Progress Now Winter 2015

Research updates and clinical trials information

by Margaret Wahl on January 5, 2015 - 9:07am

Quest Winter 2015

Readers sometimes wonder what’s happening with research for their diseases when they don’t see news about them for a while in the pages of Quest. But keep in mind: Research that seems to be for one disorder often has spillover implications for others.

In this issue: Refining the delivery of stem cells to the spinal cord in people with amyotrophic lateral sclerosis (ALS) could have implications for those with spinal muscular atrophy (SMA), while perfecting the delivery of therapeutic genes to the spinal fluid in those with SMA could have implications for those with ALS. The "antisense" strategy that underlies the drug ISIS-SMNRx, now being tested as a way to change genetic instructions in SMA, will enhance understanding of this strategy as applied to other disorders, such as ALS, Duchenne muscular dystrophy and myotonic muscular dystrophy.

To learn more about the diseases in MDA’s program, go to the online disease directory. And to stay on top of the latest research developments and news, be sure to visit

Also in this issue of Quest: Read Thinking Broadly, Acting Intentionally to learn more about Grace Pavlath, MDA's new scientific director.


News from Neuralstem

Intriguing results for neural stem cell transplantation

In fall 2014, Maryland-based cell therapy company Neuralstem announced long-term data from its phase 1 trial of transplantation of human neural stem cells into people with amyotrophic lateral sclerosis (ALS). Neurologist and study investigator Jonathan Glass described encouraging results from the highest-dose group in an ongoing phase 1 safety trial that is now closed to new participants. Of the three ALS patients who had received injections of Neuralstem’s NSI-566 human neural stem cells into the cervical (neck) and lumbar (lower back) regions of the spinal cord about three years earlier, one was showing functional improvement from a pre-treatment baseline, and two were maintaining the same level of function as they had at baseline. Those functional results aren’t typical for ALS, although they can occur, even without treatment. (Patients who received lower doses of the cells did not necessarily do as well, and some have not survived.)

A phase 2 trial, also closed to new participants, is underway at three U.S. centers. Jonathan Glass, a study investigator at Emory University in Atlanta for the phase 1 and 2 trials, is the director of the MDA/ALS center at that institution, although MDA is not funding these trials.

Studies in rats have shown that NSI-566 cells derived from a human spinal cord matured into support cells (“nurse” cells) for existing nerve cells or into “connector” nerve cells that integrated into circuits between existing nerve cells. Recent findings from after-death examinations of the spinal cords of six ALS trial participants found evidence that, at least in these patients, some of the transplanted stem cells had begun maturing into nerve cells. The autopsy results, published Oct. 22, 2014, in Annals of Clinical and Translational Neurology, showed that all six patients had surviving transplanted cells in their spinal cord and that the cells survived up to 2.5 years after transplantation.

All six trial participants had received medications to suppress their immune systems as a way to increase the likelihood that their bodies would accept the transplant. However, five of the six stopped these medications at varying time points during the study. The investigators found that survival of the transplanted cells was not correlated with the duration of medications to suppress the immune system, suggesting that prolonged immunosuppression may not be necessary after all.

To learn more about the closed but ongoing phase 2 study of neural stem cell transplantation, enter NCT01730716 in the search box at For more about Neuralstem’s research, go to Or read the full paper on survival of transplanted stem cells into ALS patients, without charge, at

U.S. Stem Cell Trial 

Study of adult stem cells derived from bone marrow tissue underway

As of late 2014, Israeli biotechnology company BrainStorm was continuing to recruit for its phase 2 study of adult stem cells derived from patients’ own bone marrow tissue at three sites in the U.S.  Interim results from earlier trials have shown that the cells, known as NurOwn, are safe and well-tolerated when injected into muscle tissue or spinal fluid, and that some trial participants have stabilized or improved.

