CLINICAL PHARMACOLOGY
Mechanism Of Action
Following the application of LEVULAN KERASTICK topical solution, photosensitization occurs through the metabolic conversion of aminolevulinic acid to protoporphyrin IX (PpIX), a photosensitizer, which accumulates in the skin.
When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen. The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from photoreactive porphyrins to molecular oxygen generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. LEVULAN KERASTICK Photodynamic Therapy of actinic keratoses is the combination of photosensitization by application of the LEVULAN KERASTICK topical solution to the lesions and subsequent illumination with BLU-U Blue Light Photodynamic Therapy Illuminator.
Pharmacodynamics
ALA does not exhibit fluorescence, while PpIX has a high fluorescence yield. Time-dependent changes in surface fluorescence have been used to determine PpIX accumulation and clearance in actinic keratoses and perilesional skin after application of the LEVULAN KERASTICK topical solution in 12 subjects. Peak fluorescence intensity was reached in 11 ± 1 hr in actinic keratoses and 12 ± 1 hr in perilesional skin. The mean clearance half-life of fluorescence for lesions was 30 ± 10 hr and 28 ± 6 hr for perilesional skin. The fluorescence in perilesional skin was similar to that in actinic keratoses. Therefore, the LEVULAN KERASTICK topical solution should only be applied to the affected skin.
Pharmacokinetics
Two human pharmacokinetic (PK) studies were conducted in subjects with minimally to moderately thick actinic keratoses on the upper extremities, having at least 6 lesions on one upper extremity and at least 12 lesions on the other upper extremity. A single dose comprising of two topical applications of LEVULAN KERASTICK topical solution (each containing 354 mg ALA HCl) were directly applied to the lesions and occluded for 3 hours prior to light treatment.
The first PK study was conducted in 29 subjects and PK parameters of ALA were assessed. The baseline-corrected mean ± SD of the maximum concentration (Cmax) of ALA was 249.9 ± 694.5 ng/mL and the median time to reach Cmax (Tmax) was 2 hr post dose. The mean ± SD exposure to ALA, as expressed by area under the concentration time curve (AUCt) was 669.9 ± 1610 ng·hr/mL. The mean ± SD elimination half-life (T1/2) of ALA was 5.7 ± 3.9 hr.
A second PK study was conducted in 14 subjects and PK parameters of ALA and PpIX were measured. The baseline-corrected PpIX concentrations were negative in at least 50% of samples in 50% (7/14) subjects and AUC could not be estimated reliably. The baseline-corrected mean ± SD of Cmax for ALA and PpIX was
95.6 ± 120.6 ng/mL and 0.95 ± 0.71 ng/mL, respectively. The median Tmax of ALA and PpIX was 2 hr post dose and 12 hr post dose, respectively. The mean AUCt of ALA was 261.1 ± 229.3 ng·hr/mL. The mean ± SD T1/2 of ALA was 8.5 ± 6.7 hr.
Clinical Studies
Actinic Keratoses Of The Face Or Scalp
LEVULAN KERASTICK for topical solution plus blue light at 6-10.9 J/cm2, has been used to treat actinic keratoses of the face or scalp in 342 subjects in seven clinical trials. Phase 3 trials ALA-018 and ALA-019 were two, identically designed, multicenter, two-arm trials using LEVULAN KERASTICK topical solution plus illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator for 1000 seconds (16 minutes and 40 seconds) for a nominal exposure of 10 J/cm2. Subjects were excluded from these trials who had a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins, photodermatosis, or inherited or acquired coagulation defects. A minimum of 4 and a maximum of 15 clinically typical, discrete, Grade 1 (slightly palpable actinic keratoses: better felt than seen), or Grade 2 (moderately thick actinic keratoses: easily seen and felt) target actinic keratoses were identified (see Table 5 for definitions). Target lesions on the face or on the scalp, but not on both locations in the same subject, received treatment. The subjects were randomized to receive treatment either with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator or vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator. Subjects were randomized at a 3 to 1 LEVULAN KERATICK topical solution to vehicle ratio. A total of 243 subjects were enrolled in two Phase 3 trials (ALA-018, ALA-019). Lesions were designated as cleared (complete response) if the lesion had completely cleared and adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when palpated. The percentage of subjects in whom 75% or more of treated lesions were cleared, and the percentage of subjects in whom 100% of treated lesions were cleared (Complete Responders), for each trial 8 weeks after treatment are shown in Table 4.
