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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).

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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.

More interesting links

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Exondys 51 slows down respiratory decline

Thanks to Bio Space, IOS Press, Science Daily for the content of this blog.

Duchenne muscular dystrophy is characterized by progressive muscle degeneration. In DMD patients, the pulmonary function becomes progressively impaired as the dystrophic process affects respiratory muscles, including the diaphragm. Strategies to arrest this severe gradual deterioration are needed to extend lives and improve quality of life.

Results of three clinical trials using eteplirsen show promising results

Sarepta, along with Harvard Medical School, The Children’s Hospital of Philadelphia, Nationwide Children’s Hospital, the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center and Ohio State University published results from three trials in the Journal of Neuromuscular Diseases.

This study conducted in three clinical trials supports that Sarepta Therapeutics’ Exondys 51 (eteplirsen) slows respiratory decline in Duchenne muscular dystrophy (DMD).

The respiratory decline in patients treated with eteplirsen was significantly lower, and this was true across all stages of the disease evaluated.

As the disease progresses, patients require increasing levels of clinical treatment. Patients are at increased risk of death once this respiratory decline reaches a critical threshold.

Eteplirsen may slow the rate of respiratory decline and therefore may delay time to milestones of decrease. This may have notable positive implications on quality of life. Longer-term follow-up is needed.

Pulmonary function

The pulmonary function can be measured by assessing different parameters of lung function. As an example, the total amount of air that can be moved through the lungs after a maximal inspiration and then exhalation (forced vital capacity [FVC]). The FVC measures output of inspiratory and expiratory muscles. This is an excellent measure of respiratory function reserve and is widely used in DMD to assess respiratory function.

About Exondys 51

  • Exondys 51 was approved in the US on September 2016.
  • Exondys 51 is approved for a specific subset of DMD patients that are amenable to exon 51 skipping therapies. That accounts for about 13% of DMD patients.
  • In September 2018, the European Medicines Agency (EMA) rejected Sarepta’s application for Exondys 51.
  • NEGATIVE OPINION FOR EXONDYS® IN EUROPE
  • The therapy costs about $300,000 US dollar per patient per year.
  • The company is awaiting an FDA decision on its exon 53-skipping therapy, Golodirsen, this summer. It would be appropriate for about 8% of DMD patients.
  • NEWS ABOUT GOLODIRSEN, SKIPPING EXON 53
  • This drug is not currently available in Canada, as Health Canada must approve its use in the Canadian market.
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PTC Provides Update on Translarna™

PTC Provides Update on Translarna™ (ataluren) Application for Label Expansion

June 28, 2019 > Original press release <

PTC Therapeutics, Inc. announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has completed their review of a proposed indication extension of Translarna™ (ataluren) for the treatment of patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) who are non-ambulatory. While the CHMP adopted a negative opinion of the extension, PTC was informed by EMA representatives that the European Public Assessment Report (EPAR) would be updated to clarify that patients who start Translarna while ambulatory are not required to discontinue treatment after the loss of ambulation.

 

Translarna is currently indicated for ambulatory Duchenne patients who are over two years of age; the requested extension would have allowed for the inclusion of non-ambulatory patients in the label. PTC plans to seek a re-examination of the procedure within the next two weeks and expects the new examination to last approximately four months. 

 

Marcio Souza, Chief Operating Officer, PTC Therapeutics, Inc – “While we are disappointed with the current outcome of the label expansion procedure and its impact on non-ambulatory patients with nonsense mutation Duchenne Muscular Dystrophy, we are pleased that patients on Translarna can remain on treatment after the loss of ambulation. We remain committed to work with the CHMP to clarify the open questions and are confident we will be able to demonstrate the pulmonary benefit of Translarna in non-ambulatory patients.”

 

The clinical data supporting the extension is based on results supporting the positive impact in the Force Vital Capacity (FVC) parameters for patients treated with Translarna in study 019, a long-term, open-label study, and study 025 (STRIDE Registry) when compared to matched natural history controls. This is in addition to currently approved labelling stating that the pharmacokinetics (PK) and safety profiles are comparable between ambulatory and non-ambulatory nmDMD patients and that no dose adjustment is necessary when patients become non-ambulatory. The CHMP opined that the comparable PK might not ensure efficacy in non-ambulatory patients since muscle mass is reduced in this patient group. PTC and members of the scientific community expressed disagreement with this understanding during the oral explanation.