Participants in the U.S. trial must have ALS; be 18–75 years old; have had onset of symptoms within the previous two years; have a respiratory capacity that is at least 65 percent of normal; live near Boston or Worcester, Mass., or near Rochester, Minn.; and meet other criteria. For details, enter NCT02017912 in the search box at For more about BrainStorm’s research, visit

Follistatin Gene Transfer

Small trial shows gene that may block muscle growth inhibitor 

A six-person, phase 1 trial of an experimental treatment for Becker muscular dystrophy (BMD) using the gene for the follistatin protein has shown encouraging results in terms of its effects on walking distance and on the appearance of biopsied muscle tissue.

Neurologist Jerry Mendell was the principal investigator on this small trial, which took place at Nationwide Children’s Hospital in Columbus, Ohio. Mendell is a longtime and current MDA research grantee and is a co-director of the MDA Clinic at Nationwide, although MDA did not fund this particular trial.

Group 1 included three men with BMD who received injections into the thigh muscles of both legs of follistatin genes encased in the shell of a type 1 adeno-associated virus (AAV1). Group 2 underwent the same procedure at a higher-dosage level. The proposed mechanism of action for follistatin is that it will increase muscle growth and strength by counteracting the myostatin protein, which is known to limit muscle growth.

In group 1, over the course of a year, two participants increased the distance they walked in six minutes by 58 meters (191 feet) and 125 meters (413 feet), respectively. The third patient’s distance increased only 9 meters (30 feet), which was considered within the usual variability for BMD.

In group 2, over the course of six months, two participants increased the distance walked in six minutes by 108 meters (356 feet) and 29 meters (96 feet), respectively. However, one participant’s six-minute walking distance decreased by 14 meters (46 feet).

When thigh muscle biopsy samples taken before the gene injections and six months later were compared, the post-treatment samples showed tissue that was more normal in appearance.

Mendell and colleagues published the results online Oct. 17, 2014, in Molecular Therapy. In their paper, they say, “The results are encouraging for treatment of dystrophin-deficient muscle diseases.” BMD and the relatedDuchenne muscular dystrophy (DMD)are caused by a lack of the dystrophin protein in muscles.

Ignoring the Stop Signs

Ataluren phase 3 trial results expected in 2015

In August 2014, ataluren, also known as Translarna, received conditional approval in Europe for ambulatory patients ages 5 and older with Duchenne muscular dystrophy (DMD) caused by specific genetic mutations known as “premature stop codons” (also known as “nonsense” mutations) in the dystrophin gene. Ataluren is being developed by PTC Therapeutics of South Plainfield, N.J., a biotech company to which MDA gave a $1.5 million grant in 2005. It’s known as a “stop codon read-through” drug, designed to coax cells to ignore (“read through”) molecular stop signals.

In September, PTC announced it had completed enrollment for its phase 3 trial of ataluren and that initial results are expected in the second half of 2015. This large-scale, 48-week, multinational trial will be necessary before full approval can be considered for ataluren in either the United States or the European Union.

In addition, full results for an earlier, phase 2b trial of ataluren, originally announced in 2010, were published in the October 2014 issue of the journal Muscle & Nerve. In this trial, all participants showed a decline in the distance they could walk in six minutes, but those treated with a particular dose of ataluren declined more slowly than those treated with a different dose or with a placebo.

Phase 3 Sarepta Trial

FDA seeks more information, new drug application expected

In fall 2014, Cambridge, Mass.-based Sarepta Therapeutics opened a large-scale, phase 3 trial of its experimental DMD drug, eteplirsen, in ambulatory boys with DMD who are 7–16 years old, as well as a phase 2 study of the drug in boys and young men with DMD ages 7–21 who can no longer walk a minimum distance.

The company had hoped to submit a new drug application for eteplirsen to the U.S. Food and Drug Administration (FDA) by the end of 2014, based largely on encouraging results from a 12-participant, phase 2b study of the drug. However, on Oct. 27, Sarepta revised its estimate of the timing of the new drug application submission from late 2014 to mid-2015, following requests from the FDA for additional information.

