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Sarepta announces top-line results for its investigational gene therapy

Sarepta Therapeutics announces top-line results for part 1 of study 102 evaluating SRP-9001, its investigational gene therapy for the treatment of Duchenne muscular dystrophy (DMD)

 

Jan. 7, 2021, >Original press release<

Sarepta Therapeutics, Inc. announced top-line results from Part 1 of Study SRP-9001 (Study 102), an ongoing, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, efficacy and tolerability of a single dose of SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin) in 41 patients with 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.

Quickly

  • The study met the primary biological endpoint of micro-dystrophin protein expression at 12 weeks post-treatment, measured by western blot, in SRP-9001-treated participants versus placebo.
  • SRP-9001-treated participants showed an increase in NSAA total score compared to placebo at 48 weeks; however, the study did not achieve statistical significance on the primary functional endpoint of improvement in NSAA total score compared to placebo at 48 weeks post-treatment  
  • In the pre-specified analysis by age-group, by which the randomization was stratified, participants aged 4-5 years at the time of treatment with SRP-9001 demonstrated a statistically significant improvement in NSAA total score age-matched placebo cohort, achieving a 4.3-point improvement on NSAA at 48 weeks post-treatment from baseline.
  • No new safety signals were identified for SRP-9001, reinforcing the favourable safety profile observed to date.

Study 102 is ongoing and remains blinded to participants, investigators, site staff and sponsor staff with direct site interaction. All 41 participants have completed their Part 1, 48-week assessment and have entered the Part 2 crossover phase. Participants continue to be monitored for safety and will undergo another biopsy at week 12 in Part 2 to assess the expression and biological markers, in addition to longer-term assessments of functional outcomes.

 

Doug Ingram, president and chief executive officer, Sarepta – “Study 102 reinforces our confidence in the potentially transformative benefits of SRP-9001, including among other things, the fact that in the Study’s pre-specified analysis, the participants in the 4-5 age group robustly achieved a statistically significant and clinically meaningful improvement in NSAA over placebo, as predicted by our prior Study 101. For the entire population, while we saw separation at every time point between the active and placebo cohorts, Study 102 did not achieve statistical significance on the primary functional endpoint. In this regard, we are very disappointed that the randomization process resulted in a significant imbalance in baseline NSAA scores between the active and placebo cohorts of the participants ages 6-7, making the 6-7 age groups non-comparable and likely substantially contributing to the inability to achieve statistical significance. Study 102 remains blinded and we will analyze the functional results for all patients, including cross-over participants, once they have achieved the 48-week timepoint in Part 2. We have already enrolled and dosed 11 participants in Study 103, using our commercial process material, and we will have biomarker and safety results from that cohort in the second quarter. And very importantly, Study 102 has provided us with a wealth of information and insight which we will use to refine and complete the protocol for our upcoming trial using commercial process material. We intend to continue to move forward with diligence and urgency to generate the evidence necessary to bring SRP-9001 to waiting Duchenne patients around the world.”

 

*The NSAA is a 17-item rating scale used to measure functional motor abilities in ambulant children with Duchenne. It is used to monitor the disease’s progression and treatment effects, which makes it suitable as an endpoint in clinical trials for Duchenne.

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 difficulty in walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms, neck 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 daily living activities such as using the restroom, bathing and feeding. Eventually, increasing breathing difficulty 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 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, the Company announced a licensing agreement granting Roche the exclusive right to launch and commercialize SRP-9001 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 Sarepta

Sarepta Therapeutics, Inc., a biopharmaceutical company, is working to unlock the potential of RNA-based and gene therapy technologies to treat serious and life-threatening diseases like Duchenne muscular dystrophy (DMD). Sarepta’s primary focus is to advance new treatments for DMD rapidly.

More interesting links

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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.

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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

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Sustained functional improvement with micro-dystrophin gene treatment

Sarepta Therapeutics reports sustained functional improvement two years after treatment with SRP-9001, its investigational micro-dystrophin gene therapy for Duchenne muscular dystrophy.