Translarna received the annual renewal of its conditional marketing authorization in June 2019 for nonsense mutation Duchenne muscular dystrophy patients who are ambulatory and two years and over. In addition, in connection with the June 2019 renewal, PTC’s specific obligation for the submission of the results of Study 041, an ongoing clinical trial of ataluren, has been extended to September 2022.

 

Translarna™ (ataluren) in Canada

Translarna™ (ataluren) has not received marketing authorization in Canada. This treatment must, first and foremost, be evaluated and approved for the Canadian market by Health Canada. To approve a drug, Health Canada must ensure that it meets certain safety, efficiency and quality requirements.

La Force Foundation hopes that Translarna™(ataluren) will be marketed in Canada as soon as possible so that all young patients can benefit.

More about Translarna (ataluren)

Pioneer in the DMD therapy > Watch the Vlog

Clinical Trials Simplified and La Force DMD join forces

Clinical Trials Simplified and La Force DMD join forces to accelerate the development of new therapies for DMD

During a conference about rare diseases, Marie-Catherine Du Berger, president of La Force DMD met Carole Abi Farah, Ph.D., General Manager and Co-founder of Simplified Clinical Trials. Clinical trials provide early access to treatments, contribute to medical knowledge about a condition, help guide future research, and have the potential to impact how people with the same condition are treated in the future. The Force is pleased to announce this new collaboration. Also, this service is offered free of charge by Simplified Clinical Trials.

A partnership to help

Clinical Trials Simplified (CTS) and La Force Dystrophie Musculaire de Duchenne (La Force DMD) announce the establishment of a joint partnership to help patients suffering from DMD across the province find clinical trials. This partnership aims to facilitate access to clinical trials for patients with DMD and to accelerate the development of new therapies for DMD.

CTS’s mission

CTS’s mission is to help the Canadian patient suffering from an incurable disease find a clinical trial that matches his/her medical condition. For more information on clinical trials currently recruiting in Canada for DMD, visit Clinical Trials Simplified.com.

To participate in a clinical trial on DMD, please complete the registration form on Clinical Trials Simplified.com. For more information, contact CTS at info@clinicaltrialssimplified.com or 1-888-982-2782.

A new section about clinical trials taking place in Canada has been added to the home page of the La Force website here.

Translarna™ (ataluren) is the First Therapy Approved in Brazil for DMD

– Ambulatory Duchenne patients who are five years and older with a nonsense mutation can now access a treatment that targets the underlying cause of DMD –

 

PTC Therapeutics, Inc. today announced that Translarna™ (ataluren) has been granted marketing approval from the Brazilian National Health Surveillance Agency (ANVISA) under rare diseases procedure, for the treatment of ambulatory children five years and older with Duchenne muscular dystrophy caused by a nonsense mutation. Patients now can have access to a treatment that targets the underlying cause.

 

Eric Pauwels, Senior Vice President and General Manager of the Americas of PTC Therapeutics, Inc.– “The regulatory approval from the Brazilian authorities will accelerate access to Translarna for the many patients who have been waiting for treatment. We are committed to working quickly to make Translarna available to all patients in Brazil who may benefit.”

 

Alexandra Prufer, Associate Professor of Pediatric Neurology, Department of Pediatrics, Medical School, The Federal University of Rio de Janeiro. – “Muscle damage in Duchenne starts very young, so early diagnosis and treatment is critical to maintain muscle function and delay disease progression. Treatment measures should be started once children are diagnosed when there is the most amount of muscle to effect.”

 

About Translarna 


Ataluren, discovered and developed by PTC Therapeutics, Inc., is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy. Translarna, tradename ataluren, is licensed in the European Economic Area for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged two years and older. Ataluren is an investigational new drug in the United States.

CLINICAL TRIAL OF ATALUREN IN CANADA

PORTRAIT OF DUCHENNE – ATALUREN: A PROMISING TREATMENT FOR DMD

About PTC Therapeutics, Inc.


PTC is a science-led, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. PTC’s ability to globally commercialize products is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need.

