(Written for annamaryas.com – Posted by Annamarya Scaccia)

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To be confined to a wheelchair for most, if not all, of your life can seem unimaginable. But it’s a reality 1 in 3,500 boys born with Duchenne muscular dystrophy (DMD) each year have to face.

This is the case for 11-year-old Max and 14-year-old Austin Leclaire of Saxtons River, Vermont. According to a Change.org petition started by mother Jennifer McNary in December, the two boys rely on wheelchairs for everyday mobility because the progressive genetic disorder they were born with—caused by an absence of the protein dystrophin—has deteriorated their muscles. This characterized degradation first affects the hip, pelvic, thigh, shoulder, leg and trunk muscles, which can begin as early as three-years-old, and eventually attacks the heart and respiratory muscle, typically by early teen-hood (Becker is a milder form of DMD, and is less predictable and progressive.)  About 1/3 of boys affected also develop some type of learning disability.

The Leclaire boys: Austin, 14 and Max, 11 (Taken from Change.org petition)

For many boys with Duchenne, wheelchair use begins sometime between 7- and 12-years-old. In a 2007 Centers for Disease Control study, 90 percent of 15- to 24-year-old males living with Duchenne/Becker muscular dystrophy were using a wheelchair, an 8 percent increase from those ages 10-14. To really illustrate DBMD’s aggression: only 29 percent of boys 5- to 9-years-old reported wheelchair use (note: the numbers reflect data from four states: Arizona, Colorado, Iowa and New York.)

And DMD is so severe that most boys do not live pass their 20s (cardiac and respiratory care advancements have improved life expectancy; it is now more common to see survival into the early 30s, with a few men living into mid-adulthood.) In fact, the CDC study showed that, in those four states, there was a 58 percent survival rate among males 20- through 24-years-old, a 27 percent decrease from males 15- through 19-years-old. Currently, the disease, one of nine muscular dystrophy types, has no known cure, and available treatments only help the symptoms rather than the cause.

“The yearly average cost in 2004 for medical care for privately insured individuals with any type of muscular dystrophy was $18,930, ranging from $13,464 at 5 through 9 years of age to $32,541 at 15 through 19 years of age.” – Health Care Utilization and Expenditures for Children and Young Adults with Muscular Dystrophy in a Privately Insured Population, J Child Neurol August 2008 23: 883-888, first published on April 10, 2008

According to a Feb. 7 Time article, Austin lost the complete ability to walk around 10-years-old, while Max could still “put one foot in front of another.” It was why Max was qualified to take part in a phase 2b extension study for its experimental drug, eteplirsen.

Developed by Sarepta Therapeutics, eteplirsen was designed to treat DMD caused by the absence of specific dystrophin exons: 45-50, 47-50, 48-50, 59-50, 50, 52, and 52-63 (Max and Austin are both missing exon 52.) It targets exon (section) 51 of the dystrophin protein gene, “coaxing” muscle fibers to abandon this exon from the protein’s genetic expression and develop functional but truncated version of dystrophin.

So far, eteplirsen has shown positive results. According to Sarepta, all trial participants showed a substantial increase in dystrophin production at 48 weeks, including those who initially received a placebo for the first 24 weeks. Additionally, the six patients who received eteplirsen for 62 weeks continued to show disease stabilization, with four on the higher dosage (50 milligrams per kilogram of body weight) showing a 68.9-foot increase in walking distance at 48 weeks. At the end of the 62-week study, those six participants walked 203.4 farther than those in the placebo/delayed-treatment group. Evidence of continued stabilization also showed in pulmonary function, cardiac function, laboratory and strength tests.

By taking part in the study, Max has seen a drastic improvement in his walking ability. The once wheelchair-bound preteen can now walk longer on his own than ever before, and was even able to march in a 2012 Halloween parade, according to the 32-year-old McNary’s petition. Particularly, notes Time, Max and 11 other participants regained 60 percent of normal dystrophin production, up from zero, since beginning the trial two years ago. He is now on a soccer team and can climb steps—and, for anyone who has or knows someone affected by muscular dystrophy, this is nothing short of extraordinary.

“I don’t look at Max and think Duchenne’s anymore,” says McNary. “His stamina is less than other kids and he gets more tired, but he really doesn’t have a whole lot of limitations.”(Time Healthland, Feb. 7, 2013)

Later this month, Sarepta plans to meet with the U.S. Food and Drug Administration (FDA) to discuss the possibility of approving eteplirsen through its Accelerated Approval program, as well as additional clinical eteplirsen studies. The program, instituted in 1992, allows earlier approvals for medications treating serious diseases, and “fill an unmet medical need” established by a surrogate endpoint (biochemical or physiological markers predictive of and substitute for clinical outcomes.) Since its inception, accelerated approvals have trimmed traditional processing times by an average of six to seven months, reports Time.

