Enzyme Replacement Therapy For Niemann-Pick Disease

  • Duyen Nguyen Master in Science - MSci Human Biology, University of Birmingham

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Niemann-Pick disease (NPD) is a rare, genetically inherited disease that belongs to a larger family of lysosomal storage disorders. It is characterised by an inability to metabolise and transport fats (such as, cholesterol and lipids) within cells. This results in an abnormal buildup of fats within cells throughout the body, which eventually causes them to become dysfunctional and die. This can affect the normal function of vital organs such as the brain, liver, spleen, and bone marrow.1 NPD causes a variety of symptoms which can have debilitating effects on patients’ quality of life, such as neurological damage and the enlargement of the liver and spleen. 

Currently, there are no treatment options available for NPD. However, several clinical studies have indicated the use of enzyme replacement therapy (ERT) to treat NPD. In this article, we will explore a novel ERT medicine called Olipudase alfa (Xenpozyme), which has currently been approved by both the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).. 

What is niemann-pick disease?

NPD is a rare genetic deficiency that is inherited in an autosomal recessive pattern. This means that both parents must pass on the faulty gene (possessing the enzyme-deficient mutation) for their child to inherit NPD.2 

NPD disease can be further categorised into four main subtypes: A, B, C, and E. Here, we will only discuss types A and B, as these are the subtypes treated by the ERT Olipudase alfa. 

NPD types A and B (NPD-A and NPD-B) were initially thought to be the distinct conditions, but research now shows that they are opposite sides of the same spectrum. At the severe end is NPD-A, which is characterised by its fatal neurological symptoms and early onset in paediatric patients. In contrast, NPD-B is milder - the disease can manifest at any point in life, and patients can survive into early adulthood. Patients who fall in between the spectrum are said to have NPD type A/B, where they experience intermediate forms of the disease. 

Both subtypes of NPD are caused by a deficiency in an enzyme called acid sphingomyelinase (ASM). For this reason, they are often referred to as acid sphingomyelinase deficiency or disorder, or ASMD for short. The enzyme ASM is important for the metabolism (breakdown and conversion into energy) of a fatty substance called sphingomyelin. Therefore, in individuals with NPD-A and -B, sphingomyelin builds  up in cells, resulting in the detrimental symptoms of NPD.2 

What causes niemann-pick disease?

NPD-A and -B are caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene.3 SMPD1 is important as it encodes the instructions for producing ASM. In individuals with NPD-A and NPD-B, the SMPD1 gene is mutated and dysfunctional, meaning that the body cannot produce enough ASM. In NPD-A, ASM activity is completely absent, whilst in NPD-B, which is less severe than NPD-A, some residual ASM activity remains.

Symptoms of niemann-pick disease

Symptoms of NPD-A usually manifest in early infancy. They may include:4,5

  • Enlargement of the liver and spleen
  • Feeding difficulties
  • Loss of reflexes and motor skills
  • Interstitial lung disease (caused by the accumulation of macrophages in the lungs)
    • This can progress into respiratory failure and become fatal by the age of 3
  • Infants develop cherry red spots in the eye (reducing their central vision)
  • Severe, progressive brain disease and impaired neurological growth 

Symptoms of NPD-B are less severe than those of type A. They may include:4,5

  • Enlargement of organs
  • Splenomegaly (swelling of the spleen)
  • Decreased lung function
  • Impaired growth
  • Increased stress on the heart 

NPD-B differs from type A as it usually has minimal impact on the brain, though patients may have similar non-neurological symptoms.

Diagnosis and treatment 

Firstly, your healthcare provider will conduct a thorough clinical history examination. Blood or samples of your skin will be tested to measure the sphingomyelinase activity in your white blood cells. Final genetic tests are carried out to confirm whether there are mutations in the SMPD1 gene.4 

Currently, there is no cure or approved medicines that can slow the progression of NPD. The only treatment is supportive and palliative therapy based on the individual’s symptoms. 

What is enzyme replacement therapy?

Although there is currently no cure for NPD, multiple enzyme replacement therapies (ERT) and gene therapies are being tested in clinical trials and are anticipated to become the mainstay of treatment in the future. As the name implies, ERT refers to a treatment where enzymes are administered to patients to replace dysfunctional enzymes and combat their enzyme deficiency.6 This results in the successful restoration of the body’s ability to perform the functions inhibited by the disease.  

ERT is usually administered parenterally through intravenous (IV) infusions, where the replacement enzyme is delivered directly into your bloodstream. The replacement enzymes are typically derived from human, plant or animal cells that have been purified and genetically modified. 

What is olipudase alfa (Xenpozyme)?

Olipudase alfa, also referred to by its brand name “Xenpozyme”, is an ERT used to treat NPD types A, A/B, and B. Xenpozyme specifically targets the non-neurological symptoms of NPD in both adult and paediatric patients. 

How does xenpozyme work?

Xenpozyme’s active substance is a replacement enzyme, olipudase alfa, which can replace the dysfunctional enzyme in patients as it is a copy of the normal acid sphingomyelinase (ASM) enzyme.7 Replacing these dysfunctional enzymes allows for the restoration of normal ASM activity, as olipudase alfa can break down the buildup of fats within cells. This leads to a reduction of sphingomyelin buildup in the liver, spleen, and lungs. Now that the fats are broken down, they can be recycled and transported within the cell normally, allowing for the alleviation of NPD symptoms. 

It is important to note that Xenpozyme is not a complete cure for NPD. It simply provides an additional source of ASM for ASM-deficient patients. Moreover, Xenpozyme can only target non-neurological symptoms, as the medicine is unable to be delivered to, or travel to, the brain tissue. This is because of the blood-brain barrier which separates the blood from the brain. Therefore, further research is still required to find a treatment that can reduce brain damage as well. 

