Xadago (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In carcinogenicity studies in mice and rats, safinamide was administered at oral doses of 0, 50, 100 and 200 mg/kg/day, and 0, 25, 50 and 100 mg/kg/day, respectively, for 2 years. The highest doses tested in both species were approximately 10 times the maximum recommended human dose (MRHD) of 100 mg/day on a body surface area (mg/m 2) basis. No evidence of tumorigenic potential was observed in either species.

Mutagenesis

Safinamide was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

In a rat fertility study in which males and females were orally administered safinamide (0, 50, 100, 150 mg/kg/day) prior to and during mating and continuing through early pregnancy in females, adverse effects on reproductive function were observed in both males (sperm abnormalities) and females (decreased corpora lutea, increased pre-implantation loss). The no-effect dose for reproductive toxicity (50 mg/kg/day) is approximately 5 times the MRHD on a mg/m 2 basis.

13.2 Animal Toxicology and /or Pharmacology

Retinal Pathology in Rats

Degeneration and loss of photoreceptor cells were observed in the retina of both albino and pigmented rats at plasma exposures lower than that in humans at the maximum recommended human dose of 100 mg/kg/day. The findings were dose- and time-dependent and progressed from minimal loss to severe outer nuclear cell layer loss after one year of oral dosing with safinamide. In a two year study, total retinal atrophy and scarring and lens opacities (cataracts) were seen at all oral doses tested (0, 25, 50, and 100 mg/kg/day).

In a study in rats dosed orally with safinamide alone or in combination with pramipexole, pramipexole, at a dose (25 mg/kg/day) that did not cause retinal changes, exacerbated the retinal pathology caused by safinamide alone (50 mg/kg/day) in both pigmented and albino rats.

Investigative studies were not able to identify a mechanism underlying the retinal toxicity; the relevance to humans is unknown.

14 CLINICAL STUDIES

14.1 Adjunctive Treatment in Patients with Parkinson’s Disease Experiencing OFF Time on a Stable Dose of Levodopa.

Two double-blind, placebo-controlled, multi-national, 24-week studies (Study 1 and Study 2) were conducted in PD patients experiencing “OFF” Time during treatment with carbidopa/levodopa and other PD medications, e.g., dopamine agonists, catechol-O-methyl transferase (COMT) inhibitors, anticholinergics, and/or amantadine. In both studies, the primary measure of effectiveness was the change from baseline in total daily “ON” Time without troublesome dyskinesia (i.e., “ON” Time without dyskinesia plus “ON” Time with non- troublesome dyskinesia), based on 18-hour diaries completed by patients for at least 3 days before each of the scheduled visits. Secondary endpoints included “OFF” Time during the diary period and reduction in Uniform Parkinson’s Disease Rating Scale (UPDRS) Part III (motor examination).

In Study 1, patients (n=645) were randomized equally to treatment with XADAGO 50 mg/day (n=217 patients), XADAGO 100 mg/day (n=216 patients), or placebo (n=212 patients), and had at least one post-baseline assessment of “ON” Time.

The percentages of patients taking stable doses of other classes of PD medications, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (61%), COMT inhibitors (24%), anticholinergics (37%), and amantadine (14%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 630 mg. The mean duration of Parkinson’s disease was approximately 8 years.

In Study 1, XADAGO 50 mg/day and 100 mg/day significantly increased “ON” Time compared to placebo (Table 2). The increase in “ON” Time without troublesome dyskinesia was accompanied by a similar significant reduction in “OFF” Time and a reduction in Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) scores assessed during “ON” Time (Table 3). Improvement in “ON Time” occurred without an increase in troublesome dyskinesia.

Table 2: Change in Mean Total Daily “ON” Time * in Study 1
NBaseline (hours) (mean ± SD) Change from Baseline to Endpoint (LSD vs. placebo) (95% CI) p-value
*
“ON” Time = “ON” Time without dyskinesia plus “ON” Time with non-troublesome dyskinesia
LSD: Least squares difference; a positive value indicates improvement
95% CI: 95% Confidence Interval
Placebo2129.3 ± 2.2
XADAGO 50 mg once daily2179.4 ± 2.20.50 (0.03, 0.96) p=0.0356
XADAGO 100 mg once daily2169.6 ± 2.50.53 (0.07, 1.00) p=0.0238
Table 3: Secondary Measures of Effectiveness in Study 1
NBaseline (hours) (mean ± SD) Change from Baseline to Endpoint (LSD * vs. placebo) (95% CI) p-value
*
LSD: Least squares difference; a negative value indicates improvement
95% CI: 95% Confidence Interval
Change in mean daily “OFF” time
Placebo2125.3 ± 2.1
XADAGO 50 mg once daily2175.2 ± 2.0-0.55 (-0.93, -0.17) p=0.0049
XADAGO 100 mg once daily2165.2 ± 2.2-0.57 (-0.95, -0.19) p=0.0037
Change in UPDRS Part III (Motor subscale)
Placebo21228.6 ± 12.0
XADAGO 50 mg once daily21727.3 ± 12.8-1.75 (-3.24, -0.36) p=0.0212
XADAGO 100 mg once daily21628.4 ± 13.5-2.48 (-3.97, -1.00) p=0.0011

