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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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Idebenone for Duchenne muscular dystrophy

February 25, 2019

Santhera Pharmaceuticals announces results from the SYROS study.

 

The primary objective of this study was to evaluate the long-term evolution of the respiratory function in patients who maintained treatment with idebenone for up to 6 years compared to their preceding off-idebenone period.

 

Respiratory Function in DMD

In boys and men with DMD, weakness of respiratory muscles leads to a progressive decline in their ability to move air into/out of their lungs, leading to sleep disturbances and respiratory infections, especially when patients have lost their ability to walk. Studies estimate 55-90% of patients with DMD die from pulmonary complications.

Acute respiratory failure can occur due to:

  • Compromised respiratory dysfunction complicated by mucus plugging and further weakening of inspiratory/expiratory muscles
  • Repeated cases of pneumonia, hospitalizations and intubations

Decreased ability to cough leads to retained secretions and high risk of recurrent respiratory tract infections.

 

The result of this study, which is consistent with outcomes from the pivotal DELOS study, demonstrated that:

  • Switching to and maintaining long-term treatment with idebenone reduced the annual rate of decline in the forced vital capacity percent of predicted (FVC%p) by 50%. Forced Vital Capacity is one of the tests of lung function. FVC is a kind of forced expiration. (Which reflects the strength of the respiratory muscles)
  • The treatment effect was consistently maintained year-on-year for up to 6 years.
  • These findings are further supported by consistent reductions in the rate of both inspiratory and expiratory respiratory function loss over the same period.
  • Prolonged treatment with idebenone also reduced the risk of important patient-relevant outcomes, including bronchopulmonary adverse events and hospitalizations due to respiratory causes.

 

“We are very excited to see that the significant treatment effect with idebenone observed in our 52- week Phase III DELOS study is maintained over the long-term. The new findings are highly relevant for DMD patients in respiratory decline who have an urgent need for a therapy to modify the declining course of respiratory function decline and ultimately delay the need for assisted ventilation.” -Kristina Sjöblom Nygren, MD, Chief Medical Officer and Head of Development at Santhera.

 

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.

 

Status

Santhera’s Raxone® (idebenone) is authorized in the European Union, Norway, Iceland, Liechtenstein, Israel and Serbia for the treatment of Leber’s hereditary optic neuropathy (LHON) and is currently commercialized in more than 20 countries. For further information, please visit www.santhera.com. Raxone® is a trademark of Santhera Pharmaceuticals.

Santhera has been granted orphan drug designation for Raxone for the treatment of DMD in Europe and the US. The US Food and Drug Administration (FDA) has also granted rare pediatric disease designation and Fast Track designation for idebenone for the treatment of DMD. Furthermore, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) designated idebenone as Promising Innovative Medicine (PIM) and as a suitable candidate for entry into Step II of the EAMS process.

 

About Santhera Pharmaceuticals

Santhera is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare and other diseases with high unmet medical needs. They are focusing on the development of treatments for neuro-ophthalmological, neuromuscular and pulmonary diseases that currently lack treatment options, such as Leber’s hereditary optic neuropathy (LHON), Duchenne muscular dystrophy (DMD), congenital muscular dystrophy (CMD) and cystic fibrosis (CF).

 

Sources

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