Niemann-Pick Disease Type C

Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and lipids inside of cells. This leads to the abnormal accumulation of these fatty substances within various tissues of the body, including brain tissue.[1] The accumulation of these substances damages the affected areas.

The estimated incidence of NPC is 1/120,000 live births reported world-wide. In the United States, prevalence from the epidemiology calculations of 2.9 per million approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.[2] NPC is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes.[3] NPC occurs in many different populations, but it occurs more often in people of Acadian and Bedouin descent. The onset of symptoms may affect individuals at different ages, from perinatal to adult. The severity of symptoms and progression of disease is highly individualized.

NORD’s Rare Disease Report on Niemann-Pick Disease Type C provides the main symptoms according to age group[4]:

Perinatal NPC (shortly before or after birth)

• Systemic symptoms

• Fetal ascites (abnormal fluid in the abdomen, leading to swelling)

• Hypotonia (weak muscle tone)

• Hepatosplenomegaly (enlarged liver and spleen)

• Jaundice (yellowing of the skin and eyes)

• Thrombocytopenia (low platelet count)

• Lung disease

• Liver failure

• Failure to thrive (poor growth and development)

• Neurological symptoms

• Hypotonia (weak muscle tone)

Early Infantile NPC (2 months to under 2 years)

• Systemic symptoms

• Hepatosplenomegaly or splenomegaly (enlarged liver or spleen, sometimes the only symptom)

• Prolonged jaundice in newborns

• Neurological symptoms

• Central hypotonia (weak muscle tone affecting the core muscles)

• Delayed developmental milestones (e.g., sitting, crawling)

• Speech delay

• Dysphagia (difficulty swallowing)

• Spasticity (stiff or rigid muscles)

• Vertical supranuclear gaze palsy (VSGP) – difficulty moving the eyes up and down

Late Infantile NPC (2 to under 6 years)

• Systemic symptoms

• Hepatosplenomegaly or splenomegaly (with or without neurological symptoms)

• History of prolonged jaundice in newborns

• Neurological symptoms

• Developmental delays or regression (losing previously learned skills)

• Speech delay

• Clumsiness and frequent falls

• Progressive ataxia (loss of coordination)

• Dystonia (involuntary muscle contractions)

• Dysarthria (speech difficulties)

• Dysphagia (trouble swallowing)

• Seizures (partial or generalized)

• Cataplexy (sudden muscle weakness, often triggered by laughter)

• Abnormal eye movements

• Hearing loss

Juvenile NPC (6 to 15 years)

• Systemic symptoms

• Hepatosplenomegaly or Splenomegaly (may or may not be present)

• Neurological and psychiatric symptoms

• Poor school performance and learning disabilities

• Loss of language skills

• Frequent falls and clumsiness

• Progressive ataxia

• Dysarthria (slurred speech)

• Dystonia (abnormal muscle movements)

• Dysmetria (difficulty with coordination)

• Dyskinesia (abnormal, involuntary movements)

• Dysphagia (difficulty swallowing)

• Abnormal eye movements (VSGP)

• Gelastic cataplexy (sudden muscle weakness triggered by laughter)

• Seizures

• Behavioral problems

Adolescent and Adult NPC (15 years and older)

• Systemic symptoms

• Splenomegaly (may or may not be present; rarely, it is the only symptom)

• Neurological and psychiatric symptoms

• Cognitive decline (memory problems, difficulty thinking clearly)

• Dementia

• Learning disabilities

• Psychiatric issues (e.g., schizophrenia, psychosis, depression)

• Clumsiness

• Progressive motor symptoms (tremors, difficulty walking, dystonia)

• Dysarthria (difficulty speaking)

• Dysphagia (difficulty swallowing)

• Abnormal eye movements (VSGP)

Neurological and psychiatric symptoms (common across ages)

• Seizures

• Cataplexy (sudden muscle weakness, often triggered by emotions like laughter)

• Dystonia (involuntary muscle contractions that cause abnormal movements or postures)

• Tremors (shaking movements)

• Sleep disturbances (e.g., narcolepsy or sleep apnea)

• Psychiatric conditions (depression, obsessive-compulsive disorder, bipolar disorder, hallucinations)

End-stage disease

• Progressive neurological decline, leading to death from complications such as

• Aspiration pneumonia (caused by food or liquids entering the lungs)

• Respiratory failure

• Uncontrollable epilepsy.