TABLE 4 – Subject Responses at Week 8
|
ALA-018 |
ALA-019 |
LEVULAN KERASTICK Topical Solution + PDT |
Vehicle + PDT |
LEVULAN KERASTICK Topical Solution + PDT |
Vehicle + PDT |
Subjects with ≥ 75% of Actinic Keratosis Lesions Cleared |
Total No. Subjects |
68/87 (78%) |
6/29 (21%) |
71/93 (76%) |
8/32 (25%) |
Subjects with Face Lesions |
57/71 (80%) |
2/21 (10%) |
57/67 (85%) |
7/19 (37%) |
Subjects with Scalp Lesions |
11/16 (69%) |
4/8 (50%) |
14/26 (54%) |
1/13 (8%) |
|
Complete Responders |
Total No. Subjects |
60/87 (69%) |
4/29 (14%) |
59/93 (63%) |
4/32 (13%) |
Subjects with Face Lesions |
49/71 (69%) |
2/21 (10%) |
47/67 (70%) |
4/19 (21%) |
Subjects with Scalp Lesions |
11/16 (69%) |
2/8 (25%) |
12/26 (46%) |
0/13 (0%) |
Because ALA-018 and ALA-019 had identical protocols, the combined results from the two trials are shown in the following tables. For actinic keratoses with a variety of thicknesses (excluding very thick, Grade 3 actinic keratoses which were not studied in the Phase 3 trials), LEVULAN KERASTICK topical solution plus
BLU-U Blue Light Photodynamic Therapy Illuminator is more effective than vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator, but as shown in Table 5, the percentage of lesions with complete responses at 8 weeks after treatment with LEVULAN KERASTICK topical solution plus blue light illumination was lower for those lesions that were thicker at baseline. Efficacy of LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator on higher grade lesions was not studied in the Phase 3 clinical efficacy trials.
TABLE 5 Lesions Complete Responses at Week 8 for Different Lesion Grades
Lesion Grade |
LEVULAN KERASTICK Topical Solution + PDT |
Vehicle + PDT |
Grade 1 (slightly palpable actinic keratoses: better felt than seen)` |
666/756 (88%) |
122/302 (40%) |
Grade 2 (moderately thick actinic keratoses: easily seen and felt) |
495/632 (78%) |
52/199 (26%) |
Grade 3 (very thick and/or hyperkeratotic actinic keratoses) |
0 |
0 |
Those subjects who were not Complete Responders at Week 8 had retreatment of the persistent target lesions at Week 8. Among the subjects undergoing retreatment, efficacy results seen at 12 weeks after the initial treatment, i.e., at 4 weeks after the second treatment, are shown in Table 6.
TABLE 6 Complete Responders at Week 12, Among Subjects Receiving Two Treatments
|
LEVULAN KERATICK Topical Solution + PDT |
Vehicle + PDT |
Total No. Subjects |
24/56 (43%) |
2/49 (4%) |
Subjects with Face Lesions |
21/40 (53%) |
2/31 (6%) |
Subjects with Scalp Lesions |
3/16 (19%) |
0/18 (0%) |
The efficacy results seen at 12 weeks after treatment, which include the results at 12 weeks for those subjects who received a single treatment as well as the results at 12 weeks for those subjects who received a second treatment at week 8, are shown in Table 7.
TABLE 7 Subject Responses at Week 12, Among Subjects Who Received One or Two Treatments
|
LEVULAN KERASTICK Topical Solution + PDT |
Vehicle + PDT |
Subjects with ≥ 75% of Actinic Keratosis Lesions Cleared |
Total No. Subjects |
158/180 (88%) |
12/61 (20%) |
Subjects with Face Lesions |
127/138 (92%) |
8/40 (20%) |
Subjects with Scalp Lesions |
31/42 (74%) |
4/21 (19%) |
|
Complete Responders |
Total No. Subjects |
129/180 (72%) |
7/61 (11%) |
Subjects with Face Lesions |
108/138 (78%) |
5/40 (13%) |
Subjects with Scalp Lesions |
21/42 (50%) |
2/21 (10%) |
Among Complete Responders at Week 8, 93% (in ALA-018) and 83% (in ALA-019) maintained complete response at Week 12. Among subjects with scalp lesions, the percentage of subjects with 100% of actinic keratosis lesions having complete response declined from Week 8 (55%) to Week 12 (50%), because there were more subjects with scalp lesions with 100% of actinic keratosis lesions cleared at Week 8 who had a recurrence of a lesion by Week 12 than there were subjects with scalp lesions who had retreatment of persistent lesions at Week 8 and who then achieved 100% of actinic keratosis lesions cleared by Week 12. Subjects did not receive follow-up past 12 weeks after the initial treatment.
