OFF Periods and Utilization of INBRIJA^® in Clinical Practice Video Transcript

Inbrija Indication

• Inbrija is indicated for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa

Selected Important Safety Information

• INBRIJA is contraindicated in patients taking or who have recently taken (within 2 weeks) nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine) due to risk of hypertension. Discontinue use of nonselective MAO inhibitors at least 2 weeks prior to initiating INBRIJA.

OFF periods and utilization of
[INBRIJA logo]
in clinical practice in patients taking carbidopa/levodopa

[Dr. Isaacson and Dr. Pahwa seated at a table together, video headshots of Dr. Pahwa and Dr. Brillman are shown, camera alternates focusing on Dr. Isaacson speaking and Dr. Pahwa speaking]

Rajesh Pahwa, MD
Salima Brillman, MD

Hello. I'm Dr. Stuart Isaacson, Director of the Parkinson's Disease and Movement Disorders Center of Boca Raton in Florida. Joining me today are Dr. Rajesh Pahwa, Director of the Parkinson's Disease and Movement Disorder Center at the University of Kansas, and also Dr. Salima Brillman, the Director of the Parkinson's Disease and Movement Disorders Center of Silicon Valley in Menlo Park, California, who is joining us remotely. Today, we're going to discuss OFF periods in Parkinson's disease and a unique approach to help manage them in our patients taking carbidopa/levodopa. So, to begin, Raj, there's a lot of discussions in neurology about OFF. What is OFF to you?

Rajesh Pahwa, MD
Department of Neurology, University of Kansas Medical Center, Kansas City, KS

So OFF periods, or OFF episodes, are times during the day for our Parkinson's patients when their dose of levodopa is not providing them with an optimal benefit. Now this could be that it is not providing any benefit, or it could be it's providing a suboptimal benefit. These symptoms may vary. It could be that they have some more tremor. It could be that they are slower. It could be that they are stiffer, and patients can often not predict when these OFF periods do occur.

[Dr. Brillman seated in a room in a remote location, speaking to the camera]

Raj, non-motor symptoms such as anxiety, mood changes, slowness of thinking, tiredness and achiness can be part of a person's OFF periods.

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera alternates focusing on Dr. Isaacson speaking and Dr. Pahwa speaking]

Stuart H. Isaacson, MD
Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL

We're going to be discussing INBRIJA today and in the INBRIJA development program, non-motor symptoms were not evaluated as OFF symptoms. So, when patients are taking their carbidopa/levodopa and it's working and their symptoms are improved, what happens that these OFF periods begin to occur?

Why do the OFF periods happen and when do they happen? Now, early on in the disease course, the patient starts levodopa. Their symptoms are under control throughout the day. And what happens is as the disease progresses, this buffering capacity is lost.

So, probably most patients have OFF periods, whether they recognize them well or not.

[Video headshots of Dr. Isaacson and Dr. Brillman are shown, with Dr. Isaacson speaking]

Boca Raton, FL
Menlo Park, CA

Salima, what do you think about some types of OFF?

[Dr. Brillman seated in a room in a remote location, speaking to the camera, two slides are shown while she speaks]

• Most patients have OFF periods, whether they recognize them or not
• As disease progresses OFF periods reappear despite adjusting baseline therapy
• Parkinson's disease medications do not take effect as expected and/or wear off earlier than expected
• Patients experience a recurrence of symptoms

Clinicians should understand that baseline therapy is aimed to reduce OFF time. However, it doesn't eliminate OFF periods. Patients will still have times when their PD medications do not take effect as expected, or they'll have recurrence of their symptoms. When the patient awakens, he or she is generally in an OFF state, what is also referred to as early morning OFF. At this point, the first oral dose of PD medication may take a while to take effect. The patient is then ON, but in due course OFF symptoms start to break through, which we call wearing OFF. This can be expected or unexpected. Alternatively, patients can experience a dose failure, where oral medication doesn't take effect as expected or a delayed ON where the response takes longer than expected. INBRIJA can be considered for any of these scenarios. If a patient consistently wears off prior to the next dose, one might consider adjusting the baseline therapy.

[Dr. Isaacson and Dr. Pahwa seated at table together, camera focuses on Dr. Isaacson speaking]

INBRIJA may be taken as needed when symptoms return. No more than 1 dose (2 capsules) per OFF period, up to a maximum of 5 doses per day.

Some of these are expected. Patients expect that after three or four hours symptoms will break through and they'll begin to enter an OFF episode. But, other times it's unexpected and they may be at physical therapy, they might be at dinner and trying to leave the restaurant, maybe trying to go through an airport or Disneyworld with their grandchildren.

