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New Drug Miplyffa Approved for Rare Niemann-Pick Disease Type 3

October is Niemann-Pick Awareness Month. FDA approved a treatment for type 3 of the ultra-rare genetic disease September 20. The quest has been ongoing for three decades, said Laurie Turner, Family Services Manager of the National Niemann-Pick Disease Foundation.

Miplyffa (arimoclomol), an oral drug taken three times a day, is prescribed for patients with Niemann-Pick disease type 3, aka NPD3, two years of age and older.

NPD3 typically begins with enlarged liver and spleen and progresses to neurological symptoms. Average length of life is 13 years.

“Impacts on patients and families are enormous,” said Janet Maynard, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine at FDA’s Center for Drug Evaluation and Research. “Despite extensive research efforts, there have not been approved treatments to meet the significant needs of patients. The first-ever approval of a safe and effective drug option will undoubtedly support the essential medical needs of those suffering.”

Miplyffa is the first drug developed to treat NPD3 specifically. It increases the activation of two transcription factors (proteins that affect the expression of specific genes) that control the balance of activities of genes in lysosomes, which are cellular organelles that function somewhat like garbage dumps. The new drug is taken with miglustat, which FDA approved for use in NPD3 in 2009. The original approved was in 2003 to treat a type of Gaucher disease. Miglustat inhibits an enzyme, which slows neurological decline and extends life by preserving essential functions such as swallowing.

But like many new treatments for a rare disease, the price is high. Sky high. Bluebird Bio developed the new drug. The seller, Zevra Therapeutics, is pricing Miplyffa at $40,000 to $106,000 per month, making annual cost from about $600,000 to $1.3 million a year.

Like many rare single-gene diseases, NPD3 is autosomal recessive. It is passed from two parents, each of whom has one copy of the mutation and does not typically have symptoms.

The Rarest of the Rare

NPD3 is exceedingly rare. It affects 1 to 9 people per 100,000, ranging from 1 in 45,000 to 1 in 286,000 in different populations. In the U.S., 900 or so people are living with NPD3. Because of its rarity, the condition isn’t on the Recommended Uniform Screening Panel that tests for genetic diseases on blood samples collected from newborns’ heels. As a result, parents must navigate the “diagnostic odyssey” of making sense of unfolding signs and symptoms, many of which are shared with other conditions.

Severity and age-of-onset vary greatly, complicating diagnosis of NPD3.

The initial enlarged liver and spleen may begin before and soon after birth, or during childhood or even later.

Neurological symptoms can manifest at any time. They progress to involuntary muscle contractions (dystonia), poor muscle tone (hypotonia), poor balance and coordination (cerebellar ataxia), difficulty speaking (dysarthria) and swallowing (dysphagia), and dementia. Psychiatric disturbances are more common in patients whose symptoms begin later.

Highly Variable

NPD3 unfurls in individualized ways.

A fetus may be diagnosed with a genetic test after ultrasound reveals an enlarged spleen. Liver or lung failure that starts in infancy may be rapidly fatal. Neurological manifestations that begin between ages 3 to 5 may be lethal.

Yet a 75-year-old woman developed telltale tremors at age 75; her 3 brothers were severely affected in childhood. With one mutation, she was a “manifesting heterozygote,” but her brothers inherited two copies of the mutation.

In many cases, health care providers assemble the puzzle pieces and order genetic testing to make the diagnosis. But sometimes astute parents figure out what’s wrong before their doctors do. Consider an anonymous post on a Facebook group.

The parents of an 8-month-old who had a large head and liver as well as muscle weakness went back to look at their genetic testing results. The mother is a carrier – could her son have a mild case? Indeed, the child is also a carrier, and a manifesting heterozygote – with one mutation and not two, he doesn’t have the full-blown syndrome.

Another Facebook post describes a sister and brother diagnosed at ages 8 and 10. The children started taking miglustat, which slowed disease progression. But the sister today has a milder case because she began the drug at a younger age than did her brother.

One parent who lives in a country where miglustat is not available reported that within a year of diagnosis without treatment, her young daughter lost the ability to walk or sit without supports, look up and down, or speak, and she has difficulty swallowing.