Currently there is no cure for NPC. Treatment is supportive and includes both pharmaceutical and non-pharmaceutical management.[5] In September 2024, in a groundbreaking move, the FDA approved two drugs specifically for NPC. On September 20, 2024, the FDA approved Miplyffa (arimoclomol) in combination with the enzyme inhibitor miglustat to treat neurological symptoms associated with NPC in adults and children 2 years of age and older.[6]  Miplyffa is the first drug approved by the FDA to treat NPC. Four days later, on September 24, 2024, the FDA approved Aqneursa (Levacetylleucine) for the treatment of neurological symptoms associated with NPC in adults and pediatric patients weighing at least 15 kilograms.[7] Our experience with the three-drug regimen has had reimbursement costs from $1.2M-$2.8M/annually depending on dosage and contract. Orsini Specialty Pharmacy can source Miglustat and MIPLYFFA™ (arimoclomol). Curant Health is the exclusive specialty pharmacy for AQNEURSA™ (levacetylleucine) per IntraBio.[8]

Developing a gene therapy for NPC has some significant challenges including the large size of the NPC1 gene, ability for the therapy to cross the blood brain barrier to reach  affected cells in the central nervous system (CNS), and potential immune response to the viral vector. The NPC1 gene is very large, it spans more than 47 kilobases (kb) and  contains 25 exons;[9] in comparison, the Survival Motor Neuron 1(SMN1) for SMA spans approximately 20kb and contains 9 exons[10]. For the therapy to cross the blood brain barrier to reach the affected CNS cells, intrathecal injection would be necessary which brings additional risks for treatment  in addition to the risks associated with utilizing viral vectors such as off-target effects, toxicity, and immune responses.

The prognosis for Niemann-pick disease type C is generally poor, with patients often experiencing significant neurological deterioration and reduced lifespan. Early diagnosis and intervention are key to managing the disease and improving the quality of life for affected individuals.

Article by Kathy Clark, RN, BSN, CMCN, RIT, Vice President, Director of Managed Care. For more information about how this may affect your plan, please contact your Summit ReSources care specialist. The following sources were used as reference material for this article:

[1] NORD. Niemann Pick Disease Type C. https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/ Accessed 09.03.2025

[2] Burton BK, Ellis AG, Orr B, Chatlani S, Yoon K, Shoaff JR, Gallo D. Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States. Mol Genet Metab. 2021 Sep-Oct;134(1-2):182-187. doi: 10.1016/j.ymgme.2021.06.011. Epub 2021 Jul 1. PMID: 34304992.

[3] Vanier, M.T. Niemann-Pick disease type C. Orphanet J Rare Dis 5, 16 (2010). https://doi.org/10.1186/1750-1172-5-16

[4] NORD. Niemann Pick Disease Type C. https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/ Accessed 09.03.2025

[5] Jan M, Akbar HM, Ashfaque M, Khan ML, Talha M, Haque MA. FDA approval of Miplyffa and Aqneursa: A dual breakthrough for the treatment of Neimann-Pick disease type C. Alzheimers Dement (N Y). 2025 Feb 24;11(1):e70029. doi: 10.1002/trc2.70029. PMID: 39995598; PMCID: PMC11848562.

[6]FDA Approves First Treatment for Niemann-Pick Disease, Type C. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-niemann-pick-disease-type-c . Accessed 09/03/2025.

[7] FDA Approves New Drug to Treat Niemann-Pick Disease, Type C. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-niemann-pick-disease-type-c  Accessed 09/03/2025.

[8] Curant Health Selected By IntraBio as the Exclusive Specialty Pharmacy for AQNEURSA™ (levacetylleucine), the First Stand-Alone Therapy for Niemann-Pick Disease Type C. https://finance.yahoo.com/news/curant-health-selected-intrabio-exclusive-133000400.html Accessed 09/03/2025.

