years of age. 

Duchenne muscular dystrophy occurs primarily in males. Early signs of DMD may include delayed ability to sit, stand or walk. There is a progressive loss of mobility, and by adolescence, patients with DMD may require a wheelchair. Cardiac and respiratory muscle problems begin in the teenage years and lead to serious, life-threatening complications. Read more here.

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Pfizer doses the first participant with Its gene therapy

Pfizer doses the first participant in phase 3 study for Duchenne muscular dystrophy (DMD) investigational gene therapy.

Pfizer Inc. announced that the first participant has been dosed in the Phase 3 CIFFREO study, which will evaluate the efficacy and safety of investigational gene therapy candidate PF-06939926 in boys with Duchenne muscular dystrophy (DMD). The CIFFREO trial is expected to enroll 99 ambulatory male patients, ages 4 through 7, across 55 clinical trial sites in 15 countries. The first patient was dosed at a site in Barcelona, Spain, on December 29, 2020.

CIFFREO is a Phase 3 global, multicenter, randomized, double-blind, placebo-controlled study. The study’s primary endpoint is the change from baseline in the North Star Ambulatory Assessment (NSAA) at one year. The NSAA is a 17-item test that measures gross motor function in boys with DMD. Regardless of the cohort, eligible participants are scheduled to receive the investigational gene therapy, either at the start of the study or after one year following treatment with placebo. Participants will be followed in the CIFFREO study for five years after treatment with the investigational gene therapy. Trial participants will receive commercially representative drug products manufactured at Pfizer’s state-of-the-art gene therapy manufacturing facility in Sanford, North Carolina.

 

Brenda Cooperstone, MD, Chief Development Officer, Rare Disease, Pfizer Global Product Development  – “The initiation of our pivotal trial, which is the first Phase 3 DMD gene therapy program to begin enrolling eligible participants, is an important milestone for the community because there are currently no approved disease-modifying treatment options available for all genetic forms of DMD. We believe our gene therapy candidate, if successful in Phase 3 and approved, has the potential to significantly improve the trajectory of DMD disease progression, and we are working with worldwide regulatory authorities to initiate this program as quickly as possible in other countries.”

 

PF-06939926 received Fast Track designation from the U.S. Food and Drug Administration in October 2020 (read article), as well as Orphan Drug and Rare Pediatric Disease designations in the United States in May 2017.

 

Silvia Avila, President, Duchenne Parent Project Spain  – “DMD is a progressive disorder, and patients and parents are waiting desperately for treatment options. The initiation of this study is an important step forward for this community, and it fuels us with hope that one day there may be treatment options for boys impacted with this devastating disease.”

 

DMD is an X-linked disease caused by mutations in the gene encoding dystrophin, which is needed for muscle membrane stability. Due to the lack of dystrophin, boys present with muscle degeneration that progressively worsens with age to the extent that they require wheelchair assistance when they are in their early teens, and unfortunately, usually succumb to their disease by the time they are in their late twenties. It is estimated that there are ~140,000 boys affected by DMD worldwide.

 

About CIFFREO

CIFFREO is a Phase 3 global, multi-center, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of PF-06939926 investigational gene therapy in 99 ambulatory male participants, ages 4 through 7 years, with a genetic diagnosis of DMD who are on a stable daily regimen of glucocorticoids. The participants are negative for neutralizing antibodies against AAV9, as measured by the test done for the study as part of screening.

Eligible participants will be randomized into Cohort 1 or Cohort 2. Treatment will consist of two single intravenous infusions, one of PF-06939926 and one of placebo; approximately two thirds will be in Cohort 1 and receive PF-06939926 gene therapy at the start of the study and placebo after one year, and approximately one third will be in Cohort 2 and receive placebo at the start of the study and receive gene therapy after one year if they remain eligible. All participants will be followed in an open-label extension study for 5 years after treatment with the gene therapy. The study’s primary endpoint is a change from baseline at one year in the North Star Ambulatory Assessment (NSAA) total score. For more information, visit ciffreoduchennetrial.com.

 

About PF-06939926

PF-06939926 is an investigational recombinant adeno-associated virus serotype 9 (rAAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle specific promotor. The rAAV9 capsid was chosen as the delivery vector because of its potential to target muscle tissue.