Subject outcomes recorded in the two Phase 3 trials are depicted in the following flowchart, in which Complete Responders are designated clear. Seven subjects in the active treatment arm and three subjects in the vehicle treatment arm withdrew or were lost to follow-up. Three subjects in the active treatment arm were treated at baseline but did not return for evaluation until Week 12. One subject in the active treatment arm and two in the vehicle treatment arm who were not clear at Week 8 did not receive retreatment.
 |
An open-label trial enrolled 110 subjects with 4 to 10 clinically typical, discrete actinic keratoses on the face or scalp, but not both locations. The target lesions were treated with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator. Any treated lesions that were not clear
at Month 2 (Week 8) were re-treated. Subjects were followed monthly for 12 months. Lesions were designated as cleared if the lesion had completely cleared and adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when palpated. The percentages of subjects in whom 100% of treated lesions were cleared (Complete Responders) by month, starting at Month 3 (Week 12), are shown in Figure 4. Of the 72 subjects with 100% of treated lesions cleared (Complete Responders) at Month 3, 53% had a recurrence by Month 12. A total of 748 individual lesions were treated; 539 were treated once and 209 were treated twice. At Month 3, 624 lesions (83%) were cleared. From Month 3 through Month 12 of the trial, 476 lesions (64%) remained clear. See Figure 5. Of the 624 treated lesions determined cleared at Month 3, 24% had recurred by Month 12, while 5% were lost to follow-up and their recurrence status is unknown.
Figure 4. Percent of Subjects With 100% of Treated Lesions Cleared (Complete Responders) by Month
(N=110 Subjects)
Figure 5. Percent of Lesions Cleared at Month 3 and Remaining Clear Through Month 12
(N=748 Lesions)
Actinic Keratoses Of The Upper Extremities
The safety and efficacy of LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator at 10J/cm2 to treat actinic keratoses of the upper extremities has been evaluated in a multicenter randomized, parallel-group, evaluator-blinded, vehicle-controlled trial of 269 subjects.
In this trial (CP0108), 269 subjects with 4 -15 mild to moderate actinic keratoses on the upper extremities (dorsal hand/forearm area between the elbow and the base of the fingers) were treated with LEVULAN KERASTICK topical solution and BLU-U Blue Light Photodynamic Therapy Illuminator. Subjects ranged from 45 to 90 years of age (mean 68 years) and 90% had Fitzpatrick Skin Type I, II or III. No subjects had Fitzpatrick Skin Type V or VI. Approximately 70% of subjects were male and all subjects were Caucasian.
Subjects were randomized to treatment in a 1:1 ratio to receive either LEVULAN KERASTICK topical solution or vehicle. Treatment was applied to 4-15 lesions on one dorsal hand/forearm on each subject, and occluded for the three-hour incubation period before treatment with 10 J/cm2 blue light delivered at 10 mW/cm2. Treatment was repeated at Week 8 if any actinic keratosis lesions were present in the treatment area.
The primary endpoint was the proportion of subjects with complete clearance of all actinic keratosis lesions in the treatment area 12 weeks after initial treatment. The results of the trial are presented in Table 8.
Table 8 – Number and Percentage of Subjects with Actinic Keratosis of the Upper Extremities Achieving Complete Clearance at Week 12
|
LEVULAN KERASTICK Topical Solution + PDT |
Vehicle + PDT |
CP0108 |
42/135 (31%) |
17/134 (13%) |
Subject outcomes recorded in the trial of the upper extremities are depicted in the following flowchart.
Subjects who achieved complete clearance at Week 12 entered a 12-month follow-up period. Subjects who received LEVULAN KERASTICK topical solution with blue light and achieved complete clearance at Week 12 in CP0108A had a recurrence rate of 58% (22/38) at 12 months, where recurrence was defined as the presence of at least one previously treated lesion in the treatment area at any visit during the 12-month follow-up period.