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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

Sources

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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

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New drug for DMD being reviewed by the FDA

Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53

Press release here: Sarepta.com

 

Sarepta Therapeutics, Inc. announced the Food and Drug Administration, Division of Neurology had accepted its New Drug Application (NDA) seeking accelerated approval for golodirsen (SRP-4053) and provided a regulatory action date of August 19, 2019. Golodirsen is a phosphordiamidate morpholino oligomer* engineered to treat those individuals with Duchenne muscular dystrophy (DMD) who have genetic mutations subject to skipping exon 53 of the dystrophin gene.

The company completed its NDA at the end of 2018 as part of a rolling submission and requested priority review, which was granted. The company previously received orphan drug designation for golodirsen.

The study demonstrated statistically significant results in favour of golodirsen on all biological endpoints.

*a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. 

 

Doug Ingram, president and chief executive officer, Sarepta: “If approved, golodirsen will serve up to another 8 percent of the Duchenne community, bringing us closer to helping as many Duchenne patients as possible.

We look forward to working with the FDA toward advancing this important therapy and rapidly bringing it to individuals with Duchenne who are amenable to exon 53 skipping.”

 

What is Golodirsen?

Golodirsen uses exon-skipping technology and works by binding to exon 53 of the dystrophin sequence to exclude, or skip, this part of the sequence. Exon skipping is intended to allow for the production of an internally truncated but functional dystrophin protein.

Positive results

Golodirsen showed potential to treat Duchenne muscular dystrophy (DMD) in a first clinical trial of DMD patients. Press release

Why do we need to skip an exon?

DMD is caused by specific errors (mutations) in the gene that codes for dystrophin. Dystrophin is a protein that plays a crucial role in the function of muscle cells and protects them from damage as muscles contract and relaxes. These mutations in the dystrophin gene lead to a lack of dystrophin protein in muscles. Without enough dystrophin, muscles gradually grow weaker until they can’t move at all, and eventually breathing and heart function are lost.

The condition is universally fatal. Death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

Sources:

 

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News about Golodirsen, Skipping Exon 53

Sarepta Therapeutics completes submission of New Drug Application seeking approval of golodirsen in patients with DMD amenable to skipping exon 53

Press Release here

Golodirsen has been studied for the treatment of exon 53 amenable patients, approximately eight percent of patients with DMD. Submission represents ongoing advancement of the company’s proprietary PMO RNA-based platform.

Sarepta Therapeutics, Inc. announced today that it had completed the submission of its New Drug Application (NDA) seeking accelerated approval for golodirsen (SRP-4053), a phosphorodiamidate morpholino oligomer engineered to treat those patients with Duchenne muscular dystrophy who have genetic mutations subject to skipping exon 53 of the Duchenne gene.

If the golodirsen NDA is filed and granted accelerated approval, the company’s ESSENCE study (4045-301) could serve as a post-marketing confirmatory study. ESSENCE, which is underway, is a global, randomized double-blind, placebo-controlled study assessing the safety and efficacy of golodirsen and casimersen, their exon 45 skipping therapy.

“We are grateful for the patients and clinicians who have participated in the study with an aim to advance treatment for all patients with Duchenne,”
“Sarepta is committed to developing therapies to benefit the greatest possible percentage of patients affected by Duchenne. Our proprietary PMO technology remains central to our commitment to patients with Duchenne. Combined, EXONDYS 51® (eteplirsen), golodirsen, and casimersen have the potential to treat nearly 30 percent of patients with Duchenne.” Said DOUGLAS S. INGRAM, President & CEO

About Golodirsen

Golodirsen exon-skipping technology to skip exon 53 of the DMD gene. Exon skipping is intended to allow for the production of an internally truncated but functional dystrophin protein.

Golodirsen uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO)* chemistry and exon-skipping technology to skip exon 53 of the DMD gene. Golodirsen is designed to bind to exon 53 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 53 skipping. Exon skipping is intended to allow for the production of an internally truncated but functional dystrophin protein.

Golodirsen is one of the investigational candidates currently being evaluated in the ESSENCE study, a global, randomized, double-blind, placebo-controlled study evaluating efficacy and safety in patients amenable to skipping exons 45 or 53.

*a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. 

More about dystrophin

Dystrophin is a protein found in muscle cells that, while present in extremely small amounts (about 0.002 percent of total muscle protein), 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 key structural role in muscle fiber function.

