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Contact sensitization, phototoxic and photoallergic potential of tirbanibulin 1% ointment in healthy volunteers

Open AccessPublished:November 15, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100170

      Abstract

      Tirbanibulin 1% ointment is approved for the topical treatment of actinic keratosis, applied once daily for 5 days.
      Three Phase 1 randomized, single-center, controlled, within-subject comparison studies were conducted to evaluate the sensitization (KX01-AK-006), phototoxic (KX01-AK-008) and photoallergic (KX01-AK-009) potential of tirbanibulin 1% ointment in healthy adults. In KX01-AK-006 and KX01-AK-009, subjects received repeated applications of tirbanibulin or vehicle for induction (followed by irradiation in KX01-AK-009) and an additional application for challenge on naïve sites. In KX01-AK-008, subjects received single applications, followed by irradiation. Sensitization was defined as a reaction scoring 3 at naïve sites, recurring at re-challenge. Photoallergy was assessed based on dermal response of erythema+edema at naïve sites. Phototoxicity was assessed based on average dermal response score (Days 3-4). Adverse events were collected.
      In KX01-AK-006, none of 229 subjects scored 3 at naïve sites. In KX01-AK-008, none of 31 subjects developed edema, not meeting the criteria for phototoxicity. In KX01-AK-009, none of 59 subjects showed reactions compatible with photoallergy. Mild to moderate contact irritations were reported.
      The evidence provided by these Phase 1 studies demonstrate that tirbanibulin 1% ointment lacks sensitization, phototoxic or photoallergic potential, and supports the safety of its topical application.

      Abbreviations:

      ANOVA (analysis of variance), AE (adverse events), AK (actinic keratosis), CI (confidence interval), FDA (Food and Drug Administration), LSM (least square means), MED (minimal erythemal dose), SE (standard error), SD (standard deviation), TEAE (treatment-emergent adverse event), UV(A/B) (ultraviolet (A/B))

      Introduction

      Tirbanibulin (Klisyri®, Almirall) is a first-in-class, anti-proliferative and pro-apoptotic agent that is approved for the treatment of actinic keratosis (AK) of the face and scalp (

      Almirall LLC. Klisyri® (tirbanibulin) prescribing information. 2020 [cited 2021 Mar 30]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

      ;

      Almirall S.A. Klisyri® (tirbanibulin) product information. 2021 [cited 2021 May 10]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/klisyri

      ). Klisyri® has been formulated as a tirbanibulin 1% ointment intended for topical application (once daily during 5 days) on these light exposed body sites, and has been shown to absorb light within the range of natural sunlight (290-400 nm). Therefore, the development program included three Phase 1 studies in healthy volunteers assessing contact sensitization potential after repeated application, phototoxic and photoallergic potential, and safety. Collective results for these studies are reported herein.