The effect of XADAGO 100 mg on “ON” Time was only slightly numerically greater than the effect of XADAGO 50 mg. In addition, the time course of improvement in total daily “ON” Time was similar between both doses (Figure 1). The time course of improvement in total daily “ON” Time showed numerically greater improvement with both XADAGO 50mg and 100 mg compared to placebo, at all post-baseline timepoints (Figure 1).

Figure 1: Mean of Change from Baseline in Total Daily “ON” Time by Week and Treatment in Study 1

Figure 1
(click image for full-size original)

Figure 2 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily “ON” Time in Study 1. The cumulative percentage of patients with a change in “ON” Time was similar for the XADAGO 50 mg and 100 mg groups. The cumulative percentage of patients with an increase in “ON” Time is higher for both XADAGO 50 mg and 100 mg treated patients than for placebo patients.

Figure 2: Study 1 Empirical Cumulative Distribution Functions (CDF) for the Change from Baseline to Week 24 in Total Daily “ON” Time

Figure 2
(click image for full-size original)

Patients who dropped out of the study because of an adverse reaction, lack of efficacy, non-compliance, or withdrawal of consent were treated as treatment failures and assumed to have the smallest change from baseline among all patients. The failure rates are 6.1%, 5.6%, and 6.9% for the placebo group, XADAGO 50 mg/day group, and XADAGO 100 mg/day group, respectively.

In Study 2, patients (n=549) were randomized to treatment with XADAGO 100 mg daily (n=274 patients) or placebo (n=275 patients) for up to 24 weeks. The percentages of patients taking stable doses of other classes of PD medication, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (74%), COMT inhibitors (18%), anticholinergics (17%), and amantadine (30%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 777 mg. The mean duration of Parkinson’s disease was approximately 9 years.

In Study 2, XADAGO was significantly better than placebo for increasing “ON” Time (Table 4). The observed increase in “ON” Time without troublesome dyskinesia was accompanied by a reduction in “OFF” Time of similar magnitude and a reduction in UPDRS III score (assessed during “ON” Time). The time course of effect was similar to that showed in the above figure for Study 1. As in Study 1, the increase in “ON” Time without troublesome dyskinesia was accompanied by a similar significant reduction in “OFF” Time and a reduction in Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) scores assessed during “ON” Time (Table 5).

Table 4: Change in Mean Total Daily “ON” Time * in Study 2
NBaseline (hours) (mean ± SD) Change from Baseline to Endpoint (LSD vs. placebo) (95% CI) p-value
*
“ON” Time = “ON” Time without dyskinesia plus “ON” Time with non-troublesome dyskinesia
LSD: Least squares difference; a negative value indicates improvement;
95% CI: 95% Confidence Interval
Placebo2739.1 ± 2.5
XADAGO 100 mg once daily2709.3 ± 2.40.99 (0.58, 1.39)< 0.001
Table 5: Secondary Measures of Effectiveness in Study 2
NBaseline (hours) (mean ± SD) Change from Baseline to Endpoint (LSD * vs. placebo) (95% CI) p-value
*
LSD: Least squares difference; a positive value indicates improvement
95% CI: 95% Confidence Interval
Change in mean daily “OFF” time
Placebo2735.36 ± 2.00
XADAGO 100 mg once daily2705.35 ± 1.98-1.06 (-1.43, -0.69) <0.001
Change in UPDRS Part III (Motor subscale)
Placebo27323.03 ± 12.75
XADAGO 100 mg once daily27022.33 ± 11.79-1.70 (-2.89, -0.50) 0.005

The time course of improvement in total daily “ON” Time showed numerically greater improvement with XADAGO 100 mg compared to placebo at all post-baseline timepoints (Figure 3).

Figure 3: Mean of Change from Baseline in Total Daily “ON” Time by Week and Treatment in Study 2

Figure 3
(click image for full-size original)

Figure 4 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily “ON” Time in Study 2. The cumulative percentage of patients with an increase in “ON” Time treated with XADAGO 50 mg to 100 mg is higher than for placebo patients.

Figure 4: Study 2 Empirical Cumulative Distribution Functions (CDF) for the Change from Baseline to Week 24 in Total Daily “ON” Time

Figure 4
(click image for full-size original)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.