 

About Pfizer Rare Disease

Rare disease includes some of the most serious of all illnesses and impacts millions of patients worldwide, representing an opportunity to apply their knowledge and expertise to help make a significant impact on addressing unmet medical needs. The Pfizer focus on rare diseases builds on more than two decades of experience, a dedicated research unit focusing on rare disease, and a global portfolio of multiple medicines within several disease areas of focus, including rare hematologic, neurologic, cardiac and inherited metabolic disorders.

Pfizer Rare Disease combines pioneering science and a deep understanding of how diseases work with insights from innovative strategic collaborations with academic researchers, patients, and other companies to deliver transformative treatments and solutions. Pfizer innovates every day, leveraging its global footprint to accelerate the development and delivery of groundbreaking medicines and the hope of cures.

Click here to learn more about their Rare Disease portfolio and how Pfizer empowers patients, engage communities in their clinical development programs, and support programs that heighten disease awareness.

The development of edasalonexent will be stopped

Catabasis Pharmaceuticals announces top-line results for the phase 3 PolarisDMD trial of edasalonexent in Duchenne muscular dystrophy.

 

PolarisDMD Trial Did Not Achieve Primary or Secondary Endpoints – The development of edasalonexent will be stopped.

Original Press release BOSTON, MA, OCTOBER 26, 2020

 

Catabasis announced that the Phase 3 PolarisDMD trial of edasalonexent in Duchenne muscular dystrophy (DMD) did not meet the primary endpoint, a change from baseline in the North Star Ambulatory Assessment (NSAA) over one year of edasalonexent compared to placebo. The secondary endpoint timed function tests (time to stand, 10-meter walk/run and 4-stair climb) also did not show statistically significant improvements. Edasalonexent was observed to be generally safe and well-tolerated in this trial. Catabasis is stopping activities related to the development of edasalonexent, including the ongoing GalaxyDMD open-label extension trial. The Company plans to work with external advisors to explore and evaluate strategic options in the future.

 

Jill C. Milne, Ph.D., Chief Executive Officer of Catabasis – “We are deeply saddened and disappointed by the results of our Phase 3 PolarisDMD trial. I want to sincerely thank all of the boys, their families and caregivers, investigators and the trial sites that participated in and enabled this program. The entire Catabasis team has worked tirelessly to find a treatment for this progressive disease. We hope that our data and work to date can be used to benefit ongoing and future research in DMD.”

 

The Phase 3 trial was a one-year placebo-controlled trial designed to evaluate the safety and efficacy of edasalonexent in boys ages 4-7 (up to 8th birthday) with DMD. The global trial enrolled 131 boys across eight countries, with any mutation type, who were not on steroids. Edasalonexent was well-tolerated, consistent with the safety profile seen to date. The majority of adverse events were mild in nature, and the most common treatment-related adverse events were diarrhea, vomiting, abdominal pain and rash. There were no treatment-related serious adverse events and no dose reductions. The global COVID-19 pandemic had no meaningful impact on the trial or its results. Data from the PolarisDMD trial will be further analyzed and are expected to be presented at an upcoming scientific conference and published.

 

Pat Furlong, Founding President and Chief Executive Officer of Parent Project Muscular Dystrophy (PPMD) – “These results are disheartening for the Duchenne community, and specifically for the boys who participated in this trial and their families. However, the results contribute to the natural history data of Duchenne and add to the knowledge base that will one day produce a foundational, long-term therapy for this disease. The continued advancement of research and the development of possible treatment options will remain of critical importance to our community. We appreciate Catabasis’ efforts and commitment to every family that is or has ever been affected by Duchenne.”

 

What is Edasalonexent?

Edasalonexent (CAT-1004 is being developed as a potential foundational disease-modifying therapy for all patients affected by DMD, regardless of their underlying mutation. It is an investigational oral small molecule. Edasalonexent inhibits NF-kB, a protein activated by DMD and drives inflammation and fibrosis, muscle degeneration and suppresses muscle regeneration. By inhibiting NF-kB, edasalonexent can decrease inflammation and fibrosis, promote muscle regeneration, and slow disease progression. Edasalonexent was designed as a stand-alone therapy and may also enhance the efficacy of dystrophin targeted therapies.

 

About Catabasis

The mission of Catabasis Pharmaceuticals is to bring hope and life-changing therapies to patients and their families.