Pioneers in DMD therapy

News provided by PTC Therapeutics, Inc.  Apr 29, 2019, 09:18 ET

Press Release > Translarna™ (ataluren) is the First Therapy Approved in Brazil for Duchenne Muscular Dystrophy

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New gene therapy for Duchenne muscular dystrophy

Audentes Therapeutics, Inc., a leading Adeno-associated virus (AAV)* based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases; announced it had expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1).

The Gene Therapy Market

Very promising and strong from its first successes, gene therapy benefits from active research and its development intensifies. Generating both hope and caution, it is about to prove its potential. The history of gene therapy is 30 years old. In 1999, the first clinical trials were carried out by the team of Professor Alain Fischer, at Necker Hospital for Sick Children, on young patients with severe immune deficiency (so-called “bubble children”).

The developments are long and require the creation of companies and industrial partnerships.

 

Gene therapy is now a real “promise” for patients and not just a “hope”.

 

In 2016, the U.S. Food and Drug Administration (FDA) approved the first drug to treat DMD, Sarepta’s Exondys 51. It was a long, dramatic and controversial approval journey involving numerous public hearings, internal FDA battles and letters from Congress and leading DMD physicians to the agency.

These deals mark the entry of gene therapy into mainstream drug development. Roche recently acquired Spark Therapeutics for $4.8 billion. Spark developed a gene therapy for rare eye disease and hemophilia. And in 2018, Novartis acquired AveXis for $8.7 billion. AveXis has a gene therapy for spinal muscular atrophy (SMA).

 

Audentes Therapeutics Partners with Nationwide Children’s Center

Published on April 8, 2019

Audentes Therapeutics, Inc., a leading Adeno-associated virus (AAV)* based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases; today announced it had expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1).

To accelerate these promising new programs, Audentes has entered into a licensing agreement and will collaborate with Nationwide Children’s Hospital, utilizing the expertise of Kevin M. Flanigan, M.D. and Nicholas S. Wein, Ph.D., two recognized leaders in the field of genetic medicines for neuromuscular diseases.

 

Matthew R. Patterson, Chairman and Chief Executive Officer – «Today’s announcement represents a significant step forward in expanding our scientific platform and deepening our pipeline of product candidates for neuromuscular diseases with high unmet medical need.

We see tremendous potential in combining AAV with validated oligonucleotide-based approaches to treat diseases that are not amenable to traditional AAV-based gene replacement.

We believe this approach, combined with our in-house large-scale cGMP (current good manufacturing practice) manufacturing capability, can deliver best-in-class therapies for the treatment of Duchenne muscular dystrophy and myotonic dystrophy.»

 

Dr. Flanigan, Director of Nationwide Children’s Center for Gene Therapy – «We are excited to be collaborating with Audentes to advance these novel, highly differentiated approaches for DMD and DM1…»

 

Audentes and Nationwide Children’s are collaborating to develop AT702, an AAV-antisense candidate designed to induce exon two skipping for DMD with duplications of exon 2 and mutations in exons 1-5 of the dystrophin gene. Audentes is currently conducting additional preclinical work and expects to commence a Phase 1/2 study at Nationwide Children’s in the fourth quarter of 2019.

The Audentes approach

Separate from the Nationwide Children’s collaboration, Audentes is also conducting preclinical work to advance AT751 and AT753, additional vectorized exon skipping candidates, to treat DMD patients with genotypes amenable to exon 51 and exon 53 skipping. Both AT751 and AT753 utilize the same vector construct backbone as AT702, enabling a potentially accelerated path into clinical development. With these initial programs, Audentes is targeting more than 25% of patients with DMD and has plans to leverage its vectorized exon-skipping platform to develop further product candidates to address up to 80% of DMD patients over time.

This approach combines the delivery power of AAV with the precision tools of antisense oligonucleotides, or ASOs, to develop potential best-in-class therapeutic candidates for these devastating neuromuscular diseases.

Adeno-associated virus (AAV)*

Adeno-associated virus (AAV) is a small virus that infects humans and some other primate species. AAV is a very attractive candidate for creating viral vectors for gene therapy, and for the creation of isogenic human disease models.

Vectorized exon skipping uses an AAV vector

Vectorized exon skipping uses an AAV vector to deliver an antisense sequence designed to induce cells to skip over faulty or misaligned sections of genetic code, leading to the expression of a more complete, functional protein. For the treatment of DMD, this approach has the potential to provide significant advantages over microdystrophin gene replacement strategies that produce a substantially truncated protein, which may limit the degree and durability of disease correction, as well as existing ASO therapies, whose efficacy is limited by poor biodistribution to muscle tissue.

