A new combined treatment for Parkinson's disease filed by Orion Pharma with the U.S. FDA

The combination tablet represents a significant new treatment option for Parkinson's disease, a chronic progressive neurological disorder, the main symptom of which is an inability to control movements in a normal way. Three different strength combinations of the three active substances, levodopa, entacapone and carbidopa, are being registered. The new medication is designed to be used either as a stand-alone therapy or in combination with other Parkinson's disease therapies.

 

The combination preparation provides a more continuous delivery of levodopa thereby prolonging the benefits of the treatment. It should also improve patient compliance by offering a more convenient and manageable means of administering the three active compounds as the number of tablets taken daily will decrease. Typical to levodopa treatment is that the frequency of the daily doses must be gradually increased as the disease progresses. Patients with advanced Parkinson's disease need to take their daily levodopa, carbidopa and entacapone medication as many as up to eight to ten times per day. Normally, several other medications are included in a PD patient's daily treatment.

 

 

 

Levodopa has maintained its status as the preferred standard therapy for Parkinson's disease ever since it was introduced over 30 years ago. This substance is converted in the brain into dopamine, a neurotransmitter, the deficiency of which causes the symptoms of Parkinson's disease. To achieve the best clinical benefit, levodopa is combined with two important additional agents, carbidopa inhibiting the enzyme DDC (dopa-decarboxylase), and entacapone inhibiting the enzyme COMT (catechol-O-methyltransferase). When they are not inhibited, they break down levodopa before it reaches the brain, leading to a lower amount of levodopa available on the site of action.

 

This year, levodopa has been reaffirmed by both the American Academy of Neurology and the Movement Disorders Society as providing the best symptom control of all currently available therapies for Parkinson's disease. It is widely accepted that almost all patients will require levodopa at some point during the course of their disease.

 

Entacapone, a proprietary medicine developed by Orion Pharma, has been available so far as a plain substance under trade names Comtess and Comtan. Since its introduction in 1998 in Europe and in 1999 in the U.S. it has been widely adopted by neurologists as an important adjunct to levodopa in the treatment of Parkinson's disease patients.

 

 

 

 

 

The triple combination tablet is a significant new product introduction for Orion Pharma. It also means the inclusion of a preparation containing levodopa in the already existing CNS portfolio of Orion Pharma.

 

Orion Pharma has a marketing agreement for the combination tablet with Novartis, who is Orion's  marketing partner also for plain entacapone. Orion Pharma has marketing exclusivity for the combination product in Germany, the UK and Ireland, the Nordic and the Baltic countries, and some other areas. Moreover, Orion has the option to co-promote or co-market it in the USA, the largest single market, and in France, Spain, Italy and ten other countries.

 

A milestone payment of USD 10 million will be paid by Novartis to Orion Pharma in association with the submission of the U.S. new drug application.

 

 

 

Orion Corporation

 

Jukka Viinanen 

President and CEO

Orion Corporation

 

Risto Miettunen

President

Orion Pharma

 

Background information about Parkinson's disease and levodopa treatment is attached to this release on pages 3-4.

 

 

 

 

 

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.

 

Since its introduction as a 'miracle' drug in the 1960s, levodopa has deservedly remained the mainstay therapy for Parkinson's disease (PD). Levodopa in combination with a dopa-decarboxylase (DDC) inhibitor (carbidopa or benserazide) provides the best symptom control of all the currently available therapies for PD. It is widely accepted that all patients will require levodopa at some point during the course of their disease.

 

After long-term use, standard levodopa therapy is compromised by the development of motor complications, such as involuntary movements (dyskinesias) and motor fluctuations. With continued treatment and disease progression, the therapeutic benefits provided by each levodopa dose become shorter and begin to 'wear-off' (resulting in 'on' and 'off' periods) before the next scheduled dose. At the same time, a variety of dyskinesias can also begin to appear. Importantly, it is now believed that the motor complications associated with levodopa therapy do not relate directly to levodopa itself, but rather to the way in which it is currently administered.

 

 

 

Catechol-O-methyl transferase (COMT) is one of the two major enzymes breaking down levodopa. The benefits of levodopa therapy can be considerably extended by adding entacapone, a COMT-inhibiting agent, to the treatment. Entacapone, a discovery by Orion Pharma, is a reversible, selective inhibitor for COMT that became available in 1998.

 

The combination of levodopa/carbidopa/entacapone ensures the delivery of more continuous and predictable levels of levodopa to the brain after each oral dose. Therapies that provide this more continuous dopaminergic stimulation are now believed to be an important means of preventing and possibly reversing the development of motor complications that commonly occur with continued treatment and disease progression.

 

Entacapone extends the half-life of each levodopa dose, and so increases the amount of levodopa that reaches the brain, without increasing peak concentration. This ensures a more continuous and physiological stimulation of dopamine receptors. This continuous dopaminergic stimulation results in improved symptom control, with reduced 'wearing-off'. These improvements in the control of the symptoms of Parkinson's disease have been directly associated with improvements in patient activities of daily living.

 

 

The world market for drugs used in the treatment of Parkinson's disease was altogether USD 1.7 billion in 2001 (IMS Health). The sales of preparations containing levodopa with carbidopa or benserazide were altogether in the region of USD 532 million. Entacapone sales were USD 102 million.

 

 

Orion Pharma is a research and development-orientated pharmaceutical division of the Orion Group (HEX:ORIA, ORIB), which is one of the leading companies in the healthcare sector in the Nordic area of Europe. Pharmaceutical R&D at Orion Pharma produces new innovative drugs in four core therapy areas: CNS therapies, cardiology and critical care, hormonal and respiratory therapies. Entacapone, a COMT enzyme inhibitor used in the treatment of Parkinson's disease, is Orion Pharma's patented molecule discovery, available globally as Comtess and Comtan. For further information please consult http://www.orion.fi.

 

Novartis AG (NYSE: NVS) is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 2001, the Group's businesses achieved sales of CHF 32.0 billion (USD 19.1 billion) and a net income of CHF 7.0 billion (USD 4.2 billion). The Group invested approximately CHF 4.2 billion (USD 2.5 billion) in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 71,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.