  • Watch this video recorded in November 2016; Dr. Joanne Donovan answers our questions about edasalonexent (CAT-1004)
  • CatabasisPharma on FacebookTwitter and Instagram if you are interested in the latest updates

 

About La Force DMD

The Force’s mission is to unite the DMD community to raise awareness around a common objective: providing access to new treatments as fast as possible and participating in the funding of promising research projects. Where access to treatments for rare diseases is concerned, it is essential that our community be strong: each member must be an active spokesperson who helps raise awareness for DMD among the general public and the challenges associated with access to treatment.

Catabasis would like to sincerely thank everyone who participated in and enabled the edasalonexent program. Read more here.

Santhera to discontinue Phase 3 SIDEROS study

Santhera to discontinue Phase 3 SIDEROS study and development of Puldysa® in Duchenne Muscular Dystrophy (DMD) and focus on vamorolone.

Original Press Release > Pratteln, Switzerland, October 6, 2020

Santhera Pharmaceuticals announces the discontinuation of its Phase 3 SIDEROS study with Puldysa® (idebenone) in patients with Duchenne muscular dystrophy (DMD) who are in respiratory decline and receive concomitant glucocorticoid treatment. Data from an interim analysis conducted by the independent Data and Safety Monitoring Board (DSMB) concluded that the study was unlikely to meet its primary endpoint. Consequently, Santhera will discontinue the study, withdraw the European marketing authorization application and end the global development program for Puldysa. The Company intends to initiate a restructuring plan to retain key functions for bringing DMD drug candidate vamorolone to patients and execute on its other pipeline programs.

Based on the now completed interim analysis tested for efficacy, the DSMB has recommended the SIDEROS study be discontinued due to futility. The interim analysis was based on the study’s primary endpoint, the change of forced vital capacity % predicted (FVC%p) from baseline to 18 months of treatment. The outcome revealed that the probability of reaching the primary endpoint at the end of the study is too small to merit the study’s continuation. There were no safety concerns noted by the DSMB.

Santhera will stop the SIDEROS trial.

Santhera will stop the SIDEROS trial (including extension), and participants who are enrolled in the study will discontinue study medication and complete the study’s follow-up evaluations. Furthermore, following up on the recommendation from the DSMB, Santhera will discuss the impact of ending the SIDEROS study on ongoing expanded access programs with the corresponding regulatory bodies.

 

Dario Eklund, Chief Executive Officer of Santhera “We would like to thank the patients and the families, as well as investigators and medical professionals, who participated in the SIDEROS study. Without their contributions, we would not be able to advance DMD research. While this is obviously not the outcome we expected, all our efforts in DMD will now be focused on progressing the promising drug candidate vamorolone which we recently licensed from ReveraGen to its next inflection point, the readout of 6-month topline data from the pivotal VISION-DMD study planned for the second quarter of 2021.”

 

In connection with this decision, Santhera intends to start a restructuring process, aligning its operations to focus on progressing vamorolone for DMD, lonodelestat for cystic fibrosis and other lung diseases discovery-stage gene therapy approach for congenital muscular dystrophy.

About SIDEROS

SIDEROS was a clinical trial in DMD, a double-blind randomized placebo-controlled Phase 3 study evaluating the efficacy of idebenone in delaying the loss of respiratory function in patients with DMD. Patients on any stable glucocorticoid treatment scheme and irrespective of the underlying dystrophin mutation or ambulatory status were randomized to receive oral idebenone (900 mg/day three times a day) or placebo for 18 months. The trial’s primary endpoint estimates the treatment difference in FVC%p (forced vital capacity % predicted). Read more about Idebenone.

About Santhera

Santhera Pharmaceuticals is a Swiss specialty pharmaceutical company focused on developing and commercializing innovative medicines for rare neuromuscular and pulmonary diseases with a high unmet medical need. Santhera has an exclusive license for all indications worldwide to vamorolone, a first-in-class anti-inflammatory drug candidate with a novel mode of action, currently investigated in a pivotal study in patients with DMD as an alternative to standard corticosteroids. The clinical-stage pipeline also includes lonodelestat (POL6014) to treat cystic fibrosis (CF) and other neutrophilic pulmonary diseases and omigapil and an exploratory gene therapy approach targeting congenital muscular dystrophies. Santhera out-licensed ex-North American rights to its first approved product, Raxone® (idebenone), to treat Leber’s hereditary optic neuropathy (LHON) to Chiesi Group. For further information, please visit www.santhera.com.  La Force DMD Blog /worldwide rights of vamorolone for DMD

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Pfizer receives FDA fast track designation for DMD gene therapy

Pfizer receives FDA fast track designation for Duchenne muscular dystrophy (DMD) investigational gene therapy.

