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

Transcript

Hello, thank you for taking the time to watch this video, where we’ll review the efficacy and safety of NOURIANZ^® (istradefylline), the first and only adjunctive therapy to levodopa/carbidopa for “off” episodes in adult patients with Parkinson’s disease (PD) that lifts the brake of adenosine.

NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease experiencing “off” episodes. NOURIANZ is the first adjunctive treatment that lifts the brake on adenosine.

Before diving into some key facts about NOURIANZ, let’s take a moment to review some Important Safety Information.

I’m Dr. Yasar Torres-Yaghi, Director of the Parkinism and Dementia Clinic at Georgetown University.

This program is sponsored by Kyowa Kirin, Inc., and is not CME accredited. I’m a paid speaker on behalf of Kyowa Kirin. All information presented is consistent with FDA guidelines.

The following is some of the Important Safety Information for NOURIANZ, specifically the Warnings and Precautions.

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.

We’ll go over more important safety information throughout this presentation.

Now for some key facts about NOURIANZ. Approved in the US in 2019, NOURIANZ...

Please continue watching for full NOURIANZ Important Safety Information throughout this video and click on the link below to access the full Prescribing Information.

...is the first and only A_2A receptor antagonist to provide a non-dopaminergic approach that complements levodopa/carbidopa therapy.

NOURIANZ has been studied in 4 pivotal clinical trials,...

Please continue watching for full NOURIANZ Important Safety Information throughout this video and click on the link below to access the full Prescribing Information.

...which we will review before jumping into the efficacy data, and has been prescribed to more than 90 thousand patients in the US and Japan.

In both studies, the primary endpoint was a change from baseline in percentage of awake...

...hours spent in “off” time per day. Here,...

...we see the trial design for the Japanese studies, which is similar in design to the studies conducted in the U.S. and Canada with one difference relating to the primary endpoint. In the Japanese studies, the primary endpoint was absolute change in “off” time and not percent change from baseline, as in studies 1 and 2.

Patients were randomized equally to treatment with once-daily NOURIANZ 20 mg, 40 mg, or placebo.

The secondary endpoint in all 4 studies was the change from baseline in “on” time without troublesome dyskinesia. “Without troublesome dyskinesia” was defined as either not having any dyskinesia or having dyskinesia that was reported as non-troublesome. All endpoints were measured using 24-hour patient diaries.

There were some similarities between baseline demographics in the…

…US/Canada and Japanese studies, such as mean age, time since… Graphic: Animates from the left.

…diagnosis, and total “off” hours per day. However, there were…

…differences in sex and total daily LD/CD dose; Japanese trials included a…

…greater percentage of female subjects and a lower total daily…

…levodopa/carbidopa dose than US/Canada trials.

All of the patients were on stable doses of levodopa/carbidopa for the duration of the studies. In the 2 Japanese trials, however, patients could have received levodopa/benserazide instead.

Patients were allowed to use concomitant medications for Parkinson’s. Across all 4 trials these included dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine, and/or anticholinergics.

So, before we begin our review of the efficacy data from the 4 pivotal trials, let’s go over a few more points of the Important Safety Information for 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.

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

OK, now let’s discuss efficacy. Here you can see the primary endpoint results from the US/Canadian pivotal trials, which was percent change in daily “off” time.

There was a statistically significant decrease in “off” time for patients treated with both the 20-mg and 40-mg daily doses at week 12.

In studies 1 and 2 at baseline, patients experienced off time for about 40% of their daily awake hours. By week 12 “off” time was reduced to 31% for NOURIANZ 20 mg vs 33% for placebo, and was reduced to 28% for NOURIANZ 40 mg compared with 34% for placebo.

In studies 3 and 4, which were conducted in Japan, we observed similar results.

Decreases in “off” time were seen as early as two weeks, and statistically significant reductions were observed at week 12 in both studies for both doses.

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 ≥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.

Now, let’s take a look at the reduction of...

...“off” time in hours per day across all 4 clinical trials. Changes in “off” time, comparing NOURIANZ with placebo, ranged from 0.65 to 1.16 hours per day.

Recall that the percent decrease in “off” time from baseline was 6.78% in study 1 and 4.57% in study 2.

Compared with patients on placebo, patients treated with 40 mg NOURIANZ plus baseline therapy experienced an increase in “on time” without troublesome dyskinesia.