[9]NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC.  https://omim.org/entry/607623#:~:text=Morris%20et%20al.,the%20coding%20and%20intronic%20sequences. Accessed 09/03/2025.

[10] Burglen, L., Lefebvre, S., Clermont, O., Burlet, P., Viollet, L., Cruaud, C., Munnich, A., Melki, J. Structure and organization of the human survival motor neurone (SMN) gene. Genomics 32: 479-482, 1996. https://www.sciencedirect.com/science/article/abs/pii/S0888754396901470?via%3Dihub Accessed 09/03/2025.

Gene Therapy and Skin Substitute Updates

Elevidys

Sarepta Therapeutics, Inc. announced Monday evening, July 21, 2015, that they are voluntarily and temporarily pausing the shipment of their gene therapy, Elevidys® (delandistrogene moxeparvovec-rokl; SRP-9001) for Duchenne muscular dystrophy in the US. This pause will allow Sarepta and the US Food and Drug Administration (FDA) to complete the safety labeling supplement process. This announcement follows two teenage boys who passed away after receiving the gene therapy, and a third death of a fifty-year-old man who was a participant in a clinical trial for a therapy developed on a similar platform. 

For more information:

Sarepta Therapeutics Announces Voluntary Pause of ELEVIDYS Shipments in the U.S. | Sarepta Therapeutics, Inc.

Cell and Gene Therapy Access Model

On July 16, 2025, CMS announced the list of 35 states and territories that are participating in the Cell and Gene Therapy Access Model which represents approximately 84% of Medicaid beneficiaries with sickle cell disease (SCD). The Model has several key elements including CMS-negotiated outcomes-based contracts with manufacturers, developed with input from state Medicaid agencies, patients, and providers and expanding access to gene therapy for sickle cell disease. In addition, the Model provides support services including fertility preservation services, travel expenses, case management, and behavioral health services. The following states and territories are participating in the CGT Access Model: Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Illinois, Kansas, Kentucky, Louisiana, Maine, Maryland, Michigan, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, and Wisconsin, as well as the District of Columbia and Puerto Rico.

For more information:

Cell and Gene Therapy (CGT) Access Model | CMS

CMS Expands Access to Lifesaving Gene Therapies Through Innovative State Agreements | HHS.gov               

Proposed Skin Substitute Changes for 2026

Skin substitutes have been reimbursed like biologicals, each with its own unique billing code and payment limit, which has led to million-dollar claims. According to Medicare claims data, Part B spending for these products rose from $252 million in 2019 to more than $10 billion in 2024, a nearly forty-fold increase.  For calendar year (CY) 2026, CMS is proposing to shift the payment of skin substitute products from biologic to incident-to supplies, and to group and pay for these products based on relevant product characteristics with a single payment rate. According to the proposed CY 2026 Physician Fee Schedule (page 1200), under this proposal, which assumes a single rate of approximately $125.38 for CY 2026, there would be an estimated savings of $9.4 billion.

• Calendar Year (CY) 2026 Medicare Physician Fee Schedule (PFS) Proposed Rule (CMS-1832-P) | CMS

• BREAKING NEWS! 2026 MPFS Proposed Rule Sets Single Payment Amount for all "Skin Substitutes" at $125.38/cm2 - Caroline Fife M.D.

• CY 2026 Physician Fee Schedule

Article by Kathy Clark, RN, BSN, CMCN, RIT, Vice President, Director of Managed Care. For more information about how this may affect your plan, please contact your Summit ReSources care specialist.

ELEVIDYS on Hold for Non-Ambulatory Patients

Since March 2025, there have been two reported deaths following treatment with ELEVIDYS. Both patients were non-ambulatory, ages 16 and 15 and both died related to acute liver failure.