Official press release > NEW YORK–(BUSINESS WIRE)

Pfizer Inc. announced that its investigational gene therapy candidate (PF-06939926) being developed to treat Duchenne muscular dystrophy (DMD) received Fast Track designation from the U.S. Food and Drug Administration (FDA). PF-06939926 is currently being evaluated to determine the safety and efficacy of this gene therapy in boys with DMD.

Fast Track is a process designed to facilitate the development and expedite the review of new drugs that are intended to treat or prevent severe conditions that have the potential to address an unmet medical need. This designation was granted based on data from the Phase 1b study that indicated that the intravenous administration of PF-06939926 was well-tolerated during the infusion period, and dystrophin expression levels were sustained over 12 months.

 

Brenda Cooperstone, MD, Chief Development Officer, Rare Disease, Pfizer Global Product Development – “The FDA’s decision to grant our investigational gene therapy PF-06939926 Fast Track designation underscores the urgency to address a significant unmet treatment need for Duchenne muscular dystrophy. DMD is a devasting condition and patients, and their parents, are waiting desperately for treatment options. We are working to advance our planned Phase 3 program as quickly as possible.”

 

DMD is a devastating and life-threatening X-linked disease caused by mutations in the gene encoding dystrophin, which is needed for proper muscle membrane stability and function. Patients present with muscle degeneration that progressively worsens with age to the extent that they require wheelchair assistance when they are in their early teens, and unfortunately, usually succumb to their disease by the time they are in their late twenties. It is estimated that there are ~10-12,000 individuals affected with DMD in the U.S.

 

About PF-06939926

PF-06939926 is an investigational, recombinant adeno-associated virus serotype 9 (rAAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle specific promotor. The rAAV9 capsid was chosen as the delivery vector because of its potential to target muscle tissue. Pfizer initiated the Phase 1b multi-center, open-label, non-randomized, ascending dose study of a single intravenous infusion of PF-06939926 in 2018. The goal of the study is to assess the safety and tolerability of this investigational gene therapy. Other objectives of the clinical study include measurement of dystrophin expression and distribution and assessments of muscle strength, quality and function.

Data from the Phase 1b DMD gene therapy program, including data from an additional nine boys, who were all administered the high dose of the investigational therapy. A total of 15 boys have now been treated with the high dose and 18 boys have been treated overall. > Sources<

  • No Serious Adverse Events (SAE) were observed among the nine additional boys who were treated using a modified immunomodulatory regimen and monitoring regimen. The prophylactic steroid treatment was also changed from 1 mg/kg to an intermediate dose of 2mg/kg.
  • Three of the nine boys were dosed with gene therapy product that was manufactured using the commercial manufacturing process developed at Pfizer’s facility in Sanford, North Carolina.
  • Based on these data, the Company plans to initiate the pivotal study in the next several weeks, with the plan to perform an interim analysis of the clinical data in 2022.

About Pfizer Rare Disease

Rare disease includes some of the most serious of all illnesses and impacts millions of patients worldwide, representing an opportunity to apply their knowledge and expertise to help make a significant impact on addressing unmet medical needs. The Pfizer focus on rare disease builds on more than two decades of experience, a dedicated research unit focusing on rare disease, and a global portfolio of multiple medicines within several disease areas of focus, including rare hematologic, neurologic, cardiac and inherited metabolic disorders.

Pfizer Rare Disease combines pioneering science and a deep understanding of how diseases work with insights from innovative strategic collaborations with academic researchers, patients, and other companies to deliver transformative treatments and solutions. Pfizer innovates every day, leveraging its global footprint to accelerate the development and delivery of groundbreaking medicines and the hope of cures.

Click here to learn more about their Rare Disease portfolio and how Pfizer empowers patients, engage communities in their clinical development programs, and support programs that heighten disease awareness.

