LUT017 Gel for Venous Leg Ulcers and Chronic Non-Healing Skin Wounds in Adults

A Phase 1, Open-Label Clinical Trial to Assess the Safety, Tolerability, and Preliminary Efficacy Study of Topically Administered LUT017 Gel for Cutaneous Wound Healing

This research study is investigating a new topical medication called LUT017, which is being developed to help heal chronic skin wounds, particularly those known as venous leg ulcers (VLUs). VLUs are open sores that commonly occur on the lower legs due to poor blood flow in the veins. These wounds can be painful, slow to heal, and difficult to treat, especially in older adults and people with conditions like diabetes or obesity.

LUT017 is a gel that will be applied directly to the surface of these wounds. The goal of the study is to find out if the gel is safe and well tolerated when applied once a week for up to 8 weeks. The researchers will also look for early signs of whether the gel helps the wounds heal more quickly or completely. The gel contains a medicine that has been shown in animal studies to activate natural skin repair processes and promote cell growth, potentially speeding up the healing process.

The study will involve between 12 and 18 adult participants who have had a chronic leg wound for at least 4 weeks. All participants will go through a screening process to make sure they are eligible. If they qualify, they will first complete a two-week "run-in" phase where their wound will be treated with standard medical bandages. This phase helps ensure that only participants whose wounds are not healing with normal care are included.

If participants remain eligible after this period, they will start the treatment phase. During this phase, they will come to the clinic once a week for 8 weeks to receive the LUT017 gel treatment directly on their wound. Each visit will include a physical exam, vital signs, wound evaluation, photographs of the wound, and blood tests to monitor safety.

After the 8-week treatment period, participants will return for two follow-up visits-one at 3 months and one at 6 months after their first treatment. These visits will help the researchers understand how long any benefits of the treatment might last and monitor for any delayed side effects.

In total, participants will be involved in the study for about 6.5 months and will have approximately 12 to 14 visits to the clinic. Participation is entirely voluntary, and individuals can withdraw at any time. The research team is committed to ensuring participant safety and privacy throughout the study.

Study Overview and Clinical Context

This is a Phase 1, open-label, dose-escalation clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary biological activity of LUT017 gel when administered topically to subjects with venous leg ulcers (VLUs) and other chronic non-healing cutaneous wounds. The study represents the first clinical investigation of LUT017 in the setting of impaired cutaneous wound healing and is intended to establish an initial safety profile, characterize systemic exposure following topical administration, and inform dose selection for future controlled studies.

Venous leg ulcers represent the most advanced clinical manifestation of chronic venous insufficiency and arise as a consequence of sustained venous hypertension, microvascular dysfunction, leukocyte trapping, and chronic inflammatory signaling within the lower extremities. The resulting wound environment is characterized by persistent cytokine activation, excessive matrix metalloproteinase activity, impaired fibroblast and keratinocyte responsiveness, oxidative stress, and altered extracellular matrix turnover. These processes lead to delayed epithelial migration, impaired re-epithelialization, and prolonged wound chronicity. Despite optimized compression therapy and local wound management, a substantial proportion of VLUs fail to heal within clinically acceptable timeframes. There are currently no approved pharmacologic agents specifically designed to activate regenerative signaling pathways in chronic wound beds.

The therapeutic hypothesis underlying this study is that localized activation of epidermal regenerative pathways may restore proliferative and migratory capacity in chronic wounds without inducing systemic toxicity. LUT017 has been developed to achieve this objective through paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type keratinocytes.

Mechanistic Rationale

LUT017 is a small-molecule inhibitor of BRAF. Although BRAF inhibitors were originally developed to suppress oncogenic BRAF V600 mutations in melanoma, it has been demonstrated that in cells expressing wild-type BRAF, particularly in the presence of upstream RAS activity, inhibition of BRAF can induce paradoxical activation of downstream MAPK signaling. This effect occurs through RAF dimerization and CRAF transactivation, leading to enhanced ERK phosphorylation. In epidermal keratinocytes, ERK activation promotes cellular proliferation, cytoskeletal reorganization, migration into the wound bed, and re-establishment of epithelial barrier integrity.

Preclinical wound-healing studies conducted in diabetic and excisional wound mouse models demonstrated accelerated wound closure following topical administration of a BRAF inhibitor analogue closely related to LUT017. Histologic evaluation revealed increased numbers of phosphorylated ERK-positive and Ki67-positive keratinocytes at wound margins, earlier onset of re-epithelialization, and enhanced epithelial tongue migration. Additional molecular analyses demonstrated activation of Wnt/β-catenin signaling and induction of follicular neogenesis within wound beds, suggesting that paradoxical MAPK activation may induce a regenerative phenotype rather than simple hyperproliferation.