Specifically, the agency asked to see data from more patients treated with eteplirsen, more information about the natural history of DMD from untreated patients, and more convincing evidence that dystrophin protein levels have increased in the muscle biopsy samples of treated trial participants.

On Oct. 30, 2014, the FDA released a statement to the DMD community in which it explains its desire for more data, assures patients and families of its commitment to DMD drug development, and says it understands the urgency of the situation.

“We understand that this news is disappointing to the DMD community, and we feel the same sense of urgency that our families do when it comes to finding effective treatments,” said neurologist Valerie Cwik, M.D., MDA’s chief medical and scientific officer. “We hope this development will not significantly delay the process as the FDA ensures eteplirsen is safe and effective before it is brought into the clinic.”

Sarepta plans to submit its eteplirsen application via the FDA’s “accelerated approval” pathway, one of several mechanisms the agency offers to speed up development of new drugs. Whether or not the company receives an accelerated approval for eteplirsen, positive results from a confirmatory, phase 3 trial will be necessary before full approval can be granted by the FDA. As of fall 2014, the confirmatory, phase 3 trial is underway, as is a phase 2 trial in boys up to age 21. A trial of eteplirsen in boys who are younger than 7 is being planned.

For details and contact information for the phase 3 trial of eteplirsen, enter NCT02255552 in the search box at For information about the trial of eteplirsen in patients who are not able to walk a minimum distance, enter NCT02286947. To see Sarepta’s online resource center for DMD-affected families, go to “Let’s Skip Ahead” at Sarepta’s pipeline for DMD drug development is at For more about the FDA’s drug approval process, read Can We Have This Drug Now?

Prosensa Forges Ahead

New FDA drug application for drisapersen, ongoing studies resumed

In October 2014, Prosensa, a Dutch biotechnology company, announced it had begun its new drug application submission to the FDA for its DMD drug drisapersen, making use of the FDA’s accelerated approval mechanism. At the same time, the company said it was on track to submit a marketing authorization application for conditional approval by the European Medicines Agency (EMA) in early 2015.

In September, Prosensa announced it had begun re-administering drisapersen to participants in ongoing studies in North America and in Europe. Administration of the drug had been temporarily halted in 2013, after a phase 3 trial of drisapersen failed to show it was better than a placebo on tests of walking distance or motor function at 48 weeks. In contrast to the phase 3 results, a U.S.-based phase 2 trial showed encouraging results in March 2014, as did a non-U.S. phase 2 trial in April 2013.

Like eteplirsen (see page 8), drisapersen targets exon 51 of the dystrophin gene and is designed to treat patients with DMD who have mutations near (but not in) this part of the gene. Prosensa is also developing compounds that target exons 44, 45, 53, 52 and 55 of the dystrophin gene. A European phase 1-2 trial of PRO044, which targets dystrophin exon 44 and is designed for patients with dystrophin mutations near that section, has been completed. A phase 2 trial of PRO045, targeting exon 45 of the dystrophin gene, is underway in Europe and the United Kingdom and is open to participants. 

For details and contact information about the continuing study of drisapersen in boys in the U.S. and Canada with DMD who have previously participated in a drisapersen trial, enter NCT01803412 in the search box at; for the trial of PRO045 being conducted outside the U.S., enter NCT01826474, and for the trial of PRO053 being conducted outside the U.S., enter NCT01957059. See Prosensa’s Patients & Family section at and Prosensa’s DMD drug development pipeline at

Showing Promise 

Researchers encouraged by Firdapse, phase 3 trial drug is available to qualified patients 

Catalyst Pharmaceuticals, a biopharmaceutical company based in Coral Gables, Fla., announced encouraging results in late September for a phase 3 trial of its drug Firdapse in patients with Lambert-Eaton myasthenic syndrome (LEMS).