      Results

      For the three studies, disposition of subjects is shown in Figure 1, and their demographic and baseline characteristics are summarized in Table 1.
      Figure thumbnail gr1
      Figure 1Subject disposition. Percentages are relative to the number of randomized subjects in each study. In KX01-AK-006 (Sensitization Study), 298 subjects were screened and 261 of them were randomized and included in the safety population. A total of 32 subjects discontinued the treatment and 229 were included in the sensitization population. In KX01-AK-008 (Phototoxicity Study), 38 subjects were screened and 31 of them were randomized and included in the safety population or phototoxicity population. Finally, in KX01-AK-009 (Photoallergy Study), 67 subjects were screened and 64 of them were ramdomized and included in the safety population. A total of 5 subjects discontinued the treatment and 59 were included in the photoallergy population.
      Table 1Demographics and baseline characteristics (safety population)
      KX01-AK-006 (Sensitization)KX01-AK-008 (Phototoxicity)KX01-AK-009 (Photoallergy)
      N2613164
      Age (years)
       Mean (SD)46.7 (15.3)52.2 (12.2)55.8 (10.5)
       Median48.053.057.0
       Range18.0-75.021.0-70.026.0-75.0
      Sex, n (%)
       Female204 (78.2)24 (77.4)57 (89.1)
      Race, n (%)
       White149 (57.1)31 (100)64 (100)
       African American110 (42.1)00
       Asian1 (0.4)00
       Other1 (0.4)a00
      Fitzpatrick skin type, n (%)b,c
       I7 (2.7)02 (3.1)
       II76 (29.1)12 (38.7)27 (42.2)
       III58 (22.2)19 (61.3)35 (54.7)
       IV52 (19.9)00
       V58 (22.2)00
       VI10 (3.8)00
      MED (seconds)d,e
       Mean (SD)NA45.5 (14.9)59.0 (17.7)
       MedianNA38.0NR
       Minimum-MaximumNA32.0-76.031.0-94.0
      a Mixed race.
      b I: always burns easily, never tans; II: always burns easily, tans minimally; III: burns moderately, tans gradually; IV: burns minimally, always tans well; V: rarely burns, tans very well; VI: never burns, deeply pigmented.
      c In the photototoxicity and photoallergy studies, only subjects with Fitzpatrick skin types I-III were eligible.
      d Seconds of exposure with the output of the solar simulator set to 661 μw/cm2
      full spectrum UVB/UVA.
      e In KX01-AK-0009, MED was determined in 62 subjects.
      MED, minimal erythemal dose; NA, not applicable; NR, not reported; SD, standard deviation; UVA/UVB; ultraviolet A/B.

      KX01-AK-006 (sensitization study)

      Cumulative irritancy

      A summary of mean and total irritation scores during the Induction Phase and pairwise comparisons are provided in Table 2. Both scores were significantly higher at tirbanibulin-treated sites compared to vehicle- and saline-treated sites.
      Table 2Summary of irritation scores during induction phase in kx01-ak-006 (cumulative irritancy population, n=232)
      Mean irritation scoreTotal irritation score
      Mean (SD)LSM (SE)p-value vs. Vehiclep-value

      vs.

      Saline
      Mean (SD)LSM (SE)p-value vs. Vehiclep-value vs. Saline
      Tirbanibulin2.09 (0.66)2.09 (0.03)<0.001<0.00118.8 (6.0)18.83 (0.25)<0.001<0.001
      Vehicle0.06 (0.25)0.06 (0.03)-0.280.6 (2.3)0.56 (0.25)-0.28
      Saline0.02 (0.09)0.02 (0.03)--0.2 (0.8)0.19 (0.25)--
      Overall p-value<0.001<0.001
      LSM, least square mean; SD, standard deviation; SE, standard error.

      Dermal responses and sensitization

      During the Challenge Phase, the maximum dermal response score at the tirbanibulin-treated site was 1 (mild erythema) in 33 subjects (14.4%; 95% confidence interval [CI] 10.1, 19.6) and 2 (moderate erythema, minimal edema or minimal papular response) in five subjects (2.2%; 95%CI 0.7, 5.0). The remaining 191 subjects had a maximum score of 0 (no response). No subjects had a maximum response of 3 at the tirbanibulin-treated site. Vehicle- and saline-treated sites showed no dermal response except in one subject (1.4%; 95%CI 0.0, 2.4), who had a maximum response score of 2 at the vehicle-treated site.

      Safety

      Adverse events (AE) are summarized in Table 3. None were treatment-related, and the most frequent were headache, nasopharyngitis and rhinorrhea. Two subjects discontinued from the study due to an AE: one had a serious AE of mild dyspnea after 10 applications of the study products, which resolved in 10 days; and the remaining subject had moderate nausea after 2 applications, which resolved in 5 days.
      Table 3Summary of adverse events (safety population)
      n (%)KX01-AK-006 (Sensitization)KX01-AK-008 (Phototoxicity)KX01-AK-009 (Photoallergy)
      Safety population261 (100)31 (100)64 (100)
      Any AE21 (8.0)1 (3.2)5 (7.8)
      Serious AE1 (0.4)00
      Fatal AE000
      Treatment-related AE01 (3.2)0
      AE leading to product withdrawal2 (0.8)01 (1.6)
      AE by SOC and preferred term
       Nervous system disorders
      Headache7 (2.7)1 (3.2)0
      Sinus headache001 (1.6)
      Dizziness1 (0.4)00
       Infections and infestations
      Nasopharyngitis6 (2.3)02 (3.1)
      Upper respiratory tract infection001 (1.6)
       Respiratory, thoracic and mediastinal disorders
      Rhinorrhea3 (1.1)00
      Dyspnea1 (0.4)00
      Nasal congestion1 (0.4)00
       Musculoskeletal and connective tissue disorders
      Neck pain1 (0.4)00
      Rotator cuff syndrome1 (0.4)00
       Gastrointestinal disorders
      Nausea1 (0.4)00
       Injury, poisoning and procedural complications
      Contusion001 (1.6)
      SOC, System Organ Class; AE, adverse events.

