Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Eisai GmbH, Lyoner Straße 36, 60528, Frankfurt am Main, Germany, E-mail: medinfo_de@eisai.net
Pharmacotherapeutic group: other antineoplastic agents
ATC code: LO1XX22
Although the molecular action of alitretinoin is thought to be mediated through interaction with the retinoid receptors, the exact mechanism of action of this medicinal product in the topical treatment of cutaneous lesions of AIDS-related KS is unknown. Alitretinoin (9-cis-retinoic acid), a naturally-occurring endogenous hormone related to vitamin A, binds to and activates all known intracellular retinoid receptor subtypes (RARα, RARβ, RARγ, RXRα, RXRβ, RXRγ). Once activated, these receptors function as ligand dependent transcription factors that regulate the expression of specific genes. The regulation of gene expression by alitretinoin controls the process of cellular differentiation and proliferation in both normal and neoplastic cells. The efficacy of Panretin gel in treating KS lesions may be related to the demonstrated ability of alitretinoin to inhibit the in vitro growth of KS cells.
Panretin gel can be expected to have local therapeutic effects only and it has no role in the prevention or treatment of visceral KS.
Two controlled, multicentre, randomised, double blind parallel group, Phase III studies provided the data for Panretin gel in the treatment of index cutaneous lesions of KS (Table 4). The patient response rate was evaluated using the AIDS Clinical Trials Group (ACTG) criteria for lesion response in KS. Study 1 included an open-label phase, in which patients themselves elected to enroll. Study 2 was followed by an open label study (Study 2a), which included only patients electing to continue from Study 2.
Table 4. Best response according to ACTG criteria for vehicle controlled phase:
| Study 1 (TID, QID)1 | Study 2 (BD)2 | |||
|---|---|---|---|---|
| Panretin N=134 | Vehicle N=134 | Panretin N=62 | Vehicle N=72 | |
| Clinical Complete Response (CCR)% | 0.7 | 0.0 | 1.6 | 0.0 |
| Partial Response (PR)% | 34.3 | 17.9 | 35.5 | 6.9 |
| Stable Disease % | 50.0 | 59.0 | 43.5 | 58.3 |
| Progressive Disease % | 14.9 | 23.1 | 19.4 | 34.7 |
| Overall Response % | 35.1 | 17.9 p=0.002 | 37.1 | 6.9 p=0.00003 |
1 Protocol-specified dose regimen was application three times a day (TID) escalating to four times a day (QID) after two weeks, with downward adjustments for toxicity.
2 Protocol-specified dose regimen was application twice a day (BD) only, with downward adjustments for toxicity.
In the open label phase of Study 1 (N=184), the overall response rate increased to 66.7%. In Study 2a (N=99), the overall response rate increased to 56.1%.
In study 1, of 110 responding patients, 36 (33%) relapsed, while all but four still being on active treatment.
Response rates were analysed both by the patient as the unit of analysis and by the lesion. Table 5 provides the individual lesion response rates for patients being treated with Panretin gel in the Phase III studies.
Table 5. Index/indicator lesion1 responses within patients during the first 12 weeks on study in initial blinded phase:
| Patients with given number of index/indicator lesion responses (CCR or PR) | ||||
|---|---|---|---|---|
| Study 1 | Study 2 | |||
| Number of Responding Lesions2,3 | Panretin (N=134) N%4 | Vehicle (N=134) | Panretin (N=62) | Vehicle (N=72) |
| N%4 | N%4 | N%4 | N%4 | |
| At Least One | 73 (54.5%) | 42 (31.3%) | 33 (53.2%) | 21 (29.2%) |
| At Least Four | 27 (20.1%) | 8 (6.0%) | 8 (12.9%) | 2 (2.8%) |
1 Study 1, 6 index lesions; Study 2, up to 8 index lesions
2 Each index lesion assessed individually for response.
3 Lesions responding during the first 12 weeks on study, initial blinded phase, confirmed over at least four study weeks (confirmation of response may have occurred after 12 weeks for some lesions in Study 1).