In Study 1, compared with placebo, patients treated with NOURIANZ 40 mg/day experienced an increase from baseline in “on” time without troublesome dyskinesia of 0.96 hours (nominal P=0.026) and in Study 2, patients treated with NOURIANZ 20 mg/day experienced an increase from baseline in “on” time without troublesome dyskinesia of 0.55 hours (nominal P=0.135).

In Study 3, compared with placebo, mean increases from baseline in “on” time without troublesome dyskinesia of 0.57 hours (nominal P=0.085) and of 0.65 hours (nominal P=0.048), respectively, were observed in patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg.

In Study 4, the mean increases in “on” time without troublesome dyskinesia were 0.83 hours (nominal P=0.008) for NOURIANZ 20 mg and 0.81 hours (nominal P=0.008) for NOURIANZ 40 mg.

The adverse events that were observed in 2% or more of patients treated with NOURIANZ and greater than placebo are shown here. Dyskinesia had the highest rate, and occurred at about twice the rate of placebo. The incidence was 15% for NOURIANZ 20 mg, 17% for NOURIANZ 40 mg, and 8% for placebo, in combination with levodopa.

The most common adverse reactions in which the frequency for NOURIANZ was at least 5%, and greater than the incidence on placebo, were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.

The incidence of treatment-emergent adverse reactions of special interest in the US and Canadian, and Japanese studies for patients treated with NOURIANZ 20 mg/day, 40 mg/day, or placebo are shown here.

The rates of falls in the placebo groups were 9.4%, and 6.5% and 6.9% with NOURIANZ 20 mg and 40 mg, respectively. The rates of nausea and vomiting were similar in the placebo and NOURIANZ 20 mg groups, at 4.7% and 4.8%, respectively, with an increase seen with NOURIANZ 40 mg to 6.9%. Impulse control disorders were seen in 0.3% of patients on NOURIANZ 40 mg, compared with none observed with patients administered NOURIANZ 20 mg or placebo.

The incidence of patients discontinuing for any adverse reaction was 5% for NOURIANZ 20 mg, 6% for NOURIANZ 40 mg, and 5% for placebo. The most frequently reported adverse reaction causing study discontinuation

To sum it all up, NOURIANZ represents...

Please continue watching for full NOURIANZ Important Safety Information throughout this video and click on the link below to access the full Prescribing Information.

...the first and only A_2A receptor antagonist indicated as adjunctive treatment to LD/CD in adult patients with PD experiencing “off” episodes. In clinical trials, NOURIANZ reduced “off” time and improved “on” time without troublesome dyskinesia.

The precise mechanism for the efficacy of NOURIANZ in the treatment of “off” episodes in PD is unknown.

Thanks for watching this presentation about the clinical data of NOURIANZ in Parkinson’s disease. For additional information about NOURIANZ for treating “off” episodes in PD, please watch the other videos in this series or go to the NOURIANZ website: www.NOURIANZHCP.com.

Visit NOURIANZHCP.com to learn more.

Transcript

Hello, thank you for taking the time to watch this video about the safety and dosing/administration data from the pivotal trials for NOURIANZ^® (istradefylline).

This program is sponsored by Kyowa Kirin, Inc., and I am a paid speaker on behalf of Kyowa Kirin. All information presented is consistent with FDA guidelines. This program is not an accredited CME program.

NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.

In addition to reviewing the NOURIANZ safety data from the pivotal trials, I’ll be highlighting the Important Safety Information throughout the presentation and will start with some of the Warnings and Precautions.

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.

As part of the clinical development program, 4 pivotal clinical trials were conducted to evaluate the efficacy and safety of NOURIANZ for the management of “off” time in PD. Study 1 was conducted in the US and Canada, and Study 2 was conducted only in the U.S. Studies 3 and 4 were conducted in Japan.

Of the patient population exposed to NOURIANZ, 50% were male, 32% White, 67% Asian, and the mean age was 65 years (range: 33 to 84 years). Of these patients, 356 received NOURIANZ 20 mg and 378 received NOURIANZ 40 mg. The safety of NOURIANZ was evaluated in 734 patients with PD taking a stable dose of levodopa/carbidopa for the duration of the studies with or without other PD medications. In the 2 trials conducted in Japan, however, patients could have received levodopa/benserazide instead.

