Formulations combining three active drug substances in one tablet for the treatment of Parkinson's Disease (PD) are under development by Orion Corporation Orion Pharma, Finland. The new treatment option could be available in 2004. A marketing agreement for the product was signed yesterday with Novartis Pharma AG of Switzerland. The preparation will contain Orion's new proprietary medicine entacapone (trade names Comtess and Comtan) in combination with levodopa and carbidopa, the first line medications in PD. The combination tablet will notably facilitate the dosing of these medicines, which are always taken concomitantly and several times per day.
Currently, the most effective and widely used treatment of Parkinson's Disease is levodopa, which in the brain turns to dopamine, a neurotransmitter the deficiency of which is behind the symptoms of the disease. To achieve the best clinical benefit, levodopa is invariably combined with a DDC (dopa-decarboxylase) inhibitor, i.e. carbidopa or benserazide, and increasingly also with a COMT (catechol-O-methyltransferase) inhibitor, entacapone. The DDC and COMT are enzymes breaking down levodopa on its way to the brain, whereby they reduce the amount of levodopa entering the brain, the site of action.
Currently available levodopa preparations contain also a DDC inhibitor, i.e. carbidopa or benserazide, whereas the COMT inhibitor entacapone, a new chemical entity discovered by Orion Pharma and launched two years ago, is available as a separate tablet. Orion Pharma is now complementing its CNS portfolio with a new treatment option that allows the co-administration of entacapone with levodopa and carbidopa in one tablet. Three different strengths of the combination tablet are being developed, to be used as a stand-alone therapy. The proportions of the substances in each tablet strength are optimised to cover the most common clinical needs for dosing. The combination tablet is expected to notably simplify the daily dosing of the three medicines, thereby optimising the quality of the treatment and improving patient compliance.
Improvement in current
As Parkinson's disease progresses, not only the amounts of levodopa but also the frequency of the daily doses must be gradually increased. Patients with advanced Parkinson's disease need to take their daily levodopa, carbidopa and entacapone medication as many as
ten times per day. Undoubtedly, a tablet providing the three active
substances in one will be easier to manage by the patients, many of which also suffer from swallowing difficulties. Several other medications are normally also included in a PD patient's daily treatment.
Orion Pharma estimates that about two-thirds of all patients treated with entacapone in line with the current indication can be ideally treated with the triple combination tablet. Patients with very complicated treatment regimes can, however, continue to be treated with levodopa-carbidopa therapy and a separate entacapone tablet.
"We expect Parkinsonian patients to welcome a new product that simplifies the dosing of their medication. We also believe that the three-in-one approach will add entacapone into the treatment regime of a larger number of patients within the range of its indication", says Jyrki Mattila, President of Orion Pharma.
EU and U.S. registration
in three years
Orion believes that the development process of the triple combination will be facilitated by the fact that all the three compounds are already on the market and used concurrently in clinical practise. Applications for marketing approvals are aimed to be submitted to the EU and the U.S. drug authorities during 2002. Accordingly, registrations in the EU and the U.S. could be anticipated in 2003, with launches and full worldwide commercialisation rolling out in 2004.
MARKETING AGREEMENT WITH NOVARTIS PHARMA
Orion Pharma signed a marketing agreement with Novartis Pharma AG yesterday on the tablet combining entacapone with levodopa and carbidopa. Novartis is already Orion's marketing partner for plain entacapone, under the trade name Comtan.
The arrangement provides Novartis with exclusive, co-promotion and co-marketing rights, depending on territory. Orion Pharma has marketing exclusivity for the product in Germany, the UK and Ireland, the Nordic countries, the Baltics and some other areas. Orion retains the possibility to co-promote or co-market the product in the USA, the largest single market, and in France, Spain, Italy and ten other countries. The rest of the world will be exclusively a market for Novartis Pharma, except Japan, which is not covered by the agreement. One trademark common to both parties will be registered for the product, except for potential co-marketing territories.
"We are glad to be building on our successful collaboration with Orion with the triple combination therapy" said Thomas Ebeling, CEO of Novartis Pharma. "The Comtan benefit of prolonging wellness and quality of life for Parkinson's Disease patients has been in evidence and gathering momentum for some time. This new concept should optimise therapy for a larger proportion of the patients currently receiving levodopa therapy."
Milestone payments by Novartis Pharma to Orion Pharma will be due in the progress of the global registration process. An upfront payment of MUSD 15 was due upon the signing of the agreement.
The world market for drugs used in the treatment of Parkinson's disease was altogether USD 1.6 billion in 1999 (IMS Health). The sales of preparations containing levodopa with carbidopa or benserazide were altogether in the region of USD 590 million. Entacapone sales were USD 27 million. Orion estimates that the triple combination tablet can increase the sales potential of entacapone remarkably.
Parkinson's Disease is reflected as movement disorders associated with the deficiency of dopamine, a neurotransmitter produced by the brain. Typical symptoms include muscle rigidity, tremor, a decrease in the range and frequency of voluntary movements, abnormalities in posture and gait, and the emergence of motor fluctuations that increasingly affect the patient's ability to perform activities of daily living. It is a gradually progressing neurological disease mainly diagnosed in elderly people, but increasingly, it is known to occur before the age of 40. About 4 million diagnosed patients suffer from the disease worldwide. The reasons for decreased dopamine levels and the actual course of the disease progression are under intensive investigation. Both environmental and hereditary factors, among others, are suggested to contribute. Today, research is largely focusing on genetics and different toxic environmental factors which can be underlying reasons for disturbances in the brain, such as the loss of those cells in the brain that produce dopamine.
The Orion Group (Hex: ORI), based in Finland, is one of the leading companies in the healthcare sector in the Nordic area of Europe. The 1999 net sales of the Group were EUR 912 million. The company employs around 5,200 people. Activities in healthcare account for 88 percent of the net sales and include the research, development, manufacture and marketing of pharmaceuticals and diagnostic products, as well as wholesale and distribution of pharmaceuticals and a broad range of medical equipment and supplies.
Orion Pharma is the core business division of the Orion Group, with strong research activity focusing on the central nervous system (CNS), cardiac insufficiency and critical care, hormone replacement therapies (HRT) and respiratory diseases. In addition to Comtess/Comtan (entacapone) for Parkinson's disease, proprietary drugs based on Orion's own research include the hormone replacement therapies Divina, Divitren and Divigel, Fareston (toremifene) for breast cancer, Precedex (dexmedetomidine) for the sedation of patients in intensive care, and the animal sedatives Domitor, Domosedan and Antisedan. Simdax (levosimendan) for decompensated heart failure is awaiting EU approval.
Novartis (NYSE: NVS), is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 1999, the Group (including Agribusiness) achieved sales of USD 21.7 billion and invested more than USD 2.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis employs about 82,400 people and operates in over 140 countries around the world. The Group recently announced plans to spin off its Crop Protection and Seeds sectors and to merge them with the agrochemicals business of AstraZeneca in the second half of 2000.