[Dr. Brillman seated in a room in a remote location, speaking to the camera]

Salima Brillman, MD
Movement Disorders Neurologist, Parkinson's Disease and Movement Disorders Center of Silicon Valley, Menlo Park, CA

Right Stu, and for those patients with unpredictable OFF periods, it's particularly challenging as they never know when OFF periods may start. For example, one oral carbidopa/levodopa dose works for three hours, but the next dose has no effect on them at all. As you can imagine, this kind of variability is very difficult. We've been talking about how baseline PD medications may stop working as effectively as the disease progresses and neurons degenerate. But there are also GI issues that have an impact on OFF periods as these affect the absorption of levodopa. One study has shown over 80% of patients had delayed gastric emptying and since levodopa is not absorbed until it reaches the small intestine, the delayed gastric emptying is going to affect it.

Gastric emptying in 80 patients with PD was compared with a healthy control group (n=40) by administering a solid meal containing ¹³C-octanoate (n=40) or a liquid meal with ¹³C-acetate (n=40). Multiple regression analysis was used to determine predictors of gastric emptying. 88% and 38% of PD patients had delayed gastric emptying of solids and liquids respectively.

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera alternates focusing on Dr. Pahwa speaking and Dr. Isaacson speaking]

And often patients take levodopa with food, and that can even slow gastric emptying further and also delay the benefits of levodopa longer, so they may really have a delayed ON time from that stand.

And protein and food can impede and compete with the absorption of levodopa through the transporter in the small intestine.

[Dr. Brillman seated in a room in a remote location, speaking to the camera]

So there is good rationale for avoiding the GI tract.

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera alternates focusing on Dr. Pahwa speaking and Dr. Isaacson speaking]

That's correct.

Another thing is we often hear from clinicians that their patients don't have OFF periods, that they're well-controlled on their oral therapies.

[Video headshots of Dr. Isaacson and Dr. Brillman are shown, with Dr. Isaacson speaking]

Boca Raton, FL
Menlo Park, CA

Salima, what are your thoughts on this and can you talk a bit about your experience with your patients?

[Dr. Brillman seated in a room in a remote location, speaking to the camera]

The majority of the patients I see have OFF periods. Although most patients have them, many patients don't bring up their symptoms during our office visits. They may not understand that the symptoms are part of their Parkinson's. Many of them don't want to acknowledge that there is a worsening of their disease and some people may accept the symptoms as a consequence of their disease and are not aware that there are treatments available. In any event, as a clinician, I know that despite my best efforts to manage baseline oral PD medications, my patients will begin to experience OFF after several years. This is just the nature of the disease.

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera alternates focusing on Dr. Pahwa speaking and Dr. Isaacson speaking]

That's right. No, I mean, in my clinic, what I do is ask my patients how they are in the morning when they wake up. They take a dose of medication. How long does it work? How long does it take to work? Does the medication work until their next dose? What happens after the next dose? I mean, all that gives me an idea how they're doing during the day, and that helps me decide how to treat them, and at times using a patient diary, "this is how I am in the morning," "this is what happens after I take a pill," might help us look at the diary and decide how they're doing.

Patients are on levodopa/carbidopa and they have OFF periods and they're on other baseline therapies and they have OFF periods. What's happening there?

So, you know, when patients have OFF periods, we try different things to help them. We may increase their levodopa dose. We may use long acting medications. We can use other adjunctive therapies for it. But unfortunately, in spite of all this, there are patients continue to have OFF periods.

And we need something that can bypass the problems of GI dysmotility.

INBRIJA is indicated for the intermittent treatment of OFF episodes in patients with Parkinson's disease treated with carbidopa/levodopa.

Yes, that's right. And I think that's where INBRIJA plays a role, as far as using it with their baseline therapies.

INBRIJA is an orally-inhaled formulation of levodopa and gets absorbed through the pulmonary route into the bloodstream.

[Dr. Brillman seated in a room in a remote location, speaking to the camera, two slides are shown while she speaks]

Right. First, it's time to onset of action was seen as early as 10 minutes. Second, because INBRIJA is inhaled, it does not rely on the gastrointestinal tract for absorption. And here we visualize the different pathways for oral pills and oral inhalation administration. For standard Parkinson's levodopa therapy, a carbidopa/levodopa tablet is swallowed and travels down the esophagus to the stomach. Passing through the stomach, it is released through the pyloric sphincter into the proximal small intestine, where the levodopa is absorbed into the systemic circulation. From there, the levodopa is delivered to the brain. In the case of INBRIJA, levodopa is orally inhaled, absorbed through the lung epithelium into the systemic circulation and from there delivered to the brain.