  • Results demonstrate continued safety and tolerability of SRP-9001 in four participants with Duchenne.
  • All four participants demonstrated improvements in The North Star Ambulatory Assessment (NSAA)* scores than baseline and showed a durable response two years after the administration of SRP-9001.

Original press release > CAMBRIDGE, Mass., Sept. 28, 2020 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc., announced two-year follow up results from four Duchenne muscular dystrophy (DMD) clinical trial participants who received SRP-9001. SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of micro-dystrophin protein. Results presented at the 25th International Annual Congress of the World Muscle Society demonstrated that two years after a one-time infusion of SRP-9001, trial participants exhibited a mean 7.0 point improvement on the North Star Ambulatory Assessment (NSAA) compared to baseline.

 

Doug Ingram, President and CEO, Sarepta – “We continue to be encouraged by the safety profile and enduring treatment response that we have seen to date with SRP-9001 gene transfer therapy. The consistent results and functional improvements sustained over two years give us added confidence as we prepare for the results from Study 102, our randomized, double-blind, placebo-controlled study of SRP-9001. We continue to work with urgency to bring this potentially transformative treatment to patients as quickly as possible.”

 

In the open-label trial, known as Study 101, four ambulatory participants between the ages of 4 and 7 were treated with an infusion of SRP-9001. The therapy was well-tolerated in all participants over the two years. All adverse events were considered mild or moderate and occurred within 90 days of treatment. There were no serious adverse events or evidence of complement activation.

At day 90, all participants had confirmed vector transduction and showed functional improvement on the NSAA scale and reduced creatine kinase (CK) levels. Participants demonstrated a mean increase of 5.5 points from baseline one year after treatment and 7.0 points from baseline two years after treatment. The NSAA is a validated scale developed to measure functional motor abilities in ambulant children with Duchenne, with scores ranging from 0-34.

As previously disclosed, micro-dystrophin protein levels for participants in Study 101 were as follows: 12-weeks post-infusion, a mean of 81.2% muscle fibres expressing micro-dystrophin with a mean intensity at the sarcolemma by immunohistochemistry of 96% compared to normal biopsies. Adjusted for fat and fibrotic tissue, western blot showed a mean expression of 95.8%.

About SRP-9001

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. In December 2019, the Company announced a licensing agreement granting Roche the exclusive right to launch and commercialize SRP-9001 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 difficulty in walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms, neck 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 Therapeutics, Inc., a biopharmaceutical company, is working to unlock the potential of RNA-based and gene therapy technologies to treat severe and life-threatening diseases like Duchenne muscular dystrophy (DMD). Sarepta’s primary focus is to advance new therapies for DMD rapidly. Learn more here.

La Force DMD / Sarepta Therapeutics / Grounded in the DMD community.

The North Star Ambulatory Assessment (NSAA)

The North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects.

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Viltolarsen, exon 53 skipping therapy, approved

N.S. Pharma’s VILTEPSO™ (viltolarsen) injection now FDA-Approved in the U.S. for the treatment of Duchenne muscular dystrophy in patients amenable to exon 53 skipping therapy.

 

  • Patients taking VILTEPSO showed an increase in dystrophin expression to an average of 5.9% of normal after 20-24 weeks of treatment.
  • Overall, in a pivotal study of VILTEPSO, 100% of patients showed an increase in dystrophin levels after treatment, and 88% of patients showed dystrophin levels of 3% of average or higher.

Press release > PARAMUS, NJ: August 12, 2020 – N.S. Pharma, Inc.

 

N.S. Pharma announced that the U.S. Food & Drug Administration (FDA) has approved VILTEPSO™ (viltolarsen) injection for patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping therapy. VILTEPSO received an Accelerated Approval by the FDA based on an increase in dystrophin, an essential protein for supporting muscle health. Since a lack of dystrophin is the underlying cause of DMD, increasing dystrophin as much and as early as possible is a key goal in the treatment of DMD. VILTEPSO is the first and only exon 53 skipping therapy to demonstrate an increase in dystrophin in children as young as four years old. The continued approval of VILTEPSO may be contingent on confirmation of a clinical benefit in the Phase 3 confirmatory trial.

