Educational materials are available for your patients to support them as they get started with NOURIANZ^® (istradefylline)

Transcript

Hello, thanks for joining me today for this discussion of the role of adenosine in Parkinson’s disease (PD) and the unique mechanism of action for NOURIANZ^® (istradefylline).

I’m Dr. Stuart H. Isaacson, Director of Parkinson's Disease and Movement Center in Boca Raton. This program is sponsored by Kyowa Kirin, Inc. I’m a paid speaker presenting on behalf of Kyowa Kirin.

NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing “off” episodes. As we look into the role of the A_2A pathway in the pathophysiology of PD, I’ll also be reviewing the Important Safety Information for NOURIANZ. So, let’s start off with the Warnings and Precautions for NOURIANZ.

Dyskinesia: NOURIANZ in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

Hallucinations / Psychotic Behavior: Because of the potential risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with NOURIANZ. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking NOURIANZ.

Impulse Control / Compulsive Behaviors: Patients treated with NOURIANZ and one or more medication(s) for the treatment of Parkinson’s disease (including levodopa) may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge, or compulsive eating, and/or other intense urges, and the inability to control these urges. In clinical trials, 1 patient treated with NOURIANZ 40 mg was reported to have impulse control disorder, compared to no patient on NOURIANZ 20 mg or placebo. We will go over additional Important Safety

The history of Parkinson’s disease is fascinating. Although PD was first identified......in 1817 by James Parkinson,...

...it was not until the 1920s that evidence was uncovered suggesting the substantia nigra may be involved. It would then take an additional 3 decades to better understand the underlying pathophysiology of Parkinson’s disease.

In 1957 dopamine was first characterized in the brain by Kathleen Montagu, which was followed by the discovery that it was highly enriched in the striatum.

dopamine in the striatum for patients with PD began, and in 1961, intravenous levodopa, the metabolic precursor of dopamine, was first used to treat patients with PD.

This culminated in the approval of oral levodopa by the FDA a decade later for the treatment of patients with PD.

The management of PD is largely focused on restoring dopamine loss resulting from the progressive degeneration of dopaminergic neurons in the substantia nigra. The cornerstone of therapy is levodopa/carbidopa.

We know that dopaminergic signaling gets progressively worse due to the continued loss of dopaminergic neurons, however, there are other important neurotransmitters and neuromodulators involved in the pathophysiology of PD. One of these neuromodulators is adenosine, which we will talk about in more detail in a moment.

In addition to dopamine, several nondopaminergic neurotransmitters and neuromodulators regulate movement through 2 distinct pathways that control motor function; these are known as the indirect (“No Go”) and direct (“Go”) pathways.

So, let’s talk a little more about the adenosine A_2A receptor. Adenosine is a neuromodulator that is widely distributed throughout the body and is involved in many physiological and pathophysiological processes. There are 4 different adenosine receptor types: A1, A_2A, A2B, and A3. Within the brain, adenosine A_2A receptors are highly enriched in striatopallidal neurons at the indirect pathway between the striatum, globus pallidus, and substantia nigra. These are brain areas that are integral to coordinating movement. In patients with PD, expression of the A_2A receptor is upregulated relative to healthy individuals, which leads to increased signaling through the indirect (“No Go”) pathway. In addition to the loss of dopamine-mediated go signals, adenosine is present acting as a brake through A_2A receptors via the indirect pathway.

As I mentioned earlier, the hallmark of Parkinson’s disease pathophysiology is the degeneration of dopaminergic neurons, primarily in the nigrostriatal pathways of the brain. “Off” episodes originate through both central and peripheral mechanisms.

Replacement of dopamine with levodopa/carbidopa improves motor symptoms but over time, “off” fluctuations emerge. Gradually, the therapeutic window of each levodopa dose diminishes.

This, coupled with the increased activation of the A_2A pathway may in part be responsible for the worsening of PD symptoms and the emergence of “off" episodes.

