SMA Daily

🌟 Walking Again: Transforming Lives, One Step at a Time!

2023-05-25T02:20:00.000-07:00

In an inspiring initiative, Dublin City University (DCU) is leading the charge to provide children in wheelchairs with the transformative experience of walking again through a groundbreaking pediatric robotic exoskeleton program. Supported by an Irish university, this pioneering project aims to become one of the first in Europe to offer children with neurological disorders the opportunity to regain their mobility. With a focus on assisting those affected by cerebral palsy, spina bifida, and various other neurological conditions, the exoskeleton program has already made a significant impact on the lives of over 100 adults, and now seeks to extend its reach to empower children.

At the core of this innovative program lies the exoskeleton, a wearable device designed to be strapped onto the legs and torso of individuals facing mobility challenges. By utilizing advanced motors and sensors, this remarkable technology assists users in simulating a natural walking motion. A computer, programmed to interpret the wearer's movements, serves as the control center for the exoskeleton.

Initially introduced to aid adults with mobility issues stemming from spinal cord injuries, strokes, and other impairments, the exoskeleton program has achieved remarkable success. Now, building upon its accomplishments, the program is directing its efforts toward improving the lives of children with neurological disorders who rely on wheelchairs for their mobility.

The benefits of the exoskeleton program extend far beyond the physical aspect, as it offers children renewed hope and confidence. Walking, a seemingly ordinary act for most, can be a monumental achievement for these young individuals who have faced substantial challenges. The exoskeleton enables them to experience the joy of movement and the sense of freedom that accompanies it, instilling a sense of independence and empowerment.

Under the guidance of dedicated experts, children participating in the program undergo a comprehensive evaluation to ensure that the exoskeleton is tailored to their unique needs. Customization is paramount, as the device must seamlessly integrate with their physique and cater to their specific conditions. Once properly fitted, the exoskeleton serves as a trusted companion, assisting them in taking their first steps toward a more inclusive future.

While the physical benefits of the exoskeleton program are undeniable, the psychological impact cannot be overlooked. By transcending their wheelchairs and engaging in a standing position, children are afforded a new perspective on the world. They gain access to eye-level interactions, fostering social connections and a sense of belonging. Furthermore, the program's holistic approach emphasizes the overall well-being of the children, providing a supportive environment that nurtures their physical, emotional, and mental development.

Collaboration serves as a cornerstone of the exoskeleton program's success. Researchers, engineers, and medical professionals work hand in hand to refine the technology, enhance its capabilities, and optimize its therapeutic effects. Ongoing research and development ensure that the exoskeletons continually evolve, offering increasingly advanced functionality and adaptability.

As the program expands its reach, DCU remains committed to breaking barriers and revolutionizing the field of pediatric rehabilitation. By actively involving children and their families, the program fosters a sense of shared ownership and a deeper understanding of the potential this groundbreaking technology holds. It serves as a catalyst for raising awareness about neurological disorders and advocating for inclusivity and equal opportunities for all.

Through the tireless efforts of the exoskeleton program, children in Ireland and beyond are discovering a renewed sense of possibility. With each step taken, barriers are shattered, limitations are defied, and dreams are reawakened. As this Irish university-backed initiative paves the way for others across Europe, it stands as a testament to the transformative power of technology, compassion, and unwavering determination. In the realm of pediatric rehabilitation, the future holds great promise, where children once confined to wheelchairs now have the opportunity to walk with confidence and embrace the world around them.

Find more information at:
DCU Exoskeleton Programme | Dublin City University | Exoskeleton

FDA Grants Priority Review to Genentech’s Risdiplam for Spinal Muscular Atrophy

2019-11-26T07:15:00.000-08:00

Genentech, a member of the Roche Group, today announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) and granted Priority Review for risdiplam, an investigational survival motor neuron-2 (SMN-2) splicing modifier for spinal muscular atrophy (SMA). Risdiplam is designed to increase and sustain SMN protein levels both throughout the central nervous system and peripheral tissues of the body. The FDA is expected to make a decision on approval by May 24, 2020.

“The FIREFISH and SUNFISH trials were designed to represent the real world spectrum of people living with SMA and include many people previously underrepresented in clinical trials,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We look forward to working closely with the FDA to explore broad access to risdiplam for all individuals in the community who might benefit.”

The risdiplam NDA submission incorporates 12-month data from the dose-finding Part 1 sections of the FIREFISH and SUNFISH pivotal studies, as well as data from the confirmatory Part 2 of SUNFISH. FIREFISH is an open-label, two-part seamless pivotal clinical trial in infants with Type 1 SMA. Part 1 was a dose-escalation study in 21 infants aged 1-7 months. The primary objective of Part 1, which evaluated efficacy as an exploratory endpoint, was to assess the safety profile of risdiplam in infants and determine the dose for Part 2, which is a pivotal, single-arm trial evaluating risdiplam in 41 infants with Type 1 SMA for 24 months, followed by an open-label extension.

SUNFISH is a two-part, double-blind, placebo-controlled pivotal clinical trial in children and young adults (2-25 years old) with Type 2 or 3 SMA. Part 1 determined the dose for the confirmatory Part 2 and evaluated efficacy as an exploratory endpoint. SUNFISH Part 2 is a large placebo-controlled trial evaluating treatment for people with Type 2 or 3 SMA. SUNFISH Part 2 recently met its primary endpoint of change from baseline in the Motor Function Measure 32 (MFM-32) scale.* No treatment-related safety findings leading to study withdrawal have been seen in any risdiplam trial to date. Safety for risdiplam was consistent with its known safety profile and no new safety signals were identified. Results will be presented at an upcoming medical congress.

If approved, risdiplam, an orally administered liquid, would be the first at-home administered medicine for people living with SMA. In addition to the studies included in the NDA submission, risdiplam is being studied in a broad clinical trial program in SMA, with patients ranging from newborns to 60 years old, and includes patients previously treated with SMA therapies.

Cure SMA to Host a Webinar on Spinraza Access

2017-02-14T01:48:00.000-08:00

On Tuesday, February 14, at 1:00pm EST (10:00am PST/11:00am MST/12:00pm CST), Cure SMA will hold a webinar updating the community on the status of Spinraza access. Among the topics covered will be adminstration sites, insurance coverage, and community resources and support programs.

They look forward to hosting an open, candid, and informal discussion of where our community stands on issues surrounding access to this first-ever approved therapy, and what our next steps will be.

They encourage you to pre-submit your questions when you register, so that they can plan to answer as many of them as possible. However, you will also have the opportunity to submit questions during the webinar itself, as part of an expanded Q&A segment.

Spinraza - the First FDA Approved SMA Treatment

2017-01-09T04:09:00.000-08:00

The U.S. Food and Drug Administration (FDA) approved Biogen’s SPINRAZA™ (nusinersen) under Priority Review for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. SPINRAZA is the first and only treatment approved in the U.S. for SMA, a leading genetic cause of death in infants and toddlers that is marked by progressive, debilitating muscle weakness.

