KYNMOBI (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1, 0.3, or 0.8 mg/kg/day) and female (0.3, 0.8, or 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 months or 23 months, respectively. In males, there was an increase in Leydig cell tumors at the highest dose tested. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in females.

In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 20 mg/kg/day (male) or 40 mg/kg/day (female).

Mutagenesis

Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in vivo micronucleus assay in mice.

Impairment of Fertility

Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day to male and female rats prior to and throughout the mating period and continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at all subcutaneous doses tested (0.3, 1, or 1.5 mg/kg/day).

In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 0.2, 0.8, or 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.

14 CLINICAL STUDIES

The efficacy of KYNMOBI for the acute, intermittent treatment of “off” episodes in patients with Parkinson’s disease was established in one randomized, double-blind, placebo-controlled, parallel-group study (Study 1; NCT02469090).

The study enrolled patients with a mean duration of Parkinson’s disease of approximately 9 years (range: 2 years to 22 years) who were Hoehn and Yahr Stage III or less in the “on” state, and who were all receiving concomitant levodopa with a stable dose for at least 4 weeks before screening. The most commonly used concomitant Parkinson’s disease medications in addition to levodopa were oral dopaminergic agonists (51%), monoamine oxidase B inhibitors (41%), amantadine derivatives (21%), and other dopaminergic agents (8%).

At baseline, the mean number of daily “off” episodes was 4 and the mean duration of “off” episodes was slightly over an hour in both groups. The study included a titration phase and a 12-week maintenance phase. Patients were titrated to the dose that achieved a full “on” response and was tolerated during the titration phase. Patients were treated with an oral antiemetic starting 3 days before the titration phase. In the titration phase, patients (N=141) arrived at the study site in an “off” state having not taken their regular morning dose of carbidopa/levodopa or any other adjunctive PD medications, as well as having taken their last dose of carbidopa/levodopa and any other adjunctive PD medications no later than midnight the night before. Treatment was initiated in the clinic with a 10 mg dose of KYNMOBI. If the patient responded to treatment and tolerated the 10 mg KYNMOBI dose, the patient was randomized in a blinded fashion to KYNMOBI or placebo in a 1:1 ratio. If the patient tolerated the dose but did not adequately respond, the patient was asked to return to the clinic within 3 days and the dose was increased by 5 mg. The titration process was continued up to a maximum KYNMOBI dose of 35 mg or until a full “on” was achieved as determined by the investigator and the patient [see Dosage and Administration (2.2)]. Dose administration was permitted up to 5 times per day in the maintenance phase. The Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS III) (motor examination) was measured predose, and at 15, 30, 45, 60, and 90 minutes postdose.

The primary endpoint of the study was the mean change from predose to 30 minutes postdose in the MDS-UPDRS III at the 12-week visit of the maintenance phase.

A total of 54 patients were randomized to KYNMOBI and 55 patients to placebo. The KYNMOBI treatment group showed a least-square mean improvement (i.e., reduction in score) of -11.1 points (95% CI: -14.0, -8.2), versus -3.5 points for the placebo group (95% CI: -6.1, -0.9). The least-square mean treatment difference between KYNMOBI and placebo was -7.6 (95% CI: -11.5, -3.7; p = 0.0002) (Table 2).

Table 2: Change from Predose to 30 Minutes Postdose in the MDS-UPDRS III Score at Week 12 (Least-Square Mean) in Study 1
Treatment Number of Patients at Week 12 Observed Predose MDS-UPDRS III Score at Week 12 Least-Square Mean Change from Predose to 30 Minutes Postdose Least-Square Mean Difference from placebo
Placebo 46 42.2 – 3.5 N/A
KYNMOBI 34 37.2 – 11.1 – 7.6 (p=0.0002)

Figure 2 describes the least-square mean change from predose in MDS-UPDRS Part III Motor Scores after administration of KYNMOBI versus placebo at week 12.

Figure 2: Estimated Least-Square Mean Change in MDS-UPDRS Part III Motor Score After Administration of KYNMOBI vs Placebo (at Week 12) in Study 1

Figure 2
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

KYNMOBI sublingual film is a blue to green rectangular film with a white printed number identifying the strength (e.g., “10” is 10 mg). Each sublingual film is individually packaged in a sealed foil pouch. Films are supplied in the following strengths and package configurations (Table 3):

Table 3: Package Configuration for KYNMOBI sublingual film
Single Film Strength (NDC Code) Package Configuration NDC Code
Trade Titration Kit
10 mg (63402-010-01)15 mg (63402-015-01)20 mg (63402-020-01)25 mg (63402-025-01)30 mg (63402-030-01) Each titration kit carton will contain a total of 10 individually packaged films of:2 – single 10 mg films2 – single 15 mg films2 – single 20 mg films2 – single 25 mg films2 – single 30 mg films 63402-088-10
Trade Product
10 mg (63402-010-01) 30 films per carton 63402-010-30
15 mg (63402-015-01) 30 films per carton 63402-015-30
20 mg (63402-020-01) 30 films per carton 63402-020-30
25 mg (63402-025-01) 30 films per carton 63402-025-30
30 mg (63402-030-01) 30 films per carton 63402-030-30

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