      KX01-AK-008 (phototoxicity study)

      Dermal responses and phototoxicity

      No subjects developed edema; therefore, none met the criteria for phototoxicity. The maximum dermal response score pre-irradiation (Day 2) was 1 (mild erythema) at test sites and 0 at the control site. On Days 3 and 4, the maximum score did not exceed 2 (moderate erythema) at test sites and 1 at the control site. Mean dermal response scores for Days 3-4 and pairwise comparisons are shown in Table 4. The mean score was <1 at the test and control sites regardless of irradiation status. Within each product (tirbanibulin or vehicle), the mean score was similar at irradiated and non-irradiated sites. When comparing tirbanibulin and vehicle, the mean score was significantly higher for tirbanibulin at non-irradiated sites, but similar to vehicle at irradiated sites. For both tirbanibulin and vehicle, mean scores at irradiated and non-irradiated sites were significantly higher compared to the irradiated control.
      Table 4Mean dermal response scores for days 3-4 and pairwise comparisons in kx01-ak-008 (phototoxicity population, n=31)
      Tirbanibulin 1% ointmentVehicle ointmentUntreated control
      IrradiatedNon-irradiatedIrradiatedNon-irradiatedIrradiated
      Mean (SD) dermal response score0.94 (0.54)0.89 (0.57)0.77 (0.43)0.69 (0.48)0.23 (0.40)
      LSM (SD) dermal response score0.9 (0.5)0.9 (0.6)0.8 (0.4)0.7 (0.5)0.2 (0.4)
       p-values:
       Tirbanibulin irradiated vs.-0.590.0800.009<0.001
       Tirbanibulin non-irradiated vs.--0.220.036<0.001
       Vehicle irradiated vs.---0.38<0.001
       Vehicle non-irradiated vs.----<0.001
      P-values (row vs. column) are from an analysis of variance of the average numerical score (sum of erythema and edema) at Days 3 and 4, with effects of subject and treatment, using Fisher’s least significant differences.
      LSM, least square mean; SD, standard deviation.

      Safety

      AE are summarized in Table 3. One subject had an AE of headache, which was considered mild and possibly related to study products. The AE resolved within the same day and did not led to study discontinuation.

      KX01-AK-009 (photoallergy study)

      Photoirritation

      Mean dermal response scores for the Induction Phase and pairwise comparisons are shown in Table 5. The mean score was <0.5 for both products regardless of irradiation status. Within each product (tirbanibulin or vehicle), the mean score was significantly higher at irradiated compared to non-irradiated sites. When comparing tirbanibulin and vehicle, the mean score was significantly higher for tirbanibulin at non-irradiated sites, but similar to vehicle at irradiated sites.
      Table 5Mean dermal response scores during induction phase and pairwise comparisons in kx01-ak-009 (photoirritation population, n=61)
      Tirbanibulin 1% ointmentVehicle ointment
      IrradiatedNon-irradiatedIrradiatedNon-irradiated
      Mean (SD) dermal response score0.41 (0.32)0.07 (0.14)0.41 (0.32)0.00 (0.01)
       p-values:
       Tirbanibulin irradiated vs.-<0.0010.80<0.001
       Tirbanibulin non-irradiated vs.--<0.0010.031
       Vehicle irradiated vs.---<0.001
      P-values (row vs. column) are from an analysis of variance of the average numerical score over all Induction Phase readings, with effects of subject and treatment, using Fisher’s least significant differences.
      SD, standard deviation.

