Phase 1/2 Multicenter, Open-label Study of Subcutaneous KK8123 in Adult Patients with X-linked Hypophosphatemia: Safety, Tolerability, and Pharmacokinetics Evaluation

Trial ID: 2023-509390-23-00
Protocol: 8123-001
Sponsor: Kyowa Kirin Inc.

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Diseases & Conditions

Hereditary hypophosphataemic rickets

Objectives

The primary objective of this study is to assess the **safety** and tolerability of KK8123 in adult patients with X-linked hypophosphatemia. In Part 1, the study aims to characterize the pharmacokinetic (PK) profile of KK8123, while Part 2 focuses on evaluating the safety and tolerability after multiple subcutaneous (SC) doses. Understanding the safety profile and tolerability of KK8123 is crucial for determining its potential as a therapeutic option for X-linked hypophosphatemia, a condition characterized by low phosphate levels leading to bone and dental problems.

Secondary objectives include:

For Part 1: Evaluating the effect of single and multiple SC administrations of KK8123 on serum phosphorus levels and assessing the immunogenicity of these administrations.
For Part 2: Characterizing the PK profile of multiple SC administrations of KK8123, evaluating their effect on serum phosphorus levels, and assessing the immunogenicity of these administrations.

Participants

The clinical trial involves a total of **17 participants** diagnosed with **X-linked hypophosphatemia**. The study population includes both male and female subjects, aged between 18 to 65 years. Participants were selected based on specific inclusion criteria, including a diagnosis of X-linked hypophosphatemia, a fasting serum phosphorus level of less than 2.5 mg/dL, and a renal TmP/GFR of less than 2.5 mg/dL. All participants are required to have an estimated glomerular filtration rate (eGFR) of at least 60 mL/min and a body weight of at least 40 kg. The trial population is characterized by a stable regimen of chronic pain medications, if applicable, and a commitment to maintaining their current diet and exercise regimen throughout the study. Participants are also required to use effective contraception methods and undergo regular pregnancy testing if applicable. The study includes a vulnerable population, and all participants have provided informed consent prior to the initiation of any research-related procedures.

Plans and Procedures

The clinical trial is designed as a **multicenter, open-label, Phase 1/2, dose-escalation and subsequent safety extension study** to evaluate the investigational product KK8123 in adult patients diagnosed with **X-linked hypophosphatemia**. The primary objectives are to assess the safety and tolerability of KK8123 and to characterize its pharmacokinetic profile. The trial is structured into two parts: Part 1 focuses on dose escalation, while Part 2 involves a safety extension with multiple subcutaneous doses. The study is expected to commence recruitment on December 5, 2024, and conclude by November 20, 2026.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, stable medication regimen, and specific laboratory values. The inclusion criteria require participants to be between 18 and 65 years old, have a documented diagnosis of X-linked hypophosphatemia, and meet specific laboratory thresholds, including fasting serum phosphorus and renal TmP/GFR values. The screening visit will also involve obtaining informed consent and conducting baseline assessments.

Following the screening, participants will attend regular follow-up visits to monitor safety and efficacy endpoints, including treatment-emergent adverse events, laboratory values, vital signs, and serum KK8123 concentrations. Secondary endpoints include changes in serum phosphorus levels and the incidence of anti-drug antibodies. The end-of-study visit will mark the completion of the trial for each participant, during which final assessments will be conducted.

The expected duration of participant involvement is contingent upon the completion of both parts of the study, with the possibility of early termination if safety concerns arise or if the participant fails to adhere to the study protocol. Participants are required to maintain a stable medication regimen and adhere to the study visit schedule throughout the trial. The investigational product, KK8123, is administered as a **solution for injection** via subcutaneous route, with a maximum daily dose of 30 mg. The study is not classified as a low-intervention trial, and the investigational product is not a pediatric formulation.

Treatment

The clinical trial involves the administration of **KK8123**, a novel recombinant human IgG1 monoclonal antibody, as the experimental medication. **KK8123** is provided in the form of a **solution for injection** and is manufactured by Kyowa Kirin Inc. The pharmaceutical formulation is specifically designed for subcutaneous injection. The maximum daily dose of **KK8123** is 30 mg, with the same amount being the maximum total dose allowed per day. The treatment period is limited to a maximum of one day. The active substance in **KK8123** is a protein of other origin, and it is not formulated for pediatric use. The primary objective of the trial is to assess the safety and tolerability of **KK8123** and to characterize its pharmacokinetic profile in adult patients with X-linked hypophosphatemia.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is structured as a multicenter, open-label, Phase 1/2 study, focusing on dose-escalation and subsequent safety extension. The administration of **KK8123** is monitored to ensure participant compliance, with dosing schedules strictly adhered to as per the trial protocol. The study aims to evaluate the safety and tolerability of **KK8123** after multiple subcutaneous doses, providing critical data on its potential therapeutic application.

Efficacy

The efficacy of the investigational product KK8123 in the clinical trial will be assessed using both primary and secondary endpoints. Primary endpoints include the evaluation of **TEAEs** (treatment-emergent adverse events), laboratory values, vital signs, 12-lead electrocardiogram, echocardiogram, renal ultrasound, and serum KK8123 concentrations over time, along with pharmacokinetic (PK) parameters. These assessments will provide a comprehensive overview of the safety and pharmacokinetic profile of KK8123.