 

More about the study

The VILTEPSO New Drug Application (NDA) submission included results from a Phase 2, a two-period study in patients aged four to less than ten years of age conducted in North America (Study 1, N=16) and a multicenter, open-label study in boys five to less than 18 years of age conducted in Japan (Study 2, N=16).

In Study 1, of those patients who received the recommended dose of 80 mg/kg/wk (N=8), 100% of patients (8/8) showed an increase in dystrophin levels after treatment with VILTEPSO and 88% of patients (7/8) showed dystrophin levels of 3% or greater than normal. Overall, after 20-24 weeks of treatment, a mean increase in dystrophin expression to nearly 6% of normal was observed with VILTEPSO (80 mg/kg/wk) versus 0.6% at baseline. The most common side effects of VILTEPSO included upper respiratory tract infection, injection site reaction, cough and fever.

 

Vamshi Rao, MD, Ann & Robert H. Lurie Children’s Hospital of Chicago – “For decades, neurologists who treat DMD have hoped for the discovery of therapies capable of significantly improving dystrophin production, and the magnitude of dystrophin increases observed with VILTEPSO are impressive. The approval of VILTEPSO is an exciting development for DMD patients amenable to exon 53 skipping therapy and may rapidly become a foundational treatment for these patients.”

 

  • In clinical studies, no patients experienced kidney toxicity during treatment with VILTEPSO. However, kidney toxicity from drugs like VILTEPSO may be possible. Your doctor may monitor the health of your kidneys before starting and during treatment with VILTEPSO.
  • The most common side effects of VILTEPSO included upper respiratory tract infection, injection site reaction, cough and fever.
  • For additional safety information, please see the full Prescribing Information.

N.S. Pharma continues to study the safety and efficacy of VILTEPSO in the confirmatory Phase 3 RACER53 trial. This study was initiated in October 2019 and is currently enrolling. The purpose of this Phase 3 trial is to confirm the clinical findings that were submitted under the Accelerated Approval pathway.

 

About VILTEPSO™ (viltolarsen) injection

Before its approval in the U.S., VILTEPSO was granted Priority Review as well as Rare Pediatric Disease, Orphan Drug and Fast Track Designations. In March 2020, VILTEPSO was approved in Japan for the treatment of patients with DMD who are amenable to exon 53 skipping therapy. Before its approval in Japan, VILTEPSO was granted the SAKIGAKE designation, Orphan Drug designation, and designation of Conditional Early Approval System.

VILTEPSO is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under Accelerated Approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VILTEPSO. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. It is an infusion that doctors administer into the bloodstream.

 

How Viltolarsen works

Viltolarsen contains an artificial piece of mRNA that masks exon 53, causing cells to “skip” this exon when they are making mature mRNA. This skip restores the so-called “reading frame” of the mRNA molecule. In other words, it ensures that the remaining exons fit together again, allowing a cell’s protein-making machinery to synthesize a shorter but working dystrophin protein.

Because viltolarsen is specific to exon 53, the treatment is effective only in those DMD patients who have a mutation that is amenable to exon 53 skipping. Thanks to Muscular Dystrophy News Today for this description.

 

N.S. Pharma

NS Pharma, Inc. is a wholly-owned subsidiary of Nippon Shinyaku Co., Ltd. For more information, please visit www.nspharma.com. N.S. Pharma is a registered trademark of the Nippon Shinyaku group of companies.

N.S. Pharma will provide families, physicians and healthcare professionals dedicated and individualized resources every step of the way through the N.S. Support program. N.S. Pharma will be hosting a series of webinars on the comprehensive care coordination available through N.S. Support. Follow them on LinkedIn and Twitter for information and registration for upcoming webinars.

 

Tsugio Tanaka, President, NS Pharma, Inc. – “On behalf of NS Pharma and Nippon Shinyaku, I would like to express our deepest gratitude to the families and physicians who participated in our clinical trials and made today’s approval possible. We are proud to now offer an important new treatment option to help address the significant unmet needs caused by this devastating disease.”

 

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.