Concomitant use of medications for PD was allowed, and across all 4 trials, 85% were on dopamine agonists, 40% were on MAO-B inhibitors, 38% were on COMT inhibitors, 33% were taking amantadine, and 13% were taking anticholinergics.

The adverse events that were observed in 2% or more of patients...

...treated with NOURIANZ and greater than placebo are shown here. Dyskinesia had the highest rate, and occurred at about twice the rate of placebo. The incidence was 15% for NOURIANZ 20 mg, 17% for NOURIANZ 40 mg, and 8% for placebo, in combination with levodopa. The most common adverse reactions in which the frequency for NOURIANZ was at least 5%, and greater than the incidence on placebo, were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Discontinuations due to adverse reactions were similar to placebo.

About 5% of placebo patients discontinued, versus 5% of 20 mg NOURIANZ patients and 6% of 40 mg NOURIANZ patients.

The most frequently reported adverse reaction causing study discontinuation was dyskinesia. 1% of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment due to dyskinesia, compared with 0% on placebo.

Similarly, 1% of patients treated with NOURIANZ 40 mg discontinued due to hallucinations, compared with 0% receiving placebo or NOURIANZ 20 mg.

Now, let’s look at treatment-emergent adverse reactions of special interest.

The rate of falls in the placebo group was 9.4%, and 6.5% and 6.9% with NOURIANZ 20 mg and 40 mg, respectively. The rates of nausea and vomiting were similar in the placebo and NOURIANZ 20 mg groups, at 4.7% and 4.8%, respectively, and 6.9% with NOURIANZ 40 mg. Impulse control disorders were seen in 0.3% of patients on NOURIANZ 40 mg, compared with none in patients administered NOURIANZ 20 mg or placebo.

Now let’s discuss the dosing recommendations for NOURIANZ.

The recommended dosage of NOURIANZ is 20 mg orally once daily and may be increased to a maximum of 40 mg once daily, which may be taken with or without food.

Since NOURIANZ is metabolized by CYP3A4, the maximum recommended dosage of NOURIANZ in combination with a strong CYP3A4 inhibitor is 20 mg once daily. In fact, NOURIANZ use should be avoided with strong CYP3A4 inducers.

It may increase CYP3A4 substrate exposure at the 40 mg dose. You should also monitor for adverse reactions when administering drugs that are P-glycoprotein substrates.

Dose adjustments with NOURIANZ are recommended when managing special populations and are summarized here.

In the NOURIANZ clinical trials, 53% of patients were ≥65 years and 13% were ≥75 years. There were no differences in effectiveness in these patients compared to those who were younger, therefore there is no recommended dose adjustment of NOURIANZ based on age.

Just to note, the safety and effectiveness in pediatric patients have not been established.

In patients with moderate hepatic impairment with a Child-Pugh B score, the maximum recommended dosage of NOURIANZ is 20 mg once daily. Patients with moderate hepatic impairment should be closely monitored for adverse reactions when using NOURIANZ. The use of NOURIANZ in patients with severe hepatic impairment based on a Child-Pugh C score should be avoided.

No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. NOURIANZ has not been evaluated in patients with end-stage renal disease (ESRD).

Based on drug-drug interactions for patients taking CYP3A4 inhibitors and inducers, P-glycoprotein substrates, and for those who smoke 20 or more cigarettes per day, or use the equivalent amount of another tobacco product, the recommended dosage of NOURIANZ is 40 mg once daily.

Some additional Important Safety Information related to special populations and overall adverse reactions observed in the pivotal trials is seen here and are as follows.

Drug Interactions
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 ≥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.

Please continue watching for full NOURIANZ Important Safety Information throughout this video and click on the link below to access the full Prescribing Information.

In summary, in the 4 pivotal trials there were several adverse events observed at a rate greater than 2% and higher than placebo.

The one with the highest incidence was dyskinesia, which occurred at about twice the rate of placebo, with a slightly higher rate in the 40 mg– treated patients.

Treatment-emergent adverse reactions of special interest were evaluated, and there was a slight dose-dependent increase compared to placebo.

Both the 20 mg and 40 mg doses demonstrated increased rates of orthostatic hypotension and neutropenia. The 40-mg dose demonstrated a slight increase in hallucinations, sleep disturbances, impulse control disorders, nausea, and vomiting. The 20-mg dose was comparable to placebo for these 4 AE categories.

The rates of falls in the placebo groups were 9.4%, and 6.5% and 6.9% with NOURIANZ 20 mg and 40 mg, respectively.