In ENDEAR, a pivotal controlled clinical study, infantile-onset SMA patients treated with SPINRAZA achieved and sustained clinically meaningful improvement in motor function compared to untreated study participants. In addition, a greater percentage of patients on SPINRAZA survived compared to untreated patients. In open-label studies, some patients achieved milestones such as ability to sit unassisted, stand or walk when they would otherwise be unexpected to do so and maintained milestones at ages when they would be expected to be lost. The overall findings of these studies support the effectiveness of SPINRAZA across the range of SMA patients, and appear to support the early initiation of treatment.

“SPINRAZA offers new hope for the SMA community and exemplifies our mission of applying cutting-edge science to make a meaningful difference in the lives of patients with devastating, life-altering diseases,” said George A. Scangos, Ph.D., chief executive officer at Biogen. “We are humbled and grateful for the commitment of the patients and families who participated in the SPINRAZA clinical trial program, the tireless efforts of our investigators, and the urgency demonstrated by the FDA in rapidly reviewing and approving this treatment. We also want to acknowledge the important work of our colleagues at Ionis, who initiated this program.”

The FDA approval of SPINRAZA was based on positive results from multiple clinical studies in more than 170 patients. The data package included the interim analysis of ENDEAR, a Phase 3 controlled study evaluating SPINRAZA in infantile-onset, as well as open-label data in pre-symptomatic and symptomatic patients with, or likely to develop, Types 1, 2 and 3 SMA.

“With the approval today of SPINRAZA, the future for those affected with SMA has changed. We are especially pleased that this sophisticated and rigorous clinical development plan has resulted in a broad label that may offer access to many patients,” said Kenneth Hobby, president at Cure SMA. “This has been a story of all groups – families, researchers, companies and the FDA – working together as one community.”

SPINRAZA will be made available for shipment in the U.S. to healthcare providers in approximately one week. Biogen anticipates there may be variation in time to treatment as institutions and treatment centers learn about SPINRAZA.

Nusinersen Might Become the First Approved SMA Drug

2016-10-20T08:30:00.000-07:00

New data from the clinical program for nusinersen (component formerly known as Isis SMN-Rx), an investigational treatment for spinal muscular atrophy (SMA), were presented by Biogen and Ionis Pharmaceuticals in the late-breaking session at the 2016 World Muscle Society Congress in Granada, Spain. The presentations included safety results from the interim analysis of the Phase 3 ENDEAR study in infantile-onset SMA (most likely to develop Type 1), encouraging preliminary results from NURTURE, a Phase 2 open-label study in pre-symptomatic infants, and a recent analysis of the ongoing Phase 2 open-label study in patients with later-onset SMA (consistent with Types 2 or 3).

“We continue to be encouraged by the consistently positive results with nusinersen across our clinical program, including our first data in infants treated before they show signs of the disease,” said Wildon Farwell, senior director SMA clinical development at Biogen. “NURTURE is the first study to evaluate an investigational therapy in pre-symptomatic infants genetically at risk for SMA. In this analysis, infants treated for up to one year achieved motor milestones in timelines more consistent with normal development than what is observed in the natural history of patients with Type 1 SMA.”

Biogen has completed the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the approval of nusinersen. Submission of the Marketing Authorization Application to the European Medicines Agency is planned in the next week. Biogen will initiate regulatory filings in other countries in the coming months.

Interim Data from Phase 3 ENDEAR Trial
In the interim analysis of the controlled, Phase 3 ENDEAR study in infantile-onset SMA, infants treated with nusinersen demonstrated a statistically and clinically significant improvement in the primary endpoint (p<0.0001), defined as the proportion of motor milestone responders as measured by the Hammersmith Infant Neurological Examination (HINE). A responder was defined as a patient who improved in more motor milestone categories (kicking, head control, rolling, sitting, crawling, standing, walking) than worsened.

Nusinersen was generally well-tolerated, with an acceptable safety profile. No adverse events (AEs) were considered related to treatment. Based on the results of the positive interim analysis, patients who elect to do so will be transitioned to SHINE, an open-label extension study, in which they will be able to receive nusinersen. Following the transition of patients, the ENDEAR study will close. Detailed efficacy data will be presented at a future medical conference once participants complete their final study visit in ENDEAR.

First Clinical Data in Pre-Symptomatic SMA Patients
The interim analysis of the ongoing, open-label, 30-month, Phase 2 NURTURE study showed that nusinersen-treated infants exhibited improvements in motor function and motor milestones such as full head control, independent sitting, standing with support, standing unaided, and walking with support, as measured by validated scales. The primary endpoint was defined as time to respiratory intervention (invasive or non-invasive ventilation for 6 hours or more per day continuously for 7 or more days or tracheostomy) or death. At the time of the interim analysis all patients were alive and did not require respiratory intervention. This analysis included data from 13 genetically diagnosed, pre-symptomatic SMA patients who had been enrolled for a minimum of 64 days and up to 13 months. Three infants experienced AEs considered possibly related to nusinersen, all of which were resolved. In addition, no infants have discontinued or withdrawn from the study and no new safety concerns have been identified. The NURTURE study is currently active and enrolling.

“These findings reinforce the potential of nusinersen, and we remain focused on bringing this investigational treatment to patients and families as quickly as possible,” noted C. Frank Bennett, Ph.D., senior vice president of research and leader of the neurological disease franchise at Ionis Pharmaceuticals. “We are grateful for the commitment and contributions of the investigators, patients and families that have made the rapid development of nusinersen possible across a range of patients.”

Supportive data from ongoing open-label Phase 2 trials
In addition, exploratory efficacy and safety data from the open-label Phase 2 trials (CS2/CS12) in twenty-eight patients with later-onset SMA (consistent with Types 2 or 3), showed that children with SMA treated with nusinersen exhibited improvement on several measures of motor function for up to nearly three years. These results contrast to the stable or slow decline in scores typically observed in patients with later-onset SMA over time. Overall, most AEs were mild to moderate and not considered related to nusinersen and there were no serious adverse events (SAEs) related to the study drug.

The Nusinersen Clinical Trial Program
The nusinersen Phase 3 program is comprised of two registrational studies, ENDEAR and CHERISH. ENDEAR is a thirteen-month study investigating nusinersen in 122 patients with infantile-onset SMA, including patients with the onset of signs and symptoms of SMA at less than or equal to 6 months of age and who are screened at an age of less than or equal to 7 months. Based on insights gained from earlier-stage studies and discussions with regulators, a primary endpoint was added to ENDEAR earlier this year that evaluates the proportion of motor milestone responders from the motor component of the Hammersmith Infant Neurological Examination (HINE). Given the results of the pre-specified interim analysis, the ENDEAR study will be stopped and participants will be able to transition into the SHINE open-label study in which all patients receive nusinersen.

CHERISH is a fifteen-month study investigating nusinersen in 126 non-ambulatory patients with later-onset SMA, including patients with the onset of signs and symptoms at greater than 6 months and an age of 2 to 12 years at screening. CHERISH was fully enrolled in March 2016.

Additionally, the SHINE open-label extension study for patients who previously participated in ENDEAR and CHERISH is open and is intended to evaluate the long-term safety and tolerability of nusinersen.