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Sarepta is seeking the approval of casimersen for DMD patients

Sarepta Therapeutics Completes Submission of New Drug Application Seeking Approval of Casimersen (SRP-4045) for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 45

  • Casimersen is designed for the treatment of exon 45 amenable patients, approximately eight percent of patients with Duchenne
  • Casimersen is the third exon-skipping medicine using the Company’s proprietary PMO RNA-based platform. 

 

CAMBRIDGE, Mass., June 26, 2020 (GLOBE NEWSWIRE) >Original press release here

Sarepta Therapeutics, Inc. has completed the submission of a rolling New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for casimersen (SRP-4045). 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 Duchenne gene.

The completion of the rolling submission includes 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 efficacy and safety in patients amenable to skipping exons 45 and 53. 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. If the casimersen NDA is accepted and granted accelerated approval, the completed ESSENCE study will serve as a post-marketing confirmatory study.

 

Doug Ingram, president and chief executive officer, Sarepta Therapeutics. – “The completion of our casimersen submission is an important milestone in our journey to advance treatments for the greatest possible number of people living with Duchenne muscular dystrophy. If approved, casimersen will be our third approved therapy for sub-populations of Duchenne. Together with our other approved therapies, we have the potential to treat nearly 30% of Duchenne patients in the United States. Our proprietary PMO platform is an important focus of our pipeline, and we owe our clinical progress to the patients and families participating in our studies.”

 

About Casimersen

Casimersen uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to skip exon 45 of the DMD 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 the production of an internally truncated dystrophin protein.

What about Canada?

At this moment, casimersen is not available in Canada. We hope that shortly, Sarepta Therapeutics will file a request for marketing approval with Health Canada.

For a better understanding

  • * The western blot is a widely used analytical technique in molecular biology, immunogenetics and other molecular biology disciplines to detect specific proteins in a sample of tissue homogenate or extract.
  • * Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and DNA are nucleic acids and, along with lipids, proteins and carbohydrates, constitute the four major macromolecules essential for all known forms of life. Like DNA, RNA is assembled as a chain of nucleotides, but unlike DNA, it is more often found in nature as a single-strand folded onto itself, rather than a paired double-strand.
  • Read more here
  • Grounded in the DMD community

About DMD

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is sporadic that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

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.

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Positive Safety and Efficacy Data from Micro-Dystrophin Gene Therapy

Sarepta Therapeutics Announces Positive Safety and Efficacy Data from the SRP-9001 Micro-Dystrophin Gene Therapy Trial Published in JAMA Neurology

 

Press release here > CAMBRIDGE, Mass., June 15, 2020 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc. announced safety and tolerability data at one year from four Duchenne muscular dystrophy (DMD) clinical trial participants who received SRP-9001 micro-dystrophin (AAVrh74.MHCK7.micro-dystrophin) have been published in JAMA Neurology. SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of micro-dystrophin protein.

 

Louise Rodino-Klapac, Ph.D., senior vice president of gene therapy, Sarepta Therapeutics –  “We are encouraged by the successful and safe systemic delivery of our micro-dystrophin transgene from our AAVrh74 viral capsid and targeted muscle expression results, demonstrating the safety and efficacy of SRP-9001 gene transfer maintained over one year in this cohort of participants living with Duchenne muscular dystrophy. Following the 9-month update we shared last year, the peer-reviewed publication of these results in JAMA Neurology further supports the potential for SRP-9001 to provide clinically meaningful functional improvements in terms of speed and magnitude of improvement for patients with DMD.  Study 102, our randomized, double-blind, placebo-controlled study of SRP-9001, is ongoing and we look forward to sharing the results in early 2021 as we work toward our ultimate goal of profoundly improving the lives of as many patients living with DMD as possible.”

 

In the open-label trial, known as Study 101, four ambulatory participants between the ages of 4 and 7 were treated with an infusion of SRP-9001 at a dose of 2×1014 VG/kg. The therapy was safe and tolerable in all participants over the one-year time period. All adverse events were considered mild or moderate, and there were no serious adverse events or evidence of complement activation.  At 12 weeks, muscle dystrophin levels demonstrated a mean of 81.2% muscle fibers expressing micro-dystrophin with a mean intensity at the sarcolemma by immunohistochemistry of 96% compared to normal biopsies. Adjusted for fat and fibrotic tissue, western blot showed a mean expression of 95.8%. All participants had confirmed vector transduction and showed functional improvement on the North Star Ambulatory Assessment scale (NSAA) and reduced creatine kinase (CK) levels that were maintained through one year.

