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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.

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Edasalonexent and COVID-19

La Force is happy to share the latest edition of the Catabasis Connection newsletter. As we are all faced with an unimaginable situation, Catabasis wanted to reach out and share information in response to questions they have been receiving about edasalonexent and COVID-19.

Catabasis is monitoring the trial for the safety of participating boys. To date, they did not identify any safety concerns related to COVID-19. We encourage reviewing your local recommendations to reduce the risk for boys and their families, and please consult your physician regarding specific medical advice. > Catabasis Connection <

Does edasalonexent affect the immune system?

Long-term toxicology studies with edasalonexent using higher doses than those in their clinical trials have found no evidence for immunosuppression using standard clinical and anatomic physiology methods. In clinical studies, now with over 100 patient-years of exposure to edasalonexent, Catabasis has found no evidence of immunosuppression or increased infections. In the Phase 3 PolarisDMD trial of edasalonexent, as well as the GalaxyDMD open-label trial, boys are not on steroids.

Should trial participants still go to the hospital for their assessments?

They are fortunate that site visits are relatively infrequent during the Phase 3 PolarisDMD trial with assessments every 3 months. Currently, they are focused on ensuring that patients have uninterrupted drug supply as well as safety monitoring. Catabasis is working closely with its clinical trial sites with frequent communication.

Will the outcome of ongoing trials be endangered by not being able to carry them out as per protocol?

Catabasis is actively monitoring the situation and has plans in place to address potential disruptions. Fortunately, they designed their clinical trial so that visits are relatively infrequent. Catabasis is working with sites to support drug supply, as well as safety and efficacy assessments.

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.

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Viltolarsen under priority review by the FDA

The U.S. Food & Drug Administration (FDA) had accepted the filing of a New Drug Application (NDA) under the priority review for viltolarsen in patients with Duchenne Muscular Dystrophy (DMD) who are amenable to exon 53 skipping therapy.

Read the full News Release

KYOTO, Japan and PARAMUS, NJ: February 7, 2020 –

Nippon Shinyaku Co., Ltd. and NS Pharma, Inc. announced that the U.S. Food & Drug Administration (FDA) had accepted the filing of a New Drug Application (NDA) under the priority review for viltolarsen in patients with Duchenne Muscular Dystrophy (DMD) who are amenable to exon 53 skipping therapy. In addition to priority review, the FDA previously granted viltolarsen with Fast Track, Orphan Drug and Rare Disease designations. The viltolarsen NDA includes results from a Phase 2 study and its long-term extension study in North America — as well as a Phase 1 and a Phase 1/2 study in Japan. Both the Phase 1/2 and Phase 2 studies evaluated changes in dystrophin levels and motor function across two doses. The PDUFA (Prescription Drug User Fee Amendments) date for viltolarsen is within the 3 rd quarter (July-September) of 2020. The PDUFA date is the target date the FDA provides a decision on the approval of a new drug. Viltolarsen represents one of the most extensively studied antisense therapies in DMD. Viltolarsen, if approved by the FDA, would represent a new treatment option for DMD patients amenable to exon 53 skipping in the United States.

About Viltolarsen

Viltolarsen has been granted a Rare Pediatric Disease Designation, Orphan Drug Designation, and a Fast Track Designation in the U.S., and “SAKIGAKE designation,” “Orphan drug designation,” and designation of Conditional Early Approval System in Japan. Viltolarsen is not approved by any regulatory authority and its safety and effectiveness have not been established.

Mechanism of Action

Exon skipping is a potential therapy that is being developed for patients with DMD. Specialized molecules are created to skip over the non-working part of the dystrophin gene and allow pieces of the puzzle to attach. It creates a smaller puzzle, but a puzzle that may produce some of the protein that muscles need to work correctly. NS-065/NCNP-01-201 Phase II dose-finding study is evaluating the safety and dosing of an investigational medication called NS-065/NCNP-01 (Viltolarsen), in the treatment of boys with DMD who have specific changes in the dystrophin gene that may be helped with the skipping of exon 53.

More links

Correcting nonsense mutations with CRISPR/cas9?

Correcting nonsense mutations with CRISPR / Cas9?

