Summary Basis of Decision for Catena ®

3.2.1 Pharmacodynamics

Primary Pharmacodynamics

The mode of action of idebenone is potentially two-fold. First, a series of studies using in vitro mitochondrial preparations from heart and brain tissue demonstrated that idebenone mediates the transfer of electrons between complex I, II and III in the mitochondrial electron transport chain thereby reconstituting the generation of ATP under pathological conditions. Second, idebenone was shown to protect against oxidative cell damage. Idebenone protected cells derived from FRDA patients from endogenous oxidative stress resulting in increased cell survival. In a mouse model of FRDA, idebenone given orally reduced disease-specific changes in cardiac tissue histopathology and function and also prolonged the life expectancy in these animals slightly, but significantly. Idebenone was also able to protect mitochondrial function in homogenates of human heart tissue. While the idebenone concentrations tested in the various in vitro studies were generally much higher than the human plasma at maximum concentration (C_max) after a high dose, idebenone was effective in in vivo models and therefore collectively, these studies provide a plausible mode of action for idebenone in the treatment of FRDA.

Secondary Pharmacodynamics:

In a series of secondary pharmacodynamic studies not directly related to treatment of FRDA, idebenone prevented vascular lesions associated with hypertension, ameliorated neurologic and energy deficits after experimental stroke, prevented cytotoxic and vasogenic cerebral edema, prolonged survival after anoxia/hypoxia, and improved cerebral ischemia-induced memory impairment. Idebenone at high concentrations also increased red blood cell deformability, possibly by increasing ATP levels, which may be the reason for reduced hemolysis and longer lifespan seen for red blood cells from hypertensive rats. Importantly there were no safety concerns identified in the secondary pharmacodynamic studies.

Safety Pharmacology

No significant safety concerns were identified in the safety pharmacology studies. No effects were seen on either the central or somatic nervous systems apart from a slight decrease in body temperature of rats given 300 mg/kg, orally. Idebenone had no effect on intestinal transport in mice or gastric secretion in rats. Inhibitory and spasmolytic effects in smooth muscle preparations were observed at high concentrations in vitro. Idebenone significantly inhibited the tail currents of the hERG channel with a concentration far above the expected therapeutic plasma concentration. There were no idebenone-related effects in electrocardiograms from dogs in the repeat-dose toxicology studies.

3.2.2 Pharmacokinetics

Absorption

Idebenone demonstrated dose-dependent absorption and rapid first-pass metabolism in all species tested. In dogs, absorption appeared to plateau between 100 and 500 mg/kg and was greater in recently fed animals.

Distribution

In vitro protein binding at concentrations from 1 to 1000 ng/mL was high, averaging 98.5% in human, 98.3% in dog, and 98.0% in rat plasma. Rats were given idebenone at oral doses of 10 and 300 mg/kg/day for 7 days. After multiple dosing, idebenone concentrations in most tissues were slightly increased over the single dose and attained steady-state within 4-7 days, with the highest concentrations in intestine, stomach, kidney, and liver. No significant amounts of parent drug or drug-derived materials accumulated in the rats during repeated dosing. Idebenone was detected in fetal plasma and tissues, indicating that the activity crossed the placenta. A relatively low concentration of idebenone was detected in rat milk. The maximum brain concentration of parent idebenone was approximately 5% of that in plasma and the concentration of metabolites was much lower. 

Metabolism

Metabolic activity consists of a progressive oxidative shortening of the side chain of parent idebenone leading successively to the metabolites. Parent idebenone and all of the shorter-chain metabolites are also glucuronidated or sulfatated resulting in conjugated forms of idebenone as well as the metabolites. The metabolites were present at much higher concentrations (>99%) than the parent idebenone (<1%) in plasma, and conjugates of the parent and metabolites were at higher levels than the non-conjugated forms. The same spectrum of metabolites was seen in humans, rats, and dogs, thus justifying the use of rats and dogs in the non-clinical safety assessment of idebenone.

Excretion

Idebenone excretion studies were conducted in rats and dogs. Rats were given idebenone orally at 10 and 300 g/kg/day for 7 days and after the 7th dose, excretion was via urine and feces (70.2% and 31.1% respectively) and no accumulation of idebenone was observed. Dogs were given idebenone orally at a dose of 3 mg/kg and intravenously (IV) at a dose of 3 mg/kg. Idebenone was almost entirely excreted via urine and feces. After oral administration, 97.26% of the idebenone dose was excreted of which 59.62% was in the urine and 36.33% in the feces. After IV administration, 88.58% of the idebenone dose was excreted of which 56.77% was in the urine and 28.12% in the feces.

Drug-Drug Interaction

Idebenone inhibited major cytochrome P450 (CYP) isoforms with IC₅₀ values of 0.81 to 3.5 µg/mL, although plasma therapeutic levels are much lower (C_max=23.6 ng/mL) suggesting this is unlikely to be clinically relevant for humans. Furthermore, the CYP inhibition assay was conducted with microsomes incubated in a protein-free buffer. Since idebenone is highly bound to plasma proteins, the free concentration in plasma would be <1 ng/mL or approximately three-folds lower than the lowest IC₅₀.