Two additional Phase 2 studies, EMBRACE and NURTURE, were designed to collect additional data on nusinersen. The EMBRACE study is collecting additional data on a small subset of patients with infantile or later-onset SMA who do not meet the age and other criteria of ENDEAR or CHERISH. NURTURE is an ongoing study in pre-symptomatic infants who are less than or equal to 6 weeks of age at time of first dose to determine if treatment before symptoms begin would prevent or delay the onset of SMA symptoms. All studies are being conducted on a global scale.

STL-182 Molecule With Therapeutic Potential for Spinal Muscular Atrophy

2016-10-20T02:23:00.000-07:00

Spotlight Innovation announced that it has obtained an exclusive, worldwide license from Indiana University Research and Technology Corp. to commercialize STL-182, an orally-available small molecule that may have therapeutic potential for treating Spinal Muscular Atrophy (SMA). SMA is an autosomal recessive disorder that is a leading genetic cause of death in infants and toddlers. Synthesis and early preclinical testing of STL-182 was accomplished through a research collaboration between Professors Elliot Androphy of Indiana University School of Medicine and Kevin Hodgetts, director of the Laboratory for Drug Discovery in Neurodegeneration at Brigham and Women's Hospital. Their work was supported in part by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD).

Spinal Muscular Atrophy affects between 1 in 6,000 and 1 in 10,000 newborns. Approximately 1 in 40 to 1 in 50 adults have only a single intact spinal motor neuron 1 (SMN1) gene, which encodes a protein (SMN) required for proper neuromuscular function. An infant who inherits no intact SMN1 gene from either parent may develop SMA and lose the ability to sit, stand, walk, swallow, and/or breathe. In about 60% of cases, patients with SMA die by age two.

Even in SMA patients, low levels of functional SMN protein are produced by an SMN1-related gene called SMN2. One therapeutic strategy to treat SMA is to increase levels of functional SMN protein encoded by SMN2. In mouse models of SMA, STL-182 may restore neuromuscular function by stabilizing endogenous SMN protein.

AveXis Reports Data from Ongoing Phase 1 Trial of Gene Therapy in Spinal Muscular Atrophy Type 1

2016-05-21T06:49:00.000-07:00

AveXis, a clinical-stage gene therapy company developing novel treatments for patients suffering from rare and life-threatening neurological genetic diseases, presented an interim analysis of data from the ongoing Phase 1 trial of AVXS-101 for the treatment of spinal muscular atrophy (SMA) Type 1. Jerry Mendell, MD, director of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital, presented the data at the 19th Annual Meeting of the American Society of Gene & Cell Therapy in Washington, D.C.

The data reported at the meeting show that AVXS-101 continues to demonstrate a favorable safety profile in patients studied, with no new treatment-related safety or tolerability concerns identified; all patients in both the low-dose and proposed therapeutic-dose cohorts remain without an “event,” defined as death or until a patient requires at least 16 hours per day of ventilation support for breathing for 14 consecutive days in the absence of an acute reversible illness, or perioperatively; and the mean motor function score continues to increase, with two patients having achieved motor function in a range considered to be normal.

Dr. Mendell said, “Given the rapid and devastating disease course of SMA Type 1, it is very encouraging to see that all patients in both dosing cohorts have remained event free, and all patients have demonstrated sustained improvements above baseline in motor function since receiving AVXS-101. Additionally, new data presented today appear to indicate that AVXS-101 may have a positive impact on both the pulmonary and nutritional support of patients in the trial suffering from SMA Type 1, which may be impacting the overall survival benefit.”

The ongoing Phase 1 study is designed to evaluate safety and preliminary indications of efficacy of AVXS-101 in patients suffering from SMA Type 1. Data as of April 1, 2016 has shown:

AVXS-101 appears to have a favorable safety profile and to be generally well tolerated in patients studied. There has been a total of 74 adverse events (AEs) reported, 22 of which were determined to be serious adverse events (SAEs). Two of the 22 were deemed treatment-related and, as previously reported, those SAEs were clinically asymptomatic liver enzyme elevations. Of the 52 non-serious AEs, 3 were treatment-related elevations in liver enzymes experienced by two patients. All elevated liver enzyme AEs and SAEs were resolved with prednisolone treatment. Other non-treatment-related AEs were expected and were associated with SMA.
No patients in either dosing cohort have experienced an “event.” The median event-free age of all 15 patients was 14.9 months, and the median event-free age of patients in Cohort 1 was 25.7 months and in Cohort 2 was 11.7 months. The natural history of the disease indicates that 25 percent of untreated SMA Type 1 patients survive event-free at 13.6 months of age and that 8 percent survive event-free at 20 months of age1.
Mean increases of 8.7 points and 19.2 points in CHOP-INTEND scores were observed in Cohort 1 and Cohort 2, respectively. Nine out of 12 patients (75 percent) and 7 out of 12 patients (58 percent) in Cohort 2 have achieved CHOP-INTEND scores of at least 40 points or 50 points, respectively. Two patients achieved the maximum score of 64. A score of 60 is considered normal. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) is a test developed to measure motor skills of patients with SMA Type 1.
The natural history of SMA Type 1 indicates that bulbar weakness leads to impaired swallowing, malnutrition and growth failure. The median age to growth failure is 7 months of age2. The median age to nutritional support is 8 months of age (IQR 6-13 months)1. AVXS reported today that 7 of 7 (100%) of AVXS-101 patients that did not require feeding support before treatment continued without feeding support as of April 1, 2016 in the ongoing Phase 1 trial. Five patients had gastric feeding tube placement prior to gene therapy. One patient in Cohort 2 who had gastric feeding tube placement prior to gene transfer is also feeding orally.
The natural history of SMA Type 1 indicates that bulbar muscle weakness, skeletal muscle weakness in the neck and intercostal muscle weakness lead to respiratory impairment, poor clearance of airway secretions, risk of aspiration and recurrent infections leading to death or permanent ventilation. The median age to permanent ventilation or death is 10.5 months (IQR 8.1-13.6 months), and by 13.6 months only 25 percent of SMA Type 1 patients are alive and free of permanent ventilation1. In the ongoing trial, 8 of 10 (80%) of AVXS-101 patients that did not use biphasic/bi-level ventilation (BiPAP) support before gene transfer continue without any ventilation support as of April 1, 2016 (the 2 exceptions being after severe illness/hospitalizations to assist recovery).

“We are encouraged by these interim results as we work diligently to bring AVXS -101 to patients who suffer from SMA Type 1, a devastating disease for which there are currently no FDA-approved therapies,” said Suku Nagendran, MD, Senior Vice President and Chief Medical Officer, AveXis. “We look forward to reviewing the ongoing data from this study over the coming year as we continue the development of AVXS-101.”

Exercise May Protect Nerve Cells in Spinal Muscular Atrophy Patients

2016-03-25T03:49:00.000-07:00

Long-term exercise appears to be beneficial for Spinal Muscular Atrophy (SMA) like mice, suggesting a potential of active physiotherapy for patient care; according to a study published in the Journal of Physiology.