Interesting links

La Force DMD talks with Dr. Jeffrey Chamberlain, a geneticist at the University of Washington, Seattle, about adenovirus-associated (AAV) micro-dystrophin gene replacement therapy.

La Force DMD / Press release from Pfizer about gene therapy

Catabasis Newsletter – Communicating clinical trial results

La Force is happy to share the latest edition of the Catabasis Connection newsletter – Communicating clinical trial results.

Catabasis understands the importance of clearly communicating clinical trial results with the Duchenne community. As they are getting prepared for the planned release of top-line results from their Phase 3 PolarisDMD trial in Q4 of this year, they are sharing in advance their plans for how those results will be communicated. As a public, pre-commercial stage company, Catabasis is making every effort to balance its reporting obligations and restrictions with the desire to inform the Duchenne community of the trial results quickly, efficiently, and in easily accessible ways. Here are their plans:

  • They will share top-line results in their newsletter and a press release simultaneously. You can sign up here.
  • They will be sharing both the newsletter and press releases on their social media. You can follow them on social media > FacebookTwitter and Instagram.
  • They will host a webinar for the Duchenne community in conjunction with PPMD within a couple of days of the release of the top-line results. The webinar will include a Q&A portion where you can ask questions.
  • Families participating in the Phase 3 PolarisDMD trial can hear about the next steps directly from their trial site personnel.

About Edalasolexent

Edasalonexent is an orally-administered small molecule designed to inhibit NF-kB. Activated NF-kB is a crucial link between the lack of dystrophin and resulting manifestation and progression of Duchenne. By inhibiting NF-kB in Duchenne, edasalonexent can limit muscle degeneration, promote muscle regeneration, and reduce inflammation and fibrosis. Edasalonexent is being developed as a monotherapy and for use with other therapies, such as exon-skipping. We believe that based on its mechanism of action, edasalonexent has the potential for use with different approaches in development, such as gene therapy. The Phase 3 PolarisDMD trial and GalaxyDMD open-label extension trial are both ongoing. Top-line results are expected in the fourth quarter of 2020.

About Catabasis

The mission of Catabasis Pharmaceuticals is to bring hope and life-changing therapies to patients and their families. There lead program is edasalonexent, an NF-kB inhibitor in Phase 3 development for the treatment of Duchenne muscular dystrophy. For more information on edasalonexent and the Phase 3 trial, please visit www.catabasis.com.

About La Force DMD

The Force’s mission is to unite the DMD community to raise awareness around a common objective: that of providing access to new treatments as fast as possible and to participate in the funding of promising research projects. Where access to treatments for rare diseases is concerned, it is essential that our community be strong: each member must be an active spokesperson who helps raise awareness for DMD among the general public and the challenges associated with access to treatment.

 

Edasalonexent is an investigational drug that is not yet approved in any territory.

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Worldwide rights of Vamorolone for DMD

Santhera exercises option to obtain worldwide rights of Vamorolone for Duchenne muscular dystrophy (DMD) and All Other Indications

La Force is happy to share this press release provided by Santhera Pharmaceuticals > Pratteln, Switzerland, and Rockville, MD, USA, September 2, 2020

 

Santhera Pharmaceuticals announces that it has signed agreements with Idorsia and ReveraGen BioPharma Inc., making Santhera a direct license holder of vamorolone. Under the agreements, Santhera has obtained an exclusive license from ReveraGen, the originator of vamorolone, for all indications worldwide. The agreements create additional value for Santhera through the transfer of rights for the previously excluded markets Japan and South Korea, the right to grant sublicenses and a share in the expected Priority Review Voucher. Vamorolone, a first-in-class anti-inflammatory drug candidate with a novel mode of action, is currently being investigated in the pivotal Phase 2b VISION-DMD study in patients with Duchenne muscular dystrophy (DMD) by originator ReveraGen and completion of study enrollment is expected shortly.