3.2.3 Toxicology

Single-Dose Toxicity

Idebenone has a very low order of acute oral toxicity in mice and rats (LD₅₀≥10,000 mg/kg). LD₅₀ values for the main metabolite were lower, but it would still be considered to have a low order of acute toxicity.

Repeat-Dose Toxicity

A 13-week repeat-dose toxicity study was conducted in mice where idebenone was administered orally at doses of 0, 210, 640, 1280, and 2000 mg/kg. There were no mortalities in this study. The no observable adverse effect level (NOAEL) was 640 mg/kg/day. There was a noticeable decrease in food intake at Week 1 in all idebenone groups. At the 2000 mg/kg/day dose, there were decreases in white blood cell counts in females and decreases in heart and adrenal gland weights in males. Also, at the 2000 mg/kg/day dose, the mice experienced focal necrosis of the liver, extra-medullary haematopoiesis, white pulp atrophy of spleen and tubular basophilia (all mild), and tubular casts in kidney.

The repeat-dose toxicity studies in rats ranged from 7 days to 52 weeks in duration and idebenone doses ranged from 0-2500 mg/kg/day. The only significant effect with repeat-dose oral administration was the development of forestomach lesions, a rodent-specific phenomenon in mice and rats at high doses of 100-2500 mg/kg/day due to direct irritation.  Due to the severity of gastrointestinal lesions, the NOAEL was 500 mg/kg/day.

The repeat-dose toxicity studies in dogs ranged from 1 week to 52 weeks in duration and idebenone doses ranged from 0-1250 mg/kg. No systemic toxicity was identified in dogs in which the only effects were gastrointestinal disturbances such as loose feces, diarrhea, and emesis which were considered to reflect direct irritation to the gastrointestinal tract. The NOAEL was considered to be 500 mg/kg/day.

Genotoxicity & Mutagenicity

Idebenone was not mutagenic in multiple bacterial assays at concentrations up to 5000 µg per plate with and without metabolic activation. Furthermore it was not clastogenic in two in vivo mouse micronucleus studies at doses up to 5000 mg/kg and two other studies conducted at doses up to 2000 mg/kg which resulted in plasma concentrations up to 175 ng/mL (>7 x human C_max) after 2000 mg/kg. Idebenone was also negative in a rat chromosome aberration study at doses up to 2500 mg/kg and did not elicit unscheduled DNA synthesis in rats given up to 2500 mg/kg. However, idebenone was clearly clastogenic in human lymphocytes in vitro at high concentrations (≥7.5 µg/mL) and equivocal at high concentrations in a mouse lymphoma assay.

Three studies were conducted to qualify Impurity A. A blended lot containing 0.68% Impurity A was used in a bacterial mutagenicity study, an in vivo mouse micronucleus assay, and a 28-day repeated dose study in rats. The results were consistent with the previous studies and the genetic toxicity studies were negative. Therefore, Impurity A can be considered qualified at the proposed level of 0.5% consistent with International Conference on Harmonisation (ICH) guidance.

Carcinogenicity

In the two mouse and two rat carcinogenicity studies, there was no clear evidence of systemic toxicity or carcinogenicity. A treatment-related low incidence of squamous and basal cell tumours of the forestomach at 500 and 1000 mg/kg in rats was attributed to the direct irritation caused by idebenone. In the supplementary rat carcinogenicity study, the incidence of benign interstitial cell adenoma of the testis was within published reference ranges. There were no treatment-related non-neoplastic findings, such as increased hyperplasia, and no increase in interstitial cell testicular tumors in rats or in mice.

A potentially treatment-related neoplastic finding in the four carcinogenicity studies was a small increase in uterine smooth muscle tumors in mice. The incidences were slightly above the conducting laboratory's historical range. The original report states that the uterine tumors were not treatment-related based on an absence of statistical significance and lack of dose dependency for the separate benign and malignant incidences. However, assuming a continuity of tumor progression and combining the benign and malignant smooth muscle tumors, the incidence would be dose dependent and likely statistically significant. Furthermore given that the doses were closely spaced and exposure in females was less than dose proportional, dose dependency in tumor incidence would not necessarily be expected. The mean parent idebenone levels in plasma were approximately 3-, 5-, and 10-times higher than the expected human plasma concentrations at the low, mid, and high dose, respectively. Uterine tumor incidences did not increase in rats at doses up to 1000 mg/kg/day. While a relationship to idebenone is uncertain, the increased incidence of uterine tumors in mice should be recognized.  

Reproductive and Developmental Toxicity

Idebenone was devoid of reproductive or developmental toxicity in the usual series of fertility (male and female rats), embryo-fetal development (female rats and rabbits) and peri- and post-natal (female rats) studies.

Immunogenicity

Idebenone was not immunogenic in the 4-week immunogenicity studies conducted in mice and guinea pigs.

3.2.4 Conclusion

The primary pharmacodynamic characterization has provided a plausible mode of action based on improving mitochondrial respiration and ATP formation. Secondary pharmacodynamic studies, safety pharmacology, long-term toxicity and carcinogenicity studies, mutagenicity, reproductive and developmental toxicity studies did not identify any specific safety concerns for the use of oral idebenone in FRDA.