NEW YORK – In a bid to improve the screening, and potentially treatment, of newborns with Duchenne muscular dystrophy (DMD), a coalition of stakeholders have embarked on a pilot study that if successful could beckon the routine screening of all babies in the US for the condition.
Additionally, data from the project could help in the development of new DMD drugs specifically for newborns.
Screening for the pilot project started this past fall, and as of late January about 3,745 infants were screened at the Wadsworth Center, New York's public health laboratory. One baby was screened as being positive for the condition, NYSDOH said.
Initially announced in late 2018 by the New York State Department of Health, the two-year project aims to gather data from about 100,000 infants. Parent Project Muscular Dystrophy (PPMD) and a consortia of biotechnology companies are providing $2.5 million to the project.
Formed in 1994, PPMD is a nonprofit based in Hackensack, New Jersey that advocates for DMD patients and invests in research into the disease and treatments. Representatives from the organization were not available for comment, a spokesperson said in an email.
Participating in the project are two healthcare systems in the New York City area: Northwell Health — which includes Long Island Jewish Medical Center; North Shore University Hospital; Maimonides Medical Center; Lenox Hill Hospital; Staten Island University Hospital, and Southside Hospital — and New York Presbyterian Hospitals, which includes Weill Cornell Medical Center; Columbia University Medical Center; Lower Manhattan Hospital; NY Presbyterian Queens; and Allen Hospital.
PerkinElmer is providing its screening assay, the GSP Neonatal Creatine Kinase-MM kit — which was authorized by the US Food and Drug Administration in December for marketing — to the effort.
Typically, DMD is a genetic disorder that primarily afflicts boys and is characterized by progressive muscle degeneration. Symptoms don't appear until the patient is about two years old, and a diagnosis isn't made until the patient is about 5 or 6 years old. DMD is the most common X-linked neuromuscular disorder, affecting approximately 1 in every 5,000 boys, according to NYSDOH.
There is no cure for the disease, and patients become wheelchair-bound eventually. While DMD patients in the past often did not live past their teens, more recent therapies have extended life expectancies of individuals with the condition into their 30s.
A primary goal of the pilot project is to determine whether screening can and should be universally performed on all newborns. PerkinElmer's test, according to the firm, is the first commercially available test for screening newborns for DMD, a genetic disorder that causes progressive muscle deterioration and weakness.
The assay leverages PerkinElmer's DELFIA technology to measure a specific isoform of creatine kinase, the MM form (CK-MM), which is a biomarker for muscle degradation, said Petra Furu, general manager of reproductive health for the Waltham, Massachusetts-based company. Short for dissociation-enhanced lanthanide fluorescence immunoassay, DELFIA is a time-resolved fluorescence intensity method that enables the development of highly sensitive assays. "You can actually detect quite low quantities [of a biomarker] compared to, for example, a typical fluorescence assay," with DELFIA, she said.
Developed in collaboration with University Hospital of Wales in the UK, the GSP Neonatal Creatine Kinase-MM is a solid-phase, two-site fluoroimmunometric assay that uses a 96-well plate format to detect CK-MM in whole blood, "and then we have a second antibody that ties to that protein, which is connected to a fluorophore, when is then detected by the instrument that is measuring it," Furu said.
According to PerkinElmer, the measuring range for the assay is between 29.2 and 8,000 ng/mL. It has a limit of detection of 2.2 ng/mL based on 720 determinations of low-level samples and a limit of quantitation of 7.9 ng/mL based also on 720 determinations of low-level samples. The technology was shown to be linear from 29.2 ng/mL to 8,620 ng/mL, it added.
Furu acknowledged that CK-MM is not unique to DMD, "but if you look at it from a newborn perspective, there are very few other disorders where there would be severe muscle degradation at birth."
Because the assay is for screening purposes only — blood samples would be taken typically between 36 and 72 hours after birth — if the result suggests a newborn has DMD, follow-up testing would be needed for a diagnosis, including a blood draw to identify whether CK-MM is in the serum. Muscle biopsy, and in some cases, next-generation sequencing of the impacted gene can also be performed, Furu said.
Screening for DMD
While newborn screening for DMD has been done — typically when a newborn's older brother had been previously diagnosed with the condition — using blood spot CK enzyme assays, the method measures the enzyme activity for several isoforms of CK, calling into question their clinical utility.
As a result, newborns are not routinely screened for DMD. One of the goals of the pilot program is to determine whether widescreen screening for the condition is feasible. In an email, NYSDOH said that in addition to conducting the screening and referring infants for diagnostic evaluation, it also will assess outcomes and work with a steering committee "to help prepare for nominating Duchenne muscular dystrophy to the federal Advisory Committee on Heritable Disorders in Newborns and Children."
In launching the pilot program, PPMD sought to build on earlier work by Jerry Mendell in the Ohio State Newborn Screening Pilot, which screened 60,000 babies in that state and identified six children with DMD. PPMD wanted to replicate the study in a state with a high birthrate, it said in a statement.
Beyond the screening goals, the pilot project could result in new drugs being developed for DMD. There is no cure for the disease, which in the past has been treated with corticosteroids to alleviate symptoms. More recently, a handful of newer drugs that target specific genetic mutations for the disease have become available, including Sarepta Therapeutics' Vyondys 53 (golodirsen), an antisense oligonucleotide that received accelerated approval from the US Food and Drug Administration in December 2019 to treat DMD patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 screening. An estimated 8 percent of DMD patients have the mutation, according to the FDA.
Sarepta is part of a consortia of biotech firms that have partnered with PPMD on the pilot program and provided some funding for it. Other consortia members include PTC Therapeutics, Solid Biosciences, Wave Biosciences, and Pfizer.
In 2016, Sarepta also received the go-ahead from the FDA for Exondys 51 (eteplirsen) for treating DMD, but to date, no drug exists specifically for newborns with DMD. In an email, a spokesperson for Sarepta noted that there are no age limits for current DMD treatments, adding that a Centers for Disease Control and Prevention population-based study found that the mean age for a DMD diagnosis is 5 years of age.
That has not changed in 20 years, despite efforts by a task force to improve early identification of childhood neuromuscular disorders. "This represents an average delay of 2.5 years between detected onset of symptoms and definitive diagnosis," Sarepta spokesperson Tracy Sorrentino said.
Newborn screening for DMD, she added, "could spare families from this long, arduous process, offer them an opportunity to plan, and with many treatments in the pipeline including gene therapies, they may be able to be treated earlier, before their muscles start wasting away."
Though there may not be age restrictions on the current DMD treatments, according to Furu, the "most severe" DMD treatments are meant, in general, for individuals starting at about 5 years of age. One reason for that is because DMD doesn't get diagnosed until patients are about that age. As a result, "there hasn't been a possibility to even do a clinical trial or treat children at a younger age," Furu said.
Outside of the pilot program, PerkinElmer is in the early stages of commercializing the GSP Neonatal Creatine Kinase-MM kit, which is also CE marked. Furu said the price for the assay will depend on the region and the end user, "so, we haven't set any specific targets for that."
Because there hasn't been routine screening for DMD, PerkinElmer is at the forefront of the effort and as the company was developing the assay, its goal was to "build the market gradually, and the New York state pilot screening is part of that program," she said.