Key clinical-trial evidence for alitretinoin

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2013.

Oral alitretinoin for hand eczema

Toctino® (oral alitretinoin) is marketed by Stiefel laboratories (UK) and is approved for the treatment of hand eczema in UK, Europe, Israel and Canada (February 2013).

The safety and efficacy of oral alitretinoin in patients with severe chronic hand eczema refractory to topical corticosteroids has been established in two randomised, double blind, placebo-controlled phase 3 studies.

Study 1

The BACH (Benefit of Alitretinoin in Chronic Hand Dermatitis Study) included 1032 severe chronic hand eczema/dermatitis patients who had no response or a transient response (initial improvement and worsening of disease despite continued treatment) to potent topical corticosteroids or who were intolerant to potent topical corticosteroids.

All phenotypes of hand eczema were included: hyperkeratosis (87%), pompholyx (27%), fingertip dermatitis (43%), and other (15%). Essentially all patients had signs of skin inflammation, comprising of erythema and/or vesicles.

The primary endpoint in these studies was the proportion of patients achieving Physicians Global Assessment (PGA) ratings of clear or almost clear hands at the end of therapy. The treatment duration was 12 to 24 weeks.

Treatment with alitretinoin led to a significantly higher proportion of patients achieving clear/almost clear hands, compared to placebo. The response was dose-dependent. Response rates for different CHE subtypes were also dose-dependent, except for patients with pompholyx.

Primary Efficacy Parameters
Alitretinoin
Primary Endpoint 10 mg 30 mg Placebo
Intention to treat (ITT) Population N=418 N=409 N=205
Physician Global Assessment (PGA):      
Total Response Rate 115 (27.5%) 195 (47.7%) 34 (16.6%)
Clear 39 (9.3%) 90 (22.0%) 6 (2.9%)
Almost clear 76 (18.2%) 105 (25.7%) 28 (13.7%)
Comparison to placebo P=0.004 P=<0.001 N/A
Response rate by CHE subtype
CHE subtypeHyperkeratosisHyperkeratosis/PompholyxPompholyx
ITT population % 64% 22% 5%
Response rate (PGA) 30mg: 54% 30mg: 33% 30mg: 33%
10 mg: 30% 10 mg: 23% 10 mg: 22%
Placebo: 12% Placebo: 12% Placebo: 30%

Patients with clear/almost clear hands at end of treatment were followed up for a further 24 weeks. During that period no active drug treatment for CHE was allowed. Relapse was defined as 75% of the initial total lesion symptom score.

In this analysis, the majority of responders given 10mg and 30mg alitretinoin did not relapse by the end of the follow-up period.

Relapse Rates* at the End of Follow-up

AlitretinoinPlacebo
  10 mg 30 mg  
N=418 N=409 N=205
Responders 115 (100%) 195 (100%) 34 (100%)
No Relapse 81 (70.4%) 122 (62.6%) 19 (55.9%)

* Corresponds to a last-observation-carried-forward (LOCF) computation

Study 2

A follow-up study (the second phase 3 study) investigated the efficacy and safety of a second course of treatment both in patients who previously responded to treatment then relapsed (Cohort A) and in patients who did not respond to therapy (Cohort B). Cohort A patients were randomised to the same dose of alitretinoin they received during initial treatment or to placebo in a 2:1 ratio.

80% of relapsing patients from cohort A, receiving repeat treatment with alitretinoin 30 mg, achieved clear/almost clear hands vs 8% in the placebo group (p<0.001).

48% of relapsing patients from cohort A retreated with alitretinoin 10 mg achieved clear/almost clear hands vs 10% in the placebo group (p=0.1).

Alitretinoin gel 0.1% for Kaposi sarcoma

The US FDA approved alitretinoin gel (Panretin®; Ligand Pharmaceuticals USA) for the treatment of cutaneous lesions in Kaposi sarcoma (KS) in 1999. The drug has since been approved in Europe and Canada.

Two multicenter, prospective, randomized, double-blind, vehicle-controlled studies evaluated the efficacy of alitretinoin gel in patients with cutaneous lesions of AIDS-related KS.

In both studies the primary efficacy endpoint was cutaneous KS tumour response rate after 12 weeks of study drug treatment.

The KS tumour response rate was assessed by evaluating 3 to 8 KS index lesions according to the modified AIDS Clinical Trials Group (ACTG) response criteria as applied to topical therapy (i.e. evaluation of height and area reductions of the index lesions only; progressive disease was scored in the treated index lesions only and not in non-index lesions and new lesions).

Photographs of lesions in patients considered responders by the modified ACTG criteria were examined by the FDA for a cosmetically beneficial response, defined as at least a 50% improvement in appearance compared to baseline, in at least 50% of the index lesions and maintained for at least 3 weeks.

A global evaluation by physicians was also carried out. It considered all of the patient’s treated lesions (index and other) compared to baseline. In this evaluation, patients with at least a 50% improvement in the KS lesions were considered responders.

Study 1

A total of 268 patients were entered from centers in the U.S. and Canada.

Patients were treated topically three to four times a day with either alitretinoin gel or a matching vehicle gel for a minimum of 12 weeks.

Responses to alitretinoin gel were seen in both previously untreated patients and in patients with prior systemic and/or topical KS treatment.

Primary efficacy parameters – study 1
ParameterAlitretinoin gel (n = 134)Vehicle gel (n = 134)
Modified ACTG response (index lesions) 34% (partial response)
1% (complete response)
16% (partial response)
p = 0.0012
Physicians’ Global Assessment (all treated lesions) 19% (partial response) 4% (partial response)
P= 0.00014
Beneficial response photographs (index lesions only) 15% 4%
p = 0.0026

Study 2

Study 2 was an international study with a planned enrollment of 270 patients.

The study was stopped early because of positive interim results in the initial 82 patient data set.

Patients were treated topically twice a day with alitretinoin gel or a matching vehicle for 12 weeks.

Responses to alitretinoin gel were seen both in previously untreated patients and in patients with prior systemic and/or topical KS treatment.

Primary Efficacy Parameters – study 2
ParameterAlitretinoin gel (n = 36)Vehicle gel (n = 46)
Modified ACTG response (index lesions) 36% (partial response) 7% (partial response)
Physicians’ Global Assessment (all treated lesions) 47% (partial response) 11% (partial response)
Beneficial response photographs (index lesions only) 19% 2%

In both studies, responses occurred in patients with a wide range of baseline CD4+ lymphocyte counts, including patients with CD4+ lymphocyte counts less than 50 cells/mm3. Nearly all patients received concomitant combination antiretroviral therapy.

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