Clinical trial design1

OPEN-LABEL
TITRATION PHASE

DOUBLE-BLIND
MAINTENANCE PHASE

The KYNMOBI clinical trial included a titration phase and a 12‐week, double‐blind maintenance phase. Patients were titrated to the dose that achieved a full ON response within 45 minutes. Then, patients were randomized 1:1 to either KYNMOBI at the tolerated dose that achieved full ON during the titration phase or matching placebo.

Patients received increasing doses from 10 mg to 35 mg in 5-mg increments until they achieved a full ON within 45 minutes

Patients completed home dosing and response diaries 2 days prior to each visit at weeks 0, 4, 8, and 12

Patients could self-administer study medication up to 5 times per day at least 2 hours apart at home when needed


Primary endpoint: Mean change from predose to 30 minutes postdose in Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (motor examination) score at Week 12.2

OPEN-LABEL
TITRATION PHASE

DOUBLE-BLIND
MAINTENANCE PHASE

The KYNMOBI clinical trial included a titration phase and a 12‐week, double‐blind maintenance phase. Patients were titrated to the dose that achieved a full ON response within 45 minutes. Then, patients were randomized 1:1 to either KYNMOBI at the tolerated dose that achieved full ON during the titration phase or matching placebo.

Patients received increasing doses from 10 mg to 35 mg in 5-mg increments until they achieved a full ON within 45 minutes

Patients completed home dosing and response diaries 2 days prior to each visit at weeks 0, 4, 8, and 12

Patients could self-administer study medication up to 5 times per day at least 2 hours apart at home when needed


Primary endpoint: Mean change from predose to 30 minutes postdose in Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (motor examination) score at Week 12.2

  • Had a response comparable to, or better than, their normal response to PD medications (eg, levodopa)
  • Felt KYNMOBI provided a benefit in regard to mobility
  • Felt capable of performing normal daily activities

IMPORTANT SAFETY INFORMATION FOR KYNMOBI SUBLINGUAL FILM (cont'd)
Warnings and Precautions:

  • Nausea and Vomiting: KYNMOBI may cause nausea and vomiting when administered at recommended doses. Because of the high incidence of nausea and vomiting with KYNMOBI when administered at recommended doses, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, is recommended beginning 3 days prior to the initial dose of KYNMOBI. Treatment with the antiemetic should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with KYNMOBI. Concomitantly administered antiemetic drugs other than trimethobenzamide have not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide) have the potential to worsen symptoms in patients with PD and should be avoided.

Fast and reliable improvement in off symptoms1,2

Statistical significance was demonstrated at 30 minutes (P=0.0002)

Statistical significance was demonstrated at 30 minutes (P =0.0002).
Statistical significance was demonstrated at 30 minutes (P =0.0002).

LS=least squares; SE=standard error.

Study description: Results from the phase 3, randomized, double-blind, placebo-controlled multicenter trial of KYNMOBI for the acute, intermittent treatment of OFF episodes in patients with PD. Patients were randomized [1:1] to receive treatment with either KYNMOBI at the tolerated dose that provided a full ON response during titration [n=54] or an identical matching placebo [n=55]. The primary endpoint of the study was the mean change from predose to 30 minutes postdose in the MDS-UPDRS Part Ill score at Week 12 visit of the maintenance phase.2,3

LS=least squares; SE=standard error.

Numerical improvements from baseline observed at 15 minutes and every measured time point1,2

IMPORTANT SAFETY INFORMATION FOR KYNMOBI SUBLINGUAL FILM (cont'd)
Warnings and Precautions (cont'd):

  • Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with dopaminergic medications, including apomorphine, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.
    Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Study description: Results from the phase 3, randomized, double-blind, placebo-controlled multicenter trial of KYNMOBI for the acute, intermittent treatment of OFF episodes in patients with PD. Patients were randomized [1:1] to receive treatment with either KYNMOBI at the tolerated dose that provided a full ON response during titration [n=54] or an identical matching placebo [n=55]. The primary endpoint of the study was the mean change from predose to 30 minutes postdose in the MDS-UPDRS Part Ill score at Week 12 visit of the maintenance phase.2,3

IMPORTANT SAFETY INFORMATION FOR KYNMOBI SUBLINGUAL FILM (cont'd)
Warnings and Precautions (cont'd):

  • Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with dopaminergic medications, including apomorphine, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.
    Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

>3X improvement in MDS-UPDRS PART III SCORE2

Significant clinical improvement was achieved at 30 minutes (P=0.0002)1,2

Mean change in MDS-UPDRS Part III score at 30 minutes postdose at week 12 (primary endpoint).
Mean change in MDS-UPDRS Part III score at 30 minutes postdose at week 12 (primary endpoint).
Patients taking KYNMOBI saw a >3X improvement in mean MDSUPDRS Part III scores vs those taking placebo (-11.1 vs -3.5, respectively). Patients taking KYNMOBI saw a >3X improvement in mean MDSUPDRS Part III scores vs those taking placebo (-11.1 vs -3.5, respectively).

