Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis.

BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment-resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality-adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration.

Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam.

Dravet syndrome (DS) is a rare, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers. This study evaluated health-care utilization over a 2-year period in patients with DS at an outpatient clinic of a German epilepsy center. Data on the course of epilepsy, anticonvulsant treatment, and direct costs were recorded using the electronic seizure diary Epivista and patients' files. We enrolled 13 patients with DS (6 females, mean age: 12.3±7.5 years) between 2007 and 2010 and evaluated them during a 1-year baseline. All patients had drug-resistant epilepsy and their seizures failed to improve with a mean number of 6.7±3.4 anticonvulsants. They had an overall mean seizure frequency of 102.1 seizures per year (median: 31, range: 3-538) with 43.2 GTCSs per year (median: 14, range: 0-228). We estimated the annual total direct costs at €6506±3974 (range: €1174-11,783) per patient with hospitalization (68.9% of total direct costs) as the major cost factor ahead of costs for anticonvulsants (24.0%). For the 1-year follow-up period, less severely affected patients were continued on conventional anticonvulsants (n=4) or switched to adjunctive treatment with stiripentol and clobazam (n=9). In the latter group, six patients (67%) were long-term responders, with between 25% and 100% seizure reduction with respect to either GTCSs or the overall seizure frequency. This reduction in seizure frequency was associated with a shift in the distribution of cost components towards higher medication costs and decreased hospitalization costs. The total direct costs increased by 42.7%, mainly due to the newly introduced stiripentol, with an annual cost of €6610. This study showed that direct costs of patients with DS were above the average European costs of drug-resistant epilepsy in children. Treatment with new anticonvulsants resulted in reduction of seizures and inpatient admissions.

Troxacitabine: BCH 4556, SPD 758, Troxatyl.

Troxacitabine [BCH 4556; SPD 758; Troxatyl] is a DNA synthesis inhibitor. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is a member of a novel class of nucleoside analogues discovered by BioChem Pharma and is the first example of a synthetic L-nucleoside analogue to have shown anticancer activity in animal models. On 11 May 2001, BioChem Pharma was acquired by, and integrated into, Shire Pharmaceuticals Group. In February 2002 Shire announced that it intended to pursue development of troxacitabine as a treatment for solid tumours. In addition, Shire indicated that it would pursue the drug's development for acute myeloid leukaemia. In March 1999, phase II trials were initiated to investigate the efficacy and tolerability of troxacitabine in a variety of solid tumours including pancreas, prostate, colorectal, renal and non-small cell lung cancers and melanoma. The trials were conducted throughout North America and were closed to patient accrual in 2000. Two phase I combination chemotherapy trials in solid tumours (one with cisplatin and another with paclitaxel) have been initiated. One of these trials is in patients with pancreatic cancer. A phase III trial in patients with pancreatic cancer is expected to begin during the second or third quarter of 2003. In addition, further clinical development was initiated in May 2000, in the form of a combination chemotherapy trial in patients with acute leukaemia. A phase II trial in patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia-blast phase (CML-BP) has reported that troxacitabine demonstrated significant activity in these cancers. However, Shire indicated that no further development for CML-BP will be conducted. The company indicated that it would focus future development in the haematological malignancy area on AML and has initiated an exploratory phase III trial of troxacitabine in previously untreated patients with poor prognosis AML. The study will compare troxacitabine in combination with either cytarabine or idarubicin, with a control drug regimen. The aim is to identify the most promising treatment regimens in a relatively small number of patients before commencing the larger pivotal trial. A pivotal phase III trial is expected to begin in the first half of 2003. In September 2002, Shire Pharmaceuticals forecast Troxatyl to reach peak sales of $US100-200 million, for the indications of pancreatic cancer and myeloid leukaemia.

Nucleoside analogues in the treatment of haematological malignancies.

The nucleoside analogues are a group of antimetabolite cytotoxics which generally have to be metabolised to the equivalent nucleotide before incorporation into DNA. Cytarabine is a well established component of the treatment of acute leukaemias and has its principal action on dividing cells. New formulations include a liposome encapsulated product for intrathecal use and oral cytarabine ocfosfate which may be suitable for long-term outpatient use. Pentostatin acts by causing accumulation of deoxynucleotides and, although active against hairy cell leukaemia, is associated with a poor tolerance profile. Cladribine and fludarabine have substantial activity in the treatment of chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Fludarabine is the more thoroughly investigated of the two and is currently being developed in combination therapies for CLL and NHL and also in a combination with cytarabine for acute myeloid leukaemia. Fludarabine's immunosuppressive activity is being exploited in the conditioning of patients for non-myeloablative stem cell transplantation. Gemcitabine is an established agent in the treatment of a number of solid tumours but also has activity in haematological malignancies which might be exploited by the use of extended infusion schedules. Newer agents including nelarabine, clofarabine and troxacitabine are undergoing clinical evaluation and show promising activity.