      Photoallergy

      The proportion of subjects with each dermal response score at the different assessments of the Challenge Phase is summarized in Table 6. At 24, 48, and 72 hours post-irradiation, most subjects had a score of 0 (no reaction) regardless of treatment and irradiation. The maximal dermal response score overall was 1, most common at 72 hours. There were no reactions suggesting photoallergy, so no re-challenges were required.
      Table 6Proportion of subjects with each dermal response score during challenge phase in kx01-ak-009 (photoallergy population, n=59)
      Tirbanibulin 1% ointmentVehicle ointmentUntreated control
      IrradiatedNon-irradiatedIrradiatedNon-irradiatedIrradiated
      Pre-application, n (%)
       059 (100)59 (100)59 (100)59 (100)0
      Pre-irradiation, n (%)
       059 (100)59 (100)59 (100)58 (98.3)58 (98.3)
       10001 (1.7)1 (1.7)
      24 hours post-irradiation, n (%)
       056 (94.9)55 (93.2)58 (98.3)59 (100)57 (96.6)
       13 (5.1)4 (6.8)1 (1.7)02 (3.4)
      48 hours post-irradiation, n (%)
       057 (96.6)59 (100)56 (94.9)59 (100)58 (98.3)
       12 (3.4)03 (5.1)01 (1.7)
      72 hours post-irradiation, n (%)
       049 (83.1)52 (88.1)58 (98.3)58 (98.3)58 (98.3)
       110 (16.9)7 (11.9)1 (1.7)1 (1.7)1 (1.7)

      Safety

      AE are summarized in Table 3. None were treatment-related, and the most frequent was nasopharyngitis. One subject had an AE of moderate sinus headache that led to study withdrawal, as the subject received a concomitant medication (aspirin) to treat the AE that was not allowed by protocol.

      Discussion

      The results of this series of phase 1 studies in healthy volunteers demonstrate that tirbanibulin 1% ointment has a favorable safety profile upon topical application. Of note, all three studies were conducted with the commercially available formulation of tirbanibulin, both in terms of concentration of active substance (1%) and vehicle composition (monoglycerides, diglycerides and propylene glycol); and the study sample sizes exceeded those indicated by regulatory standards. All these contribute to the external validity of the results.
      First, the inability of tirbanibulin to induce sensitization was assessed and demonstrated though a repeated insult patch test. Mean and total irritation scores obtained during the Induction Phase showed that tirbanibulin 1% ointment caused contact irritation which was significantly higher than that caused by the vehicle alone. The dermal responses observed during the Challenge Phase, reaching moderate erythema at most, were expected and consistent with that observed in two large, phase 3, randomized, vehicle-controlled studies with tirbanibulin in patients with AK (
      • Blauvelt A.
      • Kempers S.
      • Lain E.
      • Schlesinger T.
      • Tyring S.
      • Forman S.
      • et al.
      Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.
      ). Although these responses pointed at a potential for contact irritation, there was no evidence of sensitization.
      The effect of ultraviolet light exposure on skin treated with tirbanibulin 1% or vehicle ointments was assessed in two studies, in which there was no evidence of phototoxicity or photosensitivity for either product. In the phototoxicity study, even though erythema was reported, no subjects developed edema after a single application of the study products. The mild-to-moderate dermal responses observed can be attributed to irritation rather than phototoxicity. Also, dermal responses at tirbanibulin 1% ointment irradiated and non-irradiated sites were similar, and the same occurred for the vehicle. This further supports a lack of phototoxic activity. In the photoallergy study, although mean dermal response scores during the Induction Phase were significantly higher at irradiated versus non-irradiated sites of each product, these differences cannot be considered as clinically significant, given the low level of the dermal responses observed. As dermal responses during the Challenge Phase were either absent or mild, a photoallergic potential of tirbanibulin 1% ointment or vehicle was ruled out.
      Moreover, in these Phase 1 studies, tirbanibulin 1% ointment and vehicle ointment were well tolerated even when the number of applications exceeded those recommended in the product label. Treatment-related AE were not reported during repeated dosing in the sensitization and photoallergy studies (up to 10 and 7 applications respectively), and only one (mild headache) was reported after a single application in the phototoxicity study. Systemic AE, whether considered related or unrelated to study products, were infrequent, consistent with the minimal absorption observed in a prior Phase 1 maximum use study (
      • Yavel R.
      • Overcash J.
      • Cutler D.
      • Fang J.
      • Zhi J.
      Phase I maximal use pharmacokinetic study of tirbanibulin ointment 1% in subjects with actinic keratosis.
      ).
      This favorable safety profile was obtained in three studies with different designs and including healthy volunteers only, which may limit its generalization to patients with AK. Nevertheless, the studies were modeled after standard designs, according to Food and Drug Administration (FDA) guidance (