 

Quickly

  • The license gives Santhera worldwide rights to vamorolone, now also including the major markets Japan and South Korea, and paves the way for partnering in additional indications
  • Agreements with Idorsia and ReveraGen give Santhera immediate control over vamorolone and defer milestone-related payments
  • The transaction establishes Santhera as a leading company in rare neuromuscular diseases with two late-stage assets addressing the medical need of DMD patients from early to late disease stages

 

Dario Eklund, Chief Executive Officer of Santhera –  “We are excited about the license transfer of vamorolone to Santhera. Our decision to exercise the option now has been driven by a combination of factors including the availability of encouraging clinical efficacy and safety data with vamorolone, enhanced deal terms and the ability to gain full control over the asset. We look forward to contributing our significant expertise to advancing vamorolone in DMD and exploring additional business development opportunities. We believe that having two promising, complementary, late-stage assets for DMD in our pipeline will enable increased access to potentially transformative treatments for a wider patient population. We are grateful to Idorsia, our anchor shareholder, for enabling early access to the license, highlighting its confidence in Santhera as the best-suited company to bring vamorolone to patients.”

 

Eric Hoffman, Ph.D., Vice President of Research of ReveraGen BioPharma –  “We are delighted about the revised contractual arrangement and being able to work directly with Santhera as the licensee for vamorolone. Santhera’s experience in both development of DMD drug candidates and the commercialization of a rare disease product positions it well to bring vamorolone to patients. Our work to date clearly shows that vamorolone not only holds the potential to become a new standard of care for patients with DMD but also could benefit patients in a number of other inflammatory diseases.”

 

With Puldysa® and vamorolone, Santhera is building a complementary DMD product portfolio.

Vamorolone is in development for young DMD patients requiring an anti-inflammatory, muscle strengthening treatment before the onset of respiratory function decline. Based on the cumulative knowledge obtained from extensive non-clinical studies and Phase 1 and Phase 2a clinical studies with vamorolone, ReveraGen is currently conducting the pivotal Phase 2b VISION-DMD trial and anticipates full study enrollment shortly. Subject to positive results of the first 6-month treatment period, now expected in the second quarter of 2021 due to delays caused by the Covid-19 pandemic, this would pave the way for regulatory submission to the US FDA in the fourth quarter of 2021.

Puldysa (idebenone) for patients with DMD in respiratory function decline who are not taking glucocorticoids is currently under regulatory review in Europe for which Santhera anticipates a CHMP opinion in the fourth quarter of 2020. The Company expects the combination of vamorolone and Puldysa to address the medical needs of DMD patients, from early to late disease stages, irrespective of age, underlying dystrophin mutation or ambulatory status. 

Vamorolone and Puldysa have been granted Orphan Drug status in the US and Europe, Fast Track and Rare Pediatric Disease designations by the US FDA and Promising Innovative Medicine (PIM) status by the UK MHRA. In the UK, Puldysa is available to patients through the Early Access to Medicines Scheme (EAMS).

 

About Vamorolone

Vamorolone is a first-in-class anti-inflammatory drug candidate with a novel mode of action Vamorolone is a first-in-class drug candidate that binds to the same receptors as corticosteroids but modifies the downstream activity of the receptors. This has the potential to ‘dissociate’ efficacy from typical steroid safety concerns and, therefore, could emerge as a valuable alternative to corticosteroids, the current standard of care in children and adolescent patients with DMD. There is a clear unmet medical need in this patient group as high dose corticosteroids have significant systemic side effects that detract from the patient’s quality of life. Vamorolone is being developed by US-based ReveraGen BioPharma Inc. with participation in funding and design of studies by several international non-profit foundations, the US National Institutes of Health, the US Department of Defense and the European Commission’s Horizon 2020 program.

 

About Santhera

Santhera Pharmaceuticals is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular and pulmonary diseases with a high unmet medical need. Santhera is building Duchenne muscular dystrophy (DMD) product portfolio to treat patients irrespective of causative mutations, disease stage or age. A marketing authorization application for Puldysa® (idebenone) is currently under review by the European Medicines Agency. Santhera has an option to license vamorolone; a first-in-class dissociative steroid presently investigated in a pivotal study in patients with DMD to replace standard corticosteroids. Santhera out-licensed ex-North American rights to its first approved product; for further information, please visit www.santhera.com.

 

About ReveraGen BioPharma

ReveraGen was founded in 2008 to develop first-in-class dissociative steroidal drugs for Duchenne muscular dystrophy and other chronic inflammatory disorders. The development of ReveraGen’s lead compound, vamorolone, has been supported through partnerships with foundations worldwide, including Muscular Dystrophy Association USAParent Project Muscular DystrophyFoundation to Eradicate DuchenneSave Our SonsJoiningJackAction DuchenneCureDuchenne, Ryan’s Quest, Alex’s WishDuchenneUK, Pietro’s Fight, Michael’s Cause, and Duchenne Research Fund. ReveraGen has also received generous support from the US Department of Defense CDMRP, National Institutes of Health (NCATS, NINDS, NIAMS), and European Commission (Horizons 2020).