Would it be possible to correct nonsense mutations with CRISPR/Cas9? Some patients with DMD have a point mutation (nonsense) that leads either to the absence or to the abnormal function of dystrophin. The objective of Professor Jacques P. Tremblay’s team is to develop therapies for DMD due to such mutations.

In the last three years, new variations of the CRISPR/Cas9 technology, called base editing, permit to change a single nucleotide pair into another one. Professor Jacques P. Tremblay’s team will use this technology to correct the point mutation present in the MDX mouse model and 28 mutations detected in Canadian DMD patients according to the Canadian Neuromuscular Disease Registry database. Their knowledge and acquired experience will then subsequently be used to treat point mutations responsible for other hereditary neuromuscular diseases.

 

Professor Jacques P. Tremblay will be on Découverte on November 3 at 6:30 pm on Radio Canada. Découverte|Radio-Canada 

 

The human DNA

The human DNA present in each of our cells contains all the genetic information that we have inherited from our parents (e.g., eye colour, hair colour), including mutations responsible for hereditary diseases. 

This DNA is formed by only four chemical molecules called nucleotides:

  • A: adenosine
  • T: thymidine
  • C: cytosine
  • G: guanine

The DNA is a double helix formed by nucleotide pairs. Half of our genome originates from our mother and the other half from our father. We have received 3.2 billion nucleotide pairs from each parent. Genes coding for proteins that make our cells are sequences of these nucleotide pairs.

 

What is CRISPR/Cas9 technology?

CRISPR/cas9 technology is a technology that was first identified in bacteria. Bacteria were using this to cut up the genome of the viruses that were infecting them. About five years ago, researchers noticed that this technology allows not only to cut up virus genes but that it can also cut genes in animals, plants and especially in humans. Learn more here > Genetic engineering offers real hope of advancement.

 

About Professor Jacques P. Tremblay

Jacques P. Tremblay received a B.Sc. in Biochemistry from McGill University in 1970, and a Ph.D. in Neuroscience from UCSD (University of California in San Diego) in 1974. From 1975 to 1976, he was a postdoctoral fellow at the Laboratory of Neurobiology of l’Hôpital de L’Enfant-Jésus. His group is currently using CRISPR/Cas9 technology to correct the dystrophin gene, creating an additional deletion to produce a hybrid exon of the dystrophy gene, which not only restores the expression of dystrophin but also produces dystrophin with a regular structure.

To learn more about the work of Professor Jacques P. Tremblay: Centre de recherche du CHU de Québec

 

Interview with Jacques Tremblay

We wish to connect you, the DMD community, with the professors. We hope this video will be a good medium for understanding how CRISPR/Cas9 technology work, as related to DMD.

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Positive data with vamorolone in DMD

Santhera Announces Presentation by ReveraGen of Positive 18-Month Data with Vamorolone in Duchenne Muscular Dystrophy

 

La Force is happy to share this press release provided by Santhera Pharmaceuticals, October 7, 2019, > PRESS RELEASE <

 

Santhera Pharmaceuticals announces the presentation of data showing continued improvement of muscle function and improved tolerability compared with corticosteroids of 18-month vamorolone treatment in Duchenne muscular dystrophy (DMD). These top-line data were presented on October 5 by Eric Hoffman, Ph.D., CEO of ReveraGen at the World Muscle Society (WMS) congress.

In a late-breaking presentation at the WMS international conference in Copenhagen, Denmark, ReveraGen presented motor function and tolerability data from 23 DMD patients treated with 2.0 or 6.0 mg/kg/day with vamorolone for at least 18 months in the ongoing VBP15-LTE study.

 

Eric Hoffman, Ph.D., Chief Executive Officer of ReveraGen – “These data demonstrate that vamorolone treatment results in persistently improved motor function in DMD patients, similar to that of corticosteroids. Importantly, however, vamorolone treatment over a period of 18 months showed better tolerability with less corticosteroid-specific side effects, including no stunting of the growth of DMD children.”