Liver enzyme elevations were observed less frequently in the patients receiving 20 mg and 40 mg NOURIANZ than placebo.

Patients included in the trials were on multiple therapies, including other adjunctive therapies for the treatment of PD.

The Warnings and Precautions for NOURIANZ include dyskinesia, hallucinations, psychotic behaviors, and impulse control/compulsive behaviors.

Patients should be monitored for dyskinesia or exacerbation of existing dyskinesia while on NOURIANZ.

If hallucinations, psychotic behaviors or impulse control/compulsive behaviors occur, consider reducing the dose or stopping NOURIANZ.

Thank you for taking the time to watch this video, which reviewed the safety data from the pivotal trials for NOURIANZ. For additional information about NOURIANZ^® (istradefylline), an adenosine A_2A receptor antagonist, or to review the efficacy data from these trials in more detail, please see our other videos on these topics. You can also find additional information by visiting the NOURIANZ website for healthcare professionals at www.NOURIANZHCP.com.

Transcript

Hi, I'm Dr. Stuart Isaacson, Director of the Parkinson's Disease and Movement Disorders Center of Boca Raton. And I just want to thank you for joining us today to talk about Nourianz or istradefylline and an alternative mechanism to treat Parkinson's disease. This is a promotional presentation on behalf of Kyowa Kirin and I'm here today as a paid consultant of Kyowa Kirin.

Nourianz is an adenosine receptor antagonist indicated as adjunctive treatment to carbidopa/levodopa in adult patients with Parkinson's disease experiencing off-episodes. Throughout, we'll talk about important safety information and hear from the warnings and precautions, dyskinesia. Nourianz in combination with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 milligrams or 40 milligrams discontinued treatment because of dyskinesia compared to 0% for placebo. In Parkinson's disease, there's more to consider than dopamine. There's also adenosine. Adenosine is a neuromodulator that regulates neuronal excitability. Adenosine A_2A receptors are found in the striatum and also globus pallidus externus and related areas. These receptors, these A_2A receptors regulate the indirect pathway and activation of these receptors reduces motor activity. As Parkinson's disease progresses, striatal dopamine is lost, of course. But also adenosine A_2A receptors in the striatum may increase.

Now, we look at the cartoon of these pathways. In normal movement, we have a balance between the outflow, of the indirect and direct pathways. These pathways are made up of projections from the medium spiny neurons in the striatum. Those medium spiny neurons that can have dopamine D2 receptors make up the indirect pathways. Those with the D1 receptors make up the direct pathway. These are balanced in normal brain and it can be noted that on the indirect pathway neurons in addition to having the D2 receptors, they also have adenosine A_2A receptors. In Parkinson's disease, there's this depletion of dopamine being delivered from this nigral neurons to the striatum. A consequence of this is less activation of both the D1 and D2 receptors. This results in a reduced outflow of the direct or go pathway. And an increased outflow of the indirect or stop pathway. The combined result is less movement or Bradykinesia.

Also, note though, that there's an up-regulation on the indirect pathway neurons of adenosine A_2A receptors. When we think about treating our patients in Parkinson's disease with levodopa during off-episodes and they have off-episodes when they're being treated with levodopa very commonly. As you lose striatal dopamine, these activated adenosine A_2A receptors have a braking activity on the normal outflow from the indirect pathway. What occurs is that while we have with levodopa a better outflow from the direct or go pathway. Less stop from the indirect pathway, there's still a braking or stopping activity from the indirect pathway due to this up-regulated overactive adenosine A_2A receptors.

So when we think about or trying to address off-episodes, in addition to giving levodopa, we can also give an adenosine A_2A receptor antagonist. To block these up-regulated overactive receptors and further reduce the outflow of the indirect or stop pathway, improving movement. In this way, adenosine A_2A receptor antagonists may help to regulate these indirect and direct pathways and the balance between them. To try to facilitate movement and improve off-episodes. In essence, it's like a brake on the system. The role of dopamine is like a gas, pushing on the gas. Stimulating D1 and D2 receptors and initiating movement. Adenosine acts as a brake on the system. So if you went in a car and you tried to drive with the emergency brake on, it might go forward. But then when you release the emergency brake, it moves much more freely. So in this analogy, adenosine is like the brake.