 

Jerry Mendell, M.D., the study’s co-author and principal investigator with the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s Hospital –  “Duchenne muscular dystrophy is difficult to treat, and more options are needed to have the potential to alter the course of the disease. We are very pleased to report the successful delivery of the transgene to the nuclei corresponding to robust expression and proper localization of micro-dystrophin. This coincides with improvements in functional measurements in study participants who received SRP-9001. These results, together with biological and clinical markers of efficacy, provide proof-of-concept support for the continuation of clinical trials for assessment of SRP-9001 using single-dose gene therapy in participants with Duchenne.”

 

 

About SRP-9001

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. In December 2019, the Company announced a licensing agreement granting Roche the exclusive right to launch and commercialize SRP-9001 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 DMD

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

 

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 links

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SIDEROS, the largest ongoing trial in Duchenne

Santhera Completes Enrollment of Phase 3 SIDEROS Study with Puldysa® (Idebenone) in Duchenne Muscular Dystrophy (DMD)

Pratteln, Switzerland, May 20, 2020

Original press release

Santhera Pharmaceuticals announces the full recruitment of its Phase 3 SIDEROS study with idebenone in Duchenne muscular dystrophy (DMD). The sample-size and variability re-assessment performed according to study protocol demonstrated that with the currently enrolled patients the study has a very high power (>99%). Given the strong powering of SIDEROS, the Company is now assessing the potential of conducting an interim analysis to test for overwhelming efficacy with a view of completing the trial early.

With patient recruitment into the 18-month international SIDEROS trial in its final stages, Santhera performed the planned sample size and variability re-assessment in accordance with the study protocol to confirm adequate study power. This blinded analysis showed that variability is lower than anticipated per protocol and, with the current number of enrolled patients, the SIDEROS study has a very high power of over 99% to detect a treatment difference. On this basis, Santhera has taken the decision to complete enrollment into the SIDEROS trial. At present, approximately half of the recruited patients in SIDEROS have completed 18 months of treatment and about two-thirds of patients have completed 12 months of treatment.

Owing to the decision to complete enrollment of this advanced study, its very high power as well as the urgent unmet medical need, Santhera is assessing the potential of conducting an interim analysis to test for overwhelming efficacy with a view of completing the trial early. Such an interim analysis would be performed by the independent Data and Safety Monitoring Board (DSMB) to preserve the integrity of the study. If overwhelming efficacy is not established in the interim analysis, the study could continue as planned with the currently enrolled patients and the corresponding high power. However, if overwhelming efficacy is demonstrated, it would be considered unethical to continue with the blinded study and the Company would decide to end the study later this year. This would result in the acceleration of corresponding regulatory filings by approximately one year both in Europe and the US.

 

Gunnar Buyse, MD, Ph.D., Professor of Child Neurology at the University Hospitals Leuven (Belgium), SIDEROS Principal Investigator and Lead Investigator for Europe – “Santhera is the only company that has dedicated its clinical development program towards finding a treatment to preserve respiratory function in DMD. The large Phase 3 SIDEROS study was designed to confirm the efficacy of idebenone in patients with respiratory function decline who are concurrently taking glucocorticoids. We are truly excited that SIDEROS has completed recruitment and is on track to generate a comprehensive dataset in an area of such high unmet need.”

 

Oscar Henry Mayer, MD, Medical Director of the Pulmonary Function Testing Laboratory at the Children’s Hospital of Philadelphia and Lead Investigator for the US – “There are currently no approved treatments to slow the rate of respiratory function decline leading to respiratory failure, which remains a leading cause of premature death in young men at the advanced stages of DMD. By slowing the rate of respiratory function decline, we open the possibility of delaying the time to chronic respiratory failure and the need to assisted ventilation and reducing the risk of other life-threatening respiratory complications.”

