FDA Approved Xadago to Treatment Parkinson’s Disease

Xadago (safinamide) as an add-on treatment for levodopa/carbidopa cooperatively developed by two Italian companies-Zambon Pharma and Newron Pharmaceutical against Parkinson’s disease was approved by FDA for marketing in March. Of mention, Xadago is the first new drug got FDA approval over the recent decade for the disease, which is the second most common neurodegenerative disease among the elders. It’s estimated that about one to two in every one hundred people over 65 are in the condition. And the number is increasing with the trend of global aging, whilst few drugs are found effective to control the disease. The data released by the National Institutes of Health showed that about 50,000 people are newly diagnosed with the Parkinson’s disease annually.

There are few updates of new drugs for Parkinson’s disease in recent years and the primarily available drugs are dopamine preparation like Levodopa1, dopamine agonists (e.g. Bromocriptine2, Piribedil3, Dihydroergocryptine4, Pramipexole5, Ropinirole6, and Rotigotine7), Monoamine oxidase B (MAO-B) inhibitors (e.g. Selegiline8 and Rasagiline9), and the catechol-O-methyl transferase (COMT) inhibitors (e.g. Tolcapone10 and Entacapone11), among which Levodopa is the most effective drug and about 75% Parkinson disease patient are prescribed with it. However, long term usage of Levodopa risks fluctuation between “off” and “on” episodes. In “on” episode, all symptoms showed positive changes, and “off” episode is a time when the symptoms are worse like the increasing difficulty of walking. Thus it’s quite emergent to develop a drug that can decrease such side effects.

Xadago is a reversible MAO-B inhibitor and a dopamine reuptake inhibitor, can be applicable for the “off” episode with its ability to selectively inhibit MAO-B that inactivate dopamine, a substance helps transmit signals between the brain areas that produce smooth and purposeful movement.

Dopamine, which is an important substance in Parkinson’s disease, is normally synthesized from our diet. A simplified metabolic cycle of dopamine as it pertains to Parkinson’s disease is as follows. The amino acid tyrosine is absorbed from the intestine into the blood and crosses the blood-brain barrier via the large neutral amino acid transport system. Tyrosine is taken up by a SNC cell and converted to L-dopa via tyrosine hydroxylase (the rate-limiting step of dopamine production). L-dopa is converted to dopamine by an aromatic acid decarboxylase, and the dopamine is packaged into vesicles. When dopamine is released into the synapse, it can (1) bind a postsynaptic D1 receptor to stimulate the Direct / “go” pathway, (2) bind a postsynaptic D2 receptor to stimulate the Indirect / “stop” pathway, (3) bind a D3 autoreceptor to prevent more dopamine release, (4) be degraded by catechol-O-methyltransferase (COMT), or (5) be taken up by the presynaptic dopamine transporter (DAT) and subsequently degraded by monoamine oxidase type B (MAO-B).

The efficacy of Xadago has been shown in two clinical trials each involving 645 and 549 Parkinson’s diseases patients. Comparing with the patients taking placebo, those received Xadago experienced a much longer period of time of “on” episode and shorter “off” episode. It’s also observed that patients presented better performance in motor function with no involuntary movement during the “on” episode.

Parkinson’s diseases patients with below listed situations shouldn’t take Xadago:

Server liver issues;

Taking dextromethorphan for the treatment of cold or cough;

Taking MAOI (risk of abrupt severe increase of blood pressure)

Taking opioid drugs, antidepressants inhibitors (e.g. serotonin-norepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines) or cyclobenzaprine as they may cause fatal serotonin syndrome;

The common side effects of Xadago include uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia), and uncommon adverse effects are high blood pressure, hallucinations, compulsive behaviors, ferver etc.

At present, Xadago has been marketed into a number of European countries including German, Switzerland, Spain, Italy, Belgium, Danmark, Sweden, and the Great Bratain etc. Now it’s going into The USA and will compete with Rasagiline issued by Azilect.


  1. Levodopa (Sinemet) is an amino acid precursor of dopamine with antiparkinsonian properties.
  2. Bromocriptine, an ergoline derivative, is a dopamine agonist. It is used in the treatment of pituitary tumors, Parkinson's disease (PD), hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.
  3. Piribedil is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.
  4. Dihydroergocryptine is a dopamine agonist of the ergoline chemical class that is used as an antiparkinson agent.
  5. Pramipexole (Mirapex) is a partial/full D2S, D2L, D3, D4 receptor agonist with a Ki of 3.9, 2.2, 0.5 and 5.1 nM for D2S, D2L, D3, D4 receptor, respectively.
  6. Ropinirole is a selective D-2 agonist with Ki of 29 nM.
  7. Rotigotine is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease (PD) and Willis-Ekbom Disease.
  8. Selegiline, also known as L-deprenyl, is a substituted phenethylamine.
  9. Rasagiline, an Indapamide derivative, has been found to be a MAO-B inhibitor that could be used to against Parkinson's disease. IC50: 4.4nM.
  10. Tolcapone functions as a selective peripheral and central COMT inhibitor, exerting no effect on adrenergic, serotonergic, or cholinergic receptors or other enzymes involved in synthesis or catabolism of catecholamines.
  11. Entacapone inhibits catechol-O-methyltransferase(COMT) with IC50 of 151 nM.

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