Now, Nourianz or istradefylline is the first and only adenosine A_2A receptor antagonists for Parkinson's disease. So Nourianz istradefylline is the first and only adenosine A_2A receptor antagonist for Parkinson's disease. It has a novel structure depicted here on the slide. While the precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson's disease is not known. We think it has to do with a highly specific affinity for the adenosine A_2A receptor. Now, it also has no affinity for dopamine or other receptors. It has a novel non-dopaminergic mechanism of action that works differently than other treatments we've considered for Parkinson's disease. This novel structure also has a long half-life of about 83 hours, which lends itself to once a day dosing.

So important safety information to be aware of, warnings or cautions because of the potential risk of exacerbating psychosis. Patients who have major psychotic disorders should not be treated with Nourianz. To consider a dosage reduction or discontinuation if a patient develops hallucinations or other psychosis while taking Nourianz.

Nourianz was evaluated in four randomized 12-week multicenter, double-blind, placebo-controlled studies. Investigating 20 milligrams and 40 milligrams of Nourianz as adjunctive treatment to levodopa in patients with Parkinson's disease experiencing off-time. In these studies, the mean off-time, on entry to the studies is at six hours per day. Patients who are on other therapies in addition to baseline levodopa/carbidopa had to be on stable doses for 30 days prior to the trial and throughout the trial. These included dopamine agonists, COMT and MAO inhibitors, anticholinergics, and amantadine. The primary endpoint was a percentage of daily awake off-time in the US studies are one and two. Total daily off-time in the Japanese studies, three and four. In all four of these studies, secondary endpoints included a change from baseline and on-time without troublesome dyskinesia.

So important safety information also to be aware of is that patients treated with Nourianz and one or more medications for the treatment of Parkinson's disease, including levodopa, may experience impulse control or compulsive behaviors. In the clinical trials, one patient treated with Nourianz 40 milligrams was reported to have impulse control disorder compared to no patient on Nourianz 20 milligrams or on placebo.

In these studies, we saw a reduction in off-time across all four of the trials. Here we can see compared to placebo, both Nourianz 20 milligrams and 40 milligrams had a significant improvement over placebo. Here we have the P-values of 0.002 to 0.05 throughout the trials. This was about a delta improvement in hours between point 0.65 hours and 1.16 hours.

To be recognized drug interactions and important safety information that the maximum recommended dosage in patients, in general, is 40 milligrams. But in those taking a strong CYP3A4 inhibitor is 20 milligrams once daily. Use of Nourianz should be avoided in patients on strong CYP3A4 inducers.

Safety and tolerability. The incidence of adverse reactions seen in 2% or more percent than on either dose of Nourianz and greater in placebo are listed here. Pooled data from for trials, dyskinesia being the most common adverse reactions seen over placebo. Other side effects that are listed here on this slide that were more than placebo included constipation, nausea, hallucinations. You can see the percentages, the difference compared to placebo, Nourianz 20, and 40 milligrams. Please see additional important safety information throughout and on slide 13. Please see accompanying full prescribing information.

Treatment emergent adverse reactions of special interests are depicted in this slide. Orthostatic hypotension occurred at 5.4% of patients on placebo, 6.7% or 6.9% on Nourianz 20 and 40 milligrams. We can see here the incidence of falls and nausea and vomiting. Hallucinations were 2.8%, 2.2% or 5.8% on the 40 milligrams Nourianz. Point out here impulse control disorder we mentioned earlier. Now that one patient on the Nourianz 40 milligrams, neutropenia 0.3% on 20 milligrams 0.5% of 40 milligrams, wasn't seen on placebo. Similar incidences a bit higher on placebo for liver enzymes as well.

So we think about Nourianz for patients who have Parkinson's disease and are experiencing off-episodes while on carbidopa/levodopa, I think there's several things to keep in mind. Nourianz is the first and only non-dopaminergic adenosine A_2A receptor antagonist for adjunctive treatment in patients with Parkinson's disease, with off-episodes. It's one pill once a day with or without food. It's available in 20 milligram, which is the initial starting dose in most patients and 40 milligrams. Initial dose titration, though is not required and no adjustment in Nourianz dose is recommended on the basis of age.

The most common adverse reactions that were seen in 5% or a greater percent of patients, the 20 or 40-milligram dose versus placebo and greater than placebo. Were dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia. Kyowa Kirin who markets this drug has programs through the Kyowa Kirin Cares. Where there are Co-Pay cards for patients who are eligible, they can check on the phone and then down the website to check their eligibility. Patients can obtain Nourianz from the CVS or Walgreens Specialty Pharmacy. There's a number of programs available to try to help patients have access to this medication if prescribed to them.

