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Rare Disease

Help For Boys With Duchenne Muscular Dystrophy

The pipeline of drugs to treat the rare disease is starting to flow

by Lisa M. Jarvis
July 21, 2014 | A version of this story appeared in Volume 92, Issue 29

Photo shows a group of boys at Parent Project Muscular Dystrophy’s 2013 annual conference
Credit: PPMD
Boys showing off their strength at last year’s PPMD meeting.

Lately, staffers at the advocacy group Parent Project Muscular Dystrophy have been fielding a flurry of phone calls from parents asking for help in making a difficult decision for their children.

Two similar treatments for a subset of patients with Duchenne muscular dystrophy, a rare and fatal degenerative disease that affects boys, are suddenly much closer to approval than the DMD community had expected. More clinical studies of the drugs—one each from the biotech firms Sarepta Therapeutics and Prosensa Therapeutics—are opening up, and there’s a real possibility that one or both of the treatments could be on the market next year.

Deciding which treatment to try—a choice that PPMD, the advocacy group, can’t make—is agonizing. Parents worry that if they pick the wrong drug, the window for their son to benefit from treatment will close. Moreover, scant data exist to guide them.

But it’s a choice nonetheless, and one that 20 years ago would have been unimaginable. Thanks largely to funds from patient groups, DMD has gone over the past two decades from a disease with no treatments on the horizon to one with a growing pipeline of drugs that use multiple therapeutic approaches. None of the treatments is a magic bullet, but parents hope to one day have enough options that a combination of drugs could make the disease something their boys grow old with rather than die from.


Designing Better DMD Trials


Two treatments for Duchenne muscular dystrophy, a rare neuromuscular disease affecting boys, are finally nearing the finish line. The biotech firms Sarepta Therapeutics and Prosensa Therapeutics are expected to soon ask the Food & Drug Administration to approve eteplirsen and drisapersen, which could become the first disease-modifying DMD treatments to reach patients in the U.S.

The drugs’ journey to this point has been rocky, in no small part because of an evolving picture of how DMD progresses. Without solid information about how the disease advances in boys without treatment, it’s hard to know whether a drug candidate is helping.

Now, researchers are working to build their knowledge base for faster and smarter studies on the next wave of drug candidates. Last month, the DMD community handed FDA a lengthy draft guidance document outlining how to design better clinical trials using a wider variety of tests than the agency currently accepts.

With many drugs on the brink of Phase I and II clinical studies, smarter trials are critical. Because the patient population is limited and money is tight—many of the early trials are funded in part by patient organizations—a poorly designed trial could torpedo a reasonably effective drug.

Despite decades of work on DMD, researchers had until recently been hampered by a lack of up-to-date natural history studies—longitudinal studies that collect detailed data on how a disease progresses. In the case of DMD, that means collecting both physiological data—for example, the age at which a boy loses the ability to walk or needs a ventilator to breathe—and understanding changes over time in measurements, such as how far a boy can walk in six minutes.

Those data not only help clinicians understand whether and how effectively a drug is working but also help them enroll the right patients. For example, a boy who is on the brink of losing his ability to walk would not be a good candidate for a study that uses a walk test as the primary end point.

Although natural history data have always existed for DMD, the disease’s progression had changed since those studies were conducted, says Sharon Hesterlee, vice president of research for Parent Project Muscular Dystrophy (PPMD), a patient advocate group. “Care considerations,” or accepted practices for diagnosis and treatment of DMD, were released in 2009, and steroids swiftly became the gold standard for treatment. That change enabled most boys with DMD to gain two more years of walking time.

Prosensa, which has one of the most advanced DMD drugs in development, recently completed enrollment for a natural history study of 269 boys, according to Hans Schikan, the firm’s chief executive officer. Already, he notes, that study and others started in the past four years have substantially improved the understanding of how the disease progresses.

For example, researchers now know that even if a boy at a certain age can walk 300 meters in the six-minute walk test, he is still likely to lose ambulation soon thereafter. In retrospect, Schikan says, that knowledge would have prompted Prosensa to raise the selection criteria—set at just 75 meters—for its Phase III study of drisapersen.

Similarly, researchers have in recent years demonstrated that muscle tissue in boys with DMD is extremely heterogeneous. That means a biopsy of one area to show whether, for example, an exon-skipping drug is restoring dystrophin—a protein critical to maintaining muscle strength that is not produced in boys with DMD—is an unreliable measure. Not only are biopsies unpleasant for the boys, but they “really give you a very misleading picture,” the University of Pennsylvania’s H. Lee Sweeney told the audience at PPMD’s annual meeting, held in Chicago last month.

Sweeney is exploring whether magnetic resonance imaging could become a noninvasive way to select the right patients for clinical studies. At the conference, he discussed an observational study of 129 boys and 28 controls in which regular MRIs were taken using carefully standardized methods of data collection. Researchers could see over time the rate at which muscle in boys with DMD is replaced by fat and fibrosis and could correlate that information to their performance on a six-minute walk test.