A 10-month training programme improved muscle resistance to activity-induced damages and increased aerobic performance in mice. While swimming and running was both beneficial for motor neurons affected by SMA, different types of exercise had an impact on different motor neurons and muscle fibers. Swimming protected intermediate and fast motor neurons (the most affected type of motor neuron in SMA), and enhanced the cross-sectional area of large muscle fibers, while running only protected slow motor neurons and enhanced the cross-sectional area of intermediate muscle fibers.

Physical exercise is known to induce benefits in some neurodegenerative diseases, including Parkinson's disease, but its benefits in other diseases such as Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy, remain controversial and highly debated for its routine use in patient care.

'Physical exercise' is a term that covers a wide range of very different conditions, including long-term vs acute exercises, concentric vs eccentric contractions and power vs endurance exercises. Therefore, the type of exercise could be the key in understanding the apparently contradictory effects of exercise in a given disease.

For their study, researchers used transgenic SMA-like mice as well as a control group of mice (68 mice per group). For 10 consecutive months, 5 days/week for 10 min /day, the mice had to perform either a low intensity running exercise (favouring the use of oxidative energetic pathways) or a high intensity swimming exercise (favouring the use of anaerobic energetic pathways). Throughout the 10-month training, they evaluated morphological and behavioral adaptations, as well as the physiological adaptations.

Olivier Bondi from the Université Paris Descartes and main investigator of the study explained,
'So far, the clinical care strategy for SMA patients has been based on symptomatic alleviation and physiotherapy. Active exercise has previously been avoided to minimise damage to muscles and neurons.

'Our study shows, though, that not only could physical exercise be part of a cheap, beneficial long-term care programme for SMA patients (especially compared to pharmacological approaches and walking aids), it also highlights the importance of defining a specific exercise regimen to limit the neurodegeneration process.

'Our research could provide several clues when designing rehabilitation programs for SMA patients; and the findings have already been used to design an innovative clinical trial for SMA patients in France.

'This shift in patient care towards the prescription of appropriate exercise in neuromuscular disorders could profoundly change the view of physiotherapy in SMA but also for other neuromuscular disorders. Understanding the mechanisms of exercise-induced benefits in neuromuscular degenerative diseases could provide a platform for discover new potential pharmacological approaches in such patients.'

Discovery of an Enzyme that Plays Critical Role in Spinal Muscular Atrophy

2016-02-20T13:09:00.001-08:00

Neuroscientists have discovered a specific enzyme that plays a critical role in spinal muscular atrophy, and that suppressing this enzyme's activity, could markedly reduce the disease's severity and improve patients' lifestyles.

Spinal muscular atrophy is a debilitating disease that causes weakness and wasting of the muscles. The disease ranges in severity with patients experiencing different symptoms, from the inability to sit up and stand, to trouble walking. In its severest form, the disease results in difficulty breathing and leads to death.

"We've identified the enzyme JNK3 as a therapeutic target to treat the symptoms of spinal muscular atrophy," says Laxman Gangwani, Ph.D., an associate professor in the Center of Emphasis in Neuroscience at Texas Tech University Health Sciences Center El Paso (TTUHSC El Paso) who led the research.

In a recent study published in the December 15th issue of Human Molecular Genetics, Dr. Gangwani and his team of researchers at TTUHSC El Paso describe how mice with spinal muscular atrophy saw great improvement when the JNK3 enzyme was genetically inhibited to eliminate its activity. The finding suggests that patients with spinal muscular atrophy could also see improvement if treated with a drug that suppresses the activity of JNK3.

"We saw less muscle degeneration, more muscle growth and better muscle strength, and improvement in overall movement," says Gangwani. "What's more striking was a four-fold reduction in initial mortality period and a two-fold increase in total lifespan."

"So far, spinal muscular atrophy research has focused on targeting the genetic mutation to prevent degeneration of spinal motor neurons, but it hasn't been successful because of challenges associated with gene therapy," he says. "This is the first study done that identifies a target, JNK3, that's independent of the genetic mutation of spinal muscular atrophy for novel therapeutic development."

SMA Program Advances with Additional Product Candidate Entering Clinical Development

2016-01-10T01:08:00.000-08:00

PTC Therapeutics announced that RG7916, an additional SMN2 splicing modifier from the company's joint development program with Roche and the SMA Foundation in spinal muscular atrophy (SMA), has entered clinical development. RG7916 is designed to shift SMN2 pre-mRNA splicing toward the production of full length SMN mRNA. A Phase 1 study in healthy volunteers has been initiated to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of RG7916.

"We are pleased to initiate clinical development of a second candidate in our SMA collaboration," said Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics, Inc. "The goal of this Phase 1 study is to understand more about the safety and activity of RG7916 and be in a position to compare the profiles of each of our development compounds to determine the best path forward for our SMA program. SMA is the most common genetic cause of infant mortality and one of the most common rare diseases. Currently there are no available therapies to treat the underlying cause of the disease. PTC and our collaboration partners are committed to advancing potential solutions for SMA patients through our SMN2 alternative splicing program."

Two compounds are currently in clinical development within the SMA program, RG7800 and RG7916. The most advanced compound, RG7800, is the subject of a Phase 2 randomized, double-blind, placebo-controlled trial called Moonfish in adult and pediatric patients with SMA. Dosing in the Moonfish trial was suspended in April 2015 and the trial was placed on clinical hold to investigate a non-clinical safety finding observed in a longer-term animal study.

The SMA program was initially developed by PTC Therapeutics in partnership with the SMA Foundation in 2006 to accelerate the development of a treatment for SMA. In November 2011, Roche gained an exclusive worldwide license to the PTC/SMA Foundation SMN2 alternative splicing program. The development of RG7800 and RG7916 is being executed by Roche and overseen by a joint steering committee with members from PTC, Roche, and the SMA Foundation.

HSCI researchers find surprising similarities between SMA and ALS

2015-11-28T08:42:00.002-08:00

Harvard Stem Cell Institute (HSCI) researchers studying spinal muscular atrophy (SMA) have found what they term "surprising similarities" between this childhood disorder that attacks motor neurons and amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease.
The findings have been published online by the journal Cell Stem Cell.

The research team led by HSCI principal faculty member Lee Rubin uncovered molecular changes that explain, at least in part, why motor neurons rather than others are affected by the illness. Unlike ALS and other neurodegenerative diseases, which tend to manifest later in life, SMA strikes infants. Unlike ALS, SMA is a genetic disorder that causes a range of outcomes, with the milder form leaving some children confined to wheelchairs, and the more severe form causing paralysis and death before the second birthday.

Though not as well-known as ALS, SMA is "the most frequent fatal genetic disease of young children," said Rubin, a professor in Harvard's Department of Stem Cell and Regenerative Biology (HSCRB). About one in 50 people are carriers of SMA and about one in 5,000 children are born with the disease.

Rubin said researchers are still working to determine the mechanisms of SMA. "It has never been clear why motor neurons -- which relay signals from the brain to the muscles via the spinal column -- die selectively," Rubin said. "It is clear motor neurons die well before other kinds of cells, even other kinds of spinal-cord neurons, and the mystery has been trying to understand that."
A research team composed of HSCI investigators at the Broad Institute of Harvard and MIT and HSCRB, including HSCI principal faculty member John Rinn, worked in collaboration with the SMA Foundation's Pediatric Neuromuscular Clinical Research Network and Wendy Chung from Columbia University College of Physicians and Surgeons to make neurons from donors with SMA of varying degrees of severity.