LEMS is a disorder of the neuromuscular junctions, places where nerve and muscle fibers meet. Like myasthenia gravis (MG), it’s caused by a mistaken attack by the body’s immune system on these junctions. However, unlike MG, in which the immune system attacks the muscle side of the junction, LEMS results from an immune system attack on the nerve side. Both diseases cause fluctuating weakness.

Firdapse is Catalyst’s version of 3,4-diaminopyridine, a compound that may increase the release of the nerve-to-muscle signal at the neuromuscular junction. It’s classified as a potassium channel blocker. The drug also may have implications for certain types of MG and for some types of congenital myasthenic syndromes (CMS), which are genetic disorders that affect the neuromuscular junction.

The recent phase 3 trial included 38 LEMS patients, all of whom received Firdapse for three months and then were randomly assigned to continue receiving Firdapse or to receive a placebo for two weeks. Those who were switched to the placebo after three months did significantly worse on tests of muscle strength than those who took Firdapse during the entire trial. The drug appeared to be safe and well-tolerated.

Firdapse is now available to people with LEMS or CMS who meet certain criteria through an “expanded access” program, a mechanism that the FDA offers to allow people with serious disorders for which no treatment is available to receive investigational medications. 

To learn more about the expanded access program, go to, or have your physician call (844) Firdapse or (617) 492-1537. More information can be found by entering NCT02189720 in the search box at

New Guideline for Diagnosis, Care

A committee convened by the AAN has published new care recommendations

This fall, the American Academy of Neurology (AAN) released a guideline for the diagnosis and care of people with limb-girdle muscular dystrophy (LGMD) and the forms of distal muscular dystrophy (DD) that arise from the same genes as those that are flawed in LGMD, such as Miyoshi myopathy and myofibrillar myopathy. The term LGMD is used to describe muscular dystrophy that mainly affects the muscles of the shoulders, upper arms, hips and thighs, while DD is used to describe muscular dystrophy that mainly affects the muscles of the forearms, hands, lower legs and feet.

The guideline is based on a review of medical literature by a panel of specialists convened by the AAN that included several MDA clinic directors. It was then endorsed by several organizations, including MDA, and published Oct. 14, 2014, in Neurology, the jourrnal of the AAN.

Here are some highlights of the points the committee made about diagnosis and care in LGMD and DD.

  • Multidisciplinary clinic referral: Patients with LGMD or DD should be referred to a clinic that has access to multiple specialties and is designed specifically to care for people with muscular dystrophy. (MDA clinics meet this definition.)
  • Diagnosis: Accurate diagnosis, including genetic diagnosis, of an LGMD or DD subtype is important for predicting the course of the disease, the likelihood of cardiac or respiratory involvement, the avoidance of inappropriate treatments, and the efficient use of resources.
  • Cardiac care: Since many subtypes of LGMD or DD affect the heart, most newly diagnosed patients should undergo a cardiology evaluation, including an electrocardiogram and either an echocardiogram or a cardiac MRI, with further testing to follow for those with abnormalities on these tests or with cardiac symptoms. Subtypes LGMD2A, LGMD2B and LGMD2L were noted as unlikely to affect the heart. Treatment may involve medications, device placement or surgery.
  • Respiratory care: Some forms of LGMD and DD, particularly LGMD2I and myofibrillar myopathy, carry a high risk of respiratory muscle weakness, but subtypes LGMD2B and LGMD2L rarely cause respiratory problems. Pulmonary function testing should be conducted on most LGMD patients at diagnosis and in anyone with respiratory symptoms. A possible treatment for respiratory insufficiency is noninvasive ventilation (pressurized air delivered via a mask or mouthpiece).
  • Spinal care: People with LGMD or 
  • DD should be monitored for the development of spinal curvatures and referred to a surgeon if abnormalities are found.
  • Nutritional support: People with LGMD or DD who have difficulty swallowing or are losing weight should undergo a swallowing or gastroenterology evaluation. Treatment may include altering food consistency, instruction in safe swallowing or placement of a feeding tube.
  • Exercise: Evidence for the effectiveness of strength and aerobic training is limited, but it suggests that people with LGMD or DD can benefit from these. Gentle, low-impact, aerobic exercise combined with a supervised and moderate strength training program are probably safe and may be beneficial, but patients should be warned about the signs of overwork weakness and muscle damage and should not exercise to exhaustion.