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Patient registry demonstrating Translarna™ slows DMD progression

Here’s the latest news from PTC Therapeutics about Translarna™ (ataluren). In a recent press release, PTC announces that Translarna™ (ataluren) slows disease progression in children with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation. Enjoy reading and thank you for sharing these articles within the DMD community.

 

Analysis of data to date shows Translarna Preserved Ambulation for up to 5 Years Compared to Natural History

The data show that children and adolescents receiving Translarna in the real-world setting are continuing to walk years longer than untreated children and are staying more physically able. A time-to-event analysis for loss of ambulation has shown that patients on Translarna had a median age of loss of ambulation of 16.5 years of age – up to 5 years later than seen with natural disease progression in untreated children. The data were presented as a late breaker at the 23rd International Annual Congress of the World Muscle Society in Argentina.

 

Stuart W. Peltz, Ph.D., CEO, PTC Therapeutics: “The results from the Registry data are critical because they further substantiate the results observed in our analyses of data from previous clinical trials studying Translarna in Duchenne. Delaying the loss of ambulation is critical to these patients, as it predicts the time to loss of pulmonary function and mortality.”

 

Dr. Eugenio Mercuri, Professor, Pediatric Neurology, Catholic University: “These initial data are very encouraging because they provide the first, real-world evidence for the impact of Translarna when used routinely, longer term. We are seeing children who have been exhibiting first clinical symptoms of Duchenne at approximately three years of age and yet are still able to walk years after they would normally be wheelchair-bound, which is what matters most to patients and their families.”

 

Filippo Buccella, an author of the study and Duchenne patient advocate: “Keeping a child with Duchenne walking for as long as possible is crucial not only to maintain independence, but to delay the rapid deterioration that usually follows loss of ambulation, including loss of the use of arms, which are essential for self-care, and respiratory and cardiac complications. As a father to a son with Duchenne, slowing the progression of this devastating disease is vital to maintaining the quality of life for the patient as well as the family.”

 

About Translarna ™ (ataluren)

Discovered and developed by PTC Therapeutics, Inc., Translarna ™ (ataluren) 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. Read more here.

 

Ataluren in Canada

At this moment, PTC Therapeutics has not applied for marketing approval with Health Canada, but it has started a conversation with the legislator.

 

What is a nonsense mutation?

DMD is a devastating disease that is caused by mutations in the dystrophin gene. The mutations vary in nature and account for the deletion, faulty replication, or duplication of parts of the genetic blueprint or code for protein manufacture. In other words, mutations in the dystrophin gene disrupt how protein factories in cells read its genetic code while making the dystrophin protein. The result is the absence of functional dystrophin protein in skeletal and cardiac muscles.

A change in a single base (point) of DNA can prematurely end the translation of a gene into a protein. About 10 % to 15 % of single-point mutations are nonsense mutations. They occur during the reading of messenger RNA (mRNA), which copies the genetic code during the manufacturing process, into protein.

 

About DMD

Duchenne muscular dystrophy (DMD) is a disease that 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.

 

More Links

PR NewsWire News Releases

Learn more about ataluren (Translarna™) at www.ptcbio.com

La Force VLOG Pioneers in DMD therapy

For specific updates about ataluren, you can consult and sign in on Duchenne and you

 

2018/10/09

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Positive results in the gene therapy micro-dystrophin trial to treat DMD

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from Sarepta Therapeutics. They announce that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., presented positive updated results from the four children dosed in the gene therapy micro-dystrophin trial to treat patients with Duchenne Muscular dystrophy. Enjoy reading and thank you for sharing these articles within the DMD community. -Press release from Sarepta Therapeutics: Sarepta news release.

 

A quick overview of gene therapy micro-dystrophin

This therapy uses a virus (the adeno-associated virus, or AAV) to deliver the micro-dystrophin, a shorter version of the dystrophin gene, which contains the minimum amount of information needed to produce a functional protein of dystrophin.* We are hopeful that, one day, micro-dystrophin will be a viable treatment for Duchenne muscular dystrophy (DMD).

 

What are the positive results?

  • Robust expression of micro-dystrophin
  • A significant decrease in creatine kinase (CK)
  • Improvements in all measured functions,
  • No serious adverse events (SAEs) were observed in the study.
  • Press release from Sarepta Therapeutics: Sarepta news release.

 

Words from Dr. Mendell

“The goal of this study was to validate what we observed in preclinical models. We observed efficient transduction of our vector, AAVrh74, to all muscle types; robust expression in skeletal muscles via the MHCK7 promoter; a reduction in creatine kinase levels; and a favorable safety profile. Similar to preclinical models, we also observed in this early study that robust expression has the potential to positively impact the natural course of disease progression.”

