Pipeline
BIAL’s medicines are already making a real difference to the lives of people all over the world. We are focused on neurosciences.
- Pre-clinical
- Phase I
- Phase II
- Phase III
- Registration
- Marketed
Achievements
Parkinson’s disease (PD) is a neurodegenerative disease of unknown aetiology with an estimated incidence of 4.5-16/100 000 persons/year. Analysis of worldwide data demonstrated a rising prevalence of PD with age and affects approximately 1.6% of people over the age of 65. [1, 2] Pathologically, PD is characterised by a massive loss of the dopaminergic neurons in the substantia nigra pars compacta with a concomitant reduction of striatal dopamine levels. [3] Clinically, PD is primarily considered as a movement disorder defined by the presence of motor symptoms, such as bradykinesia, tremor and rigidity and, in later stages, postural instability. [1, 4] Apart from these dopaminergic motor symptoms, non-motor symptoms such as major neuropsychiatric symptoms, autonomous disorders, sleep disorders, and sensory symptoms also develop. Non-motor symptoms have a substantial impact on the health-related quality of life of PD patients and are reported in about 90% of idiopathic PD patients in all stages of the disease. [5]
Opicapone (OPC) is a selective and reversible catechol-o-methyltransferase (COMT) inhibitor that increases L-dopa plasma levels when co-administered with L-dopa and a peripheral DOPA decarboxylase inhibitor (DDCI). In the presence of a DDCI (carbidopa or benserazide), COMT becomes the major metabolising enzyme for L-dopa catalysing its conversion to 3-O-methyldopa (3-OMD) in the brain and periphery. OPC was evaluated in two pivotal trials in patients with PD and end-of-dose motor fluctuations (BIPARK-I and II), and the results demonstrated an acceptable tolerability profile, combined with efficacy in reducing OFF-time [6, 7]. These studies led to the approval of OPC in the European Union, South Korea, USA, Japan, Australia and other countries as adjunctive therapy to preparations of levodopa/DDC inhibitors in adult patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations [8] or OFF episodes [9].
Opicapone (OPC) is a selective and reversible catechol-o-methyltransferase (COMT) inhibitor that increases L-dopa plasma levels when co-administered with L-dopa and a peripheral DOPA decarboxylase inhibitor (DDCI). In the presence of a DDCI (carbidopa or benserazide), COMT becomes the major metabolising enzyme for L-dopa catalysing its conversion to 3-O-methyldopa (3-OMD) in the brain and periphery. OPC was evaluated in two pivotal trials in patients with PD and end-of-dose motor fluctuations (BIPARK-I and II), and the results demonstrated an acceptable tolerability profile, combined with efficacy in reducing OFF-time [6, 7]. These studies led to the approval of OPC in the European Union, South Korea, USA, Japan, Australia and other countries as adjunctive therapy to preparations of levodopa/DDC inhibitors in adult patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations [8] or OFF episodes [9].
- Committee for medicinal products for human use (CHMP). Guideline of clinical investigation of medicinal products in the treatment of Parkinson’s disease. EMA/CPMP/330418/2012 rev. 2, 21 June 2012.
- Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014 Nov;29 (13):1583-90
- Hornykiewicz O. The discovery of dopamine deficiency in the parkinsonian brain. J Neural Transm Suppl. 2006;70:9-15.
- Paulson HL, Stern MB. Clinical manifestations of Parkinson's disease. In Watts RL, Koller WC (eds). Movement Disorders Neurologic Principles and Practices. 1997; McGraw Hill:Toronto.
- Gökçal E, Gür VE, Selvitop R, Babacan Yildiz G, Asil T. Motor and Non-Motor Symptoms in Parkinson's Disease: Effects on Quality of Life. Noro Psikiyatr Ars.2017 Jun;54(2):143-148. DOI: 10.5152/npa.2016.12758.
- Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2016;15(2):154–65. doi: 10.1016/s1474-4422(15)00336-1;
- Lees AJ, Ferreira J, Rascol O, et al. Opicapone as adjunct to levodopa therapy in patients with parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol. 2017;74(2):197–206. doi: 10.1001/jamaneurol.2016.4703].
- European Medicines Agency. Ongentys® Summary of Product Characteristics, 2021. https://www.ema.europa.eu/en/documents/product-information/ongentys-epar-product-information_en.pdf
- [Food and Drug Administration. Ongentys® Highlights of Prescribing Information, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212489s000lbl.pdf]
Epilepsy is a serious neurological disorder affecting over 70 million people worldwide (1). It is a brain disorder that causes recurring, unprovoked seizures (2). Antiseizure medications (ASM) are the initial treatment choice for almost all patients with multiple seizures. Initial monotherapy is effective in rendering approximately 60% of epilepsy patients seizure free. The remaining patients are considered medically refractory and are candidates for polytherapy (3).
Despite the large number of ASMs available for the treatment of epilepsy, nearly 30% of patients have inadequate seizure control. This justifies the development of third generation antiepileptic treatments, which are both effective and well tolerated as the adverse effects of ASMs have a significant negative effect on the quality of life of patients and may reduce treatment adherence and long-term retention rates. The availability of ASMs with favourable adverse effect profiles and simplification of drug regimens with once-daily therapies could be relevant in increasing adherence, which may improve patient outcomes (4).
Eslicarbazepine acetate (ESL) is a once-daily ASM that was approved in April 2009 by the European Medicines Agency (EMA) (Zebinix™) for adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset seizures with or without secondary generalization, and in June 2017 as monotherapy in the treatment of partial-onset seizures, with or without secondary generalization, in adults with newly diagnosed epilepsy (5). FDA approved Aptiom® in November 2013 as add-on medication to treat partial seizures in adults. A new indication for monotherapy was approved in August 2015. Finally, in September 2017 Aptiom receives the FDA approval for indication in children and adolescents 4 years old and older (6).
ESL is a potent competitive blocker of voltage gated sodium channels (VGSC), interacting with site 2 of the inactivated state of the channel. ESL is a third-generation member of the dibenzazepine family of ASMs that offers some important differences to other agents in the dibenzazepine family (carbamazepine and oxcarbazepine). In contrast to carbamazepine, ESL shows no transformation to carbamazepine 10,11-epoxide leading to a more favourable AE profile (4).
Studies consistently show that ESL is generally effective at controlling partial-onset seizures, and it remains efficacious in long-term trials. For adjunctive treatment three randomized, placebo-controled, double-blind phase III trials were development, with a total of 1053 refractory patients from 125 different centers. Responder rates were around 35-40% for 800mg/day and seizure frequency was significantly lower for doses of 800mg/day and 1200mg/day. Adverse effects were all mild or moderate in severity, the most common ones being dizziness, headache, and diplopia. ESL maintains its effectiveness over time, as demonstrated by extension and retrospective studies (7).
ESL monotherapy has also been revealed to be non-inferior to controlled-release carbamazepine in a phase III trial. This study followed 815 newly diagnosed patients randomized to receive once-daily ESL or twice-daily controlled-release carbamazepine. The proportion of patients who were seizure free for at least 6 months was 71.1% in the ESL group and 75.6% in the carbamazepine group. In addition, 64.7% of patients on ESL did not experience seizures for the whole year, compared with 70.3% on carbamazepine. The study concluded ESL once daily was not inferior to twice-daily carbamazepine in patients recently diagnosed with epilepsy (7).
Oral eslicarbazepine acetate was generally well tolerated when administered as adjunctive therapy or monotherapy in adult patients and when administered as adjunctive therapy in paediatric patients, with most adverse events being of mild or moderate intensity (8).
The once-daily dose constitutes a simplification of the patient's therapeutic scheme and therefore an improvement in their quality of life (4).