 

Vamorolone is a first-in-class steroidal anti-inflammatory investigational drug in development as a treatment for DMD to substitute standard corticosteroids (prednisone, deflazacort). This trial is an extension study of the VBP15-003 trial in which 48 DMD patients treated for 6 months over a broad dose range (0.25 to 6.0 mg/kg/day) showed dose-related improvements in multiple gross motor outcomes. Upon exiting this 6-month trial, patients and their physicians preferred to continue vamorolone treatment. 45 boys transitioned to the 2-year long-term extension study VBP15-LTE and all doses were increased to 2.0 or 6.0 mg/kg/day of vamorolone.

At the WMS conference, Dr. Hoffman presented data from 23 patients treated with 2.0 or 6.0 mg/kg/day vamorolone for at least 18 months. Vamorolone treatment consistently and significantly improved standardized motor function outcomes measured as velocity to stand from supine, to run/walk 10 meters and to climb 4 stairs from baseline to month 18. Motor function outcomes for vamorolone treated patients also were consistently better than outcomes for age-matched, steroid naïve patients from an external natural history study (velocity to stand from supine: p=0.085; run/walk 10 meters: p=0.005; climb 4 stairs: p=0.036; all in favour of vamorolone treatment).

Vamorolone compared to standard corticosteroids

Motor function outcomes of vamorolone-treated DMD boys were compared to age-matched prednisone-treated patients from an external control group. Both vamorolone and prednisone treated groups showed similar improvements in these gross motor outcomes, demonstrating that vamorolone exerts therapeutic efficacy similar to standard corticosteroids. Importantly, vamorolone-treated boys showed normal growth rates, and less physician-reported weight gain and Cushingoid features compared to published studies of prednisone and deflazacort. These findings confirm earlier data that indicate a better tolerability profile of vamorolone compared to standard corticosteroids.

Together with previously reported molecular and clinical data, the new 18-month data suggest that dissociative steroidal drug vamorolone maintains efficacy and decreases adverse effects typically reported for corticosteroids in the treatment of DMD. Vamorolone has been granted Orphan Drug status in the US and Europe and has received Fast Track and Rare Pediatric Disease designations by the US FDA.

About Vamorolone – first-in-class dissociative steroid

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 replace existing corticosteroids, the current standard of care in children and adolescent patients with DMD. There is a significant unmet medical need in this patient group as high dose corticosteroids have severe systemic side effects that detract from treatment compliance and patient quality of life.

The currently ongoing 48-week Phase IIb VISION-DMD study is designed as a pivotal trial to demonstrate efficacy and safety of vamorolone compared with prednisone and placebo in 120 boys aged 4 to <7 with DMD that have not yet been treated with corticosteroids. 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. In November 2018, Santhera acquired from Idorsia the option to an exclusive sub-license to vamorolone in all indications and all countries worldwide (except Japan and South Korea).

Clinical trial in Canada

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 a 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 currently 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. Raxone® and Puldysa® are trademarks of Santhera Pharmaceuticals

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 USA, Parent Project Muscular Dystrophy, Foundation to Eradicate Duchenne, Save Our Sons, JoiningJack, Action Duchenne, CureDuchenne, Ryan’s Quest, Alex’s Wish, DuchenneUK, 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).

Links

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PolarisDMD Trial in DMD has exceeded target enrollment

Phase 3, PolarisDMD trial of edasalonexent in DMD has exceeded target enrollment

 

La Force is happy to share the latest edition of the Catabasis Connection newsletter

 

Catabasis Pharmaceuticals, Inc. announced today the completion of enrollment for the Phase 3 PolarisDMD trial of edasalonexent in Duchenne muscular dystrophy (DMD). The target enrollment of 125 boys was exceeded due to strong interest from their 40 clinical sites in 8 countries and the support of patient advocacy organizations. Top-line results from the Phase 3 PolarisDMD trial are expected in the fourth quarter of 2020 and the trial is anticipated to support a New Drug Application (NDA) filing in 2021.

