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Monday, June 3, 2024

Delaware ranked worst in US in hospital patient safety in new Leapfrog report

 Patient safety in Delaware hospitals is once again under scrutiny following the latest report from The Leapfrog Group, a nonprofit that scores hospitals twice a year based on public data and surveys.

As in past years, no Delaware hospitals have earned A's, sinking the First State to the bottom of the overall national rankings. Only five other states and Washington, D.C., failed to earn a single A.

"The fact that we have zero (A's in Delaware) just shows that there needs to be some more improvement," said Katie Stewart, director of Health Care Ratings at Leapfrog. "It starts with a commitment from leadership to put patients first and to make patient safety a priority."

The ambulance entrance at Beebe Healthcare in Lewes May 1, 2024.

The grades come from a comparison of scores across five categories: infections, problems with surgery, safety problems, practices to prevent errors, and doctors, nurses and hospital staff. Each of these is then broken down into individual components.

A lack of A's doesn't mean a lack of improvement, though.

TidalHealth Nanticoke, ChristianaCare's Wilmington Hospital and ChristianaCare's Christiana Hospital all improved from C's to B's in the latest ranking — a change that Stewart said was "really encouraging."

Bayhealth Hospital Sussex Campus maintained its B rating, while Bayhealth Kent Campus and Saint Francis Hospital maintained their C ratings.

ChristianaCare signage and segment of the hospital is featured at Ogletown Stanton Road in Christiana on Thursday, Oct. 12, 2023.

Only Beebe Healthcare saw a lower grade from the previous ratings, dropping from a C to a D.

According to Leapfrog, Beebe performs worse than average when it comes to kidney failure after surgeries, post-surgical complications, bed sores, handwashing, specially trained doctors in the ICU and staff working together to prevent errors.

Beebe Healthcare Senior Vice President and Chief Physician Executive Dr. Paul Sierzenski said that while the hospital "recognize(s) the value of independent surveys and take every opportunity for improvement seriously," it does not feel that Leapfrog's score is reflective of their "commitment, standards, and current performance in patient care and safety."

At the same time, Sierzenski said the hospital is making an effort to improve its Leapfrog score moving forward.

"We are not satisfied with this score and are committed to continuous improvement," Sierzenski said.

Questions, concerns from healthcare organizations

Beebe Healthcare is not the only Delaware organization to question the accuracy of the Leapfrog Hospital Safety Grades.

Delaware Healthcare Association President and CEO Brian Frazee said the organization, on behalf of all member hospitals, "continue(s) to have concerns about Leapfrog's methodology."

DHA has raised similar concerns in previous years, pointing to the vast difference between Leapfrog's sub-par ratings of Delaware's hospitals and those of other groups like U.S. News and World Report, which ranked Delaware's hospital quality as No. 2 in the nation.

https://www.delawareonline.com/story/news/health/2024/06/03/delaware-ranked-worst-us-hospital-patient-safety-leapfrog-report-christianacare-tidalhealth-beebe/73691355007/

Legend Data on Earliest Use to Date of CARVYKTI® in Multiple Myeloma

 

  • First analysis of CARTITUDE-2 Cohort D study investigating CARVYKTI® in multiple myeloma with suboptimal response after front-line ASCT featured in an oral presentation at the 2024 ASCO Annual Meeting show deep and durable responses with one-time infusion of CARVYKTI®
  • Subgroup analysis from the CARTITUDE-4 study in an oral presentation at ASCO shows CARVYKTI® improved PFS vs standard therapy in a functionally high-risk population as early as second line associated with poor clinical outcomes
  • Results of a CARTITUDE-4 subgroup analysis by cytogenetic risk showing the favorable efficacy results of CARVYKTI® across different cytogenetic abnormalities to be released in a poster presentation at the 2024 EHA Congress

ASCO: Sarclisa 1st anti-CD38 to improve progression-free survival in combo for multiple myeloma

 