Importantly, in two-stage skin carcinogenesis models, topical exposure to regenerative doses of BRAF inhibitors did not increase papilloma formation or squamous cell carcinoma incidence, supporting the safety of localized MAPK activation within the context of controlled topical exposure.

Investigational Product

LUT017 is a non-approved investigational BRAF inhibitor with a molecular weight of 546.94 Daltons and molecular formula C27H18ClF3N8. The compound has been optimized for topical administration and formulated as an aqueous-based gel designed to promote dermal penetration while minimizing systemic absorption. The formulation contains polyethylene glycol 400, Transcutol HP, 2-propanol, diisopropyl adipate, benzyl alcohol, Carbopol 980 NF polymer, sodium hydroxide, and purified water. The gel has a slightly viscous consistency, a pH range of approximately 5 to 7, and is supplied in 50-gram tubes for controlled clinical use. The product is stored at controlled room temperature and protected from light.

The formulation strategy was designed to balance epidermal penetration and local pharmacodynamic activity while limiting systemic exposure, thereby reducing the risk of class-associated systemic toxicities observed with oral BRAF inhibitors.

Nonclinical Safety and Toxicology

LUT017 has undergone a comprehensive nonclinical evaluation program including dermal toxicity, systemic toxicology, genotoxicity, phototoxicity, ocular irritation, and cardiovascular safety assessments. Repeated-dose dermal toxicity studies conducted in both rodent and minipig models for durations up to 56 days demonstrated no evidence of systemic organ toxicity, no clinically significant ECG (electrocardiogram) abnormalities, and no persistent laboratory abnormalities. Histopathologic examination did not reveal treatment-related organ damage at doses substantially exceeding projected clinical exposure levels. The no observed adverse effect level (NOAEL) for dermal administration was established at 5 mg/kg/day in both species.

Oral repeated-dose studies demonstrated dose-dependent but reversible laboratory changes at high systemic exposures, with a NOAEL of 25 mg/kg/day in female animals. These exposures exceed those anticipated following topical administration in humans.

Genotoxicity testing was negative in bacterial reverse mutation assays, in vitro micronucleus testing, in vivo micronucleus studies, and comet assays. Phototoxicity testing in vitro and in vivo did not demonstrate photoreactive potential at clinically relevant concentrations. Cardiovascular safety pharmacology studies in beagle dogs and telemetry-monitored minipigs demonstrated no clinically meaningful QT prolongation or arrhythmogenic signal.

Collectively, these data support initiation of clinical evaluation with appropriate monitoring and conservative dose escalation.

Study Design

This study employs a traditional 3+3 dose-escalation design across three sequential topical concentration cohorts of LUT017 gel: 0.03%, 0.1%, and 0.25%. Between twelve and eighteen subjects will be enrolled depending on the incidence of dose-limiting toxicities. Dose escalation decisions will be based on the occurrence of treatment-emergent adverse events meeting predefined dose-limiting toxicity criteria within four weeks following first administration. The maximum tolerated dose is defined as the highest dose level at which no more than one of six subjects experiences a dose-limiting toxicity.

Enrollment within each cohort will be staggered to allow adequate safety evaluation before dosing subsequent participants. No intra-subject dose escalation or modification is permitted.

Study Periods

The trial consists of four sequential phases. During the screening period, which may extend up to 28 days, participants undergo baseline assessments including physical examination, laboratory testing, electrocardiography, ophthalmologic evaluation, and wound documentation.

Following screening, participants enter a 14-day run-in period during which standardized compression therapy and optimized wound care are administered. This run-in phase serves to confirm wound chronicity under controlled management conditions and to exclude ulcers that demonstrate substantial healing with standard therapy alone.

Eligible participants then proceed to the treatment phase, during which LUT017 gel is applied once weekly directly to the designated target wound for up to eight weeks or until complete re-epithelialization. Drug application is performed in clinic by qualified investigators to ensure standardized administration and compliance.

After completion of treatment, participants enter an extended follow-up phase with visits occurring at three months and six months after first dose to assess durability of wound response and monitor for delayed adverse events. Total subject participation is approximately six and one-half months.

Safety Monitoring

Safety evaluation is the primary objective of this study. Participants undergo serial physical examinations, vital sign assessments, laboratory evaluations including complete blood count and comprehensive metabolic panel, electrocardiograms, and systematic adverse event monitoring throughout the treatment and follow-up periods. Adverse events are graded using standard toxicity criteria and assessed for relationship to study drug.

Given the known class effects of systemic BRAF inhibitors, dermatologic monitoring is emphasized. Investigators assess for development of keratoacanthomas, cutaneous squamous cell carcinoma, squamous papillomas, photosensitivity reactions, erythema nodosum-like eruptions, folliculitis, cyst formation, and other proliferative cutaneous lesions. Suspicious lesions are evaluated and managed according to standard clinical practice.