The goal was to determine whether MRI could be used to understand when a boy’s ability to walk is still improving, has reached a plateau, or—most important from a clinical trial perspective—is on the decline. Sweeney showed that a boy’s starting walking distance on the six-minute walk test was not a good predictor, but once his quadriceps reached a certain ratio of muscle to fat, as measured by MRI, he was likely to stop walking within a year.

Experts say MRI is impractical for clinical studies: It’s too expensive, and the expertise and equipment needed to appropriately capture and interpret the data are rare. But it could become a way to pick the right patients and get a quick and early read on whether a drug is having an effect.

Other new measures are coming along more quickly. Pfizer, for example, will use a four-stair climb test rather than the six-minute walk test in its Phase II study of PF-06252616, a myostatin inhibitor that works by rebuilding muscle fiber. Michael Binks, vice president of clinical research for Pfizer’s rare disease unit, notes that the measure seemed to have less variability than some of the others and that the literature includes good data on the way that steroids affect a boy’s performance on the test.

The goal in all these efforts is to have the right measure for the right subset of patients so that researchers can quickly and confidently understand whether a drug is working or not. “I’m convinced that 10 years from now, we will have different end points for various stages of the disease,” Schikan says.

DMD is caused by mutations in the gene carrying the recipe for dystrophin, a large protein critical to maintaining the strength of both skeletal and heart muscle. Each of those mutations is responsible for deleting a section of the recipe, preventing the proper protein from being made.

Without dystrophin, the muscles of boys with DMD deteriorate over time. Although the boys are treated with large doses of steroids to help maintain muscle mass, by their early teens, most of them are in wheelchairs. By their mid-20s to early 30s, most are dead.

The most-advanced drugs aim to assemble a functional dystrophin. Sarepta’s eteplirsen and Prosensa’s drisapersen use antisense technology to direct RNA to skip over the exon, or gene segment, that was deleted from the recipe, enabling the rest of the protein to be made, albeit in a shortened form. Both drugs are oligonucleotides that help form a patch over exon 51, a mutation responsible for roughly 13% of DMD cases.

Although Sarepta has tested its drug in just 12 boys, and Prosensa’s drug failed to show efficacy in a Phase III study, the Food & Drug Administration unexpectedly is allowing the companies to file for approval based on those data. But there’s a catch: The companies must conduct other studies that, if negative, could result in approval being revoked.

PTC Therapeutics, meanwhile, has won conditional approval in Europe—and is starting a Phase III study for U.S. authorities—for ataluren, a small molecule addressing the 10–15% of DMD patients with a “nonsense” mutation that causes protein production to stop before completion. Ataluren purports to allow RNA to read through the mutation to build the protein.

But the exon-skipping and read-through drugs aren’t a panacea. So far, the best-case scenario is that they stop disease progression in some boys and slow it down in others. Moreover, only a fraction of the DMD population can benefit from these approaches. For some of the rarest mutations, drugs will likely never be developed.

The exon-skipping drugs are exciting and are capturing most of the spotlight, “but I always like to remind people that there are some downstream drugs that might have just as powerful effects,” says Sharon Hesterlee, PPMD’s vice president of research. The next wave of treatments could improve life for boys with DMD and in some cases bolster the efficacy of the dystrophin-building drugs.

Treatments fall into three general buckets: Disease-modifying drugs look to restore functionality either by reconstituting dystrophin—like the exon-skipping drugs from Sarepta and Prosensa—or by turning up the production of other proteins that could do the same job as dystrophin. Other treatments try to grow or strengthen muscle fiber to enable boys to walk, run, and live longer. Last are treatments that seek to improve upon the current standard of care, steroids, to reduce the inflammation and fibrosis that are hallmarks of the disease.

Several drugs are being developed to usher in substitutes for dystrophin. The most advanced is from Summit, a British biotech firm founded after geneticist Kay Davies discovered similarities between dystrophin and utrophin, a protein critical in fetal and early muscle development. At some point early in life, utrophin production is down-regulated as dystrophin is turned up, yet researchers found they are equally good at maintaining muscle strength.

Researchers in Davies’s group identified a utrophin promoter that was specific to muscle fiber, a finding that laid the groundwork for Summit’s drug discovery efforts, according to Summit’s head of R&D, Jon Tinsley, who was working in Davies’s lab at the time.

A cell-based utrophin A promoter assay allowed Summit to screen for small molecules that turn utrophin production back up. After generating analogs from hits out of that screen, Summit struck upon SMT C1100, which it has since taken into human studies.

Because SMT C1100 is fairly insoluble, Summit had a hard time in a first Phase I trial getting enough of it into the muscles of boys with DMD. The company knows that a fatty diet improves absorption of the molecule. In its next Phase I study, Summit will explore an oral suspension that mimics the effects of a fatty meal and, it expects, enhances absorption.