What benefits does xenpozyme show in clinical studies?

Xenpozyme’s efficacy and safety have been confirmed following three major clinical trials. The first trial was conducted on 36 adults.8 The second in 20 paediatric patients.9 Then the final additional long-term trial enrolled 30 adults and 8 paediatric patients.10 

Overall, all three trials showed that Xenpozyme was effective in improving lung function and reducing spleen volume (they all reported significant reductions in sphingomyelin buildup). 

Side effects

Adverse effects of Xenpozyme were reported to be mild to moderate. 

Common side effects observed in adult patients were:

Common side effects observed in paediatric patients were:

  • Pyrexia (fever)
  • Fatigue
  • Cough 
  • Diarrhoea
  • Rhinitis
  • Abdominal pain
  • Vomiting
  • Headache
  • Urticaria (hives)
  • Nausea
  • Rash
  • Arthralgia (joint pain)
  • Pruritus (itching)
  • Pharyngitis (sore throat)

Infusion-associated reactions

Xenpozyme should always be administered by trained staff and where resuscitation facilities are available. Serious infusion-associated reactions (IARs) may occur, but this can be prevented via premedication with a prescribed antihistamine, antipyretic, and corticosteroid. 

During clinical trials, IARs were reported to occur in approximately 1 in 2 adults and 2 in 3 children. The most severe side effect observed in these studies was extrasystoles (a type of heart palpitation). However, this was observed in a patient with existing damage to their heart muscle.


Niemann-Pick disease (NPD) is a rare, inherited metabolic disorder that affects lipid metabolism and has fatal effects on patients. Currently, there is no cure for NPD; however, enzyme replacement therapy (ERT) poses a promising future for improving the treatment of NPD. With the recent approval of Xenpozyme, we anticipate the assimilation of ERT to treat patients with NPD types A and B. Although this ERT medicine has been shown to have significant clinical benefits, further research is still required to improve the treatment of neurological symptoms. 


What drugs are used to treat niemann-pick disease?

Apart from Xenpozyme, there are currently no NPD-specific medicines available to treat people with NPD type A or B. However, people with NPD type C may use Miglustat (Zavesca), to help slow neurological decline.11 

What is the life expectancy of someone with ASMD?

The prognosis is dependent on the onset of the illness and the type of NPD. For children with NPD type A (the more severe form of ASMD), children may live up to the age of 4. However, most patients die during infancy. Whereas for NPD type A/B or B (the less severe form of ASMD), patients may survive until late childhood or early adulthood. In the US, the life expectancy at birth of type A/B or B patients was 37 years.12

In general, patients with NPD have poor survival and the quality of life is low due to the significant burden of illness.


  1. Thurm A, Chlebowski C, Joseph L, Farmer C, Adedipe D, Weiss M, et al. Neurodevelopmental characterization of young children diagnosed with niemann-pick disease, type c1. J. Dev. Behav. Pediatr. [Internet]. 2020 [cited 2024 Jan 12];41(5):388–96. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592416/
  2. Bajwa H, Azhar W. Niemann-pick disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2024 Jan 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK556129/
  3. Simonaro CM, Park JH, Eliyahu E, Shtraizent N, McGovern MM, Schuchman EH. Imprinting at the smpd1 locus: implications for acid sphingomyelinase–deficient niemann-pick disease. AMHG [Internet]. 2006 May 1 [cited 2024 Jan 12];78(5):865–70. Available from: https://www.sciencedirect.com/science/article/pii/S0002929707638191 
  4. NPUK [Internet]. [cited 2024 Jan 12]. Niemann-pick diseases. Available from: https://www.npuk.org/niemann-pick-diseases/ 
  5. Niemann-pick disease | national institute of neurological disorders and stroke [Internet]. [cited 2024 Jan 12]. Available from: https://www.ninds.nih.gov/health-information/disorders/niemann-pick-disease 
  6. Enzyme replacement therapy. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012 [cited 2024 Jan 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK548796/ 
  7. Beninger P. New drug capsule: olipudase alfa. Clin Ther. 2023 Apr;45(4):384–5. 
  8. Wasserstein M, Lachmann R, Hollak C, Arash-Kaps L, Barbato A, Gallagher RC, et al. A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (Asmd) in adults: One-year results. Genet Med. 2022 Jul;24(7):1425–36. 
  9. Diaz GA, Giugliani R, Guffon N, Jones SA, Mengel E, Scarpa M, et al. Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results. Orphanet J. Rare Dis. 2022 Dec 14;17(1):437. 
  10. Lachmann RH, Diaz GA, Wasserstein MP, Armstrong NM, Yarramaneni A, Kim Y, et al. Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (Asmd): sustained improvements in clinical outcomes after 6.5 years of treatment in adults. Orphanet J. Rare Dis. 2023 Apr 25;18(1):94.
  11. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007 Sep;6(9):765–72. 
  12. Pulikottil-Jacob R, Dehipawala S, Smith B, Athavale A, Gusto G, Chandak A, et al. Survival of patients with chronic acid sphingomyelinase deficiency (Asmd) in the United States: A retrospective chart review study. Mol. Genet. Metab. Rep. 2024 Mar;38:101040. 

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Duyen Nguyen

Master in Science - MSci Human Biology, University of Birmingham

Duyen is a creative and enthusiastic writer with an MSci in Human Biology. She has an extensive scientific background and is highly proficient in cancer biology and Drosophila genetics. Her research project investigated the importance of calcium transporters, Itpr and SERCA, in the regulation of apoptosis-induced proliferation. She is an aspiring medical writer and strives to create accessible and engaging content that effectively translates research to a range of audiences.

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