Read the full guideline at or a summary written for patients and families at

Taking Aim at Protein Clumps

Cabaletta testing begins outside the U.S., but U.S. trial possible

Israeli biotechnology company BioBlast Pharma is developing an experimental drug designed to treat oculopharyngeal muscular dystrophy (OPMD) and is testing it in a phase 2-3 clinical trial at sites in Jerusalem and Montreal.

The company hopes to open a trial site in the Los Angeles area as soon as possible and also will soon open a multicenter study of the natural history (usual course) of OPMD. The FDA must first approve these studies.

BioBlast’s experimental OPMD drug, known as Cabaletta  (the active ingredient is a sugar molecule called trehalose), is a chemical “chaperone,” a type of molecule that helps to prevent abnormal clumping (aggregation) of misfolded proteins and enhances cellular protein self-digestion (autophagy) to clear abnormally accumulating proteins. In laboratory animal models, Cabaletta appears to prevent abnormal aggregation of proteins inside cells and improve muscle power. The drug is given by intravenous infusion. 

In September 2014, BioBlast announced that no drug-related adverse events had occurred in the first 11 patients in the Cabaletta trial and that the company had gained a deeper understanding of how the drug is handled by the body and how it can best be directed to targeted tissues.

For details and contact information on the trial of Cabaletta in OPMD, enter NCT02015481 in the search box at For more about OPMD and Cabaletta, visit

Lumizyme for All

FDA now allows Lumizyme to be prescribed for Pompe patients of all ages

Biopharmaceutical company Genzyme of Cambridge, Mass., has received permission from the FDA to market its drug Lumizyme to U.S. patients with the metabolic muscle disorder Pompe disease, regardless of their age. Until August 2014, the FDA had required that Lumizyme be used to treat patients with Pompe disease who were at least 8 years old and that Genzyme’s related drug, Myozyme, be prescribed for those younger than age 8.

Pompe disease results from a complete or partial deficiency of the acid maltase (also known as acid alpha-glucosidase) enzyme in muscle tissue and can result in severe weakness, as well as cardiac and respiratory abnormalities. Myozyme and Lumizyme are laboratory-engineered versions of the acid maltase enzyme and are designed to replace it in cells. The drugs are given intravenously.

In October 2014, Genzyme announced that all U.S. Pompe patients would have access to Lumizyme immediately and that Myozyme would no longer be available after Dec. 31. The company recommended that patients on Myozyme or their parents discuss the transition to Lumizyme with their doctors.

Questions about Pompe treatment can be directed to Genzyme Case Management at (800) 745-4447, option 3. 

Making Sense From Antisense

Interim phase 2 results suggest functional benefits; two phase 3 trials are now open

ISIS-SMNRx, an “antisense”-based drug in development to treat spinal muscular atrophy (SMA), continues to show encouraging results in two phase 2 trials, one in infants up to 7 months old and another in children ages 2 to 15 years old. Two phase 3 trials — one in infants and one in children ages 2 to 12 — are now underway and are open to new participants.

SMA is caused by a deficiency of a protein called SMN (survival motor neuron) in nerve cells, as a result of mutations in a gene called SMN1. SMA patients, however, produce a small to moderate amount of full-length, functional SMN protein from another gene, known as SMN2. ISIS-SMNRx is designed, using antisense technology, to alter the way the genetic instructions for SMN2 are read by cells so that more of the full-length SMN protein is produced from this gene. Isis Pharmaceuticals of Carlsbad, Calif., is developing and testing ISIS-SMNRx, in collaboration with Biogen Idec of Cambridge, Mass. MDA has supported laboratory development of antisense strategies for SMA.