  • Sarclisa, in combination with standard-of-care bortezomib, lenalidomide and dexamethasone (VRd) followed by Sarclisa-Rd reduced the risk of recurrence or death by 40% versus VRd followed by Rd in the investigational use for transplant-ineligible newly diagnosed multiple myeloma patients
  • Key primary endpoint of progression-free survival met, demonstrating Sarclisa's potential as a first-in-class combination to address gaps in care for newly diagnosed transplant-ineligible patients
  • Full data simultaneously published in NEJM and formed the basis of regulatory submissions

'Chicken and Egg Problem of Fighting Another Flu Pandemic'

 Even a peep of news about a new flu pandemic is enough to set scientists clucking about eggs.

They worried about them in 2005, and in 2009, and they’re worrying now. That’s because millions of fertilized hen eggs are still the main ingredient in making vaccines that, hopefully, will protect people against the outbreak of a new flu strain.

“It’s almost comical to be using a 1940s technology for a 21st-century pandemic,” said Rick Bright, who led the Health and Human Services Department’s Biomedical Advanced Research and Development Authority (BARDA) during the Trump administration.

It’s not so funny, he said, when the currently stockpiled formulation against the H5N1 bird flu virus requires two shots and a whopping 90 micrograms of antigen, yet provides just middling immunity. “For the U.S. alone, it would take hens laying 900,000 eggs every single day for nine months,” Bright said.

And that’s only if the chickens don’t get infected.

The spread of an avian flu virus has decimated flocks of birds (and killed barn cats and other mammals). Cattle in at least nine states and at least three people in the U.S. have been infected, enough to bring public health attention once again to the potential for a global pandemic.

As of May 30, the only confirmed human cases of infection were dairy workers in Texas and Michigan, who experienced eye irritation. Two quickly recovered, while the third developed respiratory symptoms and was being treated with an antiviral drug at home. The virus’s spread into multiple species over a vast geographic area, however, raises the threat that further mutations could create a virus that spreads from human to human through airborne transmission.

If they do, prevention starts with the egg.

To make raw material for an influenza vaccine, virus is grown in millions of fertilized eggs. Sometimes it doesn’t grow well, or it mutates to a degree that the vaccine product stimulates antibodies that don’t neutralize the virus — or the wild virus mutates to an extent that the vaccine doesn’t work against it. And there’s always the frightening prospect that wild birds could carry the virus into the henhouses needed in vaccine production.

“Once those roosters and hens go down, you have no vaccine,” Bright said.

Since 2009, when an H1N1 swine flu pandemic swept around the world before vaccine production could get off the ground, researchers and governments have been looking for alternatives. Billions of dollars have been invested into vaccines produced in mammalian and insect cell lines that don’t pose the same risks as egg-based shots.

“Everyone knows the cell-based vaccines are better, more immunogenic, and offer better production,” said Amesh Adalja, an infectious disease specialist at Johns Hopkins University’s Center for Health Security. “But they are handicapped because of the clout of egg-based manufacturing.”

The companies that make the cell-based influenza vaccines, CSL Seqirus and Sanofi, also have billions invested in egg-based production lines that they aren’t eager to replace. And it’s hard to blame them, said Nicole Lurie, HHS’ assistant secretary for preparedness and response under President Barack Obama who is now an executive director of CEPI, the global epidemic-fighting nonprofit.

“Most vaccine companies that responded to an epidemic — Ebola, Zika, covid — ended up losing a lot of money on it,” Lurie said.

Exceptions were the mRNA vaccines created for covid, although even Pfizer and Moderna have had to destroy hundreds of millions of doses of unwanted vaccine as public interest waned.

Pfizer and Moderna are testing seasonal influenza vaccines made with mRNA, and the government is soliciting bids for mRNA pandemic flu vaccines, said David Boucher, director of infectious disease preparedness at HHS’ Administration for Strategic Preparedness and Response.

Bright, whose agency invested a billion dollars in a cell-based flu vaccine factory in Holly Springs, North Carolina, said there’s “no way in hell we can fight an H5N1 pandemic with an egg-based vaccine.” But for now, there’s little choice.