      U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry. Skin irritation and sensitization testing of generic transdermal drug products. 1999.

      ). Furthermore, a good safety profile for tirbanibulin 1% ointment has also been observed in larger clinical studies conducted for tirbanibulin in AK patients (
      • Blauvelt A.
      • Kempers S.
      • Lain E.
      • Schlesinger T.
      • Tyring S.
      • Forman S.
      • et al.
      Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.
      ;
      • Kempers S.
      • DuBois J.
      • Forman S.
      • Poon A.
      • Cutler E.
      • Wang H.
      • et al.
      Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results.
      ). This is a relevant point as there is evidence (
      • Erntoft S.
      • Norlin J.M.
      • Pollard C.
      • Diepgen T.L.
      Patient-reported adherence and persistence to topical treatments for actinic keratosis: a longitudinal diary study.
      ;
      • Neri L.
      • Peris K.
      • Longo C.
      • Calvieri S.
      • Frascione P.
      • Parodi A.
      • et al.
      Physician-patient communication and patient-reported outcomes in the actinic keratosis treatment adherence initiative (AK-TRAIN): a multicenter, prospective, real-life study of treatment satisfaction, quality of life and adherence to topical field-directed therapy for the treatment of actinic keratosis in Italy.
      ;
      • Shergill B.
      • Zokaie S.
      • Carr A.J.
      Non-adherence to topical treatments for actinic keratosis.
      ) as well as consensus among physicians (
      • Stockfleth E.
      • Peris K.
      • Guillen C.
      • Cerio R.
      • Basset-Seguin N.
      • Foley P.
      • et al.
      A consensus approach to improving patient adherence and persistence with topical treatment for actinic keratosis.
      ) that tolerability of topical medications affects the quality of life of patients with AK and their compliance with treatment. In a Phase 2 study including 168 AK patients who received daily applications of tirbanibulin 1% ointment for 3 or 5 days. Twelve (7%) patients presented treatment-related AE (TEAE); none was serious or led to study withdrawal, and most were application site pruritus and pain (
      • Kempers S.
      • DuBois J.
      • Forman S.
      • Poon A.
      • Cutler E.
      • Wang H.
      • et al.
      Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results.
      ). Finally, in the two Phase 3 studies, 702 AK patients applied tirbanibulin 1% or vehicle ointments daily for 5 days. The most common AE were application-site pruritus or pain; most were mild or moderate and all resolved spontaneously. No TEAE were serious or led to study withdrawal (
      • Blauvelt A.
      • Kempers S.
      • Lain E.
      • Schlesinger T.
      • Tyring S.
      • Forman S.
      • et al.
      Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.
      ).
      In conclusion, the evidence provided by this set of Phase 1 studies demonstrate that tirbanibulin 1% ointment lacks sensitization, phototoxic or photoallergic potential, and support the safety of its topical application.

      Materials and Methods

      The three studies were approved by the Institutional Review Board of the participating center (TKL Research Inc., Fair Lawn, NJ, USA), and were conducted in accordance with good clinical practice, the Declaration of Helsinki, International Council for Harmonisation Guidelines and applicable regulatory requirements. All subjects provided informed written consent.

