Summary Basis of Decision for Toctino

3.3.1 Pharmacodynamics

The exact mechanism of action of alitretinoin with respect to chronic hand eczema (CHE) in particular, remains unclear. However, the efficacy of alitretinoin in CHE is unquestioned, owing to the favourable results from clinical studies in patients suffering from moderate or severe CHE.

Analysis of human skin samples of patients suffering from nickel allergy demonstrated an overexpression of CXCR3 ligands and CCL20 chemokines. In vitro studies evaluated the immunomodulatory and anti-inflammatory effect of alitretinoin. The findings demonstrated that structural cells of the skin including epidermal keratinocytes and endothelial cells, as well as, leukocyte subsets are targets for alitretinoin. Within structural cells, alitretinoin markedly suppressed pathogenically relevant chemokine expression of CXCR3 ligands and CCL20 suggesting that this drug may impair the recruitment of distinct leukocyte subsets to sites of skin inflammation. It was also shown that alitretinoin markedly inhibits the expansion of pro-inflammatory cytokine activated T-lymphocytes and antigen presenting leucocytes subsets. Through these mechanisms alitretinoin may interfere with the initiation, as well as, the maintenance of contact dermatitis lesions.

Mean plasma levels of retinol/retinol ester and retinol binding protein decreased by 25% and 35%, respectively, 24 hours after administration of the first dose in subjects receiving 40 mg alitretinoin. No further decrease was observed for either parameter at later assessments. No conspicuous change was observed for either marker in subjects receiving 20 mg alitretinoin. These results are consistent with the dose-dependent decrease in plasma retinol associated with single dose administration of alitretinoin. The absence of further decrease in retinol plasma level with repeated dosing suggests that a plateau effect may have been reached before the end of the 14-day administration. All observed values remained well above the threshold levels associated with mild changes in dark adaptation. Electroretinography was conducted in subjects treated with the 40 mg dose of alitretinoin, and revealed no effect of alitretinoin on retinal function.

3.3.2 Pharmacokinetics

Absorption

Peak plasma concentrations of alitretinoin were observed within 3 to 4 hours after drug intake following oral administration of 5, 15, 40, 80, and 150 mg alitretinoin in healthy volunteers.

Chronic administration of alitretinoin for up to 24 weeks did not result in accumulation or time-dependent changes in the disposition of alitretinoin or its major metabolite, 4-oxo-alitretinoin, at a dose of 10 to 30 mg administered orally. In addition, systemic exposure to alitretinoin and 4-oxo-alitretinoin was linear over the dose range of 10 to 30 mg.

The systemic exposure was increased when alitretinoin was administered with food.

Comparative Bioavailability Studies

A pivotal comparative bioavailability study (BAP00300) was conducted under fed conditions to bridge the 10 and 20 mg Toctino (alitretinoin) capsules that were administered in the pivotal Phase III clinical studies to the proposed commercial 10 mg and 30 mg Toctino capsules. The data from Study BAP00300 met the applicable Health Canada standards for comparative bioavailability, however, due to outstanding concerns with the analytical method that was used to analyze the subject samples, the data from pivotal Study BAP00300 was not considered to be reliable. Additionally, the data from the food-effect study (BAP00007) was deficient and as a result there was insufficient data to characterize the effect of food on the rate and extent of absorption of alitretinoin from the proposed Toctino capsules. These outstanding concerns from the review were issued to the sponsor in a Notice of Non-Compliance (NON) dated February 11, 2009.

The concerns regarding the bioavailability of the Phase III capsules compared to the proposed commercial preparation for the 10 and 30 mg dosage were addressed by the sponsor in the NON-Response. The response was considered acceptable. As well, discussions regarding the food-effect study resulted in the agreement that an additional food-effect study was not required. It is well known that the absorption of this class of drugs is enhanced by food, and that the clinical trials were done in a fed-state. Therefore, providing clear information in the labelling and the Product Monograph stating that the medication must be taken with food is found to be acceptable. The presentation of this information in this manner is in line with other marketed retinoids.

Distribution

In plasma of humans, alitretinoin was highly bound (99%) to plasma proteins. The volume of distribution was not determined in humans. In the animal studies, the volume of distribution was greater than the plasma volume.