BARDA has stockpiled hundreds of thousands of doses of an H5N1-strain vaccine that stimulates the creation of antibodies that appear to neutralize the virus now circulating. It could produce millions more doses of the vaccine within weeks and up to 100 million doses in five months, Boucher told KFF Health News.

But the vaccines currently in the national stockpile are not a perfect match for the strain in question. Even with two shots containing six times as much vaccine substance as typical flu shots, the stockpiled vaccines were only partly effective against strains of the virus that circulated when those vaccines were made, Adalja said.

However, BARDA is currently supporting two clinical trials with a candidate vaccine virus that “is a good match for what we’ve found in cows,” Boucher said.

Flu vaccine makers are just starting to prepare this fall’s shots but, eventually, the federal government could request production be switched to a pandemic-targeted strain.

“We don’t have the capacity to do both,” Adalja said.

For now, ASPR has a stockpile of bulk pandemic vaccine and has identified manufacturing sites where 4.8 million doses could be bottled and finished without stopping production of seasonal flu vaccine, ASPR chief Dawn O’Connell said on May 22. U.S. officials began trying to diversify away from egg-based vaccines in 2005, when avian flu first gripped the world, and with added vigor after the 2009 fiasco. But “with the resources we have available, we get the best bang for our buck and best value to U.S. taxpayers when we leverage the seasonal infrastructure, and that’s still mostly egg-based,” Boucher said.

Flu vaccine companies “have a system that works well right now to accomplish their objectives in manufacturing the seasonal vaccine,” he said. And without a financial incentive, “we are going to be here with eggs for a while, I think.”

https://kffhealthnews.org/news/article/bird-flu-potential-pandemic-vaccine-chicken-egg-quandary/

Prenatal exposure to high doses of anti-seizure drugs may influence executive function

 No differences in creativity emerged between children whose mothers had epilepsy and other children, new MONEAD cohort data showed.

Scores on the Torrance Test of Creative Thinking-Figural (TTCT-F) creativity index (difference of -3.2 points, 95% -9.0 to 2.7, P=0.286) and associations with fetal exposure to anti-seizure medications (difference of -2.6 points, 95% -11.0 to 5.7, P=0.530) showed no difference between children of women with epilepsy at age 4.5 years and children of healthy women, reported Kimford Meador, MD, of Stanford University in Palo Alto, California, and co-authors in Neurologyopens in a new tab or window.

On the parent-completed Behavior Rating Inventory of Executive Function -- Preschool Version (BRIEF-P) rating scale, however, children of women with epilepsy showed exposure-dependent effects in executive function (P=0.001), which were most pronounced in children of women taking levetiracetam (P=0.004).

"The main finding of no difference in creativity between children of healthy mothers and children of women with epilepsy is consistent with the finding that the large majority of women on the newer antiseizure medications -- lamotrigine and levetiracetam -- have normal pregnancies and children," Meador told MedPage Today. "Unfortunately, there are still many antiseizure medications for which we don't know the risk to the fetus."

Prior research showed that prenatal exposure to valproate -- which carries a boxed warningopens in a new tab or window about fetal malformations and decreased IQ -- impaired creative fluencyopens in a new tab or window and originality when children were age 4.5 years. In 2011, the FDA issued a safety communicationopens in a new tab or window stating that women of childbearing age treated with valproate should use effective birth control.

Growing evidence points to topiramate exposureopens in a new tab or window as also having an increased risk of adverse neurodevelopmental outcomes, observed Eliza Honybun, MPsych, and Piero Perucca, MD, PhD, both of the University of Melbourne in Australia, in an accompanying editorialopens in a new tab or window. "For valproate and topiramate, these adverse effects seem to be dose-dependent, with higher doses being associated with poorer outcomes," they said.

"Of note, previous analyses of the MONEADopens in a new tab or window cohort had found higher third-trimester blood concentrations of levetiracetam to be associated with poorer cognitive outcomesopens in a new tab or window at age 3 years and worse adaptive functioningopens in a new tab or window at 4.5 years," Honybun and Perucca wrote.