PRESS RELEASE

 

Joanne Donovan, M.D., Ph.D., Chief Medical Officer of Catabasis “We are thrilled to reach this important milestone. The interest and feedback from families and trial sites has been overwhelmingly positive. At a time when there are multiple trials for Duchenne, we are very pleased that physicians and families chose the Phase 3 PolarisDMD trial for edasalonexent. Edasalonexent has the potential to be a foundational therapy, providing benefit to boys, regardless of their underlying mutation, with the potential to benefit muscle function, as well as cardiac function and bone health. We look forward to completing the trial next year and are working diligently toward the goal of making edasalonexent available to patients.”

 

The PolarisDMD trial enrolled 130 boys ages 4 to 7 with any mutation type and who had not been on steroids for the past 6 months. The trial is a randomized, double-blind, placebo-controlled trial with 2 to 1 randomization such that two boys receive edasalonexent for each boy that receives a placebo. At the completion of 52 weeks, all boys and their eligible siblings are expected to have the option to enroll in GalaxyDMD, an open-label extension study designed to assess the long-term safety of edasalonexent. Boys can begin or continue treatment with an approved exon skipping therapy in the GalaxyDMD trial, which has a streamlined schedule with visits to trial sites every six months. Read more about these studies here.

 

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 Phase 3 PolarisDMD Trial

The global Phase 3 PolarisDMD trial is a one-year, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of edasalonexent in patients with DMD. The trial enrolled patients ages 4 to 7 regardless of mutation type who had not been on steroids for at least 6 months. Boys on a stable dose of eteplirsen were also eligible to enroll. The primary efficacy endpoint is change in the North Star Ambulatory Assessment score after 12 months of treatment with edasalonexent compared to placebo. Key secondary endpoints include the age-appropriate timed function tests: time to stand, 4-stair climb and 10-meter walk/run. Assessments of growth, cardiac and bone health are also included as important potential areas of differentiation. For each boy that receives a placebo, two boys are receiving 100 mg/kg/day of edasalonexent and after 12 months, all boys are expected to receive edasalonexent in the open-label extension study GalaxyDMD. The PolarisDMD trial design was informed by discussions with regulators as well as input from treating physicians, patient organizations and families of boys affected by Duchenne. Top-line results from the Phase 3 PolarisDMD trial are expected in the fourth quarter of 2020. More information about the Phase 3 PolarisDMD clinical trial is available on clinicaltrials.gov.

 

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.

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Sarepta Therapeutics receives Complete Response Letter for golodirsen

Sarepta Therapeutics receives Complete Response Letter from the US Food and Drug Administration for golodirsen New Drug Application

Sarepta Therapeutics, Inc announced it had received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the New Drug Application (NDA) seeking accelerated approval of golodirsen injection for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 53 skipping. – News Release

 

What is an FDA Complete Response Letter CRL?

Receiving one of these letters means that the FDA has completed its review of a new drug application and decided not to approve it in its present form.

The U.S. Food and Drug Administration (FDA) sends a complete response letter to communicate it has completed its review of a new or generic drug application, and it decided that it will not approve it for marketing in its present form. Receiving one of these letters from the FDA is never good news, but their long-term impact varies. – The Motley Fool

The CRL cites two concerns:

  • The risk of infections related to intravenous infusion ports
  • Renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten-fold higher than the dose used in clinical studies.

Renal toxicity was not observed in Study 4053-101, on which the application for golodirsen was based.

 

Doug Ingram, president and chief executive officer, Sarepta – “We are very surprised to have received the complete response letter this afternoon. Over the entire course of its review, the Agency did not raise any issues suggesting the non-approvability of golodirsen, including the issues that formed the basis of the complete response letter.”

 

Doug Ingram, president and chief executive officer, Sarepta – “We will work with the Division to address the issues raised in the letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen. We know that the patient community is waiting.”

 

What is the next step?

Sarepta will immediately request a meeting with the FDA to determine next steps. The ESSENCE study (4045-301), a global, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of golodirsen and casimersen, our exon-45 skipping agent, is ongoing.

More about golodirsen

Like Exondys 51, golodirsen, which Sarepta hopes to sell under the name Vyondys 53, is designed to treat a group of Duchenne patients with a particular type of mutation. Exondys 51 works for about 13% of DMD patients—those whose disease is amenable to exon 51 skipping. If approved, golodirsen would offer treatment to patients with a mutation in exon 53—about 8% of the DMD population.

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