Nourianz indication is as an adenosine receptor antagonists that's indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease experiencing off-episodes. Important safety information, the warnings and precautions to be aware of. Dyskinesia. Nourianz in combination with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 milligrams or 40 milligrams discontinue 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 dose reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking Nourianz. Impulse control or compulsive behaviors. Patients treated with Nourianz and one or more medications 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, one patient treated with Nourianz 40 milligrams was reported to have impulse control disorder. Compared to no patient on Nourianz 20 milligrams or placebo.

Drug interactions. The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 milligrams 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 dose of Nourianz in patients with moderate hepatic impairment is 20 milligrams once daily. Avoid use in patients with severe hepatic impairment. Adverse reactions. The most common adverse reactions with an incidence greater than or equal to 5% and occurring more frequently than with placebo, was dyskinesia, 15%, 17%, and 8%. Dizziness, 3%, 6%, and 4%. Constipation, 5%, 6%, and 3%. Nausea, 4%, 6%, and 5%. Hallucinations 2%, 6%, and 3%. Insomnia, 1%, 6%, and 4%. For Nourianz 20 milligrams, 40 milligrams, and placebo respectively. You are encouraged to report suspected adverse reactions to Kyowa Kirin at this phone number here or to the FDA at the phone number or website. Please see full prescribing information for Nourianz as well.

Nourianz resources are available on a number of different websites, can be contacted to find out more information about Nourianz, its mechanism of action, as well as its prescribing information. Also, resources for patients that can help describe how Nourianz works as well as the patient brochure and access in patient support and a patient PI.

Transcript

Hi, I'm Dr. Stuart Isaacson, Director of the Parkinson's Disease and Moving Disorder Center of Boca Raton. Thank you for joining us to review this slide deck about Nourianz istradefylline and its efficacy and safety. This is a promotional presentation on behalf of Kyowa Kirin and I am here today as a paid consultant of Kyowa Kirin.

Nourianz is an adenosine receptor antagonist indicated as adjunctive treatment to carbidopa/levodopa in adult patients with Parkinson's disease experiencing off-episodes. We'll talk a bit about important safety information, the warnings and precautions here. Dyskinesia can occur, Nourianz in combination with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 milligrams or 40 milligrams discontinue treatment because of dyskinesia, compared to 0% for placebo.

The Parkinson's disease there is more to consider than dopamine. There's also adenosine. We haven't thought a lot about adenosine but adenosine is a neuromodulator that regulates neuronal excitability. Now, adenosine receptors can be widespread in the brain but the subtype, the adenosine A_2A receptor subtype is found in the striatum, in the globus pallidus external and related nuclei. Adenosine A_2A receptors tend to regulate the indirect pathway and their activation reduces motor activity. We know that as Parkinson's disease progresses, not only is striatal dopamine reduced but also adenosine A_2A receptors in the striatum may increase.

This cartoon here demonstrates this loss of presynaptic dopamine-producing neurons from the nigra in the box. You see the dropout and the loss of presynaptic dopaminergic neurons. If you look at the postsynaptic side, we can see two groups of neurons. One is the direct or go pathway, the medium spiny neurons making up the direct or go pathway. Then we have the indirect or stop pathway. Those neurons that make up the indirect or stop pathway have not only dopamine receptors but also adenosine A_2A receptors. These are up-regulated in Parkinson's. When the adenosine A_2A receptors are up-regulated, it tends to act as a brake on movement. The role of dopamine is to stimulate the dopamine receptors D1 and D2. It's like pushing down on the gas of a car and initiating movement. In contrast, the role of adenosine, the stimulation of adenosine A_2A receptors is like applying a brake, which tends to suppress movement. By analogy, if you get into a car and the emergency brake is still on and you start to drive. It drives very slow and you release the emergency brake, you facilitate the movement to the car. It moves more freely.

That is sort of what we're thinking about doing with adenosine antagonists in Parkinson's disease. Nourianz istradefylline the first and only adenosine A_2A receptor antagonists for Parkinson's disease. While we don't know the precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson's disease. It's just a novel non-dopaminergic mechanism of action that we think works differently than other treatments. By antagonizing the A_2A receptors, which seem to be up-regulated overactive in the striatum, acting as this brake on the system.