Metabolism

Alitretinoin is metabolized by oxidation in the liver by CYP3A4 into the metabolite 4-oxo-alitretinoin, and then further metabolized to give all-trans retinoic acid and 4-oxo-all-trans retinoic acid. Similar to the parent compound, maximum plasma concentrations of all metabolites occurred between 2 and 5 hours after dosing followed by a rapid decline.

Excretion

After the oral administration of radiolabelled alitretinoin, total urinary and faecal recovery of the radiolabelled material was considered as complete with individual values ranging from 90-99% within 5-7 days. Alitretinoin appeared to be completely absorbed and extensively metabolized. Metabolic clearance was the major pathway of elimination.

Drug Interactions

Co-administration with strong CYP3A4 or human P-glycoprotein (Pgp) inhibitors, such as ketoconazole, increased levels of alitretinoin. The drug exposure of alitretinoin, as measured by the area under the curve (AUC) values, was approximately 40% higher with the coadministration of ketoconazole.

Single and repeat administration of alitretinoin did not alter the pharmacokinetics of ciclosporin or ketoconazole. A slight reduction of simvastatin levels was observed when co-administrated with alitretinoin.

CYP3A4 substrates such as ciclosporin and simvastatin did not affect the pharmacokinetics of alitretinoin. Strong inhibition of CYP3A4/PgP by ketoconazole significantly increased alitretinoin levels but not that of the 4-oxo-metabolites. Exposure to alitretinoin and 4-oxo-metabolites remained constant with time, with no indication of accumulation or auto-induction, and therefore, dose proportionality can be assumed up to 30 mg.

Alitretinoin was well-tolerated alone or in combination with single doses of interaction drugs and no new safety signals were identified.

3.3.3 Clinical Efficacy

The efficacy and safety of Toctino were primarily evaluated from two pivotal randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase III studies, Study BAP00089 and Study BAP00091.

Study BAP 00089 included 1032 patients in the intent-to-treat (ITT) population. Patients in this study had severe CHE refractory to high potency topical corticosteroids, and had disease duration of at least six months. Treatment was for 12 or 24 weeks, with either 10 or 30 mg of Toctino, or placebo. The primary endpoint was to demonstrate that the response rate based on Physician Global Assessment (PGA) in one or both Toctino groups is superior to the response rate in the placebo group at the end of therapy (Week 12 or Week 24), or at the latest assessment for patients withdrawn prematurely.

Secondary endpoints included: the proportion of patients achieving at least mild disease, time to achieving clear to almost clear hands, reduction in total lesion symptom score, the patient global assessment (PaGA) of disease severity, and reduction in extent of disease. Women of childbearing potential were required to use two types of contraception and received extensive instructions and counselling in order to avoid pregnancy.

At the end of therapy, 115 (27.5%) patients in the Toctino 10 mg group, 195 (47.7%) patients in the Toctino 30 mg group, and 34 (16.6%) patients in the placebo group were responders [that means (i.e.), patients for whom the PGA rating was clear or almost clear]. In the ITT analysis, the difference between placebo and Toctino yielded p-values of p=0.004 for the 10 mg dose and p <0.001 for the 30 mg dose. Therefore, both of the Toctino doses (10 mg and 30 mg) were statistically significantly superior to placebo with respect to the PGA at the end of therapy. The response was dose dependent. Response rates for different CHE subtypes were also dose dependent, except for patients with pomphlyx. The secondary efficacy endpoints were consistent with the primary efficacy endpoint (PGA at end of therapy).

Study BAP00091 comprised of 360 patients in two cohorts. Cohort A included patients who had responded to treatment in Study BAP00089 and then relapsed. Cohort B included patients who were non-responding to treatment in Study BAP00091 after 12 weeks of treatment with 30 mg of alitretinoin. Patients who remained classified as "severe" after initial treatment were not included in the study. Responding patients in Cohort A received the same dosage of Toctino as they previously received (10 or 30 mg) and the non-responding patients in Cohort B received 30 mg of Toctino. Responding patients who had received a placebo in the original study continued to receive placebo. Primary and secondary efficacy endpoints were the same as the original study (Study BAP00089). Patients were treated for 12 or 24 weeks.