Normally, dopamine facilitates motor function by acting on the direct and indirect pathways, also known as the “Go” and “No Go” pathways, respectively. Balance between the opposing direct (“Go”) and indirect (“No Go”) pathways is responsible for coordinating normal motor function.

In the direct (“Go”) pathway, dopamine binds D1 receptors to facilitate movement, while in the indirect (“No Go”) pathway dopamine binds to D2 receptors to provide balance. However, in PD, upregulation of the A_2A pathway enhances the indirect (“No Go”) pathway to inhibit movement.

As PD progresses there is further dopamine loss in the striatum. This, coupled with the increased expression of A_2A receptors in the indirect ("No Go") pathway, can contribute to further impairment in motor function.

To use an analogy, the direct (“Go”) and indirect (“No Go”) pathways work like the gas and brake pedals of a car. Increased signaling through the direct (“Go”) pathway is like pressing on the gas pedal, while signaling through the indirect (“No Go”) pathway is like pressing on the brake. Motor activity can be facilitated by pressing on the gas and also by releasing the brake.

OK, so let’s use the gas and brake pedal analogy to visualize what is happening in the direct (“Go”) and indirect (“No Go”) pathways in PD.

Stimulation of D1 dopamine receptors can be thought of like pushing down on the gas pedal of a car, which initiates movement through the direct (“Go”) pathway.

To coordinate normal motor function, there needs to be a complimentary signaling mechanism that acts as the brake. Stimulation of adenosine A_2A receptors is like applying the brake, which suppresses movement. Adenosine is a neuromodulator that acts as a brake through the indirect (“No Go”) pathway, opposing dopamine-mediated activation of movement through the direct (“Go”) pathway.

Now, let’s use the gas/brake analogy to describe the coordination of signaling through the nigrostriatal pathways.

If there is not enough pressing on the gas pedal, dopamine activity, due to loss of dopaminergic neurons, and if pressing on the brake is increased, adenosine activity, due to an increased number of A_2A receptors, the signaling balance is lost, and movement is impeded.

Pressing more on the gas pedal through the direct (“Go”) pathway by using levodopa may help for some time, but the gas pedal can only be pushed so far. However, lifting the brake of adenosine by blocking the A_2A receptor may work to facilitate movement by providing an alternative mechanism to target the indirect ("No Go") pathway.

So, based on what we have discussed about the gas/brake analogy, in theory lifting the brake of adenosine could be achieved by the adjunctive use of an A_2A receptor antagonist in conjunction with levodopa, to help address the imbalance between the pathways. This suggests that the A_2A pathway is a viable target for therapeutic intervention in PD.

Now let’s discuss the pharmacology of NOURIANZ.

This is where NOURIANZ plays a role as the first and only adenosine A_2A receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with PD experiencing “off” episodes.

It has a novel nondopaminergic mechanism of action that works differently than other approved treatments for patients with PD experiencing “off” episodes.

The precise mechanism of action by which NOURIANZ exerts its therapeutic effect in PD is not known.

However, in in vitro studies and in vivo animal studies, NOURIANZ was demonstrated to be an adenosine A_2A receptor antagonist.

Now let’s review some additional Important Safety Information regarding special populations.

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily. Avoid use of NOURIANZ with strong CYP3A4 inducers.

Specific Populations Pregnancy: Based on animal data, may cause fetal harm. Hepatic impairment: The maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment is 20 mg once daily. Avoid use in patients with severe hepatic impairment.

Adverse Reactions The most common adverse reactions with an incidence of ≥5% and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%) for NOURIANZ 20 mg, 40 mg, and placebo, respectively. You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Thanks for watching this presentation about the role of adenosine and the use of istradefylline as an adjunctive treatment for “off” episodes in adult patients with Parkinson’s disease. For information about the clinical data supporting the safety and efficacy of NOURIANZ for treating “off” episodes in PD, please watch the other videos in this series or go to the NOURIANZ website: www.NOURIANZHCP.com.