Nourianz istradefylline is highly specific and has high affinity for the adenosine A_2A receptor with no interaction or affinity for dopamine receptors. This novel structure depicted here on the slide has a long half-life when delivered of about 83 hours, lending itself to once-daily dosing. Some important safety information. Because of the potential risk of exacerbating psychosis, patients with major psychotic disorders should not be treated with Nourianz. Consider dose reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking Nourianz.

The efficacy of Nourianz was evaluated in four pivotal trials, leading to its regulatory approval. Studies one and two were carried out in the United States. Both of these studies compared istradefylline to placebo and one study 40 milligrams of istradefylline added to carbidopa/levodopa and other medications as well could be used. These other medications would have to, of course, be kept stable. All of these studies are for 30 days prior to the trial and throughout the trial. The second US study, 20 milligrams of istradefylline was compared to placebo. The pre-specified primary endpoint in these studies where changed from baseline in percent to wait time spent in off per day and key secondary endpoints included on-time without troublesome dyskinesia. Patients treated with Nourianz and one or more medication for the treatment of Parkinson's disease, including levodopa, may experience intense urges to gamble or other intense urges and the inability to control these urges. In clinical trials, one patient treated with Nourianz 40 milligrams was reported to have an impulse control disorder compared to no patient on Nourianz 20 milligrams or placebo.

On the slide, we see the design of the two Japanese clinical trials studies three and four. In these studies, there were three arms, placebo, istradefylline 20 milligrams, and then the 40 milligram. Primary endpoint was similar but in this case, was a change from baseline in hours spent in off-time with similar secondary endpoints. While the maximum recommended dose in patients for Nourianz is 40 milligrams. Those who take a strong CYP3A4 inhibitor, the maximum dose is 20 milligrams once daily. Avoid the use of Nourianz with strong CYP3A4 inducers. Now, the primary endpoint of these studies off-time here in the US studies one and two. The percent of awake time off seen here for Nourianz plus baseline therapy versus placebo plus baseline therapy. We see an improvement in percent off-time, awake off-time in the Nourianz treated groups over placebo. In both the 20 and the 40 milligrams in the two studies. The P-values here are 0.007 and O.025. What this represents is that baseline, patient spent 37% to 40% of their awake time off. At week 12 off-time was reduced to 27% to 30% for Nourianz and for about 33% to 34% for placebo.

Important safety information to be aware of. May cause fetal harm. The maximum recommended dosage of Nourianz in patients with moderate hepatic impairment is 20 milligrams once daily. It should be avoided in patients with severe hepatic impairment. A reduction in off-time across all four studies is seen here on this slide. We can see an improvement over placebo in each of these studies with the 20 or 40 milligram for both arms. Important safety information. By adverse reactions, the most common adverse reactions with an incidence of greater, that are equal to 5%. That are more frequent in placebo with dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia.

Importantly, though, when we looked at this key secondary endpoint of on-time without troublesome dyskinesia. We can see an improvement in on-time without troublesome dyskinesia. The Nourianz is treated the arms of both the 20 and 40 milligrams over placebo. Here we can see the deltas, other important safety information to be aware of. That Nourianz in combination with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 or 40 milligrams discontinued treatment because of dyskinesia compared to 0% for placebo.

Here we see a slide that really gets to some of our clinical strategies, in trying to reduce off-time and improve on-time without troublesome dyskinesia. Here we can see in all four of these trials an improvement on the lower half of the slide in off-time with both the 20 and or the 40-milligram dose of Nourianz. On the top half of the slide, the improvement in on-time without troublesome dyskinesia in all four of these trials. Important safety information to highlight. Also is that because of the potential risk of exacerbating psychosis, patients with major psychotic disorders should not be treated with Nourianz. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking Nourianz. Safety and tolerability is on this chart here showing the incidents of adverse reactions that occurred in 2% or greater percent of either dose of Nourianz and greater than placebo. This is pooled data from the four studies. Here we can see dyskinesia being the most common adverse reaction. We see these other adverse reactions here compared to placebo. I'll point out the hallucinations 3% on placebo, 2% on 20 milligrams, 6% on Nourianz. Nauseous 5%, 4%, and 6% and all of these here. Please see additional important safety information throughout and on slide 17, please see accompanying full prescribing information.

