(19) TZZ ZZ _T (11) EP 2 070 526 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/16 (2006.01) A61P 25/16 (2006.01) 26.02.2014 Bulletin 2014/09 (21) Application number: 09154864.4 (22) Date of filing: 08.04.2004 (54) Methods for treatment of Parkinson’s disease Verfahren zur Behandlung von Parkinson-Krankheit Procedes de traitment de la maladie de Parkinson (84) Designated Contracting States: • Benatti, Luca AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 20091 BRESSO (MI) (IT) HU IE IT LI LU MC NL PL PT RO SE SI SK TR (74) Representative: Minoja, Fabrizio (30) Priority: 11.04.2003 US 462205 P Bianchetti Bracco Minoja S.r.l. Via Plinio, 63 (43) Date of publication of application: 20129 Milano (IT) 17.06.2009 Bulletin 2009/25 (56) References cited: (62) Document number(s) of the earlier application(s) in EP-A- 0 400 495 US-A- 5 391 577 accordance with Art. 76 EPC: US-A- 5 945 454 04726590.5 / 1 613 296 • ANONYMOUS: "Newron Releases Positive (73) Proprietor: Newron Pharmaceuticals S.p.A. Preliminary Phase II Data for Salfinamide in 20091 Bresso (MI) (IT) Parkinson’s Disease" PRESS RELEASE OF 03.01.03, [Online] XP002290820 Retrieved from (72) Inventors: the Internet: URL:http://www.newron.com/ • Ruggero, Fariello press.asp?Action =news&intNewsID=1> 20091 BRESSO (MI) (IT) [retrieved on 2004-08-01] • Cattaneo, Carlo • BRUSA ET AL: "Pramipexole in comparison to L- 20091 BRESSO (MI) (IT) Dopa; a neuropsychological study.", • Salvati Patricia J.NEURAL.TRANSM., vol. 111, 5 March 2003 20091 BRESSO (MI) (IT) (2003-03-05), pages 373-380, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 070 526 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 070 526 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to a new compositions and methods of treating secondary and psycosocial symptoms of Parkinson’s disease. More specifically, the invention relates to methods for treating Parkinson’s Disease through the administration of safinamide, and a dopamine agonist. BACKGROUND OF THE INVENTION 10 [0002] Parkinson’s Disease (PD) currently affects about 10 million people world-wide. PD is a highly specific degen- eration of dopamine-containing cells of the substantia nigra of the midbrain. Degeneration of the substantia nigra in Parkinson’s disease causes a dopamine deficiency in the striatum. Effective management of a patient with PD is possible in the first 5-7 years of treatment, after which time a series of often debilitating complications, together referred to as 15 Late Motor Fluctuations (LMF) occur (Marsden and Parkes, Lancet II: 345-349,1997). It is believed that treatment with levodopa, or L-dopa, the most effective antiparkinson drug, may facilitate or even promote the appearance of LMF. Dopamine agonists are employed as a treatment alternative, but they do not offer the same degree of symptomatic relief to patients as L-dopa does (Chase, Drugs, 55 (supp1.1): 1-9,1998). [0003] Symptomatic therapies improve signs and symptoms without affecting the underlying disease state. Levodopa 20 ((-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid) increases dopamine concentration in the striatum, es- pecially when its peripheral metabolism is inhibited by a peripheral decarboxylase inhibitor (PDI). Levodopa/PDI therapy is widely used for symptomatic therapy for Parkinson’s disease, such as combinations with Ilevodopa, with carbidopa ((-)-L-alpba-hydrazino-alpha-methyl-beta-(3,4-dibydroxybenzene) propanoic acid monohydrate), such as SINEMET®; levodopa and controlled release carbidopa (SINEMET-CR®), levodopa and benserazide (MADOPAR®, Prolopa), lev- 25 odopa plus controlled release benserazide (2-Amino-3-hydroxy-propionic acid N’-(2,3,4-trihydroxybenzyl)-hydrazide), MADOPAR-HBS. [0004] COMT (catechol-O-methyltransferase) inhibitors enhance levodopa treatment as they inhibit levodopa’s me- tabolism, enhancing its bioavailability and thereby making more of the drug available in the synaptic cleft for a longer period of time. Examples of COMT inhibitors include tolcapone (3,4-dihydroxy-4’-methyl-5-nitrobenzophenone) and 30 entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-NN-diethyl-2-propenamide). [0005] Dopamine agonists provide symptomatic benefit by directly stimulating post- synaptic striatal dopamine recep- tors. Examples include bromocriptine ((5 α)-2-Bromo-12’-hydroxy-2’-(1-methylethyl)-5’-(2-methylpropyl)ergotaman-3’,6’, 18-trione), pergolide (8B-[(Methylthio)methyl]-6-propylergoline), ropinirole (4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2H- indol-2-one), pramipexole ((S)-4,5,6,7-Tetrahydro-N6-propyl-2,6-benzothiazolediamine), lisuride (N’-[(8α)-9,10-didehy- 35 dro-6-methylergolin-8-yl]-N,N -diethylurea), cabergoline ((8β)-N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]- 6-(2-propenyl)ergoline-8-carboxamide), apomorphine ((6aR)-5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline- 10,11-diol), sumanirole (5-(methylamino)-5,6-dihydro-4H-imidazo {4,5,1-ij} qumolin-2(1H)-one), rotigotine ((-)(S)- 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol), talipexole (5,6,7,8-Tetrahydro-6-(2-propenyl)-4H-thi- azolo[4,5-d]azepm-2-amine), and dihydroergocriptine (ergotaman-3’,6’,18-trione,9,10-dihydro-12’-hydroxy-2’-methyl- 40 5’- (phenylmethyl) (5’α)). Dopamine agonists are effective as monotherapy early in the course of Parkinson’s disease and as an adjunct to levodopa in more advanced stages. Unlike levodopa, dopamine agonists directly stimulate post- synaptic dopamine receptors. They do not undergo oxidative metabolism and are not thought to accelerate the disease process. In fact, animals fed a diet including pergolide were found to experience less age-related loss of dopamine neurons. 45 [0006] Amantadine (1-Aminotricyclo (3,3,1,13,7) decane) is an antiviral agent that was discovered by chance to have anti-parkinsonian activity. Its mechanism of action in PD has not been established, but it was originally believed to work by increasing dopamine release (Bailey et al., Arch. Int. Pharmacodyn. Ther., 216: 246-262, 1975). Patients who receive amantadine either as monotherapy or in combination with levodopa show improvement in akinesia, rigidity and tremor (Mann et al., Neurology, 21: 958-962, 1971; and Parkes et al., Lancet, 21: 1083-1086, 1971). 50 [0007] Other medications used in the treatment of Parkinson’s disease include MAO- B inhibitors. Inhibition of L-dopa metabolism through inactivation of the monoamino oxidase type B (MAO-B) is an effective means of enhancing the efficacy of both endogenous residual dopamine and that exogenously derived from its precursor, L- dopa (Youdim and Finberg, Biochem Pharmacol. 41: 155-162,1991). Selegiline (methyl-(1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine) is a MAO-B inhibitor. There is evidence that treatment with selegiline may slow down disease progression in PD by blocking 55 the formation of free radicals derived from the oxidative metabolism of dopamine (Heikkila et al., Nature 311: 467-469, 1984; Mytilineou et al., J Neurochem., 68: 33-39, 1997). Another MAO-B inhibitor under development is rasagiline (N- propargyl-1-(R)aminoindan, TEVA Pharmaceutical Industries, Ltd.). Other examples of MAO B inhibitors include lazabemide (N-(2-Aminoethyl)-5-chloro-2-pyridinecarboxamide) and caroxazone Oxo-(2-2H-1,3-benzoxazine-3 2 EP 2 070 526 B1 (4H)-acetamide). SUMMARY OF THE INVENTION 5 [0008] The presentinvention isbased, in part, on theunexpected finding that the combinationof safinamide, a dopamine agonist and provides a more effective treatment of secondary and psychosocial symptoms of Parkinson’s Disease (PD). [0009] In one embodiment, the invention relates to methods for treating Parkinson’s Disease through the administration of safinamide and dopamine agonists. When safinamide is used in combination with other types of drugs, an unexpected, synergistic effect is achieved. The improvement of symptoms and the delay of disease progression are more evident in 10 patients treated with the combination of drugs than those treated with a single type of drug alone. When safinamide was administered alone, patients improved only by an average 6.9% whereas when safinamide was added to a stabilized dose of a variety of dopamine agonists, the average improvement reached 27.8%. [0010] Safinamide, or safinamide derivative, may be administered at a dosage of generally between about 0.1 and about 10mg/kg/day, more preferably from about 0.5 to about 1, 2, 3, 4 or 5 mg/kg/day. 15 [0011] Safinamide is an anti-PD agent with multiple mechanisms of action. One mechanism of safinamide may be as a MAO-B inhibitor. [0012] Dopamine agonists include, but are not limited to, bromocriptine, pergolide, ropinirole, pramipexole, lisuride, cabergoline, apomorphine, sumanirole, rotigotine, talipexole and dihydroergocriptine. [0013] In one aspect, a combination therapy for PD includes safinamide, and a dopamine agonist. In one embodiment, 20 a combination therapy for PD includes safinamide and one or more of bromocriptine, cabergoline, lisuride, pergolide, ropinirole, apomorphine, sumanirole, rotigotine, talipexole, dihydroergocriptine, and pramipexole, for treating a patient in need of PD treatment. [0014] Administration of the therapies and combination therapies of the invention may be orally, topically, subcutane- ously, intramuscularly, or intravenously. 25 [0015] The invention further relates to kits for treating patients having Parkinson’s Disease. Such kits include a ther- apeutically effective dose of an agent for treating or at least partially alleviating the symptoms of Parkinson’s Disease, bromocriptine, pergolide, ropinirole, pramipexole, lisuride, cabergoline, apomorphine, sumanirole, rotigotine, talipexole, dihydroergocriptine and safinamide either in the same or separate packaging, and instructions for its use.