4 Percentages calculated as number of patients with responding lesions divided by total number of patients in the initial blinded phase.
In one trial, 29% of the lesions that had reached a partial response (PR) but had not attained clinical complete response (CCR) within the first 12 weeks of treatment developed a CCR during continuing treatment beyond 12 weeks. The projected time for lesions that were in partial response (PR) to later attain clinical complete response (CCR) was 168 days. It is recommended that Panretin gel should be applied for an initial treatment period of up to 12 weeks. In lesions that have responded to treatment during this time, application may be continued provided that the response improves or is maintained and the product continues to be tolerated. If a complete response of a lesion occurs, no further application of Panretin gel should be made to the responding lesion.
There are no data regarding the efficacy of Panretin gel when applied to complicated lesions (e.g., when lymphoedema is present).
Plasma concentrations of 9-cis-retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of Panretin gel for up to 60 weeks. A subset of these patients were followed during treatment of up to 64 lesions (range 4-64, median 11.5 lesions) for up to 44 weeks (range 2-44, median 15 weeks). In this latter group, the range and frequency of detection of quantifiable 9-cis-retinoic acid plasma concentrations in patients with KS after application of the medicinal product were comparable to the range and frequency of detection of quantifiable plasma concentrations of circulating, naturally-occurring 9-cis-retinoic acid in untreated individuals.
Three doses of alitretinoin (0.01%, 0.05%, or 0.5%) in a topical gel formulation were given to rats in a 28-day dermal toxicology study. Observed effects at the application site included erythema, epidermal thickening, scaling and loosening of the stratum corneum. Clinical pathology evaluations revealed significant increases in absolute polymorphonuclear leukocyte counts, monocyte counts, percentage of monocytes and decreases in percentage of lymphocyte differential white blood cell counts on day 29 of rats treated with alitretinoin 0.5% gel. Clinical chemistry evaluations revealed biologically relevant significant increases in the mean BUN and alkaline phosphatase values in females after the 28-day treatment. Serum LDL was increased in both male and female groups at Day 29. There were no biologically relevant haematology differences or serum chemistry differences after the 14-day period. Observed increases in mean heart-to-final body weight differences were attributed principally to the difference in the terminal body weights. Following treatment with alitretinoin 0.5% gel, mean plasma concentrations in the female rats were generally below the lower limit of quantitation (5 nMol) and mean plasma concentrations in the male rats were about 200 nMol. In contrast to these findings in rats, plasma concentrations of 9-cis-retinoic acid in patients with KS applying Panretin gel never exceeded 0.638 ng/ml (2.13 nMol). This level is about 1/100 the mean concentration measured in male rats.
Alitretinoin was studied for genotoxic potential using the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test. The medicinal product was not genotoxic.
Studies have not been performed to determine the carcinogenic potential of alitretinoin. However, the mutagenic potential has been evaluated, and alitretinoin has tested negative in the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test.
In an oral dose-ranging study in rabbits, alitretinoin induced gross malformations at a dose 35 times the topical human dose. This dose in rabbits resulted in plasma concentrations more than 60 times the highest observed plasma concentration in patients with KS following topical application of Panretin gel. No gross malformations were observed following oral administration to rabbits of doses 12 times the human topical dose (which resulted in plasma concentrations 60 times the highest observed plasma concentration in patients with KS following topical application of the gel). However, an increased rate of fused sternebrae was observed.
The phototoxicity potential of alitretinoin was assessed based on its chemical properties and data from a battery of in vitro tests. The results suggest that alitretinoin absorbs light in the UV range and is subject to photodegradation to other isomers (predominantly all-trans-retinoic acid). Alitretinoin was shown to have a weak potential to be a photo-irritant based on histidine and photoprotein binding. In cell-based in vitro assays, alitretinoin showed weak phototoxic potential.
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