The researchers first determined that the neurons in a dish behaved similarly to the way neurons would behave in an SMA patient. Not only did motor neurons die before other types of neurons, but motor neurons derived from patients with severe SMA died very quickly in comparison to those made from patients with a milder form of the disease.
Then, using a method of intracellular cell labeling developed in HSCI co-director Doug Melton's lab, the researchers separated motor neurons from other types of neurons in the dish, carried out an RNA sequencing analysis, and compared SMA motor neurons to those from healthy individuals.

Cytokinteics Presents Results from Phase I Studies of CK-2127107

2015-07-21T06:08:00.002-07:00

Cytokinetics announced that results from three double-blind, randomized, placebo-controlled Phase I studies of CK-2127107 in healthy volunteers were presented in a poster at the 19th International SMA (Spinal Muscular Atrophy) Researcher Meeting held during the 2015 Annual SMA Conference at the Westin Crown Center in Kansas City, MO. In a pharmacodynamic study that was designed to assess the translation of the mechanism of CK-2127107 to humans, treatment with the fast skeletal muscle activator increased muscle force produced by the tibialis anterior muscle in response to nerve stimulation. Cytokinetics is developing CK-2127107 in collaboration with Astellas Pharma Inc.

"We are encouraged by the findings from our Phase I clinical studies program of CK-2127107 and the potential of CK-2127107 to improve skeletal muscle function,” said Fady I. Malik, M.D., Ph.D., Cytokinetics' Senior Vice President, Research and Development. “Based on these results, we look forward to initiating a Phase II trial in patients with SMA later this year in collaboration with our partner, Astellas.”

The poster titled, “Pharmacokinetics and Pharmacodynamics of the Selective Fast Skeletal Muscle Troponin Activator, CK-2127107,” was presented by Andrew Wolff, MD, FACC, Cytokinetics’ Chief Medical Officer, and included data from Phase I studies that evaluated the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of CK-2127107 in healthy volunteers. In these studies, CK-2127107 was well-tolerated at single doses up to 4000 mg and the PK profile of CK-2127107 was linear and dose-proportional across the range of doses studied. Data from the Phase I studies also showed significant dose-, concentration-, and frequency-dependent increases in the force of muscle contraction elicited by nerve stimulation in healthy volunteers. The increases in force were most evident in the mid-range of nerve stimulation frequency, consistent with preclinical studies. By directly increasing skeletal muscle function, CK-2127107 may enhance physical performance in patients with neuromuscular diseases including SMA. These data support further evaluation of CK-2127107 and its potential to effect measures of muscle performance and function.

Russian Scientists Find New Way to Repair DNA that May Cure Spinal Muscular Atrophy

2015-07-17T12:49:00.000-07:00

A group of Russian scientists have discovered a new method of DNA repair which may be able to prevent and cure neurodegenerative diseases, such as Alzheimer’s or Parkinson’s or Spinal Muscular Atrophy (SMA) and even stop the process of cell death.

The research team led by Vasily M. Studitsky, professor at the Lomonosov Moscow State University, published their findings in an article “Structure of transcribed chromatin is a sensor of DNA damage” in the Science Advances journal.

“Early detection and repair of damaged DNA is essential for cell functioning and survival,” says the study, according to a report by Russia Today.

The paper raises the question of single-strand breaks (SSBs) which are called in the research “common DNA damages generated during various processes of cell metabolism.”

“Unrepaired SSBs can interfere with transcription, replication, and DNA repair; induce accumulation of double-stranded DNA breaks; increase genomic instability and apoptosis [process of programmed cell death]; and lead to severe neurodegenerative diseases.” Alzheimer’s, Parkinson’s disease and spinal muscular atrophy are examples of such diseases.

Studitsky told science portal Psys.org that the team of scientists “has shown, not yet in the cell but in vitro, that the repair of breaks in the other DNA chain, which is ‘hidden’ in the nucleosome, is still possible.”

“According to our hypothesis, it occurs due to the formation of special small DNA loops in the nucleosome, although normally DNA wounds around the histone ‘spool’ very tightly," he added.
As the DNA molecule is chemically unstable, its damage detection and repair are needed.
“These observations raise the possibility that nucleosomal structure could affect the process of detection and repair of DNA damages,” the study says.

The researchers added that their findings can suggest “the existence of a chromatin-specific, transcription-dependent mechanism that allows detection of NT-SSBs that are otherwise hidden in the chromatin structure.”

New stem cell research uncovers causes of Spinal Muscular Atrophy

2015-07-14T10:00:00.000-07:00

New research from the Advanced Gene and Cell Therapy Lab at Royal Holloway, University of London has used pioneering stem cell techniques to better understand why certain cells are more at risk of degenerating in Spinal Muscular Atrophy than others.

Dr Rafael Yáñez and his team from the School of Biological Sciences used Induced Pluripotent Stem Cells (iPSCs) which are created by treating cells from a skin biopsy, a hair follicle – or almost any body part – with chemicals and genes in the lab. The iPSCs were then ‘reprogrammed’ and coerced into forming motor neurons, the cells from the spinal cord which control movement and breathing.

The findings can now be used for testing therapies in the Induced Pluripotent Stem Cells and motor neurons.

Dr Rafael Yáñez, said: “We have observed a progressive reduction of SMN and PLS3 proteins during differentiation of induced pluripotent stem cells to motor neurons, similar to some reports in animals and some controversial data from human development. These changes may underpin the susceptibility of motor neurons to spinal muscular atrophy. We now will investigate the reason for the changes, and more importantly, progress our research for novel therapies taking these protein changes into account. The research also shows how we are trying to reduce reliance on animal experiments whenever possible, as these stem cells now allow the production of human cells that cannot be obtained directly from patients and we can study the cells in lab dishes.”

For this research Dr Yáñez collaborated with clinicians and scientists from the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, the Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry, France and the Beckman Research Institute, California, USA. The research in Dr Yáñez’s lab was funded by the Spanish government and the Spanish Spinal Muscular Atrophy Foundation FundAME (project GENAME), the 6th EU Framework Programme (project CLINIGENE) and Royal Holloway.”

Study on fruit flies and brewer's yeast may provide clues about cause of Spinal Muscular Atrophy

2015-07-14T00:39:00.002-07:00

Scientists at the University of Malta and the Institut de Génétique Moléculaire de Montpellier (CNRS/Université de Montpellier) have shown that fruit flies and brewer's yeast can reveal clues about the cause of Spinal Muscular Atrophy (SMA), the most common genetic killer of infants.

SMA is a devastating neuromuscular disorder that robs children of their ability to walk, eat, or breathe. Mostly caused by an inherited flaw in the Survival Motor Neuron (SMN) gene, SMA is presently without a cure. A key reason is the lack of detailed information on how the SMN protein works in living organisms.