Posts to the FB group range from children who die in infancy to those given dire prognoses but who are presently adults. So predicting disease course is challenging, and sometimes wrong.

A Classic Lysosomal Storage Disease

The diagnostic odyssey narrows down the list of conditions that might explain the enlarged spleen, jaundice, and neurological symptoms, accounting for different possible explanations at different ages.

Babies and toddlers are evaluated for rare single-gene conditions such as Niemann-Pick types A and B, Wolman disease, Gaucher disease, and neonatal hepatitis. For older individuals, Wilson disease and mitochondrial diseases must be ruled out, and for the oldest patients, ALS, dementias, and psychiatric conditions.

In about 95% of affected individuals, mutations are in a gene, NPC1, on chromosome 18 that encodes a glycoprotein. In the other 5% of cases, mutations are in the NPC2 gene, on chromosome 14. It’s encoded protein binds cholesterol.

Both NPC1 and NPC2 proteins reside in the membranes of lysosomes, the “suicide sacs” within cells that house enzymes that dismantle bulky molecules. NPC1 and NPC2 proteins detect lipids, like cholesterol, and signal the lysosomes to eject them. When lysosomal proteins don’t work, specific lysosomal storage diseases result. The genetic glitch stifles the lysosomes’ function as cellular garbage disposals, and gunk builds up.

Cholesterol accumulating in many cell types causes the varied symptoms of NPD3. Neurons fray from both ends, the axons and the dendrites, in response to signals from malfunctioning, nearby astrocytes. Experiments in mice with a natural mutation, human fibroblasts growing in culture, and “monkey brain homogenates” revealed how NPC1 and NPC2 send lipids out of lysosomes, triggering the neurodegeneration.

Testing

Genetic testing can identify or verify NPD3. Another diagnostic tool is the antibiotic filipin, which fluoresces with cholesterol buildup. Biomarkers include fatty molecules like oxysterols and lysosphingomyelin.

At the cellular level in NPD3, macrophages, the huge, wandering sentinel cells of the immune system, may swell with cholesterol, earning the name “foam cells.” And a bone marrow test might reveal telltale “sea-blue histiocytes,” which are white blood cells that stain a bright blue and indicate an enlarged spleen.

Because NPD3 is autosomal recessive – passed from two (usually) unaffected carrier parents – pre-conception testing can identify carriers. A test from Invitae, for example, detects the two genes behind the disease (NPC1 and NPC2) with a cheek, saliva, or blood sample – but an individual would not know to request a test without a family history of the condition.

If both parents are found to be carriers, then amniocentesis or chorionic villus sampling can identify a fetus that has inherited the condition. Each child of two carriers has a 25% risk of inheriting NPD3.

A Well-designed Clinical Trial

Small patient populations complicate testing treatments for a rare disease. The clinical trial for the new drug, Miplyffa, cleverly used a crossover design that compares the same participant with and without the treatment.

A randomized, double-blind, placebo-controlled 12-month trial evaluated the safety and effectiveness of Miplyffa. Patients were aged 2 to 19 years and had a molecularly-confirmed diagnosis of NPD3. Fifty patients were randomized 2:1 to receive the drug or placebo by mouth three times a day. Thirty-nine of the participants also took miglustat during the trial.

Evaluation included rating scales to measure disease progression, including ambulation, speech, ability to swallow, and fine motor skills. The higher the score, the greater the severity. And comparison to natural history studies track signs and symptoms that emerge as a disease progresses without treatment.

Compared to placebo, Miplyffa with miglustat slowed disease progression in the 12-month study. An additional 48-month study in which the patients knew what they were taking confirmed the effect, compared to a natural history study.

“Effective management of Niemann-Pick Disease type C requires multiple treatment options due to the complexity of the disease. Until today, there were no approved therapies in the US. FDA approval of Miplyffa marks a significant moment for those living with NPC and the global NPC community. With this labeled indication, patients will now have more access to treatments to tackle this devastating disease,” said Elizabeth Berry-Kravis, Director of the Pediatric Neurosciences F.A.S.T. Center for Translational Research at Rush University Medical Center.


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