The New Anti-Parkinson's Drug Safinamide

In March 2017, the FDA approved safinamide (Xadago) for clinical use in the United States. Safinamide is the first new drug approved by the FDA to treat Parkinson’s disease in more than 10 years. It is a form of adjunctive, or add-on treatment, used in combination with levodopa.

Parkinson’s Disease Explained

Parkinson’s disease is a movement disorder which gradually progresses and typically begins at around age 60. Symptoms include trembling, stiffness, slowed movement, and poor balance. This disease eventually results in difficulties with walking, talking, and other routine activities of daily living. In the United States, about 50,000 people are diagnosed with Parkinson’s disease each year.

Although there is no cure for Parkinson’s disease, there are treatments that help with symptom management, including the following:

• levodopa
• dopamine agonists (e.g., apomorphine, bromocriptine, ropinirole, and pramipexole)
• monoamine oxidase inhibitors or MAO-B inhibitors (e.g., selegeline and rasagaline)
• catechol-O-methyl-transferase (COMT) inhibitors (e.g., entacapone and tolcapone)
• amantadine
• anticholinergic drugs, such as Artane and Cogentin (usually given to younger people in whom tremor is the main symptom)

Unfortunately, there are no treatments that slow or stop the progression of Parkinson’s disease.

Levodopa is the most potent and prominent drug used to treat Parkinson’s disease; however, its effect tends to wear off over time and can lead to negative side effects including dyskinesia.

Drugs including COMT inhibitors, dopamine agonists, and non-dopaminergic treatments—such as anticholinergic treatments and amantadine—can be used as alternatives to levodopa, in addition to levodopa, or in combination with one another.

In people with advanced Parkinson’s disease, when medications fail, deep brain stimulation (brain surgery) can be considered to help alleviate symptoms.

Typically, medications are reserved for people whose symptoms have become severe enough to interfere with activities of daily living. Levodopa is usually the drug of choice in people aged 65 and older whose lifestyles are seriously compromised. People younger than 65 can be treated with a dopamine agonist.

Drugs are started at the lowest effective dose and treatment is typically delayed as long as possible. However, the research supporting the guiding tenet of “start low and go slow” with dosages of levodopa is mixed. According to author Peter Jenner:

"The introduction of L-Dopa [levodopa] in those with longer disease duration or in high doses may result in a shortened period of good effect before motor complications appear. Very recently, keeping the dose of L-dopa below 400 mg per day in early PD was shown to reduce the risk of dyskinesia induction."

However, Jenner goes on to note the following:

"The early use of L-dopa was also shown to be the most effective treatment for motor symptoms and not to affect the long-term risk of dyskinesia."

Verily, such conflicting evidence underscores how little we know about the pathology and treatment of Parkinson’s disease.

How Does It Work?

In people with Parkinson’s disease, the brain doesn’t produce enough of a neurotransmitter called dopamine. The cells that produce dopamine either die or become impaired. Dopamine is necessary for proper motor control and movement.

Specifically, dopamine transmits signals in the brain that are involved in smooth, purposeful movements like eating, writing, and typing. Like selegeline and rasagaline, safinamide is a type of MAO-B inhibitor, which prevents the breakdown of dopamine and thus increases its levels in the brain.

Of note, safinamide also modulates glutamate release; however, the specific effect of this action on the drug’s therapeutic actions is unknown.

Unlike other MAO-B inhibitors, which can be prescribed alone for those with early-stage Parkinson’s disease, safinamide is intended to be used in conjunction with other types of antiparkinson drugs for the later-stage disease, most notably levodopa as well as dopamine agonists.

When people first start treatment for Parkinson’s symptoms, drugs tend to work pretty well and symptoms are controlled throughout the day. Between five and 10 years, however, the efficacy of conventional Parkinson’s drugs wanes in many people, and symptom control becomes more difficult to alleviate.

Specifically, in people with mid- to late-stage Parkinson’s disease, motor fluctuations or involuntary muscle movements (dyskinesia and freezing) begin to crop up.

Dyskinesia is most pronounced in people taking levodopa and is an adverse effect of drug treatment. The manifestation of dyskinesia bodes poorly with respect to prognosis and should preferably be delayed as long as possible. Furthermore, non-motor symptoms, such as dementia, depression, and hallucinations, which are affected little if at all by dopaminergic drugs, also become a problem.