Using extensive genetic manipulations, the research team found that SMN forms an alliance with a set of diverse proteins known as Gemins. So incredibly fragile is this alliance that it can be broken if the perfect balance in protein levels is upset. The consequences are catastrophic. They range from death in flies to muscles that are too weak to support flight. The breakthrough discovery, which was published in the journal PLOS ONE, strengthens the fight against SMA.

"Our study is the first to show that the special relationship between SMN and Gemins exists in a living model system," said the study's lead author Ruben Cauchi, PhD, a senior lecturer at the University of Malta Faculty of Medicine & Surgery. "Furthermore, what we see in Game of Thrones is intriguingly true in cells. Upsetting the delicate balance of power leads to grave repercussions," he added with a smile.

SMN in partnership with Gemins is thought to have a role in assembling the constituents of the gigantic machine that edits messenger RNA, the genetic mail carrier of instructions for building proteins. Whether a fault in this process is to blame for the neuromuscular problems experienced by patients is still an open question.

Cauchi's team recently showed that a selective deficiency of Gemins within the motor system leads to flies with similar problems as when SMN levels are reduced. These findings coupled with those in the present study, show that a collapse of the SMN-Gemins alliance is responsible for Spinal Muscular Atrophy.

Right now the researchers are hunting for friends and foes of the alliance to find a therapy. "Current treatments being developed are based on boosting SMN levels. Broadening the therapeutic targets is essential to develop an effective treatment. Model organisms, like flies and yeast, hold the key for the successful implementation of this strategy," remarked Rémy Bordonne, PhD, CNRS Principal Investigator and study co-author.

AveXis Gains Orphan Drug Designation from the European Medicines Agency for Gene Therapy Treatment in Spinal Muscular Atrophy

2015-07-06T13:21:00.002-07:00

AveXis, a leading gene therapy company developing treatments for rare and life-threatening genetic diseases, announced that the European Medicines Agency (EMA) has granted Orphan Drug designation to its gene transfer therapeutic currently in clinical development in the United States for the treatment of type 1 Spinal Muscular Atrophy (SMA). The company received Orphan Drug designation for SMA in the United States in October 2014.

The EMA grants Orphan Drug designation to medicines intended to treat, prevent or diagnose life-threatening and debilitating diseases, with a prevalence no greater than five in 10,000 in the European Union (EU). There are between 25,000 and 50,000 SMA patients in the United States, Europe and Japan combined. Following Orphan Drug designation, sponsors can access a number of incentives including protocol assistance, scientific advice and receive regulatory exclusivity for a ten-year period following approval.

BioBlast Pharma Announces Positive Preclinical for its Read-through Drug Candidate

2015-06-26T02:00:00.000-07:00

BioBlast Pharma, a clinical-stage orphan disease-focused biotechnology company, announced positive preclinical in vitro and in vivo proof-of-concept study results for its Read-through drug candidate (BBrm02) for Spinal Muscular Atrophy (SMA). BBrm02 is a proprietary, intrathecal formulation of azithromycin (19th International SMA Researcher Meeting, Kansas City, MO).

In a series of cell and mouse studies BBrm02 was effective in creating high levels of full length SMN2 protein (Survival Motor Neuron 2) in the central nervous system resulting in a high degree of cellular and disease phenotypic rescues. Significant levels of full length SMN2 protein were detected following treatment with BBrm02 in several different patient cell lines representing different stages of disease severity. This SMN2 protein was tested for biological activity and was found to be highly functional.

In two different mouse models of Spinal Muscular Atrophy, BBrm02 was effective in preventing weight loss, increasing animal survival, and in normalizing a range of neurological functions, including, among others, the ability of the mouse to return to four feet from a supine position (“time-to-right” test) and to walk on a narrow tube (“tube-test”), both of which measure equilibrium and muscle strength.

Colin Foster, BioBlast’s President and CEO commented: “We are excited to share this comprehensive proof-of-concept as it establishes the efficacy of our lead drug candidate in our Read-through Platform for Spinal Muscular Atrophy. Importantly, given that BBrm02 is a repurposed drug (azithromycin), we believe there is a reasonable possibility for a shorter developmental process. We plan to start a Phase 2a study with BBrm02 at year-end, 2015.”

Mr. Foster also noted that there are no drugs approved today for SMA, which is an orphan disease with approximately 30,000 patients in the U.S. and an equal number in Europe.

Data From ISIS-SMN Rx Phase 2 Study in Infants With Spinal Muscular Atrophy Looking Good

2015-06-18T23:55:00.000-07:00

Isis Pharmaceuticals provided an update on its ongoing open-label Phase 2 clinical study of ISIS-SMNRx in infants with Type I spinal muscular atrophy (SMA). Previously the company reported data from this study on event-free survival, measures of muscle function and assessments of developmental milestones. The data reported last week show continued increases in median event-free survival and muscle function scores as well as achievement of developmental milestones. The safety and tolerability profile of ISIS-SMNRx to date continues to support further development. Isis is currently collaborating with Biogen to develop and potentially commercialize ISIS-SMNRx to treat patients with SMA.

The study was designed to evaluate the safety and tolerability of ISIS-SMNRx in infants with Type I SMA and to explore potential efficacy endpoints to support the Phase 3 program. A total of 20 infants with SMA were dosed with either 6 mg or 12 mg of ISIS-SMNRx. SMA infants 7 months or younger entered the study sequentially, such that the dosing of infants in the 12 mg cohort began five to 15 months after the first infant was dosed in the 6 mg cohort. Nineteen infants completed the three induction doses and are evaluable for efficacy. Clinical efficacy endpoints include event-free survival, as defined by time to permanent ventilation or death; CHOP-INTEND motor function scores; and assessments of developmental milestones. An analysis as of April 17, 2015 showed that since the last analysis as of September 2, 2014 (seven and a half months ago):

The median event-free age has increased for infants in both dosing cohorts, from 16.3 months to 19.9 months for the four infants in the 6 mg cohort, and from 11.6 months (n=12) to 16.7 months (n=15) for the infants in the12 mg cohort.
For the seven infants in the 12 mg cohort who were in the original group and reported on at the American Academy of Neurology meeting in 2014, the median event-free age has increased from 9.6 months on April 7, 2014 to 21.4 months on April 17, 2015.
Two of the four infants in the 6 mg cohort remain enrolled in the study and are now older than 27 months of age. In the 12 mg cohort, 11 of 15 infants (73%) are still event-free and older than 15 months of age.

Muscle function scores have increased from baseline.
Infants have achieved motor milestones since their baseline evaluations.
Only a single event has occurred: One infant in the 12 mg cohort required permanent ventilation. There have been no deaths since the previous analysis.

As of April 17, 2015, the median time in study was 13.2 months. The lumbar puncture procedure in infants with SMA has been well tolerated and shown to be feasible. There have been no drug-related serious adverse events (SAEs) and the majority of SAEs were related to respiratory infections. Most of the adverse events (non-SAEs) have been mild or moderate in severity. There were no changes in the safety profile with repeated doses of ISIS-SMNRx.

Results of Novartis' High Throughput Screening Campaign

2015-06-10T05:30:00.001-07:00

Researchers at the Novartis Institutes for BioMedical Research (NIBR) report discovered a molecule that increases production of survival motor neuron (SMN) protein in cell and animal models. The discovery was published online in Nature Chemical Biology on June 1. Lack of SMN is seems to be the major cause of spinal muscular atrophy (SMA).