[Graphic of digestive system shows capsule progression when swallowed)

[Graphic of pulmonary system shows capsule progression when inhaled)

Selected Important Safety Information
INBRIJA is not recommended in patients with asthma, COPD, or other chronic underlying lung disease because of the risk of bronchospasm.
Please see additional Important Safety Information throughout this video

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera focuses on Dr. Isaacson speaking]

And INBRIJA is taken in people who are already taking carbidopa/levodopa. It doesn't replace the carbidopa/levodopa they take orally, but it's added to it for OFF periods.

['Levodopa Plasma Concentrations After a Dose of 84 mg INBRIJA or 25/100 mg Oral Carbidopa/Levodopa' chart and 'Individual Levodopa Plasma Concentrations' chart are shown with voice over from Dr. Brillman]

There's a study that very nicely shows INBRIJA elevating levodopa plasma levels more rapidly than oral carbidopa/levodopa. Again, not having to pass through the GI tract is an essential factor here. In this particular study, 23 patients with Parkinson's took either an oral dose of carbidopa/levodopa or a dose of INBRIJA right after eating a standardized high fat, high protein meal about four to five hours after the patient's usual morning oral carbidopa/levodopa dose. The patients' levodopa blood concentration levels were measured over the next four hours. We can see here after a single inhaled dose of INBRIJA 84 mg, levodopa plasma levels rose rapidly, with a mean increase of about 140 ng/mL by five minutes, which was the first time point measured, and a mean increase of about 240 ng/mL by 15 minutes. In contrast, after one oral dose of carbidopa/levodopa 25 mg/100 mg, no increase in mean levodopa plasma concentrations were seen until an hour after taking the dose. The median time to maximum levodopa concentration was 15 minutes for INBRIJA, compared with two hours for oral carbidopa/levodopa. Next, we see that the between-subject levodopa plasma variability of INBRIJA was generally less than that of oral carbidopa/levodopa 25 mg/100 mg. So, this study neatly illustrates what we've been saying here today - INBRIJA was more rapidly absorbed and demonstrated less inter-subject variability than oral carbidopa/levodopa. Again, this is because oral carbidopa/levodopa absorption is slowed by having to pass through the GI tract, so it is likely subject to delayed gastric emptying and competition with food in the proximal small intestine.

Selected Important Safety Information

• Patients treated with levodopa, the active ingredient in INBRIJA, have reported falling asleep during activities of daily living, including operation of motor vehicles, which sometimes resulted in accidents. Many patients reported somnolence but some reported no warning signs (sleep attack). This may occur more than a year after initiating treatment. Reassess patients for drowsiness/sleepiness including occurrence during specific activities. Advise patients of potential for drowsiness and ask about factors that may increase this risk (e.g., sedating medications, sleep disorders).
  • Consider discontinuing INBRIJA in patients who report significant daytime sleepiness or falling asleep during activities that require active participation. If continuing INBRIJA, advise patients not to drive and to avoid activities that may result in harm. There is insufficient information that dose reduction will eliminate episodes of falling asleep during activities of daily living.

[Dr. Isaacson and Dr. Pahwa seated at a table together, camera alternates focusing on Dr. Pahwa speaking and Dr. Isaacson speaking]

So, Raj, what are the major points do you think that we should remember?

So one thing we have to keep in mind, that the patients are very likely to experience OFF periods despite regular oral therapy, and that OFF symptoms can be bothersome, so it's important to ask questions to identify these OFF periods.

These OFF periods can be really disruptive. Salima, what are some messages that people should remember about OFF periods?

[Two slides are shown, with Dr. Brillman speaking off-camera]

• Most PD patients who have had PD for some time will have OFF periods, despite regular oral therapy
• OFF symptoms are frequently unpredictable and can differ from patient to patient and from day to day for the same patient
• Physicians need to understand patients' OFF periods to help treat them
  • Ask patients straightforward, general, questions to see how troublesome OFF symptoms and OFF periods are
• Inbrija is an orally-inhaled levodopa therapy that can help patients taking carbidopa/levodopa who are experiencing OFF periods treat their OFF symptoms when they start to return.
• Because Inbrija provides levodopa via a pulmonary route and avoids the GI route and its accompanying food effects and GI dysfunction, Inbrija provides a more rapid increase in blood levodopa levels than oral carbidopa/levodopa
• Inbrija can be taken by patients as needed up to 5 doses a day with a maximum of one dose per OFF period
• INBRIJA is not recommended in patients with asthma, COPD, or other chronic underlying lung disease because of the risk of bronchospasm.
• The most common adverse reactions (≥ 5% and > placebo) were cough (15% vs 2%), upper respiratory tract infection (6% vs 3%), nausea (5% vs 3%), and sputum discolored (5% vs 0%).