Tivorsan Pharmaceuticals, a Providence, R.I., start-up based on technology developed at Brown University, is taking a different route to increasing utrophin in muscle fiber. The biotech firm wants to deliver a recombinant form of biglycan, an extracellular protein that regulates both utrophin and components of the protein complex in which utrophin sits. That complex is thought to be essential to maintaining muscle integrity.

“With proteins, as in real estate, it’s all about location,” Justin Fallon, a Brown University neurobiologist and Tivorsan cofounder, told the audience at PPMD’s annual meeting, held last month in Chicago. “It’s necessary to have the protein made, for sure, but you also need to have it in the right complex.”

Tivorsan is now finishing manufacturing optimization of its recombinant biglycan. “We want to get the boys something we understand fully, is well characterized, and works,” Fallon said. The firm is conducting the final studies to allow the start of human tests and hopes to begin Phase I clinical trials in 2015.

While some researchers seek to reconstitute the components of muscle fiber, others are trying to bolster existing muscle mass with the hope of allowing boys to be mobile longer. The big pharma firms Pfizer and Bristol-Myers Squibb are both developing antibodies that block myostatin, a protein that keeps muscle cells from growing. Scientists have shown that inhibiting myostatin in healthy dogs improves their racing performance; it also slows down disease progression in golden retrievers with a canine form of DMD.

By the end of the year, Pfizer expects to start a Phase II study on PF-06252616 in six- to 10-year-old boys who can walk and have been taking steroids, according to Michael Binks, vice president of clinical research for Pfizer’s rare disease unit.

In May, Bristol-Myers Squibb initiated a Phase I study of its myostatin inhibitor, BMS-986089. That trial will look at the drug’s safety in healthy adults, but the company says it will pursue its use in DMD as part of a broader plan to develop an early-stage pipeline in genetically defined diseases.

The muscle-building approach isn’t new: In 2005, Wyeth, which was later acquired by Pfizer, initiated early-stage studies of the antibody MYO-029 in types of muscular dystrophy that surface in adulthood. But that drug didn’t prove effective and had safety issues. PF-06252616 binds to fewer off-target proteins than MYO-029 did, Binks says, a feature that should help it avoid the safety worries of earlier programs.

Researchers say the antibodies could work synergistically with exon-skipping drugs. That’s because new muscle generated by inhibiting myostatin will still lack dystrophin and thus could benefit from the gene-correcting therapies. And it will work the other way, PPMD’s Hesterlee points out. “You can only skip exons where you have muscle tissue,” she says.

The third leg of the strategy to turn DMD into a livable disease is devising better drugs to address the associated inflammation and fibrosis. Currently, boys take a regimen of steroids that, although it extends the time they’re able to walk and improves their breathing, weakens their bones, stunts their growth, and causes weight gain.

“When you add up the benefit and the side effects, you get the overall benefit, but it could be better,” says Eric Hoffman, director of the Center for Genetic Medicine Research at Children’s National Medical Center in Washington, D.C.

Hoffman is a founder of ReveraGen, which is developing a glucosteroid analog code-named VBP15. The company recently secured funding from advocacy groups to start enrollment in a Phase I study in October. It plans to begin Phase II studies just six months later in boys with DMD between the ages of four and seven, Hoffman says.

Akashi Therapeutics, which in June changed its name from Halo Therapeutics, is also working on a drug, HT-100, that addresses inflammation and fibrosis. Derived from a Chinese herb, HT-100 was discovered during World War II as part of the U.S. military’s quest for antimalarials. After a scientist in Israel showed the drug’s powerful antifibrotic effect in the mouse model of DMD, Halo, a biotech firm founded in 2011 by patient advocacy groups, acquired it.

As with the muscle growth treatments, researchers hope HT-100 will enhance the performance of disease-modifying drugs. With DMD, the ability to get enough drug to muscle fiber is a constant challenge. Fibrosis “creates a physical barrier for the vasculature,” says Marc B. Blau­stein, Akashi’s CEO. By lowering that barrier, you provide a better environment for muscle repair and regeneration and make it easier for the exon-skipping or utrophin-modulating drugs to reach their target.

In addition to novel therapies, several approved drugs could also prove valuable in treating DMD. The most prominent example is Eli Lilly & Co.’s tadalafil, marketed as Cialis for erectile dysfunction. Tadalafil is now in a 300-person, Phase III trial testing whether increasing blood flow can help preserve the boys’ muscles. If successful, the new indication would add extra life to the Cialis patent, which is set to expire in the U.S. in 2017.

As the next crop of treatments winds its way through the pipeline, chances are high that more families will soon be grappling with tough choices over which clinical studies to enroll their sons in. Already, the DMD community is bracing itself for the highs and lows inherent in drug development. “We’ve had a lot of wins lately, and people are feeling good about it,” Hesterlee says. “People are tired, but many now recognize that it’s a slog.”

Table shows some of the DMD therapies in clinical development.


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