They’ve also demonstrated how the compound—which is being tested in a clinical trial in Europe—might work.

“Our compound can potentially boost SMN production by coaxing complex cellular machinery known as the spliceosome to help out,” says Susanne Swalley, who is a co-first author on the paper and an investigator in Developmental & Molecular Pathways at NIBR.

You can read more on their discovery at NIBR blog.

PTC Therapeutics Phase 1 Clinical Data on RG7800

2015-05-26T00:06:00.001-07:00

PTC Therapeutics presented Phase 1 clinical data from the company's joint development program with Roche and the SMA Foundation in spinal muscular atrophy (SMA) at the 2015 American Academy of Neurology 67th Annual Meeting.

Findings from the Phase 1 study indicated that RG7800, an investigational oral therapy for SMA, showed a favorable safety profile and was well tolerated at all dose levels studied. In addition, proof of mechanism was demonstrated by a dose-dependent effect on Survival Motor Neuron 2 (SMN2) splicing towards the production of full length SMN2 mRNA. The Phase 1 study was a single ascending dose, placebo-controlled, double-blind study in 48 healthy volunteers testing single oral doses from 0.5 to 90 mg.

"The ability to demonstrate proof of mechanism in this Phase 1 study was a major achievement both for our SMA collaboration as well as PTC's alternative splicing platform," stated Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics, Inc. "Given its mechanism of action, RG7800 targets the underlying cause of the disorder, and has the potential to restore functional SMN protein levels in the nervous system, muscle, and other tissues throughout the body. We are encouraged by the progress that is being made in the ongoing Phase 2 Moonfish study in SMA patients that was initiated late last year and look forward to the results of this study in 2016."

SMA is a genetic neuromuscular disease caused by a missing or defective SMN1 gene, which results in reduced levels of SMN protein. The homologous SMN2 gene is predominantly spliced to a shortened mRNA, and only produces small amounts of SMN protein. Insufficient levels of SMN protein are responsible for the loss of motor neurons within the spinal cord leading to muscle atrophy and death in infants and toddlers in its most severe form. It is estimated that this devastating disease affects 1 in every 11,000 children born. There are no marketed therapies for SMA.

RG7800 is an orally available small molecule being investigated for its ability to selectively modify the splicing of the SMN2 gene, which is present both in healthy individuals and SMA patients, towards the production of full length mRNA. Preclinical studies in animal models of SMA demonstrated an increase in functional full length SMN protein with significant efficacy benefits on survival and motor function.

Stem Cell Scientists at UCLA Develop More Effective Way to Create Motor Neurons

2015-05-21T03:58:00.001-07:00

A team lead by Bennett Novitch, Ph.D. at the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, published new research using embryonic stem cells enhances the study of this intricate and perplexing system. Such discoveries are vital to the understanding and treatment of devastating disorders such as amyotrophic lateral sclerosis (commonly known as ALS or Lou Gehrig’s disease) and spinal muscular atrophy (SMA), which are caused by the loss or degeneration of motor neurons – the nerves that control muscle movement.

The research, which provides a more efficient way to study the functions of motor neuron diseases through the power of stem cells, was published by the journal Nature Communications.

Voluntary muscle movement—such as breathing, speaking, walking and fine motor skills—is controlled by several different subtypes of motor neurons. Originating in the spinal cord, motor neurons carry signals from the brain to muscles throughout the body. Loss of motor neuron function causes several neurological disorders for which treatment has been hindered by the inability to produce enough of the different kinds of motor neurons to accurately model and potentially treat neurodegenerative diseases, as well as spinal cord injuries. Specifically, efforts to produce ‘limb-innervating’ motor neurons in the lab were only about 3 percent effective. This special subtype of motor neuron supplies nerves to the arms and legs and is most acutely affected by motor neuron diseases such as ALS or SMA.

Novitch, an associate professor of neurobiology at UCLA and member of the Broad Stem Cell Research Center, studies the developmental mechanisms that drive muscle movements in order to better understand motor neuron diseases and discover new ways to treat them. Through the study, Novitch, the study’s first author Katrina Adams and their team sought to produce a better method to expand the range of motor neuron subtypes that could be created from stem cells, focusing on the subtype that innervates the limbs. Results from the study are impressive; the research found that the new method increased production of stem-cell-derived limb-innervating motor neurons from the previous 3 percent to 20 percent, more than a fivefold increase.

“Motor neuron diseases are complex and have no cure; currently we can only provide limited treatments that help patients with some symptoms,” said Novitch, the senior author on the study. “The results from our study present an effective approach for generating specific motor neuron populations from embryonic stem cells to enhance our understanding of motor neuron development and disease.”

Embryonic stem cells are ‘pluripotent’ which means they have the capability to turn into any other cell in the body. The process by which they turn into other cells in the body is called differentiation. Human embryonic stem cells are produced from stored frozen embryos donated by individuals or couples who have completed in vitro fertilization.

Using mouse and human embryonic stem cells, Novitch and his team directed the formation of limb-innervating motor neurons using a ‘transcriptional programming’ approach. This approach adds a transcription factor, which is a protein that acts in the cell nucleus to regulate gene function. Like a conductor guiding an orchestra, transcription factors tell the genes in a cell to turn off and on or express themselves a little louder or a little quieter.

Gene Therapy Stops or Stabilizes Spinal Muscular Atrophy in Animal Model

2015-05-13T05:10:00.001-07:00

Researchers from The Ohio State University, Nationwide Children's Hospital and the University of Bern in Switzerland found that protein replacement gene therapy helped stabilize an animal model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death, but until now had not been modeled in a large animal to predict human outcomes. The disease is caused by an abnormal or missing survival motor neuron gene 1 (SMN1) and retention of the SMN2 gene. The genes produce the SMN protein, however SMN2 produces considerably less than SMN1, causing motor neurons in the spinal cord to degenerate.

The researchers found that correcting levels of the SMN protein prior to symptom onset resulted in complete correction of the disease, while correction of SMN levels while the animal showed symptoms resulted in a marked correction and no further motor neuron loss.

Although remaining motor neurons are capable of sprouting and improving muscle function following early intervention gene therapy, neurons lost cannot be restored.

“We also showed that the biomarkers of motor neuron function that can be used in both man and pig show a marked response to treatment, and will have predictive value in human clinical trial assessment,” said Arthur Burghes, PhD, a professor and researcher in the Department of Molecular and Cellular Biochemistry at Ohio State's College of Medicine, in a press release.

The researchers are now beginning a phase I trial of the gene therapy in SMA patients.

Mechanistic insights into spinal muscular atrophy suggest new paths for treatment

2015-05-11T00:55:00.000-07:00

Researchers from Cold Spring Harbor Laboratory (CSHL) shed new light on the underlying pathology of spinal muscular atrophy (SMA), a rare but devastating disease that causes muscle weakness and paralysis and is the leading genetic cause of infant deaths. The newly obtained insights may prove valuable as scientists currently work to define optimal treatment strategies for patients.