      KX01-AK-006 (sensitization study)

      Design and objective

      Randomized, single-center, controlled, within-subject comparison study, aimed at determining the sensitization potential of tirbanibulin 1% ointment after repeated topical application.

      Subjects

      Men and women ≥18 years old, of any Fitzpatrick skin type or race as long as pigmentation allowed for discernment of erythema.

      Treatment

      Tirbanibulin 1% ointment, vehicle ointment, and negative control (0.9% saline) were applied at three adjacent, randomly assigned test sites (2x2 cm2 each) in the left or right infrascapular area. During the Induction Phase, each product was applied 3 times weekly for 3 weeks, under open patch conditions. After a rest period (10-14 days) subjects entered the Challenge Phase, during which products were applied once to a naïve site on the opposite side of the back and removed 48 hours later. Subjects showing signs of contact sensitization during this phase were re-challenged at an additional naïve site ≥2 weeks later.

      Assessments

      Assessments were done by trained evaluators blinded to study products. During the Induction Phase test sites were examined prior to each application, and irritancy was scored from 0 (none) to 3 (fissures/exudate/erosions and/or scabs). During the Challenge Phase, the naïve site was examined 30 minutes and 24, 48, and 72 hours following removal of products; dermal response was scored from 0 (none) to 3 (erythema/edema/vesicular eruption). Potential for contact sensitization was defined as dermal response scoring 3 during the Challenge Phase and recurring at re-challenge in at least one subject. AE were collected during the whole study; severity and relation to study products were assessed.

      Analyses

      The cumulative irritancy population encompassed all subjects who completed the Induction Phase; the sensitization population, those who completed the Challenge Phase; and the safety population, those receiving treatment. Mean dermal response scores were calculated for each subject and product considering all 9 assessments of the Induction Phase; these values are presented as means and standard deviation (SD), and as least square means (LSM) and standard error (SE). Pairwise comparisons between products were conducted in the context of an analysis of variance (ANOVA) considering subject and product effects without interactions; p-values were obtained using Fisher’s least significant differences, with a threshold of 0.05 for significance. AEs are presented as frequencies and relative percentages. The maximum dermal response score during the Challenge Phase for the tirbanibulin-treated site are presented as percentages with 95% confidence intervals (CI). All statistical processing was performed using the SAS® system (version 9.2).

      KX01-AK-008 (phototoxicity study)

      Design and objective

      Randomized, single-center, controlled, within-subject comparison study, aimed at determining the phototoxic potential of tirbanibulin 1% ointment after a single topical application followed by light exposure.

      Subjects

      Men and women ≥18 years old, with Fitzpatrick skin types I-III and no prior history of photosensitivity or photoallergy.

      Treatment

      The minimal erythemal dose (MED) was first determined for each subject. An area of approximately 50 cm2 divided in six equal sites was delimited in the infrascapular area. Sites were successively irradiated with full spectrum ultraviolet (UV) light (UVA/UVB), each site receiving a 25% greater UV dose than the preceding. Sites were evaluated two days after irradiation, and the lowest exposure producing erythema was selected as MED.
      To assess phototoxicity, four application sites of 2x2 cm2 each (different from those used for MED determination) were delimited in each subject’s infrascapular area. An additional site was delimited as control. On Day 1, tirbanibulin 1% ointment and vehicle ointment were applied at two sites each, randomly assigned. The control site was left untreated. Test sites were kept under semi-occlusive patch conditions for approximately 24 hours. On Day 2, patches were removed and one site per product (plus the control site) were irradiated with 16 J/cm2 of UVA followed by 0.5 times the MED of UVA/UVB.

      Assessments

      Assessments were done by trained evaluators blinded to study products. The test and control sites were evaluated before irradiation (Day 2), and 24 hours (Day 3) and 48 hours (Day 4) after. At each site, erythema was scored from 0 (none) to 3 (marked/severe) and edema from 0 (none) to 2 (definite edema with erosions/vesicles). Dermal response score at each day was the sum of erythema and edema scores. The parameter used for phototoxicity was the average dermal response score for Days 3 and 4, which could range from 0 (none) to 5 (maximum response) but, for a reaction to be suspected as phototoxicity, both erythema and edema had to be observed. AE were collected during the whole study, and severity and relation to study products were assessed.