Results showed that there was a response rate of 50.4% (rated clear or almost clear) for patients who did not respond to the 10 mg dose in the previous study but had taken 30 mg dose in this study. Additional treatment with the 30 mg dose in non-responders demonstrated a 39.1% response rate. In Cohort A, 79.6% of the patients treated with 30 mg responded compared to 8.3% in the corresponding placebo arm. The difference between the 10 mg group and corresponding placebo group did not reach statistical significance (47.6% versus 10%; p=0.10) but this may be explained by the low number of patients assigned to this group (10 received Toctino and 1 received placebo). Overall, the data showed that either a higher dose or a treatment prolongation can benefit patients who fail to respond to Toctino treatment initially.

3.3.4 Clinical Safety

Toctino, given at 10 mg or 30 mg once daily for up to 24 weeks, was generally well-tolerated in the treatment of patients with severe CHE in both pivotal studies; Study BAP00089 and Study BAP00091 (see 3.3.3 Clinical Efficacy).

In Study BAP00089, the most frequent adverse event (AE) in patients treated with Toctino was headache, with the percentage in the 30 mg dose group almost twice as high as that in the 10 mg dose group. Other frequent AEs were nasopharyngitis, eczema and erythema, and dry lips. Erythema and dry lips were also considerably more frequent in patients treated with 30 mg compared to those that were treated with 10 mg. Lab results showed increased levels of triglycerides with treatment. Other known retinoid effects included decreased haemoglobin, decreased TSH, decreased T4 levels, and increased creatine phosphokinase (CPK) levels. The frequency of treatment-emergent AEs leading to treatment discontinuation was higher in the 30 mg dose group compared to the 10 mg dose group. The most frequent treatment-emergent AEs (i.e., those occurring in at least 5 patients overall) leading to treatment discontinuation were headache, and various skin and subcutaneous tissue disorders. The number of AEs requiring treatment was considerably higher in the 30 mg dose group than the 10 mg dose group, mostly because of the higher incidence of headache associated with the higher dose of Toctino. One patient died in this study due to a myocardial infarction. The investigator assessed this event as being unrelated to the study medication.

In Study BAP00091, the proportion of patients experiencing moderate, severe, or life-threatening AEs was greater in the Toctino 30 mg dose groups (Cohort A and Cohort B) compared to the Toctino 10 mg group or the placebo group. Headache was the most frequently reported AE. All reports of headache occurred in the 30 mg dose groups (Cohort A 30 mg: 7 patients, 14%; Cohort B 30 mg: 29 patients, 11.9%). The frequency of dry lip, dry mouth, and cheilitis (mucocutaneous events often associated with retinoid use) was not noticeably higher in the active treatment groups compared to the placebo group. Laboratory changes included increased serum cholesterol and triglycerides, and changes in T₄, CPK, TSH, and haemoglobin. During the study period, there was one patient death (acute cardiac failure) that was unrelated to the study drug.

A supportive open-label safety study (BAP00626) included 248 patients that were administered 30 mg of alitretinoin once daily for 24 weeks. The AEs were typical class effects of oral retinoids such as headache, flushing, nasopharyngitis, and skin disorders. A total of 21 patients withdrew due to AEs, mostly due to headache. The most commonly observed changes in laboratory parameters were changes in serum cholesterol, triglycerides, and TSH, consistent with the class effects of oral retinoids. There were no deaths reported in this study. One serious AE, angioneurotic oedema, was assessed as being remotely related to study treatment.

Review of a thorough QTc study in 48 healthy volunteers showed a dose-related increase in heart rate with Toctino use. In subjects receiving Toctino 30 mg for 3 days, the maximum mean increase in heart rate was 4.4 bpm at 3 hours post-dosing. In subjects receiving a single dose of Toctino 60 mg, significant increases in heart rate were observed from 3 to 12 hours post-dosing, with a maximum mean increase of 10.6 bpm at 8 hours post-dosing. The incidence of heart rate values greater than 100 bpm and =25% higher than baseline was 8.7% for the placebo treatment, 8.3% for the Toctino 30 mg treatment, and 23.9% for the Toctino 60 mg treatment. It is not possible to exclude from this limited size study a moderate effect on QTcF after the exposure of 30 mg Toctino.