 

Words from Doug Ingram, Sarepta’s president and chief executive officer

“The encouraging results that we previously saw and reinforced in the fourth patient strengthen our resolve to rapidly move to a confirming trial and, assuming successful, to bring this therapy to the Duchenne community around the world with a sense of urgency.”

 

Words from Mr. Ingram

“These results create for us an obligation to patients around the globe living with and being damaged by this cruel disease. We are investing our energy, resources and creativity to moving the development forward, planning meetings with the FDA and other agencies around the world to take their input, building compelling access and reimbursement package, and establishing sufficient manufacturing capacity to fully serve the community if our program is successful.”

 

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

Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying Duchenne muscular dystrophy (DMD) drug candidates. For more information, please visit www.sarepta.com.

 

More Links

La Force VLOG: Sarepta, grounded in the DMD community

Source: Sarepta Therapeutics, Inc.

Press release from Sarepta Therapeutics: Sarepta news release

Clinical trial: clinicaltrials.gov

*Muscular Dystrophy News Today: Microdystrophin Gene Therapy Shows Promising Interim Results in Phase 1/2 Trial

La Force BLOG: Gene therapy and exon skipping

La Force BLOG: Gene replacement therapy

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Deflazacort over prednisone/prednisolone?

Here’s the latest news from PTC Therapeutics about Deflazacort (EMFLAZA®). A publication of data in Muscle & Nerve comparing the efficacy and safety of deflazacort and prednisone/prednisolone from the placebo arm of the ACT DMD study has been published in Muscle & Nerve. Enjoy reading and thank you for sharing these articles within the DMD community.

 

The results demonstrated a clinically differentiated benefit of deflazacort over prednisone/prednisolone in slowing disease progression as measured using physical function endpoints and the time to delay loss of ambulation. Duchenne muscular dystrophy patients treated with deflazacort had notably less decline from baseline in 6-minute walk distance at Week 48 than those treated with prednisone/prednisolone.

 

Stuart W. Peltz, Ph.D. Chief Executive Officer of PTC Therapeutics, Inc. said:

 

“This publication supports the benefit of deflazacort in slowing the progression of Duchenne compared to other corticosteroids,”

“The data indicates that deflazacort should be the standard of care for all patients with Duchenne. The availability of deflazacort, a treatment that has the potential to alter the natural history of Duchenne, supports the need for early diagnosis in patients with this disease.”

 

What is Deflazacort

Deflazacort is a corticosteroid that works through receptors in the body to effectively inhibit inflammation.

Clinical studies demonstrated that Emflaza:

  • delayed the loss of muscle strength of Duchenne patients
  • improved the ability to accomplish tasks related to standing, climbing stairs, to run or walk 30 feet
  • Slowed the loss of muscle strength over time

More on Emflaza.com

 

Access Deflazacort in Canada

In Canada, eligible patients can ask to receive deflazacort through a Special Access Program (SAP). This Health Canada program enables doctors to prescribe a drug not approved for sale or distribution in Canada to patients with a severe or life-threatening disease that has no other viable treatment.  Special Access Programme

 

About PTC Therapeutics

PTC Therapeutics was one of the first pharmaceutical companies to develop a treatment for Duchenne muscular dystrophy (DMD). Developing ataluren (Translarna™), a treatment that works on a nonsense mutation in the dystrophin gene took 20 years. When PTC started its research, there was no North Star Ambulatory Assessment (NSAA), a mobility test that measures the results of treatment. The company began with a blank sheet. Its hard work and persistence encouraged other pharmaceutical companies to jump in and investigate new therapies for DMD. More at About PTC (vloglaforcedmd.com)

 

 

More interesting link

Ptc Therapeutics announces publication data demonstrating he Clinical Differentiated Benefit of Deflazacort: News Releases (ir.ptcbio.com)

Effects of Deflazacort Versus Prednisone on Bone Mass, Body Composition, and Lipid Profile: A Randomized, Double-Blind Study in Kidney Transplant Patients: Effects of Deflazacort Versus Prednisone (academic.oup.com)

A Comparison of the Effects of Deflazacort and Prednisone Versus Placebo on Timed Functional Tests in Boys with Duchenne Muscular Dystrophy: A Comparison of the Effects of Deflazacort (n.neurology.org)

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Negative opinion for EXONDYS® in Europe

 

Here’s the latest news from Sarepta Therapeutics press release about EXONDYS® (eteplirsen). EXONDYS® (eteplirsen) is designed to treat patients with Duchenne muscular dystrophy (DMD) amenable to skipping exon 51 of the dystrophin gene. Enjoy reading and thank you for sharing these articles within the DMD community.