ELEVIDYS is the only FDA approved gene therapy for patients with Duchenne Muscular Dystrophy (DMD). It was first approved on June 22, 2023, for the treatment of ambulatory pediatric patients aged 4 through 5 years with confirmed DMD gene mutation but excluded those with deletions in exon 8 and/or exon 9. On June 20, 2024, the FDA expanded the indication to include patients over the age of 4 years, ambulatory and non-ambulatory, with confirmed DMD gene mutation, but excluded those with deletions in exon 8 and/or exon 9. Worldwide, ELEVIDYS has been given to more than 900 individuals.

Following the second death, Sarepta issued press release on June 15, 2025, titled “Sarepta Provides Safety Update for ELEVIDYS and Initiates Steps to Strengthen Safety in Non-Ambulatory Individuals with Duchenne.” As it examines the data, the company has initiated several safety initiatives as noted in the following excerpts from the press release.

• Evaluating and Enhancing Immunosuppressive Regimen: As part of a comprehensive review of safety data, Sarepta is taking proactive steps to mitigate the risk of acute liver failure in non-ambulatory patients. Sarepta is working to immediately convene an independent group of leading experts in Duchenne and liver health to consider an enhanced immunosuppression regimen for ELEVIDYS. This panel will evaluate data and assess our proposed regimen, which includes sirolimus and is supported by preclinical data demonstrating the effectiveness of additional immunosuppression in moderating liver enzyme elevations, a key factor in mitigating potential safety events. Sarepta will share the panel's recommendations with the U.S. Food & Drug Administration (FDA), and implementation of any new regimen will be subject to FDA guidance and allowance.

• Suspending Shipments of ELEVIDYS for Non-Ambulatory Patients: Sarepta is temporarily suspending shipments of ELEVIDYS for non-ambulatory patients while an enhanced immunosuppressive regimen is evaluated, discussed with regulatory bodies, and put in place.

  For ambulatory patients, no treatment changes are being proposed and the current practice of administering corticosteroids before and after ELEVIDYS infusion, along with post-treatment monitoring, remains the same.

• ENVISION Study Paused: Sarepta has voluntarily paused dosing in the ENVISION clinical study (also known as Study SRP-9001-303). FDA concurs with this action. The pause will allow for the evaluation of a protocol amendment to incorporate an enhanced immunosuppressive regimen for the non-ambulatory patient cohort and incorporate any additional feedback from the FDA. Regulatory alignment is needed before screening and dosing in ENVISION may resume.

  ENVISION is a global, randomized, double-blind, placebo-controlled trial evaluating ELEVIDYS in older ambulatory and non-ambulatory individuals living with Duchenne muscular dystrophy. In the U.S., it serves as the confirmatory trial required under the FDA’s accelerated approval pathway for non-ambulatory patients.

Although gene therapies like ELEVIDYS offer an opportunity to address the underlying genetic cause rather than just managing symptoms for diseases with few alternatives, the benefit is not without risk. Severe immune system response is a known risk and continues to be a challenge for gene therapies that use adeno-associated viral vectors.

Article by Kathy Clark, RN, BSN, CMCN, RIT, Vice President, Director of Managed Care. For more information about how this may affect your plan, please contact your Summit ReSources care specialist. The following sources were used as reference material for this article: 

(1) Sarepta Provides Safety Update for ELEVIDYS and Initiates Steps to Strengthen Safety in Non-Ambulatory Individuals with Duchenne https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-provides-safety-update-ELEVIDYS-and-initiates-steps?_ga=2.137210743.63220694.1750092019-638846657.1750092019  Accessed 6/16/2025.

(2) Bilodeau, K. March 21, 2025. A recent gene therapy death shines a light on AAV safety. PharmaVoice. https://www.pharmavoice.com/news/sarepta-ELEVIDYS-gene-therapy-duchenne-death-aav-safety/743824/  Accessed 6/16/2025.