Still, drug approvals based on surrogate endpoints aren’t a guarantee. They’re only given on the condition that the projected clinical benefit is confirmed by post-marketing clinical trials, known as a confirmatory trial. In the case of eteplirsen, it could mean launching a study verifying that the stabilization seen in the phase 2b trial actually predicts both an increased survival rate and quality of life improvement.

“We don’t want to introduce anything that is not going to work and does more harm than good,” Deputy Director of the FDA Office of Public Affairs Erica Jefferson told Time. “But this is an acknowledgment that there are treatments out there that can be potential game-changers.”

According to The Motley Fool, the pharmaceutical company has yet to file for accelerated approval—a decision, said Sarepta CEO Chris Garabedian, that won’t be made until after talks. Nevertheless, the FDA’s position on eteplirsen, writes Fool, will rest on how it views the drug’s safety profile, and whether it can be manufactured with high quality levels. According to a Jan. 25 Bloomberg BusinessWeek article, analyst Edward Nash predicts eteplirsen will be approved in 2016, and might be used to treat approximately 1,500 patients on the onset.

Safety-wise, there is little to worry about. A Dec. 7 Sarepta press release notes that eteplirsen was determined to be safe with no “clinically significant treatment-related adverse events, no serious adverse events, and no discontinuations.” One patient did, however, experience a temporary urine protein elevation but it did not result in any clinical symptoms or interruption of treatment.

But the FDA is cautious with accelerated approval. According to Time:

In 2011, just 10 percent of 30 new drugs qualified under the agency’s accelerated approval program; in 2012, only four made the cut. The agency is under heavy scrutiny to make sure that drugs are safe before they’re made widely available. The pressure may be even more intense when it comes to drugs for children, whose developing bodies are still developing…

“It is very hard to anticipate what the FDA will require for eteplirsen approval. There are a variety of registration paths available, such as accelerated approval and the traditional phase 3 study pathway,” Garabedian told Muscular Dystrophy Association’s (MDA) research and health magazine, Quest in January. “An important regulatory advance for rare diseases, PDUFA V (5), was signed into law this year. PDUFA V promotes accelerated access for patients to new therapies and accelerated development of promising therapies. There is language encouraging the FDA to use flexibility in disease areas of high unmet medical need like DMD. However, we need to meet with the FDA to understand how this language will apply in a real-world setting, such as with a drug like eteplirsen for DMD.”

By starting the petition in late 2012, McNary hoped she could help push the FDA to put eteplirsen through its accelerated process by gathering public support. McNary, co-founder of DMD Hero, and the Jett Foundation presented the petition, which has received over 176,000 signatures, to the organization on Feb. 13 (Olympic swimmer Ryan Lochte and radio personality Angela Yee are among the signers.) They were joined by Rep. Mike Fitzpatrick (R-Pa.), and Christine McSherry, parent and co-founder of Duchenne Alliance, a group of independent organizations advocating for DMD. The meeting was followed by discussions with Congress members, including Rep. Peter Welch and Sen. Patrick Leahy, both of Vermont.

“We don’t want anything to hold up drugs for this life limiting disorder, every day that passes, boys lose function, we cannot waste a single day,” McNary told the Jett Foundation.  She also met with Director of the FDA, Dr. Janet Woodcock on Feb. 15. “If a drug shows real promise in a trial and is safe, there needs to be a regulatory pathway that helps it move out to those who need it as quickly as possible.”

If approved—even temporarily—eteplirsen would be the first drug of its kind on the market, meaning individuals with DMD, like Austin, would finally have access to a drug that can possibly change and save their lives, much like it has done for Max. In the meantime, Sarepta is in the process of developing other exon-skipping drug candidates targeting additional patients with DMD.

There are also at least 32 open clinical trials recruiting participants with DMD and BMD, some of which are testing experimental treatments. Ataluren, another experimental drug meant to treat people with DMD/BMD, was shown to slow the declining rate of walking ability in a recent phase 2b study. PTC Therapeutics, the company behind the medication, has planned a global, phase 3 confirmatory trial for some time in the first quarter of 2013.

To sign the petition, click here.

Click here to learn more about the MD CARE Act of 2001 Re-authorization.

This post is dedicated to my shining light.

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One thought on “Eteplirsen: The End to Duchenne Muscular Dystrophy?

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