Treatment emerging adverse reaction to special interest are on this slide here. We can see orthostatic hypotension, for instance, 5.4% on placebo, 6.7 and 6.9% on the two doses of Nourianz. All these adverse reactions listed here compared to placebo, falls were a bit more common on placebo. You can see hallucinations 2.8, 2.2, and a bit more common 5.8% on Nourianz 40 milligrams.

Now, Nourianz was discontinued due to adverse reactions at a similar rate to placebo. 5% discontinued on placebo, 5% on Nourianz 20 milligrams, and 6% on Nourianz 40 milligrams. There was a 1% of rate of discontinuation due to dyskinesia with either Nourianz 20 or 40-milligram dose, compared to no patients on placebo. There are no overall differences in effectiveness observed between elderly and younger patients.

Recommended dosage adjustments are seen here. There's no dose adjustment needed for renal impairment and neither mild nor severe and not for mild hepatic impairment. The maximum recommended dosage of Nourianz for moderate hepatic impairment is 20 milligrams daily. Its use should be avoided in patients with severe hepatic impairment. Other important safety information. Patients treated with Nourianz in one or more medications for the treatment of Parkinson's disease, including levodopa. May experience impulse control or compulsive behaviors, difficult inability to control these urges. In the clinical trials, one patient treated with Nourianz 40 milligrams was reported to have impulse control disorder compared to no patient on Nourianz 20 milligrams or placebo.

Other drug driving interactions CYP3A4 substrates, P-glycoprotein substrates may affect the dosage of Nourianz. That listed here, you should also be aware that strong inhibitors of CYP3A4 the maximum recommended dose is 20 milligrams. Strong induces, you should avoid your use of Nourianz. In those patients who are tobacco smokers, the recommended dose of Nourianz is 40 milligrams daily.

So think when you have patients with Parkinson's who are experiencing off-episodes while on carbidopa/levodopa, a Nourianz can be considered as the first and only non-dopaminergic adenosine A_2A receptor antagonist. For adjunctive treatment to carbidopa/levodopa in patients with Parkinson's disease. The most common adverse reactions that were seen in 5% or greater percent, Nourianz 20 or 40 milligrams versus placebo. More than placebo with dyskinesia, dizziness, constipation, nausea, hallucinations, and insomnia. Discontinuation rates was similar to placebo. Nourianz is administered one pill, once a day with or without food. It's available in 20 and 40 milligrams tablets. An initial dose titration is not required and no adjustment of Nourianz dosage is required or recommended on the basis of age. There's a number of programs that can help eligible patients get access to the medications, to see if they're eligible for a Co-Pay card program, a website, and a phone number. Patients who are prescribed Nourianz can obtain it from a CVS or Walgreens Specialty Pharmacy.

Nourianz indication is as adenosine receptor antagonist that's indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease, experiencing off-episodes. Important safety information, the warnings, and precautions to be aware of. Dyskinesia. Nourianz in combination with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia. In clinical trials, 1% of patients treated with either Nourianz 20 milligrams or 40 milligrams 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 dose reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking Nourianz. Impulse control or compulsive behaviors. Patients treated with Nourianz and one or more medications 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. The inability to control these urges. In clinical trials, one patient treated with Nourianz 40 milligrams was reported to have impulse control disorder compared to no patient on Nourianz 20 milligrams or placebo.

Drug interactions. The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 milligrams 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 dose of Nourianz in patients with moderate hepatic impairment is 20 milligrams once daily. Avoid use in patients with severe hepatic impairment. Adverse reactions. The most common adverse reactions with an incidence greater than or equal to 5% and occurring more frequently than with placebo with dyskinesia, 15%, 17%, and 8%. Dizziness, 3%, 6%, and 4%. Constipation, 5%, 6%, and 3%. Nausea, 4%, 6%, and 5%. Hallucinations, 2%, 6%, and 3%. Insomnia, 1%, 6%, and 4% for Nourianz 20 milligrams, 40 milligrams, and placebo respectively.

You are encouraged to report suspected adverse reactions to Kyowa Kirin at this phone number here or to the FDA at the phone number or website. Please see full prescribing information for Nourianz as well. Nourianz resources are available on a number of different websites. Can be contacted to find out more information about Nourianz mechanism of action, as well as its prescribing information. also resources for patients that can help describe how Nourianz works as well as the patient brochure and access and patient support and a patient PI.