SMA is a motor neuron disease, meaning that it leads to the degeneration of nerves that control muscles and voluntary movement. These neurons require a protein known as Survival of Motor Neuron (SMN). Normally, all cells contain the instructions for two variants of the protein, called SMN1 and SMN2. In healthy patients, SMN1 is abundant, while SMN2, due to a quirk of molecular editing, is produced primarily in a shortened, unstable form.

In patients with SMA, however, the instructions to produce SMN1 are faulty and cells no longer generate the protein. Therefore, cells are forced to rely on small amounts of full-length SMN2 protein that are produced alongside the shorter, nonfunctional version.

CSHL Professor Adrian Krainer, in collaboration with Isis Pharmaceuticals, has developed a drug that allows the correct editing to occur, thereby greatly increasing the amount of functional SMN2 protein in neurons. The drug, known as an antisense oligonucleotide (ASO), showed great promise in preclinical mouse models of SMA. It is now in Phase 3 clinical trials in SMA patients.

The drug is delivered directly into the cerebrospinal fluid of infants and children with SMA. “It is largely believed in our field that SMN is essential in the central nervous system (CNS) – not in peripheral tissues like the limbs or liver – so most efforts have been focused on increasing full-length SMN levels in the CNS,” explains Krainer. “But over the last few years, evidence has been building that challenges our assumptions about the pathology of the disease. The question is: do we need to increase SMN levels in the CNS, in peripheral tissues, or both?”

In their new work, reported in Genes & Development, the researchers developed a method to restore SMN production only in peripheral tissues, allowing them to define the role of the drug both inside and outside of the CNS. The team treated well-established mouse models of SMA with the ASO subcutaneously. Consistent with previous results, the drug increased SMN levels in both the CNS and peripheral tissues; in newborn mice, but not in older mice, some of the drug injected in the periphery can reach the CNS. The treatment effectively cured the animals.

ISIS SMN-Rx Enters Phase 3 Trial

2014-12-19T06:31:00.001-08:00

Isis Pharmaceuticals announced the pivotal Phase 3 study evaluating ISIS-SMN_Rx in approximately 120 non-ambulatory children with spinal muscular atrophy (SMA). The Phase 3 study, CHERISH, is the second Phase 3 study Isis has initiated in a global late-stage clinical development program for ISIS-SMN_Rx. Isis is also evaluating ISIS-SMN_Rx in the Phase 3 study, ENDEAR, in infants with SMA. Isis is conducting both Phase 3 studies with agreement from the U.S. Food and Drug Administration (FDA) for special protocol assessments, or SPAs.

"CHERISH is the second pivotal Phase 3 study of ISIS-SMN_Rx we have initiated this year. The speed at which we have moved this drug from a preclinical development candidate to a late-stage development reflects the successful collaboration we have with Biogen Idec and the support from the SMA community. It is our hope that this study will build upon the encouraging results we observed in our open-label Phase 2 studies. Both Phase 3 studies are designed to evaluate the efficacy of ISIS-SMN_Rx in either infants or children with SMA and to further assess the safety profile in these patients. We are further encouraged by the FDA's agreement on the trial design and planned analysis for both of these Phase 3 studies on ISIS-SMN_Rx," said B. Lynne Parshall, chief operating officer at Isis Pharmaceuticals. "Together with our partner Biogen Idec, we are also in the planning stages for additional clinical studies as part of our commitment to the clinical program for ISIS-SMN_Rx."

"SMA is a devastating disease that robs people of physical strength by affecting the motor nerve cells in the spinal cord. SMA is the number one genetic cause of death for infants. Children with SMA grow weaker as their disease progresses. Although the genetic cause of SMA is well understood, currently there are no effective drugs available for children with SMA," said Kenneth Hobby, president of Cure SMA. "We applaud Isis for investing in and leading drug development efforts for SMA. We remain hopeful that potential treatments, like ISIS-SMN_Rx, will be able to provide therapeutic benefit."

CHERISH, a Phase 3 study of ISIS-SMN_Rx, is a randomized, double-blind, sham-procedure controlled fifteen month study in approximately 120 children who are non-ambulatory with SMA between the ages of 2-12. The study will evaluate the efficacy and safety of a 12 mg dose of ISIS-SMN_Rx with a primary endpoint of a change in the Hammersmith Functional Motor Scale-Expanded (HFMSE), a validated method to measure changes in muscle function in patients with SMA. Additional efficacy endpoints are also included in the study. For further study information, please visit www.clinicaltrials.gov or the ISIS-SMN_Rxstudy site at www.smastudy.com.

In addition to the current Phase 3 clinical studies ENDEAR and CHERISH,Biogen Idec plans to conduct two additional ISIS-SMN_Rx studies, which could begin in the first half of 2015:

NURTURE will be a Phase 2 clinical study evaluating ISIS-SMN_Rx in up to 25 pre-symptomatic newborns that are genetically predisposed to the disease.

EMBRACE will be a Phase 2 clinical study evaluating safety and exploratory efficacy of ISIS-SMN_Rx in approximately 20 patients with infantile or childhood-onset SMA. This study will bridge the gap in a small subset of patients that do not meet the age and inclusion criteria of the current Phase 3 studies ENDEAR and CHERISH.

ISIS SMN-Rx Advances into Phase 3 Study in Infants with Spinal Muscular Atrophy

2014-08-02T13:58:00.000-07:00

Isis Pharmaceuticals, announced the initiation of a pivotal Phase 3 study evaluating ISIS-SMNRx in infants with spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. Isis plans to dose the first infant in this study within the next few week. The Phase 3 study, ENDEAR, is the first of several planned studies in a broad and comprehensive late-stage clinical development program for ISIS-SMNRx. Isis plans to initiate a second pivotal study in children with SMA later this year.

"The successful advancement of ISIS-SMNRx from a preclinical drug candidate to late-stage studies within just a few years reflects the effectiveness of our strategic alliance with Biogen Idec and the benefit of working closely together with combined expertise, and the support from the SMA community. As we continue development of ISIS-SMNRx and initiate the two pivotal studies in infants and children with SMA, we are in the planning stages for clinical studies in additional patient populations," said B. Lynne Parshall, chief operating officer at Isis. "The clinical and preclinical data we have generated to date, including data in multiple open-label clinical studies, across multiple measures with ISIS-SMNRx, support the initiation of these studies, which fully assess the safety and efficacy benefits of this experimental treatment."

"Families of SMA is pleased that Isis is advancing to the next phase of clinical trials for ISIS-SMNRx. Controlled trials are the gold standard in proving the safety and efficacy of any drug," said Kenneth Hobby, president of Families of SMA. "SMA is a devastating disease with no current therapeutic options. Families of SMA applauds Isis for progressing its development program in an expedient manner, and looks forward to additional trials in patients with SMA beginning later in 2014."

ENDEAR, a Phase 3 study of ISIS-SMNRx, is a randomized, double-blind, sham-procedure controlled thirteen month study in approximately 110 infants diagnosed with SMA. The study will evaluate the efficacy and safety of a 12 mg dose of ISIS-SMNRx with a primary endpoint of survival or permanent ventilation. Additional efficacy endpoints are also included in the study.