Those patients who decompensate after adequate treatment that has lasted some time are difficult to treat in a fashion that maintains mobility and quality of life.

In other words, once levodopa stops working as well, in part because we don’t understand the pathology of this decompensation, it’s hard to get people back to a stable baseline and a quality of life experienced earlier during disease when levodopa and other dopaminergic agents were working.

Moreover, even if motor difficulties are reined in, non-motor issues like mood disorders, sleep disorders, and dementia become troublesome to those with late-stage Parkinson’s disease.

Unfortunately, we can’t predict which people with late-stage Parkinson’s disease will develop fluctuations and motor complications. Overall, disease duration, disease stage, length of treatment with levodopa, levodopa dosages, gender, and body weight are all believed to play a role in eventual decompensation.

On Times and Off Times

"ON time" refers to periods when medications are adequately working and the symptoms of Parkinson’s disease are controlled.

"OFF time" refers to periods when the medications wear off and Parkinson’s symptoms, such as tremor, rigidity, and difficulty walking reappear.

The addition of safinamide to drug regimens of people with advanced Parkinson’s disease taking levodopa increases the amount of ON time and decreases OFF time.

Safinamide Clinical Trials

Results from two randomized clinical trials have shed light on the potential benefits of safinamide use among people with more advanced Parkinson’s disease. These participants had been diagnosed with Parkinson’s disease at either three or five years’ duration.

The first clinical trial assessed 669 participants with motor fluctuations. These participants either received safinamide in addition to their other antiparkinson medications or placebo (no safinamide) and their other antiparkinson drugs.

Average ON time for the participants was between 9.3 and 9.5 hours. After six months of testing, ON times increased in both sets of patients; however, ON times were about 30 minutes longer in those taking safinamide.

After two years of treatment, the average ON time stayed about the same in those taking safinamide but decreased in those taking a placebo. Thus after two years on average, participants taking safinamide along with levodopa as well as other antiparkinson medications experienced about one more hour of effective treatment for Parkinson’s disease symptoms.

Of note, safinamide reduced OFF time by about 35 minutes. Remember that OFF times refer to periods when antiparkinson drugs wear off, and symptoms like tremor are once again exacerbated.

In addition to lengthening ON times and shortening OFF times, safinamide also improved movement (motor scores) in those taking it. Furthermore, at a higher dosage, safinamide also helped with activities of daily living and quality of life.

Similarly results from the second trial, which involved 549 participants, suggest an increase in ON time by about one hour in those taking safinamide as compared with those taking placebo as well as reductions in OFF time. Additionally, improvements in functioning and quality of life scores were also observed.

Safinamide Negative Side Effects

Because of negative side effects, 3.7 percent of participants taking safinamide dropped out of clinical trials as compared with 2.4 percent of those taking a placebo.

Common adverse effects observed during these clinical trials included the following:

• jerky or fragmented motions (i.e., dyskinesia)
• falls
• nausea
• insomnia

Of these symptoms, dyskinesia was about twice as common in people taking safinamide as compared with those not taking it (i.e., those taking placebo).

Less common but more serious adverse effects include the following:

• worsening high blood pressure
• visual hallucinations and psychotic behavior
• falling asleep during the day
• serotonin syndrome (when used with MAO inhibitors, antidepressants, and opioids)
• problems with impulse control or compulsive behavior (think OCD)
• fever and confusion
• retinal problems

Here are some drugs that you shouldn’t take if you’re also taking safinamide:

• certain antidepressants (serotonin-norepinephrine reuptake inhibitors, tricyclics, and tetracyclics)
• cyclobenzaprine
• dextromorphan (found in certain cough medications)
• opioids
• St. John’s Wort

Although people with kidney impairment can take safinamide, those with severe liver problems should not take the drug.

Bottom Line

Safinamide is most useful in those with mid- to late-stage Parkinson’s disease who experience motor fluctuations (i.e., dyskinesia) and a decrease in the effectiveness of their medications (i.e., OFF times). Safinamide could be a better add-on therapy to primary treatment with levodopa than other add-on treatments, including other MAO-B inhibitors as well as COMT inhibitors. Safinamide is not used alone.

The most common negative side effect of safinamide is dyskenesia or an increase in involuntary movements. People with severe liver problems or those taking certain antidepressants or other medications should not take safinamide.