FDA Approves Tecelra, First T Cell Therapy for Solid Tumors

On August 2, 2024, the FDA granted accelerated approval for Tecelra (afamitresgene autoleucel) a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, 16 -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. Tecelra is contra-indicated in adults who are heterozygous or 52 homozygous for HLA-A*02:05P.[i]

Synovial sarcoma is an uncommon and aggressive cancer that can form in soft tissues such as muscles, fat, joint linings, and ligaments. It is often found in the arm, leg, or foot, and near joints such as the wrist or ankle. It can also form in soft tissues in the lung or abdomen. Although synovial sarcoma can affect people at any age, it is known to occur more commonly in adolescents and adults younger than 30.[ii] Adults with metastatic synovial sarcoma at diagnosis have a 5-year overall survival rate of 10%, versus 76% for those with localized disease at diagnosis.[iii]

Synovial sarcoma (SS) accounts for up to 10% of all soft-tissue sarcomas. In the US, 800-1000 new cases of SS are diagnosed annually. According to an analysis of the Surveillance, Epidemiology, and End Results (SEER) database study, the age-adjusted incidence rate of SS in the US is 0.177 per 100,000 (approximately 580 incident cases) with a prevalence rate of 0.65 per 100,000 (approximately 2129 prevalent cases).[iv]

Tecelra is an autologous T cell immunotherapy composed of a patient’s own T cells. T cells in Tecelra are modified to express a TCR that targets MAGE-A4 expressed by cancer cells in synovial sarcoma. After the patient undergoes leukapheresis, cells are sent for manufacturing. It takes about six weeks for the Tecelra to be returned to the provider, though that time may vary.

The patient is admitted to the hospital and receives a lymphodepleting chemotherapy regimen of fludarabine 30 mg/m2/day intravenously for four days starting on the seventh day before Tecelra infusion (Day-7 to Day -4), and cyclophosphamide 600 mg/m2/day intravenously for 3 days starting the seventh day before Tecelra infusion (Day -7 to Day -5).  Tecelra is administered over an hour as a single intravenous infusion on Day 1.  The patient will remain hospitalized for at least seven days after the infusion. The patient should plan to stay close to a healthcare facility for at least four weeks.[v]

The safety and effectiveness of Tecelra were evaluated in a multicenter, open-label clinical trial. Effectiveness was evaluated based on overall response rate and the duration of response to treatment with Tecelra. Among the 44 patients in the trial who received Tecelra, the overall response rate was 43.2% and the median duration of response was six months. Tecelra was approved under an accelerated approval pathway and a confirmatory trial is ongoing to verify Tecelra’s clinical benefit.[vi]

A Black Box Warning has been issued because patients may experience cytokine release syndrome. Patients may also exhibit Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS).

The current list price for  Tecelra is $727,000. This does not include the pre-treatment or hospitalization costs associated with the administration of the therapy.

Article by Kathy Clark, RN, BSN, CMCN, Vice President, Director of Managed Care. For more information about how this may affect your plan, please contact your Summit ReSources care specialist. The following sources were used as reference material for this article:

[i] FDA Package Insert-Tecelra. https://www.fda.gov/media/180565/download?attachment. Accessed 8/12/2024.

[ii] National Cancer Institute. Synovial Sarcoma. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-soft-tissue-tumors/synovial-sarcoma#:~:text=Synovial%20sarcoma%20is%20a%20cancer,also%20be%20called%20malignant%20synovioma. Accessed 8/12/2024.

[iii]Blay JY, von Mehren M, Jones RL, Martin-Broto J, Stacchiotti S, Bauer S, Gelderblom H, Orbach D, Hindi N, Dei Tos A, Nathenson M. Synovial sarcoma: characteristics, challenges, and evolving therapeutic strategies. ESMO Open. 2023 Oct;8(5):101618. doi: 10.1016/j.esmoop.2023.101618. Epub 2023 Aug 23. PMID: 37625194; PMCID: PMC10470271. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470271/ Accessed 8/12/2024.

[iv] Mangla A, Gasalberti DP. Synovial Cell Sarcoma. [Updated 2023 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK587366/. Accessed  8/12/2024.

[v] FDA Package Insert-Tecelra. https://www.fda.gov/media/180565/download?attachment. Accessed 8/12/2024.

[vi] FDA. FDA Approves First Gene Therapy to Treat Adults with Metastatic Synovial Sarcoma. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-metastatic-synovial-sarcoma. Accessed 8/12/2024.