This study is currently recruiting participants.
Generalized lipodystrophy (GLD) is a rare disease that causes a loss of body fat under the skin. People with GLD have low levels of a hormone called leptin. This can cause many issues, such as severe hunger and diabetes. Many people develop resistance to the current drug (metreleptin) used to treat low leptin levels. Better treatments are needed.
To test a new drug (mibavademab) in people with GLD.
People aged 2 years and older with GLD. They must have taken metreleptin for at least 6 months with no change in the dose for the most recent 3 months.
Participants will be screened. They will have a physical exam. They will have blood and urine tests. Data on their blood sugar levels will be collected from the prior year. They will stop taking metreleptin 1 day before their first dose of the study drug.
On the first day, mibavademab will be administered through a tube attached to a needle inserted into a vein.
Beginning the second day, the study drug will be administered as up to 3 injections under the skin. Participants or their caregivers will be shown how to administer the injections.
Participants will continue to inject themselves with the study drug once a week for 1 year. They will be given a blood sugar monitor and asked to keep an eDiary. They will have 4 clinic visits during the year.
Participants will have follow-up visits at 8 and 16 weeks after study treatment ends.
INCLUSION CRITERIA:
A participant must meet the following criteria to be eligible for inclusion in the study:
1. Individuals >=2 years of age at the screening visit (Note: participants <18 years of age will only be enrolled where permitted by local legislation).
2. Diagnosis of congenital or acquired GLD as defined by Multi-Society Practice Guidelines.
3. Treatment with metreleptin for >=6 months at time of screening at a stable dose, defined as no change in dose within the last 3 months prior to screening.
4. Generally stable diet (based on participant s recall) and stable medication regimen for diabetes and/or dyslipidemia (in addition to metreleptin), for the last 3 months prior to screening.
5. Willing and able to comply with clinic visits and study-related procedures. Participants who are unable/unwilling to self-inject, but are willing to have a capable caregiver inject, are considered eligible.
6. Willing and able to provide, or have the treating physician provide, values of HbA1c and fasting triglycerides from at least 6 months prior to screening.
Note: Screening may be repeated in case these data are not available for a 6-month period at the initial screening visit.
7. Provide informed consent signed by study participant or legally acceptable representative; participants <18 years of age may also provide assent as directed by local regulation.
8. Able to understand and complete, or have a caregiver understand and complete, study-related monitoring and diaries.
EXCLUSION CRITERIA:
A participant who meets any of the following criteria will be excluded from the study:
1. Treatment with over-the-counter or prescription medications for weight loss within 3 months prior to the screening visit.
2. Current chronic treatment with high-dose corticosteroids, defined as use of higher than physiologic doses (>7.5 mg or more than 0.5 mg/kg/day of prednisone or equivalent, whichever is lower) for more than 2 weeks, or plans to begin chronic treatment with high-dose corticosteroids during the study period.
3. Any malignancy, eg, lymphoma, within the past 1 year, prior to screening visit except for fully treated basal cell or squamous epithelial cell carcinomas of the skin or carcinoma in situ of the cervix or anus.
4. Estimated GFR of <30 mL/min/1.73 m^2 based on CKD-EPI/Schwartz equation at screening. Assessment can be repeated once.
5. History of heart failure hospitalization, diagnosis of a myocardial infarction, stroke, clinically significant arrhythmia (eg, ventricular tachycardia, or any arrhythmia requiring medication adjustment to control), transient ischemic attack, unstable angina, percutaneous or surgical revascularization procedure (coronary, carotid, or peripheral vascular), or intracardiac device placement (eg, pacemaker) within 3 months before the screening visit.
6. Advanced heart failure (New York Heart Association Class 3 to 4) or severe and uncontrolled hypertension at screening.
7. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the sponsor.
8. Participation in any clinical research study evaluating an IP (except for metreleptin) or therapy within 3 months or less than 5 half-lives of IP prior to the screening visit, whichever is longer. Participation in clinical research studies that only involve procedures (eg, muscle biopsies, glycemic clamps) or testing (eg, MRI) that will not interfere with the current study is permitted.
9. Is committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
10. Pregnant or breastfeeding women.
11. Women of childbearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last dose. Highly effective contraceptive measures include:
a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
c. bilateral tubal occlusion/ligation;
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
e. sexual abstinence**,***.
Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile.
*WOCBP are defined as women who are fertile following menarche or Tanner stage 3, whichever is earlier and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. It must be considered that participants may not be heterosexually active, as defined by engaging or potentially engaging in any behaviors that could lead to pregnancy and thus not of reproductive potential. While these women might not be considered WOCBP, investigators are cautioned to assess the reliability of the self-report of these behaviors. Study site staff should document assessment that the participant has not reached reproductive potential and continuously reassess reproductive potential during the study as a participant s contraception needs may change over time. If a participant reaches reproductive potential or is heterosexually active, contraceptive counseling, contraception, and pregnancy testing are required as specified by the protocol.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the Clinical Trial Facilitation Group (CTFG) guidance.
**Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.
***Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
12. Sexually active men (males with Tanner stage 3) who are unwilling to use the following forms of medically acceptable birth control during the trial and for 4 months after the last study drug administration: vasectomy with medical assessment of surgical success or consistent use of a condom. Sperm donation is prohibited during the trial and for 4 months after last study drug administration.
13. Has a history of drug or alcohol abuse within a year prior to the screening visit. Detection of a confirmed prescribed drug (eg, pain medication) will not result in disqualification.
14. History of human immunodeficiency virus (HIV) or HIV seropositivity at the screening visit.
15. Uncontrolled infection with hepatitis B or hepatitis C infection or known active tuberculosis at screening. Participants will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening. Participants with hepatitis B (HBV sAg+) who have controlled infection (serum HBV DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Participants with controlled infections must undergo periodic monitoring of HBV DNA per local standards. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. Participants who are hepatitis C virus antibody-positive (HCVAb+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
16. Has a known allergy or hypersensitivity to components of the study drug.
17. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the participant by their participation in the study.