EndocrinologyZavesca(R) (miglustat) First Treatment Available In UK And Ireland For Rare Progressive Niemann-Pick Type C Disease
Actelion Ltd (SIX: ATLN) announced the launch of Zavesca® (miglustat) in the UK and Republic of Ireland; the first and only licensed treatment available for people with Niemann-Pick type C (NP-C) disease [1]. NP-C is a rare, genetic disease with significant neurological deterioration that can be fatal and affects infants, children and adults [2,3].
Currently there is no cure for NP-C. Prior to Zavesca® patient management was restricted to symptom relief [4]. Zavesca® is licensed for the treatment of progressive neurological manifestations in adult patients and paediatric patients [1]. Neurological deterioration is the key feature of NP-C, which manifests in a variety of symptoms including: eye movement disorders (vertical supranuclear gaze palsy [VSGP] progressing to horizontal saccadic eye movement [HSEM] problems); balance disorders (ataxia); difficulty swallowing (dysphagia); slurred and irregular speech (dysarthria); a lack of muscle control (dystonia) and seizures. Intellectual decline which often leads to dementia, is also common and in the final stages of the disease the patient is often bedridden [2,5].
In a clinical trial (OGT918-007) where patients were given either 200mg of Zavesca® three times a day (in paediatric patients the dose was adjusted to body surface area) or standard of care for 12 months; in the majority of these patients symptoms were seen to improve or stabilise. This included the primary endpoint of HSEM velocity (the ability to move eyes rapidly from side-to-side), as well as other endpoints of swallowing capacity; hearing ability and mobility [4].
In an extension study, where all patients were treated with Zavesca® for a further 12 months, adult and juvenile patients with NP-C were seen to stabilise in important markers of neurological disease progression. Mobility remained stable in 67% of patients; swallowing capacity was improved or stable in 79% of patients with water, 86% of patients with both puree and soft lumps and in 93% of patients with cookies [6].
Ed Wraith, M.D., Royal Manchester Children"s Hospital, commented: "For the first time we have an approved therapy for NP-C. The data on the effects of treatment with Zavesca® obtained in a clinical trial and in a retrospective cohort study consistently showed a favorable clinical response. As a treating physician I am acutely aware of the importance of reducing progression of neurological symptoms."
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "I am very proud that Actelion - together with the scientific community - has been able to demonstrate the role of Zavesca® in reducing the progression of clinically relevant neurological symptoms in patients with NP-C. I would like to thank both the patients and their families who, over the years, have been involved in our clinical programme with so much dedication, as well as all the clinical experts for their continuous support. Actelion will continue to support the rare disease community in its efforts to advance science and medicine for the patient".
Zavesca® has been shown to be well tolerated in patients with NP-C, with the most common adverse events being - among others - diarrhoea and weight loss, whose prevalence decreased over time [4].
Zavesca®, which was granted orphan drug status allowing for a faster approval process, is now approved in all EU countries for the treatment of patients with NP-C and is available in all the EU countries according to the local reimbursement process. Regulatory proceedings to extend the use of Zavesca® in patients with NP-C are ongoing in other countries worldwide.
About Zavesca®
In order to gain approval for Zavesca® in Niemann-Pick type C disease, a set of clinical data were obtained from one clinical trial OGT918-007 and two multicenter retrospective cohort studies in patients with NP-C.
In the clinical trial OGT918-007, adult and juvenile patients with NP-C (n=29, age ò‰¥12 years) were randomised to either miglustat 200 mg t.i.d. (n=20) or standard of care (n=9) for 12 months [4]. In addition, 12 children aged 4-12 years received miglustat at a dose adjusted for body surface area. All patients were then given miglustat for another 12 months. Horizontal saccadic eye movement (HSEM) velocity was the primary endpoint. Other endpoints included swallowing, ambulation, neurological examination, neuropsychological assessment, tremor and quality of life. At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028) [4]. Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years [4].
A first retrospective cohort study was performed in 25 centers in 12 countries to assess data on changes of neurological status and overall utility of treatment with miglustat in 66 NP-C patients receiving miglustat outside of the clinical trial OGT918-007 for a mean duration of 1.5 years. The mean age of patients was 9.7 years at diagnosis and 12.8 years at miglustat initiation. A subset of 19 patients was also included in a natural history cohort with a mean age of 13.6 years at diagnosis and 18.7 years miglustat initiation [7]. A disease-specific disability scale was used to evaluate the severity of dysphagia (swallowing), dystonia (manipulation), ataxia (ambulation) and dysarthria (language articulation) at diagnosis, treatment initiation and last visit. A majority of patients remained at least stable after treatment with regard to the four parameters, indicating that miglustat provides clinically relevant benefits on neurological disease progression in patients with NP-C. Stabilisation of important neurological symptoms was seen in all age groups, but was greater in older patients [7].
A second retrospective cohort study was performed in 7 centers in 6 countries to assess data on changes in neurological status in 57 patients not treated with miglustat during the natural course of the disease for a mean duration of 5.5 years. The mean age of patients was 10.7 years at diagnosis and 16.2 years at last visit to clinician [8]. The same disease-specific disability scale was used to evaluate the severity of dysphagia, dystonia, ataxia and dysarthria at the time of diagnosis until the last visit. In line with previous data, the study showed the neurological disease in patients with NP-C was continuous, unbroken progression and the neurological disease progression was dependent on age at disease onset and higher in patients who were diagnosed at a younger age [8].
Zavesca® (100 mg miglustat capsule) is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Zavesca® may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable. It is approved in the European Union, the United States, Canada, Switzerland, Brazil, Australia, Turkey and Israel.
Zavesca® is indicated for the treatment of progressive neurological manifestations in adult patients and paediatric patients with Niemann-Pick type C disease [1].
References
1. Zavesca Summary of Product Characteristics. Accessible at http://www.emc.medicines.org.uk. Accessed March 2009.
2. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK: Blackwell Publishing, 2007
3. Patterson MC. Niemann-Pick disease Type C. Gene Reviews 2007a (updated 9 July). Accessible at http://www.geneclinics.org. Accessed October 2008.
4. Patterson MC, et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007; 6:765-772
5. Patterson MC. A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C. Neurologist 2003; 9:301-310.
6. Patterson MC, et al. Miglustat in Niemann-Pick disease Type C (NP-C): long-term data from a clinical trial. Proceedings of 58th Annual meeting of the American Society of Human Genetics, 2008; abstract # 766.
7. Pineda M, et al. A multicentre retrospective cohort study of miglustat in patients with Niemann-Pick disease type C. 19th Meeting of the European Neurological Society, 2009; abstract # 105
8. Wraith JE,et al. Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. 19th Meeting of the European Neurological Society, 2009; abstract # 109
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