"A recent population-based study across five Nordic countries also suggested an association between prenatal exposure to levetiracetam and increased risks of anxiety and ADHD [attention deficit-hyperactivity disorder] in children and adolescents," the editorialists added. "Thus, it seems that even levetiracetam, an antiseizure medication widely regarded as one of the safest when used in pregnancy, can affect postnatal neurodevelopment, at least at higher doses."

Meador and colleagues studied 251 children of women with epilepsy and 73 children of healthy women. Among women with epilepsy, the most prevalent third-trimester antiseizure drug regimen was monotherapy (72.5%), followed by polytherapy (21.9%). About 5% were not on antiseizure treatment.

Lamotrigine and levetiracetam were the most common monotherapies (44.5% and 37.4% of all monotherapies, respectively). Lamotrigine combined with levetiracetam was the most common polytherapy (41.8% of all polytherapies).

The primary outcome for children age 4.5 years was the TTCT-F creativity index. TTCT-F scores are normalized; a score of 100 is the mean for the norms and the standard deviation is 20, Meador noted. Secondary outcomes included scores on the BRIEF-P, an assessment completed by the child's parent.

On the TTCT-F creativity index, adjusted mean scores were 90.5 points (95% CI 87.8–93.2) for children of women with epilepsy and 93.7 points (95% CI 88.6–98.8) for children of healthy women. A second primary analysis found no significant relationship between TTCT-F creativity scores and in utero third-trimester blood concentrations of antiseizure drugs.

On the BRIEF-P, worse scores emerged with increasing third-trimester antiseizure medication exposure. Higher blood concentrations of levetiracetam were associated with worse performance on the BRIEF-P global executive composite score, inhibitory self-control index, and emergent metacognition index.

Lamotrigine monotherapy showed no exposure-dependent effects on the BRIEF-P, but higher concentrations of lamotrigine combined with levetiracetam were associated with poorer performance on the flexibility index and the emergent metacognition index. Samples sizes for other drugs were too small to assess individually.

"Our findings highlight that even for epilepsy medications that are generally considered to be safe in pregnancy, dose adjustments should be made with a goal of reaching an optimal balance between controlling seizures and minimizing negative effects on the developing child," Meador said.

MONEAD participants were recruited from tertiary centers and results may not apply to all epilepsy patients, the researchers acknowledged. Selection bias may have been present, and unmeasured confounding may have influenced outcomes.


Disclosures

The study was supported by the NIH's National Institute of Neurological Disorders and Stroke.

Meador reported relationships with NIH, Eisai, Medtronic, the Epilepsy Study Consortium, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

Co-authors reported relationships with nonprofit organizations and pharmaceutical companies.

Honybun reported support from the Australian Government Research Training Program. Perucca reported relationships with Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma.

Primary Source

Neurology

Source Reference: opens in a new tab or windowMeador KJ, et al "Association of prenatal exposure to antiseizure medications with creative and executive function at age 4.5 years" Neurology 2024; DOI: 10.1212/WNL.0000000000209448.

Secondary Source

Neurology

Source Reference: opens in a new tab or windowHonybun E, Perucca P "Adverse neurodevelopmental outcomes after in utero exposure to antiseizure medications: an ever-expanding story" Neurology 2024; DOI: 10.1212/WNL.0000000000209553.


https://www.medpagetoday.com/neurology/seizures/110444

Newborn Screening for Duchenne Muscular Dystrophy

 The X-linked neuromuscular disorder Duchenne muscular dystrophy (DMD), which historically has been diagnosed in boys between the ages of 3 and 6 years, has become an important candidate for newborn screening.

"Early diagnosis of DMD is critical," said Stephen Chrzanowski, MD, PhD, of Boston Children's Hospital.