IMPORTANT SAFETY INFORMATION FOR KYNMOBI SUBLINGUAL FILM (cont'd)
Warnings and Precautions (cont'd):

  • Falling Asleep During Activities of Daily Living and Somnolence (cont'd): Before initiating treatment with KYNMOBI, advise patients of the risk of drowsiness and ask them about factors that could increase the risk with KYNMOBI, such as concomitant sedating medications and the presence of sleep disorders.
    • If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.). KYNMOBI should ordinarily be discontinued. If a decision is made to continue KYNMOBI, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Fast and Reliable Efficacy1,2

Statistically significant improvement in the motor examination was demonstrated at 30 minutes, with the first numerical improvements observed at 15 minutes, and the last numerical improvement observed at 90 minutes.
Statistically significant improvement in the motor examination was demonstrated at 30 minutes, with the first numerical improvements observed at 15 minutes, and the last numerical improvement observed at 90 minutes.

IMPORTANT SAFETY INFORMATION FOR KYNMOBI SUBLINGUAL FILM (cont'd)
Warnings and Precautions (cont'd):

  • Hypersensitivity: Oral soft tissue swelling (lips, tongue, gingiva, and mouth) was reported as an adverse reaction in patients treated with KYNMOBI. It is not known whether these events are related to apomorphine, sodium metabisulfite, or another KYNMOBI excipient. KYNMOBI rechallenge is not generally recommended after discontinuation as oral adverse reactions may recur and may be more severe than the initial reaction.
  • Syncope/Hypotension/Orthostatic Hypotension: KYNMOBI may cause syncope, hypotension or orthostatic hypotension. Patients treated with KYNMOBI should receive an assessment for hypotension/orthostatic hypotension, especially if they have a history of hypotension or cardiovascular disease, or if they are currently using antihypertensive medication. Patients should be informed of this risk.
    Hypotensive effects of KYNMOBI may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid alcohol when using KYNMOBI. Patients taking KYNMOBI should lie down before and after taking sublingual nitroglycerin. Monitor patients taking concomitant anti hypertensive medications for hypotension and orthostatic hypotension.
  • Oral Mucosal Irritation: KYNMOBI may cause oral irritation. Rechallenge is not generally recommended after discontinuation as oral adverse reactions may recur and be more severe than the initial reaction.
  • Falls: Patients with PD are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat PD. KYNMOBI might increase the risk of falling by simultaneously lowering blood pressure and altering mobility.
  • Hallucinations/Psychotic-Like Behavior: Patients with a major psychotic disorder should ordinarily not be treated with apomorphine because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of PD and may decrease the effectiveness of KYNMOBI.
  • Impulse Control/Compulsive Behaviors: Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking one or more medications, including KYNMOBI, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients oheir caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge eating or other urges while being treated with KYNMOBI. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking KYNMOBI.
  • Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature. muscular rigidity, altered consciousness. elevated serum creatine kinase. and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of. or changes in antiparkinsonian therapy.
  • QTc Prolongation and Potential for Proarrhythmic Effects: QTc prolongation with KYNMOBI cannot be excluded.
    Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases (20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of KYNMOBI at recommended doses in clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes.
    The risks and benefits of KYNMOBI treatment should be considered prior to initiating treatment with KYNMOBI in patients with risk factors for prolonged QTc.
  • Fibrotic Complications: Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, whether other, nonergot derived dopamine agonists, such as KYNMOBI, can cause these reactions is unknown.
  • Priapism: Apomorphine may cause prolonged painful erections in some patients. Severe priapism may require surgical intervention.

Examine the safety
of KYNMOBI


References: 1. CTH-300 study. Data on file. Sunovion Pharmaceuticals Inc. 2. Kynmobi. Prescribing information. Sunovion Pharmaceuticals Inc; May 2020. 3. Olanow CW, Factor SA, Espay AJ, et al; for the CTH-300 Study Investigators. Apomorphine sublingual film for off episodes in Parkinson’s disease: a randomized, double-blind, placebo-controlled phase 3 study. Lancet Neurol. 2020;19[2]:135-144.

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