The drug developer in October 2014 provided the SMA community with an interim report on four infants who received 6-milligram injections into the spinal fluid of ISIS-SMNRx in a phase 2 trial and on 12 infants who received 12-milligram injections. In the lower-dose group, there had been one death and one infant placed on permanent ventilation. In the higher-dose group, there had been three deaths and one infant placed on permanent ventilation. Higher levels of SMN protein were seen in the spinal cords of infants treated with ISIS-SMNRx compared to those seen in untreated SMA-affected infants, which supports that the drug is working by the mechanism proposed for it. Increases in muscle function scores were seen in infants in both dosage groups, with safety and tolerability supporting continued development of ISIS-SMNRx. This study is ongoing but is not open to new participants.

In the same update, Isis issued an interim report on 56 children ages 2–15 who received single or multiple injections of ISIS-SMNRx into the spinal fluid at doses ranging from 1 milligram to 12 milligrams. There was an average increase in muscle function scores in these children, and in the 10 ambulatory trial participants, the average distance walked in six minutes increased. As in the infant group, safety and tolerability supported continued development of the drug. This study is ongoing but is not open to new participants.

Participants in the phase 3 study of ISIS-SMNRx in SMA-affected infants must be up to 210 days (7 months) old, have an SMA diagnosis, have two copies of the SMN2 gene, and meet other study criteria. For details and contact information, enter NCT02193074 in the search box at Participants in the phase 3 study of ISIS-SMNRx in SMA-affected children must be 2 to 12 years old, have an SMA diagnosis, have experienced onset of symptoms after 6 months of age, be able to sit independently but not walk, and meet other study criteria. For details and contact information, enter NCT02292537 in the search box at For more, visit and

Delivering New Genes

Could gene transfer help treat SMA?

In addition to changing how cells read instructions from the SMN2 gene, a strategy for increasing levels of the needed, full-length SMN protein in SMA is direct injection of genes for the full-length SMN protein. This type of strategy is known as “gene transfer” or “gene therapy.”

Dallas-based biotechnology company AveXis, which is developing gene therapy for SMA, announced in October 2014 that administration of its experimental gene transfer compound to the first three patients in a phase 1 trial in infants with type 1 SMA (the most severe form of the disease) was complete. The nine-infant trial is ongoing and, as of late 2014, was continuing to recruit new participants, who will receive a higher dosage level of the drug than the first group.

AveXis’ SMA drug, known as chariSMA, contains the gene for the full-length SMN protein, encased in the shell of a type 9 adeno-associated virus (AAV9 “vector”) as a delivery vehicle. The AAV9 virus may be uniquely suited to treating SMA, AveXis says, because it does not cause disease in humans, and it can cross biological barriers to reach SMA-affected cells in the central nervous system.

The phase 1 trial of intravenous SMA gene therapy is being conducted at Nationwide Children’s Hospital in Columbus, Ohio, under the direction of neurologist Jerry Mendell, a longtime MDA research grantee and co-director of the MDA clinic at his institution. (MDA is not, however, funding this trial.) A second trial for babies with type 1 SMA, in which the drug will be infused into the spinal fluid, is being planned for the first half of 2015, and a trial of the compound in patients with type 2 SMA (a less severe form of the disease than type 1) is being considered for 2015. 

Participants in the intravenous gene transfer trial in type 1 SMA must be no more than 9 months old at study entry, have experienced SMA symptoms by 6 months of age, have a mutation in both copies of the SMN1 gene, have exactly two copies of the SMN2 gene and meet other criteria. Contact study coordinator Sohyun McElroy at Nationwide Children’s in Columbus at (614) 355-2606 or For details, enter NCT02122952 in the search box at

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