"As a rare disease, families unfortunately often face a tortuous and confusing diagnostic odyssey to identify DMD, long after injury and damage has occurred to muscle, or siblings may have also been born with DMD," Chrzanowski pointed out. "Additionally, mothers who are carriers for DMD may also be affected, requiring their own monitoring and care."

Despite improved screening diagnostic techniques and new treatment options, DMD is rarely screened for at birth, Chrzanowski noted.

The creatine kinase-MMopens in a new tab or window (CK-MM)–specific assay has been approved by the FDA, and DMD should be considered for the Recommended Uniform Screening Panelopens in a new tab or window (RUSP) for newborn screening, he added.

DMD has a prevalence of less than 10 cases per 100,000 males. It is very rare in girls, occurring in less than one case per 1 million females.

DMD is caused by variants of the DMD gene located on the X chromosome; mutations in the geneopens in a new tab or window prevent the production of dystrophin.

"With the concurrence of novel therapies and FDA-approved screening techniques, we are at an opportune time to recommend and implement newborn screening for DMD on a national level," Chrzanowski said.

New DMD Treatments

Since 2016, four exon-skipping antisense oligonucleotides received accelerated FDA approval, based on the surrogate endpoint of increased dystrophin production: eteplirsenopens in a new tab or window (Exondys 51), viltolarsenopens in a new tab or window (Viltepso), golodirsenopens in a new tab or window (Vyondys 53), and casimersenopens in a new tab or window (Amondys 45).

A novel corticosteroid vamoroloneopens in a new tab or window (Agamree) was approved in 2023, and the histone deacetylase (HDAC) inhibitor givinostatopens in a new tab or window (Duvyzat) was approved in 2024. The first gene therapy, delandistrogene moxeparvovecopens in a new tab or window (Elevidys), received accelerated approval in 2023, and another gene therapy, fordadistrogene movaparvovecopens in a new tab or window (PF-06939926), is being evaluated in a phase III clinical trial.

The four exon-skipping drugs are "collectively applicable to approximately 30% of the DMD population owing to their variant-specific mechanisms of action," Chrzanowski and co-authors wrote in a JAMA Neurologyopens in a new tab or window viewpoint article.

"Intuitively, earlier treatment and diagnosis may lead to improved long-term outcomes, though a paucity of data to support this exists, as we have not had the opportunity to perform newborn screening until recently," Chrzanowski said.

Newborn Screening Panels

The RUSP is a list of disorders that HHS recommends for states to screen as part of their universal newborn screening programs. A condition must be nominated, then reviewed by the advisory committee on Heritable Disorders in Newborns and Children. DMD was nominatedopens in a new tab or window for the RUSP in 2023.

The RUSP provides recommendations for implementation but specifics, including cut-offs, may vary by state, Chrzanowski pointed out.

"For example, different states utilize different multi-tiered approaches, using an initial cost-effective and sensitive screening assay for creatine-kinase followed by genetic testing," he said. "To address this, we need more data to provide more quantitative and data-driven recommendations for states to implement their own newborn screening guidelines."

Two recent studies showed the feasibility of newborn screening. In New Yorkopens in a new tab or window, a 2-year pilot study referred newborns with elevated CK-MM for genetic counseling and testing, including deletion or duplication analysis and next-generation sequencing of the DMD gene, followed by next-generation sequencing for a panel of neuromuscular conditions if no pathogenic variants were found. Of 36,781 newborns screened, 42 (including 25 males) were referred for genetic testing. DMD gene deletions or duplications consistent with DMD or Becker muscular dystrophy were found in four males, and one female DMD carrier was identified.

In North Carolinaopens in a new tab or window, 2 years of newborn screening began with CK-MM, followed by total creatine kinase and next generation sequencing of an 86-neuromuscular gene panel, including the DMD gene, if indicated. Of 13,354 newborns screened, the program identified two males with DMD. Birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improved the sensitivity and specificity of screening.