 

Sjöblom Nygren, MD, Chief Medical Officer and Head of Development of Santhera – “We are delighted to have reached such an important milestone and wish to express our sincere thanks to patients and families, caregivers, physicians and study personnel for their support and commitment.”

 

About SIDEROS

SIDEROS, the largest currently ongoing clinical trial in DMD, is 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 primary endpoint of the trial estimates the treatment difference in FVC%p (forced vital capacity % predicted). Patients completing the trial are offered the opportunity to enroll in an open-label extension study where all patients receive idebenone. The study is currently conducted in 62 sites in the United States, Europe and Israel. Further information is available at ClinicalTrials.gov NCT#02814019.

About idebenone

Idebenone is a synthetic molecular formula similar to coenzyme Q10. Chemically, it is an organic compound of the family of quinones that can slow the loss of respiratory function.

Mitochondria are specialized structures in the human body that serve as batteries, powering various functions of the cell and the organism as a whole.

Mitochondria produce the energy necessary for the cell functioning through a process called “cellular respiration” which requires oxygen and provides energy. During cellular respiration, some toxic forms of oxygen (called oxygen free radicals) can be produced. These free radicals must be neutralized by other substances to avoid cellular damage.

Idebenone is expected to act as a neutralizer of these toxic forms of oxygen. Thus, idebenone is expected to have an antioxidant effect, and consequently prevent cellular damage.

Idebenone is optimized to dissolve in water and lipids and able to cross the mitochondrial membrane.

Idebenone is a medicine that is under investigation for the treatment of DMD. It has not yet been approved by the U.S. FDA, and the safety and efficacy continue to be evaluated in clinical trials.

More about idebenone

About Santhera Pharmaceuticals

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 anti-inflammatory drug candidate with a novel mode of action, currently investigated in a pivotal study in patients with DMD to replace standard corticosteroids. The clinical-stage pipeline also includes lonodelestat (POL6014) to treat cystic fibrosis (CF) and other neutrophilic pulmonary diseases, as well as 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), for the treatment of Leber’s hereditary optic neuropathy (LHON) to Chiesi Group. For further information, please visit www.santhera.com. Raxone® and Puldysa® are trademarks of Santhera Pharmaceuticals.

Sources

EU Globe News Wire

Santhera’s SYROS Study Shows Long-term Efficacy with Idebenone in Slowing Respiratory Function Loss in Patients with Duchenne Muscular Dystrophy

www.siderosdmd.com

Raxone-guides-spring-2019

www.takeabreathdmd.com

www.breatheduchenne.com

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Press release from Pfizer about gene therapy

Pfizer’s new phase 1b results of gene therapy in ambulatory boys with Duchenne muscular dystrophy (DMD) support advancement into pivotal phase 3 study

Read the press release here.

Friday, May 15, 2020
Pfizer Inc. announced updated Phase 1b clinical data on PF-06939926, an investigational gene therapy being developed to treat Duchenne muscular dystrophy (DMD). The preliminary data from 9 ambulatory boys with DMD, aged 6 to 12 indicate that the intravenous administration of PF-06939926 was well-tolerated during the infusion period, with encouraging efficacy and manageable safety events, even when considering those adverse events that were more severe in nature. The treatment provided durable and statistically significant improvements across multiple efficacy-related endpoints measured at 12 months post-infusion, including sustained levels of mini-dystrophin expression and improvements on the North Star Ambulatory Assessment (NSAA) rating scale, which is a validated measure of muscle function. Three serious adverse events (SAEs) were recorded, two of which reflected likely complement activation. While these two SAEs were severe in nature, all three events fully resolved within 2 weeks, providing encouragement that close monitoring and early intervention can help mitigate the effects of complement activation. This new dataset, which includes updated 12-month results on safety, dystrophin expression, and exploratory functional endpoints for 3 additional boys, was presented for the first time during a virtual oral session at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting.