Predefined stopping rules require temporary study suspension if severe or unexpected toxicity thresholds are reached, including treatment-related death or multiple grade 4 adverse events attributable to study drug.

Pharmacokinetic Assessment

To characterize systemic exposure following topical administration, plasma pharmacokinetic sampling is performed at prespecified time points including pre-dose and one hour post-dose on Day 0, and pre-dose sampling on Days 7, 14, 21, and 28. These data will allow estimation of peak concentration, trough levels, and accumulation, and will confirm whether systemic exposure remains minimal as anticipated based on nonclinical modeling.

Statistical Considerations

This early-phase study is not powered for confirmatory efficacy testing. Safety data will be summarized descriptively. Wound healing parameters, including reduction in wound area and complete re-epithelialization rates, will be analyzed descriptively and may be explored using time-to-event methodologies such as Kaplan-Meier estimation. No formal hypothesis testing is planned.

Risk-Benefit Considerations

The potential risks of topical LUT017 include localized cutaneous hyperproliferation, inflammatory dermatologic reactions, and theoretically minimal systemic exposure-related effects. These risks are mitigated through conservative dose escalation, staggered enrollment, intensive monitoring, and predefined stopping criteria. The anticipated benefit is acceleration of wound closure and restoration of epithelial integrity in chronic wounds that have failed to respond to standard therapy.

Inclusion Criteria

1. Subjects with venous leg ulcers (VLU), defined by open skin lesion of the leg as a result of venous hypertension.

2. Subject must be ≥ 18 years of age.

3. Active lower extremity ulceration (CEAP classification of C6).

4. Non-healing VLU ≥ 4 weeks but not greater than 24 months.

5. Ulcer size ≥ 2cm2 ≤ 20cm2.

   a. Target ulcer will be defined as the largest ulcer on the affected limb. Only one wound per subject will be designated as the study wound and treated with the investigational gel. If a subject has two wounds separated by less than 1 cm of intact skin, these wounds will be considered a single study wound, and the surface areas of both wounds will be added together for eligibility purposes; if the combined area exceeds 20 cm², the subject will be excluded from the study. Although only one wound will be directly treated, local activation of the MAPK pathway may result in biological stimulation of the adjacent untreated wound when wounds are separated by less than 1 cm.

6. Chronic venous insufficiency confirmed by ultrasound within previous 12 months.

7. Adequate perfusion confirmed within the past 12 months.:

   1. Dorsalis Pedis (DP) or Posterior Tibial (PT) systolic pressure ≥ 60mmHg on the study limb.
   2. Transcutaneous partial pressure oxygen (TcP02) > 30mmHg.
   3. Great toe systolic pressure > 40mmHg.

8. Must be able and willing to provide informed consent prior to study participation.

9. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at baseline (Day 0). They should agree to use highly effective methods of birth control, defined as those with failure less than 1%, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUD's), sexual abstinence, or a vasectomized partner. Such subjects should agree to have monthly pregnancy test documented.

Exclusion Criteria

1. Target ulcer has exposed of tendon, muscle, or bone.

2. Target ulcer is of non-venous etiology.

3. Target ulcer has been treated with living cellular therapy within 4 weeks of the randomization.

4. Target ulcer shows any signs of infection (only non-infected ulcers are eligible).

5. Patient has undergone endovenous ablation or other venous surgery within 4 weeks of enrollment.

6. Unable to tolerate multi-layer bandages or compression garments.

7. Decompensated congestive heart failure within 4 weeks of screening.

8. Active soft tissue or bone infection requiring antibiotics.

9. Skin cancer on the target limb within the last 24 months.

10. Actively receiving chemotherapy and/or radiation therapy for cancer.

11. Treatment with a serine/threonine-protein kinase BRAF inhibitor, including but not limited to Zelboraf® (vemurafenib), Tafinlar® (dabrafenib), BraftoviTM (encorafenib) or Nexavar® (sorafenib), within 30 days or 5 half-lives of the drug prior to Screening, whichever is longer.

12. Blood chemistry or counts values as follows:

    1. White Blood Cells (WBC)< 1.5 x 109/L.
    2. Absolute < 0.9 x 109/L.
    3. Platelet count < 50 x 109/L.
    4. Alanine aminotransferase > 3 x upper limit of normal.
    5. Aspartate aminotransferase > 3 x upper limit of normal.
    6. Serum albumin <2.0 g/dL.
    7. HbA1c value of > 12% within the past three (3) months.

13. Current use of systemic corticosteroids > 5 mg daily or equivalent within 4 weeks.

14. Currently pregnant or trying to become pregnant.

15. Inability or unwillingness to participate in all aspects of study protocol or as determined by the Investigator.

16. Known hypersensitivity to the ingredients of the study drug.