Potential Obstacles

One potential problem with the CK-MM test is that creatine kinase at birth may be falsely elevated for reasons unrelated to DMD. "It's likely that newborn screening through a screening-CK assay will identify non-DMD conditions without treatment, such as congenital myopathies or limb girdle muscular dystrophies," Chrzanowski noted.

Clear guidelinesopens in a new tab or window are available for how to undergo follow-up confirmatory genetic testing and how and when to inform families of such diagnoses. "Though disease-modifying treatments may not yet be available, providing supportive treatments -- physical and occupational therapy -- and genetic counseling will be valuable to these families," Chrzanowski said.

Another potential challenge is that access to the multidisciplinary care that DMD patients need varies throughout the country. "Newborn screening is the ultimate 'equalizer' to provide equity of care, as DMD is a non-discriminatory disease, affecting all socioeconomic, ethnic, and racial groups," Chrzanowski observed.

Despite potential problems, about 80% of caregivers and 61% of health providers said they see a net benefit to newborn DMD screening in a recent surveyopens in a new tab or window.

"We are at a unique juncture with the emergence of adequate screening techniques and novel therapeutics that may be more efficacious with earlier treatment, making this an opportune time to implement newborn screening for DMD," Chrzanowski said. "Newborn screening will identify pre-symptomatic boys with DMD, allowing for more systemic application of therapy with the hope of better longitudinal clinical outcomes."

Disclosures

Chrzanowski reported no conflicts of interest.


https://www.medpagetoday.com/spotlight/dmd/110453

8 DMD therapies are approved, all since 2016

 Eight therapies are approved for Duchenne muscular dystrophy (DMD) in the U.S., and all have been approved since 2016.

"It took 30 years from the discovery of the gene associated with Duchenne muscular dystrophy in 1986 to arrive at the first FDA approval of a therapy for this devastating disease," noted Peter Kang, MD, of the University of Minnesota in Minneapolis, in a recent editorialopens in a new tab or window.

Now, we're in an era that would have been inconceivable a few years ago, Kang said: "U.S. FDA approvals for DMD have become a regular occurrence."

Treatment Landscape

The eight approved therapies -- corticosteroids, a nonsteroidal anti-inflammatory drug, exon-skipping anti-sense oligonucleotides, and an adenovirus-associated virus (AAV)-based gene therapy -- affect the heterogeneous pathology of DMD from different angles.

The DMD treatment landscape is ultimately defined by the disease, which is X-linked and historically diagnosed in boys ages 3 to 6 years. Functional defects of visceral and vascular smooth muscle, heart muscle, and brain/nerves -- in addition to skeletal muscle -- underlie multi-systemic involvement over time. DMD typically progresses to wheelchair use when patients are in their teens and premature death when they are in their 30s or 40s, often due to respiratory and particularly heart involvement.

Two approaches to treatment are 1) slowing decline by reducing harmful inflammation and immune activation with corticosteroids or anti-inflammatory drugs and 2) increasing production of functional dystrophinopens in a new tab or window through exon-skipping drugs or gene therapy.

Of note, exon-skipping oligonucleotides and gene therapy in DMD have been approved under the FDA's accelerated approvalopens in a new tab or window program, using a surrogate marker instead of clinical benefit as an endpoint. Each approval was based on trials that showed small increases in patients' dystrophin levels, which the agency said was reasonably likely to predict clinical benefit. Confirmatory trials are required, and if those trials do not show clinical benefit, the FDA has regulatory procedures in place that could lead to removing a treatment from the market.

Anti-Inflammatory Treatments

The standard of care for DMD is glucocorticoid treatmentopens in a new tab or window, with prednisone and prednisolone sometimes used off-label.

"Corticosteroids have been a first-line treatment for DMD for many years, but their utility has always been limited by the side effect profile, which includes weight gain, short stature, and decreased bone density, among others," said Sharon Hesterlee, PhD, chief research officer of the Muscular Dystrophy Association.