 

Sarepta receives negative CHMP opinion for EXONDYS® (eteplirsen) in Europe

Sarepta Therapeutics, Inc., announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had adopted a negative opinion for EXONDYS® (eteplirsen).

 

Request for re-examination

Sarepta will request a re-examination of the opinion, which will result in the assignment of a new rapporteur and co-rapporteur. The company will also request a Scientific Advisory Group (SAG) on DMD to be called so that neuromuscular specialists experienced with working on treatments for these patients can provide expert guidance and insight into, among other things, the validity of the external controls used and the importance of certain functional endpoints, including, for instance, the relevance of meaningful slowing pulmonary decline in patients with this difficult to treat disease. The re-examination process is expected to be completed by year-end 2018.

 

EXONDYS® a treatment using the exon-skipping technique

This treatment uses a specific exon-skipping technique to jump over a portion of genetic machinery that produces a non-working, mutated form of dystrophin in children with DMD. It aims to restore the machinery’s ability to read genetic code, so it can produce a less mutated form of dystrophin that works in children with DMD.

The production of partly functional dystrophin may delay muscle destruction and extend mobility in children with this devastating, rare disease. More specifically, Exondys 51 (eteplirsen) triggers the skipping of exon 51, which occurs in 13% of children with DMD.

 

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.

 

More interesting link:

Please visit: www.sarepta.com

Video Professor Georges Dickson

Press Release

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Solid Biosciences announces new preclinical data about gene transfer

 

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from a recent Solid Bioscience press release about SGT-001, the Company’s lead microdystrophin gene transfer candidate. Enjoy reading and thank you for sharing these articles within the DMD community.

 

Solid Biosciences announces new preclinical data at the American Society of Gene and Cell Therapy Annual Meeting

Solid Biosciences Inc. announced new preclinical data from its gene therapy development programs for Duchenne muscular dystrophy (DMD). New data for SGT-001 further demonstrate its potential to produce long-term and body-wide microdystrophin expression that correlates with significant improvements in muscle function.

 

“Solid remains steadfast in our mission to bring important therapies to patients with DMD, where a significant unmet need exists. These data further support the investigation of SGT-001 as a potential new treatment option for those living with this devastating disease, as well as reinforce our commitment to advancing cutting-edge innovations through our next generation gene therapy pipeline,” said Carl Morris, Ph.D., Chief Scientific Officer of Solid Biosciences.

 

 

About SGT-001

SGT-001 is a novel adeno-associated virus* (AAV) vector-mediated gene transfer under investigation for its ability to address the underlying genetic cause of DMD. SGT-001 is a systemically administered* candidate that delivers a synthetic dystrophin gene, called microdystrophin, to the body. This microdystrophin encodes for a functional protein surrogate that is expressed in muscles and stabilizes essential associated proteins.

  • Adeno-associated virus > is a small virus which infects humans and some other primate species. Link
  • Systemically administered > Systemic forms of administration affect the whole body (in general).

Data from Solid’s preclinical program suggests that SGT-001 has the potential to slow or stop the progression of DMD, regardless of genetic mutation or disease stage. SGT-001 is based on pioneering research in dystrophin biology by Dr. Jeffrey Chamberlain of the University of Washington and Dr. Dongsheng Duan of the University of Missouri.

 

Status

SGT-001 has been granted Rare Pediatric Disease Designation or RPDD in the United States and Orphan Drug Designation in both the United States and European Union. The Phase I/II clinical trial for SGT-001, IGNITE DMD, is currently on clinical hold. Microdystrophin gene transfer trial on hold

 

About Solid Biosciences

Solid Biosciences is a life science company focused solely on finding meaningful therapies for Duchenne muscular dystrophy (DMD). Founded by people touched by the disease, Solid Biosciences is a center of excellence for DMD, bringing together experts in science, technology and care to drive forward a portfolio of candidates that have life-changing potential. Currently, Solid Biosciences is progressing from programs across four scientific platforms: corrective therapies, disease-modifying therapies, disease understanding and assistive devices. For more information, please visit this website: www.solidbio.com.

 

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.

 

To know more

SOLID BIOSCIENCES INITIATES CLINICAL TRIAL FOR GENE TRANSFER

GLOBE NEWSWIRE: Solid-Biosciences-Announces-New-Preclinical-Data-at-the-American-Society-of-Gene-and-Cell-Therapy-Annual-Meeting