A Single and Multiple Ascending Dose Trial of KT-474 in Healthy Adult Volunteers and Patients With Atopic Dermatitis (AD) or Hidradenitis Suppurativa (HS)

Atopic Dermatitis Clinical Trial

Official title:

A Phase 1 Randomized, Placebo-controlled, Single and Multiple Ascending Dose Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered KT-474 in Healthy Adult Volunteers and Patients With Atopic Dermatitis (AD) or Hidradenitis Suppurativa (HS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04772885
• Other study ID #: KT474-HV-101
• Status: Completed
• Phase: Phase 1
• Start date: February 23, 2021
• Est. completion date: October 20, 2022

Study information

• Verified date: October 2022
• Source: Kymera Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

KT-474 is an oral heterobifunctional small molecule IRAK4 degrader being developed for the treatment of interleukin-1 receptor (IL-1R)/toll-like receptor (TLR)-driven immune-inflammatory diseases. This first-in-human (FIH) study will characterize the safety, tolerability and the pharmacokinetics/pharmacodynamics (PK/PD) of a single ascending dose and multiple ascending doses of KT-474 in healthy volunteers and patients with atopic dermatitis (AD) or hidradenitis suppurativa (HS). The effects of food on the absorption of KT-474 will also be evaluated in healthy volunteers.

Description:

This is a first-in-human (FIH), Phase 1 randomized, placebo-controlled, single and multiple ascending dose trial of KT-474 that will characterize the safety, PK and PD of orally administered KT-474 after a single dose (Part A) and after repeated dosing first in healthy adult volunteers (Part B) and then in patients with AD or HS (Part C). Initially, a dose range of KT-474 in single ascending dose (SAD) escalation cohorts will be explored in healthy subjects. Up to five single dose cohorts of healthy subjects is also planned to understand food effects (FE) on the PK of KT-474. Enrollment of healthy subjects into 2-week multiple ascending dose (MAD) escalation cohorts will be initiated once sufficient safety and PK data from multiple SAD cohorts are available to inform the safe starting dose for the 2-week MAD portion of the study. After the MAD portion in healthy subjects is completed, the safety, PK, and PD of a dose of KT-474 that was found to be safe in healthy subjects when administered for 2 weeks will then be evaluated in AD or HS subjects for 28 days of dosing. Separately, additional multiple dose cohorts evaluating once every other day and/or twice weekly dosing schedules at or below previously evaluated dose levels in healthy volunteers may be initiated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 154
• Est. completion date: October 20, 2022
• Est. primary completion date: October 20, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Healthy Volunteer (Parts A and B) Inclusion Criteria:

1. Male and female subjects, including female subjects of child bearing potential, between the ages of 18 and 55 with a weight at least 50 kg and a body mass index (BMI) between 18.0 and 30.0 kg/m2.

2. Subjects confirmed as negative in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection test at Screening and on Day -2.

3. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

4. Agreement and ability to comply with all contraception requirements if applicable.

5. All subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Healthy Volunteer (Parts A and B) Exclusion Criteria:

1. Evidence or history of a clinically significant medical condition or other condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug, or place the subject at an unacceptable risk as a participant in this study.

2. Healthy volunteers who have a clinically relevant history or presence of respiratory, GI, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, or connective tissue diseases or disorders.

3. Healthy volunteers who have any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease.

4. Female Healthy volunteers who are pregnant, trying to become pregnant or lactating or breastfeeding.

5. Healthy volunteers who have participated in any investigational drug or device clinical study within 3 months prior to first dosing on this study.

6. Healthy volunteers who have previously participated in a study with an investigational product or device involving the dosing of a biological targeted at any immune pathway within 1 year prior to Screening.

AD or HS Patient (Part C) Inclusion Criteria:

1. Male or female patients aged 18 years to 55 years (inclusive) at the time of Screening, and in generally good health, except for AD or HS, and has a BMI of 17.5 to 35.0 kg/m2; and a total body weight >50 kg (110 lb).

2. Diagnosis of AD or HS for at least 6 months.

3. Patients with AD: having at least 10% treatable percentage body surface area at Screening or on Admission (excluding the scalp and designated venous access areas).

4. Willingness and ability to comply with all contraception requirements as applicable based on reproductive status.

5. Has adequate venous access with venous access sites having AD-unaffected, non-infected skin to permit repeated PK sampling.

6. Female patients must have a negative result for the serum pregnancy test at the Screening Visit and on admission.

7. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.

8. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

9. Patients with HS: A total Abscess and Inflammatory Nodule count of =4 at baseline

AD or HS Patient (Parts C) Exclusion Criteria:

1. Has any clinically significant medical disorder, condition, disease (including active or potentially recurrent dermatological conditions other than AD or HS), significant physical examination or laboratory findings that may interfere with study objectives, in the Investigator's opinion (eg, conditions or findings that may expose a patient to unacceptable risk by study participation, confound the evaluation of treatment response or adverse events, or otherwise interfere with a patient's ability to complete the study).

2. Has an active systemic or soft tissue infection, including known actively-infected AD or HS skin lesion.

3. Treatment with an investigational product within 30 days or 5 half-lives preceding the first dose of investigational product (whichever is longer).

4. Use of prescription or nonprescription drugs including topical corticosteroids, vitaminic and dietary supplements within 14 days or 5 half-lives (whichever is longer) prior to the first dose of investigational product.

5. Blood donation (excluding plasma donations and platelet donations) of approximately =400 mL within 3 months or =200 mL within a month prior to dosing.

6. History of sensitivity to heparin or heparin-induced thrombocytopenia.

7. Unwilling or unable to comply with the protocol procedures and/or assessments.

8. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.

9. Patients with HS: Fistula and Tunnel count of >20 at baseline.

10. Patients with AD: Active herpes infection or history of eczema herpeticum.

Related Conditions & MeSH terms

• Atopic Dermatitis
• Dermatitis
• Dermatitis, Atopic
• Eczema
• Healthy Volunteer
• Hidradenitis
• Hidradenitis Suppurativa

Intervention

Drug:
• KT-474/Placebo
KT-474 or matching placebo oral tablet(s)
• KT-474
KT-474 oral tablet(s)

Locations

Country	Name	City	State
United States	U.S. Dermatology Partners Jollyville	Austin	Texas
United States	Encore Medical Research, LLC. - Boynton Beach	Boynton Beach	Florida
United States	U.S. Dermatology Partners Cedar Park	Cedar Park	Texas
United States	TKL Research	Fair Lawn	New Jersey
United States	Encore Medical Research, LLC. - Hollywood	Hollywood	Florida
United States	Research Centers of America	Hollywood	Florida
United States	Dermatology and Skin Cancer Center of Leawood	Leawood	Kansas
United States	Dermatology and Skin Cancer Center of Lee's Summit	Lee's Summit	Missouri
United States	Dermatology and Skin Cancer Center of Overland Park	Overland Park	Kansas
United States	Medical Dermatology Specialists	Phoenix	Arizona
United States	Southwest Skin Specialists 32nd St	Phoenix	Arizona
United States	Southwest Skin Specialists Tatum	Phoenix	Arizona
United States	Beatrice Keller Clinic	Sun City West	Arizona
United States	Encore Medical Research, LLC. - Weston	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Kymera Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	IRAK4 levels in peripheral blood mononuclear cells		up to 28 days
Other	IRAK4 levels in skin		up to 28 days
Other	Percentage Change from baseline in Total Abscess and Inflammatory Nodule (AN) Count, Skin Pain Numerical Rating Scale (NRS), Peak pruritis NRS, and HS Physician's Global Assessment (HS-PGA) in HS patients		up to 42 days
Other	Percentage Change from baseline in Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS) and Investigator Global Assessment (IGA) in AD patients		up to 42 days
Primary	Incidence and severity of treatment emergent Adverse Events		up to 28 days
Primary	Incidence and frequency of use of concomitant medication		up to 28 days
Secondary	Area under the curve plasma concentration from time zero to infinity [AUC(0-8)] (single dose only)		up to 28 days
Secondary	Area under the curve plasma concentration from time zero to last measurable concentration [AUC(0-last)]		up to 28 days
Secondary	Area under the plasma concentration-time curve during a dosing interval [AUC(0-tau)]		up to 28 days
Secondary	Maximum observed plasma concentration (Cmax)		up to 28 days
Secondary	Time to maximum observed plasma concentration (Tmax)		up to 28 days
Secondary	Apparent clearance (CL/F)		up to 28 days
Secondary	Apparent volume of distribution (Vz/F)		up to 28 days
Secondary	Terminal elimination half-life (t1/2)		up to 28 days
Secondary	Mean residence time (MRT)		up to 28 days
Secondary	Renal clearance (CLR)		up to 28 days