      Analyses

      The phototoxicity population encompassed all subjects completing the study, and the safety population all subjects receiving treatment. Average scores for Days 3-4 were summarized as mean (SD) and LSM (SD), and pairwise comparisons were conducted in the context of ANOVA and considering subject and product effects without interactions. P-values were obtained using Fisher’s least significant differences, with a threshold of 0.05 for significance. AE were summarized as frequencies and relative percentages.

      KX01-AK-009 (photoallergy study)

      Design and objective

      Randomized, single-center, controlled, within-subject comparison study, aimed at determining the photoallergic potential of tirbanibulin 1% ointment after repeated topical application followed by light exposure.

      Subjects

      Men and women ≥18 years old, with Fitzpatrick skin types I-III and no prior history of photosensitivity or photoallergy.

      Treatment

      The MED was first determined for each subject as previously described. The study consisted of two phases. For the Induction Phase, four test sites of 2x2 cm2 each (different from those used to assess the MED) were delimited at one side of each subject’s infrascapular area. On Day 1, tirbanibulin 1% ointment and vehicle ointment were randomly assigned to two sites each; one site per product was designated for irradiation. Products were applied twice weekly for 3 weeks. Following each application, sites were left under open-patch conditions for approximately 24 hours, after which the sites designated for irradiation were exposed to two times the subject’s MED of UVA/UVB. Subjects completing the Induction Phase entered a rest period (10-17 days), followed by the Challenge Phase, in which photoallergy was assessed. Four naïve test sites (2x2 cm2 each) and an additional control site were delimited on each subject’s infrascapular area. Tirbanibulin and vehicle were applied once to two randomly assigned sites each and left under open-patch conditions. Approximately 24 hours later, one site per product and the control site were irradiated. If a cutaneous response was observed, subjects could be re-challenged as soon as the reaction resolved.

      Assessments

      Assessments were performed by trained evaluators blinded to study products. After each application of the Induction Phase, sites were examined pre-irradiation and 48-72 hours post-irradiation. During the Challenge Phase, sites were examined pre-application, pre-irradiation, and 24, 48 and 72 h post-irradiation. For each site and time point assessed, erythema was scored from 0 (none) to 3 (marked/severe) and edema from 0 (none) to 2 (definite edema with erosions/vesicles); dermal response was the sum of erythema and edema scores. Investigators determined whether a reaction was consistent with photoallergy based on dermal reactions in the Challenge Phase but, in general, both erythema and edema had to be present. Suspected photoallergy could be confirmed by re-challenge. AE were collected during the whole study; severity and relation to study products were assessed.

      Analyses

      The photoirritation population encompassed all subjects who completed the Induction Phase; the photoallergy population, those who completed the Challenge Phase; and the safety population, all subjects receiving treatment. For each test/control site, dermal response scores obtained during the Induction Phase were averaged and summarized as mean (SD). Pairwise comparisons were conducted for these means in the context of ANOVA and considering subject and product effects without interactions. P-values were obtained using Fisher’s least significant differences, with a threshold of 0.05 for significance. Dermal response scores during the Challenge Phase and AE were summarized as frequencies and relative percentages.

      Acknowledgments

      The authors wish to acknowledge Edwin A. Peets, PhD, consultant for Athenex, for his insightful guidance in the planning and conduct of these studies. Medical writing support, under the direction of the authors, was provided by Beatriz del Val, MsC, from TFS HealthScience, Barcelona, Spain.

      References

      1. Almirall LLC. Klisyri® (tirbanibulin) prescribing information. 2020 [cited 2021 Mar 30]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

      2. Almirall S.A. Klisyri® (tirbanibulin) product information. 2021 [cited 2021 May 10]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/klisyri

        • Blauvelt A.
        • Kempers S.
        • Lain E.
        • Schlesinger T.
        • Tyring S.
        • Forman S.
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