Despite the large number of ASMs available for the treatment of epilepsy, nearly 30% of patients have inadequate seizure control. This justifies the development of third generation antiepileptic treatments, which are both effective and well tolerated as the adverse effects of ASMs have a significant negative effect on the quality of life of patients and may reduce treatment adherence and long-term retention rates. The availability of ASMs with favourable adverse effect profiles and simplification of drug regimens with once-daily therapies could be relevant in increasing adherence, which may improve patient outcomes (4).
Eslicarbazepine acetate (ESL) is a once-daily ASM that was approved in April 2009 by the European Medicines Agency (EMA) (Zebinix™) for adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset seizures with or without secondary generalization, and in June 2017 as monotherapy in the treatment of partial-onset seizures, with or without secondary generalization, in adults with newly diagnosed epilepsy (5). FDA approved Aptiom® in November 2013 as add-on medication to treat partial seizures in adults. A new indication for monotherapy was approved in August 2015. Finally, in September 2017 Aptiom receives the FDA approval for indication in children and adolescents 4 years old and older (6).
ESL is a potent competitive blocker of voltage gated sodium channels (VGSC), interacting with site 2 of the inactivated state of the channel. ESL is a third-generation member of the dibenzazepine family of ASMs that offers some important differences to other agents in the dibenzazepine family (carbamazepine and oxcarbazepine). In contrast to carbamazepine, ESL shows no transformation to carbamazepine 10,11-epoxide leading to a more favourable AE profile (4).
Studies consistently show that ESL is generally effective at controlling partial-onset seizures, and it remains efficacious in long-term trials. For adjunctive treatment three randomized, placebo-controled, double-blind phase III trials were development, with a total of 1053 refractory patients from 125 different centers. Responder rates were around 35-40% for 800mg/day and seizure frequency was significantly lower for doses of 800mg/day and 1200mg/day. Adverse effects were all mild or moderate in severity, the most common ones being dizziness, headache, and diplopia. ESL maintains its effectiveness over time, as demonstrated by extension and retrospective studies (7).
ESL monotherapy has also been revealed to be non-inferior to controlled-release carbamazepine in a phase III trial. This study followed 815 newly diagnosed patients randomized to receive once-daily ESL or twice-daily controlled-release carbamazepine. The proportion of patients who were seizure free for at least 6 months was 71.1% in the ESL group and 75.6% in the carbamazepine group. In addition, 64.7% of patients on ESL did not experience seizures for the whole year, compared with 70.3% on carbamazepine. The study concluded ESL once daily was not inferior to twice-daily carbamazepine in patients recently diagnosed with epilepsy (7).
Oral eslicarbazepine acetate was generally well tolerated when administered as adjunctive therapy or monotherapy in adult patients and when administered as adjunctive therapy in paediatric patients, with most adverse events being of mild or moderate intensity (8).
The once-daily dose constitutes a simplification of the patient's therapeutic scheme and therefore an improvement in their quality of life (4).
- Mula. The comorbidities of epilepsy explained. EXPERT REVIEW OF NEUROTHERAPEUTICS 2020, VOL. 20, NO. 12, 1207–1209 https://doi.org/10.1080/14737175.2020.1840979
- www.epilepsy.com. Accessed Nov 2022
- St. Louis. Truly “Rational” Polytherapy: Maximizing Efficacy and Minimizing Drug Interactions, Drug Load, and Adverse Effects. Current Neuropharmacology, 2009, 7, 96-105
- Rocamora. A review of the efficacy and safety of eslicarbazepine acetate in the management of partial-onset seizures. Ther Adv Neurol Disord 2015, Vol. 8(4) 178–186 DOI: 10.1177/ 175628561558971
- https://www.ema.europa.eu/en/medicines/human/EPAR/zebinix. Accessed Nov 2022
- https://www.drugs.com/history/aptiom.html. Accessed Nov 2022
- Galiana. Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures. Drugs R D (2017) 17:329–339
- Heo. Eslicarbazepine Acetate: A Review in Focal-Onset Seizures. CNS Drugs 2020 Sep;34(9):989-1000. doi: 10.1007/s40263-020-00751-3
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