Zevra Therapeutics Announces Presentations on MIPLYFFA® (arimoclomol) at Niemann-Pick Disease Conference
Zevra Therapeutics announced that MIPLYFFA® (arimoclomol), the first FDA-approved treatment for Niemann-Pick disease type C (NPC), will be featured in...
Breakthrough Clinical Results
Zevra Therapeutics announced that MIPLYFFA® (arimoclomol), the first FDA-approved treatment for Niemann-Pick disease type C (NPC), will be featured in presentations at the National Niemann Pick Disease Foundation Conference. Presentations will cover data from a pivotal study showing MIPLYFFA, used with miglustat, halted disease progression at 12 months and a 48-month open-label extension confirming its effectiveness and safety. The presentations also include in vitro data providing mechanistic evidence of arimoclomol's action in targeting NPC through multiple pathways. MIPLYFFA is indicated for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years and older.
Key Highlights
- MIPLYFFA® (arimoclomol) presentations at the National Niemann Pick Disease Foundation Conference.
- Pivotal study data shows MIPLYFFA, in combination with miglustat, halted disease progression in NPC patients at 12 months.
- 48-month open-label extension confirms the effectiveness and safety of MIPLYFFA.
- In vitro data provides mechanistic evidence of arimoclomol's action in targeting NPC.
Incidence and Prevalence
Incidence and Prevalence of Niemann-Pick Disease Type C
Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene.
Prevalence Estimates
According to a 2014 observational, multicentre genetic screening study across the EU and USA, the frequency of NP-C patients was 1.2% (95% CI; 0.3%, 3.5%) among adults with neurological and psychiatric symptoms. This suggests there may be an underdiagnosed pool of NP-C patients.
This study included 250/256 patients from 30 psychiatric and neurological reference centres with a median age of 38 years (range 18-90 years).
In a Spanish study of 236 patients with suspected NP-C, 10 patients (4%) had a confirmed diagnosis based on gene sequencing, all with two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients.
Disease Characteristics
The adult form of the disease concerns a small proportion (5%) of the people affected and is usually expressed as a neurological form.
NP-C is characterized by a wide range of symptoms that are not specific, such as neurological, systemic or psychiatric symptoms. This non-specific, heterogeneous nature of signs/symptoms makes diagnosis challenging.
Diagnostic Approaches
Diagnostic approaches include plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) measurements in conjunction with the NP-C suspicion index (NP-C SI).
In the multicentre study, three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient).
Prognosis and Management
Most NP-C affected patients die prematurely. The early diagnosis is fundamental to deploy the best follow-up care, and patients should be in contact with a reference centre.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Niemann-Pick Disease Type C
Disease Pathophysiology and Therapeutic Targets
Niemann Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by both visceral and neurological impairment with cognitive decline. The neurodegeneration observed in NPC is associated with deposition of amyloid-β and abnormal tau aggregations, similar to what is seen in Alzheimer disease (AD). The dementia in NPC relates to intracortical circuiting abnormalities that can be detected through neurophysiological procedures.
Recent research has identified several key therapeutic targets and mechanisms of action:
Established Treatments
Miglustat
- The only approved treatment for NPC
- Works through small molecule inhibition of glucosylceramide synthase
- Limits ganglioside accumulation
- Also known as N-butyldeoxynojirimycin (NB-DNJ)
- Clinically approved for treating both NPC and Gaucher disease type 1
- Functions as an inhibitor of glucosylceramide synthase (GCS)
Emerging Therapeutic Approaches
N-acetyl-l-leucine (NALL)
- Shown to improve neurologic manifestations of NPC after 12 weeks in a placebo-controlled trial
- Administered orally 2-3 times per day in weight-based dosing
- After 12 months of treatment, demonstrated a 118% reduction in annual disease progression
- After 18 months, the mean change was +0.05 (±2.95) compared to +2.25 (±4.74) in the historical cohort
- Well tolerated with no treatment-related adverse events
- Associated with a significant reduction in NPC disease progression
- Demonstrates a disease-modifying, neuroprotective effect
2-hydroxypropyl-B-cyclodextrin
- Functions as a lipid chelator
- Relieves the lysosomal to endoplasmic reticulum blockage
- Markedly increases life expectancy in the murine model
NPC1L1 Targeting
- Niemann-Pick C1-Like 1 (NPC1L1) is identified as a crucial target involving in cholesterol cellular uptake
- Ezetimibe is the first and only NPC1L1 inhibitor approved for treating hypercholesterolemia
- Works by decreasing cholesterol absorption
- Research shows that a variant genotype (TT/CT) of rs4720470 on NPC1L1 gene was associated with increased risk for high-degree coronary artery calcification (CAC) in male patients
- Development of NPC1L1 inhibitors faces challenges but offers promising therapeutic opportunities
Combination Approaches
Research suggests that stabilizing treatment strategies based on the removal of presumably toxic metabolites show promise. Ultimately, strategies targeting the primary biochemical lesion in cells will likely be combined to provide a synergistic cocktail approach to treating NPC.
Neurophysiological Insights
Studies using transcranial magnetic stimulation (TMS) have revealed that NPC patients with multidomain cognitive impairment show F-Florbetaben uptake in brain frontal areas, with abnormalities in short-latency afferent inhibition (SAI) and short-interval intracortical inhibition (SICI). This suggests that cognitive impairment in NPC is associated with cortical amyloid deposition, and that similar mechanisms may underlie both NPC and AD dementia.
Drug used in other indications
Alternative Indications for Miglustat
Miglustat for Gaucher Disease Type 1
Miglustat (Zavesca®) has been established as an effective treatment for Gaucher disease type 1. It functions as an oral substrate reduction therapy and is positioned as a second-line treatment option for adult patients with mild to moderate Gaucher disease type 1 who cannot or do not wish to receive lifelong intravenous enzyme infusions.
Efficacy and Clinical Evidence
The efficacy and safety of miglustat for Gaucher disease type 1 have been well-documented through both short-term clinical trials and long-term, open-label extension studies.
Intervention Models for Miglustat Trials
The clinical investigation of miglustat for Gaucher disease type 1 has employed several intervention models:
- Long-term open-label extension studies that follow patients after 12 months of initial treatment
- Dosage regimens of 100-300 mg three times daily
- Treatment durations extending to 36 months (3 years) or longer, with one case report documenting 8 years of continuous treatment
- Use as maintenance therapy in patients with stable Gaucher disease type 1 who have been switched from previous enzyme replacement therapy
These intervention models have helped establish miglustat's role in the long-term management of Gaucher disease type 1, providing an oral alternative to traditional enzyme replacement therapies.
No information is available in the provided context regarding alternative indications for MIPLYFFA (arimoclomol) beyond Niemann-Pick disease type C.