Antisense therapy (ASO)

Antisense therapy is a form of treatment for genetic disorders or infections. When the genetic sequence of a particular gene is known to cause a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene “off”. This is because mRNA has to be single-stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA.

About Audentes Therapeutics, Inc.

Audentes Therapeutics (Nasdaq: BOLD) is a leading AAV-based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases. We are leveraging our AAV gene therapy technology platform and proprietary manufacturing expertise to develop programs across three modalities: gene replacement, vectorized exon skipping, and vectorized RNA knockdown. Our product candidates are showing promising therapeutic profiles in clinical and preclinical studies across a range of neuromuscular diseases. Audentes is a focused, experienced and passionate team driven by the goal of improving the lives of patients. For more information regarding Audentes, please visit www.audentestx.com.

 

About Nationwide Children’s Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2018-19 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. Nationwide Children’s has a staff of more than 13,000 providing state-of-the-art pediatric care during more than 1.4 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Research Institute at Nationwide Children’s Hospital is one of the top 10 National Institutes of Health-funded freestanding pediatric research facilities. More information is available at NationwideChildrens.org.

 

Myotonic dystrophy

Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, with a worldwide prevalence of 14 per 100,000 population. More on muscle.ca

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Phase 3 PolarisDMD trial of edasalonexent is now open for enrollment in Canada

Catabasis is enrolling boys ages 4 to 7 (up to 8th birthday), any mutation type, who have not been on steroids for at least the past six months.

 

What is Edasalonexent?

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

 

Potential bone health benefits of edasalonexent

Why is bone health so important in Duchenne?

Boys with Duchenne are at an increased risk of bone fractures and should be monitored yearly to check for fractures. Early detection is critical. Strong bones are essential to help boys grow taller! Some therapies used to treat Duchenne have an additional negative impact on bone health and can increase the frequency of long bone and spine fractures.

Catabasis believes that edasalonexent has the potential to benefit bone health, which is why they are studying it in their Phase 3 PolarisDMD trial. Because edasalonexent is an NF-kB inhibitor, it has the potential to reduce inflammation and promote muscle regeneration, and that can strengthen bones. Catabasis will perform x-rays and body scans at the beginning and end of the study to check on bone health!

 

PolarisDMD in Canada

If you’d like to learn more, contact Catabasis at DMDtrials@catabasis.com. Catabasis is also sharing updates on edasalonexent @CatabasisPharma on Facebook, Twitter and Instagram if you are interested in the latest updates. Get the story behind the PolarisDMD experience! – Here

Ontario

  • Children’s Hospital-London Health Sciences Centre, this site is expected to be enrolling soon
    • Principal Investigator: Craig Campbell
  • Children’s Hospital Eastern Ontario, this site is expected to be enrolling soon
    • Principal Investigator: Hugh McMillian

Alberta

  • Alberta Children’s Hospital is actively recruiting
    • Principal Investigator: Jean Mah

Quebec

  • Sainte-Justine Hospital, this site is expected to be enrolling soon
    • Principal Investigator: Cam-Tu Nguyen

 

Sources and for more information

More about Catabasis: www.catabasis.com

Portrait of Duchenne – edasalonexent cat-1004 – La Force DMD

Blog post La Force

More information about the Polaris DMD trial: Catabasis – Polaris DMD

Phase III Study of Edasalonexent in Boys With Duchenne Muscular Dystrophy (PolarisDMD)

 

 

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Sarepta Therapeutics announces positive results from the ESSENCE study

Sarepta Therapeutics, Inc., a leader in precision genetic medicine for rare diseases, announced positive results from its interim analysis of muscle biopsy endpoints comparing casimersen treatment to placebo in the ESSENCE study.

ESSENCE is a global, randomized double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of casimersen and golodirsen in patients amenable to skipping exons 45 or 53, respectively.