Stu, it's this: most patients who've had PD for some time will be having OFF periods, even if they haven't yet identified them as such. They occur even if the patient is on oral therapy. OFF symptoms frequently occur unpredictably and can differ from patient to patient and from day to day for the same patient. We physicians need to understand how bothersome these OFF period symptoms are, so we can better help our patients. Asking patients straightforward questions about how they feel will help us get a better picture of how troublesome OFF symptoms and OFF periods are. INBRIJA is an orally inhaled levodopa therapy that can help patients who are experiencing OFF periods and are taking carbidopa/levodopa to treat OFF symptoms when they start to return. Because INBRIJA provides levodopa via the pulmonary route and avoids the GI route and its accompanying food effects and GI dysfunction, INBRIJA provides a more rapid increase in blood levodopa levels than oral carbidopa/levodopa. Lastly, I should add that INBRIJA can be taken by patients as needed up to five times a day with a maximum of one dose per OFF period. We must keep in mind, of course, that INBRIJA is associated with the same risks as oral carbidopa/levodopa and is not recommended in patients with asthma, COPD or other chronic underlying lung disease.

[Dr. Isaacson and Dr. Pahwa seated at a table together, Dr. Isaacson speaking]

Before we conclude, please listen to the remaining Important Safety Information for INBRIJA.

Additional Important Safety Information

• Neuroleptic malignant syndrome-like symptoms, for example elevated temperature, muscular rigidity, altered consciousness, autonomic instability, have been reported with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy.
• Hallucinations (with or without confusion, insomnia and excessive dreaming) may occur and may respond to reducing levodopa therapy. Abnormal thinking and behavior may present with paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
• INBRIJA should ordinarily not be used in patients with major psychotic disorder due to risk of exacerbating psychosis. Dopamine antagonists used to treat psychosis, may exacerbate symptoms of Parkinson's Disease and may decrease INBRIJA efficacy.
• Patients on medications that increase central dopaminergic tone such as INBRIJA can experience intense urges to gamble or spend money, increased sexual urges, binge eating, and/or intense urges and inability to control them. In some cases, these urges stopped with dose reduction or medication discontinuation. Since some patients may not recognize these behaviors as abnormal, ask patients or their caregivers about development of new or increased urges and consider stopping INBRIJA if this occurs.
• INBRIJA may cause or exacerbate dyskinesias. If troublesome dyskinesias occur, consider stopping INBRIJA or adjusting other PD medications.
• INBRIJA is not recommended in patients with asthma, COPD, or other chronic underlying lung disease because of the risk of bronchospasm.
• Monitor patients with glaucoma for increased intraocular pressure.
• Abnormalities in laboratory tests may include elevations of liver function tests, for example alkaline phosphatase, AST, ALT, lactic dehydrogenase, bilirubin, blood urea nitrogen, hemolytic anemia, and positive direct antibody tests. Increased levels of catecholamines in the metabolites in plasma and urine may result in false-positive results suggesting pheochromocytoma.
• The most common adverse reactions (≥ 5% and > placebo) were cough (15% vs 2%), upper respiratory tract infection (6% vs 3%), nausea (5% vs 3%), and sputum discolored (5% vs 0%).
• Use of selective MAO-B inhibitors with INBRIJA may be associated with orthostatic hypotension. Monitor patients taking these drugs concurrently.
• Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce levodopa efficacy; monitor for worsening symptoms.
• Iron salts or multivitamins with iron salts may reduce levodopa bioavailability.
• INBRIJA should be used during pregnancy/nursing only if potential benefit justifies potential risk. There are no adequate data on INBRIJA in pregnant women or breastfed infants. Animal data shows carbidopa/levodopa is developmentally toxic (including teratogenicity). Levodopa may affect milk production, interfering with lactation. Levodopa has been detected in human milk.
• Safety and effectiveness in pediatric patients have not been established.
• Geriatric patients (n=56) experienced more of the following adverse reactions than patients <65 (n=58): cough (25% vs 5%), upper respiratory tract infection (11% vs 2%), nausea (7% vs 3%), vomiting (4% vs 2%), pain in extremities (4% vs 0%), and discolored nasal discharge (4% vs 0%).

Please see accompanying Full Prescribing Information at InbrijaFullPI.com

[Dr. Isaacson and Dr. Pahwa seated at table together, Dr. Isaacson speaking]

Thank you all for joining us today.

[Slide is shown with References and INBRIJA logo]

ACORDA THERAPEUTICS, the stylized ACORDA THERAPEUTICS logo, INBRIJA, and the INBRIJA logo are all trademarks of Acorda Therapeutics, Inc. © 2021 Acorda Therapeutics, Inc. All rights reserved.

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11/21 INB11535