In 2017, the FDA approved the corticosteroid deflazacortopens in a new tab or window (Emflaza), based on a phase III trialopens in a new tab or window showing that the treatment led to improvements in muscle strength compared with placebo at 12 weeks in boys with DMD, though by 52 weeks the benefit was no longer evident. In 2022, the FOR-DMDopens in a new tab or window trial showed prednisone or deflazacort given every day was superior to prednisone on a 10-days-on, 10-days-off schedule for boys with DMD.

In 2023, vamoroloneopens in a new tab or window (Agamree), a dissociative steroid, received FDA approval, after showing similar efficacy to traditional corticosteroids in treating DMD with fewer negative downstream effects. A 30-month assessmentopens in a new tab or window of boys with DMD showed vamorolone was associated with maintained muscle strength and function up to 30 months and improved height velocity.

The histone deacetylase inhibitor givinostatopens in a new tab or window (Duvyzat) became the first nonsteroidal anti-inflammatory drug approved for DMD in 2024. In its pivotal trialopens in a new tab or window, givinostat slowed physical decline, measured by stair-climbing speed, for a subset of boys with DMD.

Exon-Skipping Antisense Oligonucleotides

DMD is caused by mutations in the DMD geneopens in a new tab or window that prevent the production of the muscle isoform of dystrophin.

The large DMD gene has 79 exonsopens in a new tab or window. For DMD patients with suitable mutations, exon skipping is one way to convert out-of-frame mRNA translation to a properly aligned reading frame.

Oligonucleotides specific for a targeted mRNA exon bind to it, preventing translation of a given region. Adjacent exons are translated and spliced into variably functional dystrophin.

Since 2016, four exon-skipping drugs have received accelerated approval for DMD: eteplirsenopens in a new tab or window (Exondys 51; exon-skipping 51), golodirsenopens in a new tab or window (Vyondys 53; exon-skipping 53), viltolarsenopens in a new tab or window (Viltepso; also exon-skipping 53), and casimersenopens in a new tab or window (Amondys; exon-skipping 45).

The controversial eteplirsen approval was based on trial data showing the treatment boosted dystrophin productionopens in a new tab or window and improved functional ability compared with historical controls. In granting approval, the FDA overruled its advisory committeeopens in a new tab or window, which voted 7-6 that eteplirsen failed to meet the minimum standards for accelerated approval. In 2022, an open-label phase III studyopens in a new tab or window showed eteplirsen-treated patients showed increased exon skipping and dystrophin protein versus baseline.

Confirmatory trials for three of the DMD antisense oligonucleotides -- eteplirsen, golodirsen, and casimersen -- have been delayed and remain incomplete. In May 2024, preliminary data from drugmaker NS Pharma showed that viltolarsen failedopens in a new tab or window the phase III RACER53 trial.

Gene Therapy

Also controversial was the 2023 accelerated approval of delandistrogene moxeparvovecopens in a new tab or window (Elevidys), the first gene therapy for DMD. The treatment delivers a gene that codes for a novel engineered protein called microdystrophin. It was approved for ambulatory DMD pediatric patients ages 4 to 5 years.

The FDA's advisors narrowly supportedopens in a new tab or window delandistrogene moxeparvovec in an 8-6 vote, but in briefing documentsopens in a new tab or window submitted before the advisory committee meeting, FDA reviewers said that no epidemiologic or pathophysiologic evidence of microdystrophin's function existed.

In October 2023, Sarepta Therapeutics announced the EMBARK phase III confirmatory trial of delandistrogene moxeparvovec missed its primary endpointopens in a new tab or window, though some secondary measures suggested improvement.

The FDA is considering whether to convert accelerated approval for delandistrogene moxeparvovec to traditional approvalopens in a new tab or window, and whether to expand the treatment's indication by removing age and ambulation restrictions. The agency's review goal date is June 21.

Disclosures

Kang reported relationships with Lupin Pharmaceuticals, Neurogene, NS Pharma, TeneoFour, France Foundation, PeerVoice, Edgewise Therapeutics, ML Bio Solutions, and Sarepta Therapeutics.


https://www.medpagetoday.com/spotlight/dmd/110454