After soliciting feedback from the FDA, Sarepta conducted an interim analysis for levels of dystrophin protein expression in those patients who are amenable to exon 45 skipping to determine the potential for a New Drug Application (NDA) filing based on dystrophin as a surrogate endpoint. With these results, the Company intends to work toward submission of an NDA for casimersen in the middle of 2019. News release

 

“We are pleased to see that the anticipated exon skipping after treatment resulted in a statistically significant mean increase of dystrophin protein, as measured by western blot*.” -Professor Francesco Muntoni, University College London

“This is the third exon-skipping agent to have shown a statistically significant increase in dystrophin production, and reinforces our confidence in the exon-skipping approach for treating Duchenne patients with amenable mutations.” -Professor Francesco Muntoni, University College London

“The casimersen results and submission of our application for golodirsen earlier this year further validate our RNA* research engine. If golodirsen and casimersen are approved, nearly a third of the boys and young men living with DMD in the United States could benefit from our RNA therapies. We continue to advance toward our ultimate goal of profoundly improving the lives of as many patients around the world with DMD as possible.” -Doug Ingram, Sarepta Therapeutics’ president and chief executive officer

ESSENCE study

ESSENCE is a global Phase 3 study evaluating the efficacy and safety of casimersen and golodirsen in patients amenable to skipping exons 45 or 53, respectively. Golodirsen and casimersen rely on the same approach than Exondys 51.

Positive results

The interim analysis found a statistically significant increase in dystrophin production in casimersen-treated participants compared to baseline and placebo. Golodirsen and casimersen rely on the same approach than Exondys 51.

Submitting to the FDA

Based on positive results, the company intends to schedule a pre-NDA (New Drug Submission) meeting with FDA (Food and Drug Administration) US and plans to submit an NDA for casimersen in the middle of 2019.

Key findings from the interim analysis include:

  • Dystrophin protein increased to 1.736%. By comparison, treatment with Exondys 51 was shown to result in dystrophin levels of 0.93% of normal after 180 weeks.
  • A statistically significant difference in the mean change from baseline to week 48 in dystrophin protein was observed between the casimersen-treated arm compared to the placebo arm.
  • A statistically significant positive correlation between exon 45 skipping and dystrophin production was observed.
  • The study is ongoing and remains blinded to collect additional efficacy and safety data.

Sarepta exon skipping therapy

  • Exondys 51 > skipping exon 51 = 13% DMD patients
  • Golodirsen > skipping exon 53 = 8% DMD patients
  • Casimersen > skipping exon 45 = 8% DMD patients

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.

Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin

Dystrophin is a protein found in muscle cells that, while present in minimal amounts, is crucial in strengthening and protecting muscle fibers. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a critical structural role in muscle fiber function. Progressive muscle weakness in the lower limb’s spreads to the arms, neck and other areas of the body. The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

RNA-targeted therapeutics are powerful tools

Humans have about 22,000 genes, which contain the blueprints for producing proteins that perform essential functions in the body.

Proteins are molecular workhorses involved in almost every function in our bodies, and defective proteins often result in disease. More specifically, some diseases may be caused by the over-production of one or more proteins, while other diseases are caused by protein deficiencies.

Proteins are produced in cells, where genes in the DNA are “transcribed” into RNA templates, which are then processed and “translated” into proteins by  the cellular machinery.

RNA-targeted therapeutics direct the cellular machinery involved in making proteins. These drugs can be designed to increase or decrease the production of a protein involved in a disease.

By working at the genetic level, RNA-targeted therapeutics are powerful tools with the potential to address diseases that otherwise could not be treated with traditional small molecule or biologic drugs.

Watch Sarepta video here

What is Exon Skipping

Mutations in the dystrophin gene are one cause of DMD. Most commonly, one or more exons (a portion of a gene) are missing, and the remaining exons don’t fit together correctly. (Think of a zipper that doesn’t work correctly, because teeth are missing.)

Because of this error, cells cannot make the dystrophin protein that muscles need to work properly. Without it, muscle cells become damaged and, over time, are replaced with scar tissue and fat.

To fix the broken genetic machinery, scientists are developing drugs that skip over parts that contain missing or defective exons. In this way, the machine can produce a less defective dystrophin protein, which may improve muscle function in children with exon mutations.

Sarepta investigational therapies in the ESSENCE study use a technique referred to as exon skipping. Skipping a specific exon next to the mutation is intended to allow the body to make a shortened form of the dystrophin protein.

Sources

Sarepta Therapeutics, Inc.

Clinical Trials

Biopharma Dive

Cure Duchenne

Golodirsen