 

Seng Cheng, Ph.D., Chief Scientific Officer, Pfizer Rare Disease Research Unit – “Based on the encouraging preliminary efficacy data and manageable safety events from our Phase 1b study, we believe we may have a potential breakthrough therapy for boys with Duchenne muscular dystrophy, a devastating disease for which there remains a significant medical need. We are advancing our Phase 3 program as quickly as possible and plan to begin dosing patients in the second half of 2020 pending regulatory approval. Our program has the potential to be the first DMD gene therapy Phase 3 trial start using a commercial-scale manufacturing process. If the program is successful, this manufacturing capability is expected to help position us to deliver this medicine to patients quickly following regulatory approval.”

 

Preliminary Safety Results

The primary endpoint of the Phase 1b study is to assess the safety and tolerability of this investigational gene therapy in ambulatory boys with Duchenne muscular dystrophy through 12 months following treatment. Based on the data to date, the most common adverse events (AEs) suspected to be related to PF-06939926 (occurring in >40% of patients) were vomiting, nausea, decreased appetite, and pyrexia (fever). There was no evidence of clinically relevant anti-dystrophin responses or hepatic dysfunction with the protocol-defined daily glucocorticoid regimen. Continue reading here.

Results from Secondary and Exploratory Endpoints

Secondary endpoints of the clinical study included measurement of mini-dystrophin concentration by liquid chromatography-mass spectrometry (LCMS) and distribution within muscle fibers by immunofluorescence.

Read more about: dystrophin concentration, dystrophin distribution and the functional assessment here.

 

Seng Cheng, Ph.D., Chief Scientific Officer, Pfizer Rare Disease Research Unit – “Taken together, we believe these data support the view that administration of PF-06939926 at a dose of 3E14 VG/kg can lead to the expression of potentially therapeutic levels of mini-dystrophin that may translate to a measurable improvement in muscle function and health in DMD patients. We also want to give our heartfelt thanks to all the patients, their families, the researchers, investigators, other clinicians and advocacy organizations for their passion, expertise and engagement in helping to advance clinical research and care for the Duchenne muscular dystrophy community.”

 

About PF-06939926

PF-06939926 is an investigational, recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle specific promotor. The AAV9 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, as well as assessments of muscle strength, quality and function.

 

About Pfizer

Pfizer’s innovative portfolio focuses on the discovery and development of new medicines and vaccines. By focusing on the best science and patient experience, Pfizer’s leadership and significant investments support faster delivery of breakthrough medicines that can fulfill unmet needs.

Interesting link

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

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Latest edition of the Catabasis Connection newsletter

La Force is happy to share the latest edition of the Catabasis Connection newsletter with updates on edasalonexent and information that Catabasis shared at the MDA Virtual Poster Session.

Earlier this month, Catabasis shared data from three scientific posters during the Muscular Dystrophy Association (MDA) Virtual Poster Session. Learn more about edasalonexent and its potential to provide positive effects in Duchenne here.

In this newsletter you can read:

  • Boys with Duchenne demonstrate capsule swallowing abilities
  • Phase 3 PolarisDMD trial enrolled expected patient population
  • Age-normative growth and normal adrenal function observed with edasalonexent

About Edasalonexent (CAT-1004)

Edasalonexent (CAT-1004) is an investigational oral small molecule designed to inhibit NF-kB that is being developed as a potential foundational therapy for all patients affected by DMD, regardless of their underlying mutation. In DMD the loss of dystrophin leads to chronic activation of NF-kB, which is a key driver of skeletal and cardiac muscle disease progression. Our ongoing global Phase 3 PolarisDMD trial is evaluating the efficacy and safety of edasalonexent for registration purposes. Edasalonexent is also being dosed in the open-label extension trial GalaxyDMD. In our MoveDMD Phase 2 trial and open-label extension, we observed that edasalonexent preserved muscle function and substantially slowed disease progression compared to rates of change in a control period, and significantly improved biomarkers of muscle health and inflammation. The FDA has granted orphan drug, fast track, and rare pediatric disease designations and the European Commission has granted orphan medicinal product designation to edasalonexent for the treatment of DMD. For a summary of clinical results, please visit www.catabasis.com.

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, as well as for the challenges associated with access to treatment.

 

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