 

More links

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FDA Acceptance of Casimersen

Sarepta Therapeutics Announces FDA Acceptance of Casimersen (SRP-4045) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 45

Original press release, CAMBRIDGE, Mass., Aug. 25, 2020 (GLOBE NEWSWIRE)

Quickly

  • FDA grants Priority Review Status and sets regulatory action date for February 25, 2021
  • FDA has indicated it does not currently plan to hold an advisory committee meeting to discuss the application
  • Received FDA’s conditional approval of AMONDYS 45™ as a brand name for casimersen
  • Casimersen has been studied for the treatment of exon 45 amenable patients, approximately eight percent of patients with Duchenne

About the FDA Acceptance of Casimersen

Sarepta Therapeutics, Inc. announced the U.S. Food and Drug Administration (FDA) has accepted the Company’s New Drug Application (NDA) seeking accelerated approval for casimersen (SRP-4045) and provided a regulatory action date of February 25, 2021. The FDA has indicated it does not currently plan to hold an advisory committee to discuss the application. In addition, the Company has received conditional approval of AMONDYS 45 as the brand name for casimersen. Casimersen, a phosphorodiamidate morpholino oligomer (PMO), is engineered to treat patients with Duchenne muscular dystrophy (DMD) who have genetic mutations that are amenable to skipping exon 45 of the dystrophin gene.

The Company submitted its NDA filing in June 2020 and requested priority review, which the FDA granted. The NDA included data from the casimersen arm of the ESSENCE study (also known as Study 4045-301), a global, randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of casimersen in patients amenable to skipping exons 45. An interim analysis from ESSENCE demonstrated a statistically significant increase in dystrophin production as measured by western blot in patients who received casimersen compared to baseline and placebo. The study is ongoing and remains blinded to collect additional efficacy and safety data.

Doug Ingram, president and chief executive officer, Sarepta Therapeutics – “The FDA’s acceptance of our NDA for casimersen is an important step toward our goal of rapidly bringing therapies to patients living with Duchenne muscular dystrophy. If it is approved, casimersen, our third exon-skipping medicine in our PMO RNA-based platform, will offer treatment to the 8% of Duchenne patients who are amenable to exon 45 skipping.”

About Casimersen

Casimersen uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to skip exon 45 of the Duchenne gene. Casimersen is designed to bind to exon 45 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon skipping is intended to allow for the production of an internally truncated dystrophin protein. Read more here.

About the ESSENCE Study

The ESSENCE study is a double-blind, placebo-controlled, multi-center Phase 3 study evaluating the efficacy and safety of casimersen (SRP-4045) and golodirsen (SRP-4053, approved as VYONDYS 53™). Eligible patients with out-of-frame deletion mutations amenable to exon 45 or 53 skippings are randomized to receive once-weekly intravenous (IV) infusions of 30 mg/kg of SRP-4045 or 30 mg/kg of SRP-4053, respectively (combined-active group) or placebo for up to 96 weeks. This is followed by an open-label extension period in which all patients will receive open-label active treatment for 48 weeks, up to week 144 of the study.

Clinical efficacy is being assessed at regularly scheduled study visits, including functional tests such as the six-minute walk test (6MWT). All patients undergo a muscle biopsy at baseline and will undergo a second muscle biopsy either at week 48 or week 96.

Safety is being assessed through the collection of adverse events, laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations throughout the study.

About Sarepta Therapeutics

The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and in gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Company’s programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visit www.sarepta.com or follow them on TwitterLinkedInInstagram and Facebook.

More about DMD

DMD is caused by genetic mutations that prevent dystrophin production. Patients with DMD experience progressive and irreversible muscle loss with symptoms appearing as early as two years of age. 

Duchenne muscular dystrophy occurs primarily in males. Early signs of DMD may include delayed ability to sit, stand or walk. There is a progressive loss of mobility, and by adolescence, patients with DMD may require the use of a wheelchair. Cardiac and respiratory muscle problems begin in the teenage years and lead to serious, life-threatening complications. Read more here.