Secondary endpoints focus on the therapeutic efficacy of KK8123, specifically targeting changes in serum phosphorus levels. The parameters include the change in serum phosphorus levels over time, change from baseline in serum phosphorus levels, achieving serum phosphorus levels within the normal range through the last dosing interval, and achieving average serum phosphorus levels within the normal range across all dosing intervals. Additionally, the incidence of anti-drug antibodies over time will be monitored to assess the immunogenicity of KK8123. These endpoints will be measured at specified intervals throughout the study to determine the efficacy of the treatment in patients with X-linked Hypophosphatemia.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients aged 18 to 65 years inclusive at the time of signing the ICF.
Provide a signed ICF after the nature of the study has been explained, and prior to any research-related procedures initiation.
Agree not to change diet and exercise regimen from one week prior to dosing to end of study.
Have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study (female participants only).
Part 2: Completion of relevant cohort in Part 1 of the study.
Part 2: Provide a signed informed consent after the nature of Part 2 of the study has been explained.
Part 2: Negative pregnancy test at Screening of Part 2 and be willing to have additional pregnancy tests during the study.
Part 2: If taking chronic pain medications, must be on a stable regimen and be willing to maintain medications at the same stable dose(s) and schedule throughout the study.
Part 2: Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with all the assessments.
If taking chronic pain medications (including narcotic pain medications/opioids), must be on a stable regimen for at least 21 days prior to the Screening visit, and be willing to maintain medications at the same stable dose.
WOCBP who are sexually active must be willing to use a method of contraception following local country guidelines while participating in the study and for 30weeks after the last dose.
Must, in the opinion of the investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments.
Diagnosed with XLH (as documented by the investigator).
Have a value of fasting serum phosphorus < 2.5 mg/dL (0.81 mmol/L) at Screening.
Have a value of renal TmP/GFR < 2.5 mg/dL (0.81 mmol/L) at Screening.
eGFR ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration equation) at Screening.
Have a corrected serum calcium level < 10.8 mg/dL (2.7 mmol/L) at Screening.
Body is weight at least 40 kg.
Part 2: Body is weight at least 40 kg
Part 2: WOCBP who are sexually active must be willing to use a method of contraception following local country guidelines while participating in the study and for 30weeks after the last dose.

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Exclusion Criteria

For XLH patients previously treated with other drugs, use of them within 7 months prior to ICF signature.
Part 2: Use of any investigational product other than KK8123, or investigational medical device, within 30 days prior to Week 0 of Part 2, or requirement for any investigational agent prior to completion of all scheduled study assessments.
Part 2: Use of any therapeutic mAb other than KK8123 within 90 days prior to Week 0 of Part 2.
Serum iPTH ≥ 2.5 × ULN at Screening.
Part 2: Use of pharmacologically active vitamin D, its metabolites or analogs, oral phosphate for treatment of XLH, aluminum hydroxide antacids, acetazolamide, thiazide diuretics, and/or systemic corticosteroids within 14 days prior to Week 0 of Part 2.
Part 2: Use of medication to suppress PTH (e.g., calcimimetics) within 2 months prior to Week 0 of Part 2.
Part 2: Use of oral bisphosphonates following completion of Part 1 of the study.
Use of any IP or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
Part 2: Use of teriparatide or abaloparatide in the 2 months prior to Week 0 of Part 2.
Part 2: Planned or recommended orthopedic surgery during the study.
Part 2: History of traumatic fracture or orthopedic surgery within 6 months prior to Week 0 of Part 2.
Grade 3 or greater nephrocalcinosis as confirmed by renal ultrasound.
Part 2: Current active and symptomatic COVID-19 infection, or a history of suffering any long-term sequalae from COVID-19 infection.
Part 2: Presence or history of any condition that, in the view of the investigator, places the participant at high risk of poor treatment compliance or of not completing the study.
Use of any therapeutic mAb within 90 days prior to Screening.
Planned or recommended orthopedic surgery during the study.
Use of pharmacologically active vitamin D, its metabolites or analogs, oral phosphate for treatment of XLH, aluminum hydroxide antacids, acetazolamide, thiazide diuretics, and/or systemic corticosteroids within 14 days prior to Screening.
Use of medication to suppress PTH (e.g., calcimimetics) within 2 months prior to Screening and for the duration of the study.
Use of denosumab within 6 months prior to Screening.
Use of oral bisphosphonates in the 2 years prior to Screening.
Use of teriparatide or abaloparatide in the 2 months prior to Screening.
Prior history of positive test for human immunodeficiency virus antibody, positive test for hepatitis B surface antigen, and/or hepatitis C virus antibody at Screening.
History of traumatic fracture or orthopedic surgery within 6 months prior to Screening.
Current active and symptomatic COVID-19 infection.
Presence or history of any condition that, in the view of the investigator, places the participant at high risk of poor treatment compliance or of not completing the study, or that would confound safety or interpretation of results.
History of hypersensitivity to any ingredient of any therapeutic monoclonal antibody.
Have an active infection.
Part 2: Use of burosumab following completion of Part 1 of the study.
History of donation of blood within 60 days prior to Screening.
Uncontrolled diabetes mellitus at Screening.
History of known immunodeficiency.
History of alcoholism or drug abuse.
Part 2: have an active infection.
Part 2: Donation of blood within 60 days prior to Week 0 of Part 2.
Participants who are lactating.
Part 2: Participants who are lactating.