Primary: To compare the pharmacokinetics (PK) of the once daily (QD) and once weekly (QW) formulations of setmelanotideSecondary Objectives:To assess the safety of the QW formulation of setmelanotide with up to 6 months (26 weeks) of drug…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Comparison of steady-state PK parameters (maximum plasma concentration [Cmax,],
time to maximum plasma concentration [Tmax], trough plasma concentration
[Ctrough], area under the plasma concentration-time curve over the dosing
interval [AUC0-tau]) for QW compared with QD setmelanotide
Secondary outcome
Secondary endpoints :
Safety outcomes, including AEs/SAEs, ISRs and changes in laboratory parameters,
vital signs, ECG recordings, and physical examination findings, etc.
Exploratory endpoints:
Proportion of patients who achieve the following change in body mass index
(BMI) from baseline to Week 14 for QW vs QD setmelanotide groups:
1. > -2.5% and < 2.5% change
2. equal or more than 2.5% increase
3. equal or more than 2.5% decrease
Change and percent change in BMI from baseline to Week 14 for QW vs QD
setmelanotide groups, and for up to 6 months (26 weeks) for all patients
Change and percent change in body weight in adult patients >18 years of age,
and change in BMI Z-score and change in percentage of 95th
percentile of age- and sex-predicted BMI for patients <18 years of age, from
baseline to Week 14 for QW vs QD setmelanotide groups, and for
up to 6 months (26 weeks) for all patients.
Change from baseline to Week 14 for in the QW vs QD setmelanotide groups, and
for up to 6 months (26 weeks) for all patients in:
- waist circumference,
- lipid levels, and
- HbA1c
Change in average daily most/worst hunger and global hunger scores from
baseline to Week 14 for QW vs QD groups and for up to 6 months (26 weeks) for
all patients.
Change in total score from baseline to Week 14 in Symptoms of Hyperphagia
(patient/caregiver versions) for QW vs QD groups and for up to 6 months (26
weeks) for all patients.
Background summary
In a subset of individuals with obesity, rare genetic variants may result in
severe obesity. The identification of key genetic determinants of the neuronal
pathways and signaling molecules (e.g., leptin) regulating appetite and body
weight has led to the discovery of multiple rare genetic disorders of obesity
(RGDO). A key neuronal pathway, the central melanocortin and melanocortin-4
receptor (MC4R) pathway, plays an important role in appetite, hunger, and
energy utilization. In humans and animal models, genetic defects in the MC4R
pathway, such as POMC deficiency, result in severe forms of early-onset obesity
and hyperphagia. Patients with rare genetic variants in leptin receptor (LEPR)
and patients with Bardet-Biedl syndrome (BBS, a rare pleiotropic autosomal
recessive disorder caused by mutations in as many as 24 different genes) also
present with unremitting hunger and severe obesity caused in part by a lack of
activation of the MC4R pathway. As a result of hyperphagia, individuals with
RGDO have increased calorie intake leading to early-onset, severe obesity, and
obesity-related comorbidities such as type 2 diabetes. The Sponsor is
developing setmelanotide (also known as RM-493), an MC4R agonist, as a
treatment for patients with RGDO. Setmelanotide bypasses upstream signaling
defects to directly activate MC4R. The purpose of this study is to compare the
QW and QD formulations of setmelanotide in patients with biallelic PPL (POMC
[pro-opiomelanocortin], PCSK1 [proprotein convertase subtilisin/kexin Type 1],
LEPR [leptin receptor]), heterozygous PPL, and patients with BBS. QW dosing is
expected to provide a more convenient dosing regimen for these patients and
would be more suitable for younger patients than QD dosing. In addition, QW
dosing would be expected to improve compliance, especially given the long-term
requirement for continued dose administration in order to achieve sustained
benefits.
Study objective
Primary:
To compare the pharmacokinetics (PK) of the once daily (QD) and once weekly
(QW) formulations of setmelanotide
Secondary Objectives:
To assess the safety of the QW formulation of setmelanotide with up to 6 months
(26 weeks) of drug administration
Study design
This study is designed to compare the safety, pharmacokinetics (PK), and
efficacy of the QW and QD formulations of setmelanotide, as well as to evaluate
the safety and efficacy of up to 6 months of QW setmelanotide administration in
patients with BBS, biallelic PPL, or heterozygous PPL. Eligible patients are
those who are currently taking QD setmelanotide in Study RM-493-022, referred
to as the long-term extension (LTE) study, for at least 6 months with
acceptable safety and tolerability, and who wish to continue with setmelanotide
treatment, and who otherwise meet all inclusion and exclusion criteria.
Approximately 30 patients will be targeted in 3 age groups as follows:
approximately 20 patients >=18 years old; approximately 6 patients >=12 to <18
years old; and approximately 4 patients >=6 to <12 years old at the time of
study entry.
The study consists of a Screening Period for transition from the LTE study, a
Run-in Period of up to 1 week of continuation on the patient*s current dose
level of QD setmelanotide (2, 2.5, or 3 mg), a 13-week double-blind phase in
which the patients will be randomized to either QD or QW setmelanotide, a
13-week non-randomized open-label phase where all patients will receive
open-label QW setmelanotide, and a 3-week follow-up period in which all
patients will return to their run-in dose level of QD setmelanotide to prepare
for re-enrollment into Study RM-493-022 or to resume the QD formulation in some
other way.
The safety and tolerability of setmelanotide will be assessed by the frequency
and severity of AEs/serious adverse events (SAEs) and ISRs, as well as changes
in physical examinations (to include comprehensive skin examinations),
electrocardiograms (ECGs), vital signs (including resting blood pressure [BP]
and heart rate [HR]), routine laboratory evaluations, development of anti-drug
antibodies (ADA), and the Columbia-Suicide Severity Rating Scale (C-SSRS).
Efficacy assessments include: body weight, Hunger Questions, Symptoms of
Hyperphagia Questions, laboratory evaluations of lipids, glucose, and
glycosylated hemoglobin (HbA1c), and waist circumference.
Intervention
Daily and/or weekly subcutaneous administration of setmelanotide from 2, 2,5 or
3 mg (QD) and 20, 25 or 30 mg (QW)
Venipunctures for blood determinations
Skin examination for suspicious lesions at screening, week 27 and week 30
Full physical examination at screening and End of Trial (EoT, week 30), a brief
physical examination at the other visits.
An echocardiogram (heart film) at visit 1, visit 3, visit 11, visit 16, visit
20 and visit 21.
Parents are asked to complete daily hunger and hyperphagy questions in an
electronic diary
Parents are asked to complete questionnaires on hunger and suicidal ideation.
Questionnaires on suicidal ideation at Visit 1, 2, 3, 7, 11, 16, 18, 19, 20 and
21.
Study burden and risks
In patients with RGDO, setmelanotide has been associated with clinically
meaningful reductions in weight and improvement in hunger. In particular, in
patients with POMC or LEPR deficiency obesity, who are characterized by
early-onset obesity, severe hunger and progressive weight gain, setmelanotide
has demonstrated clinically meaningful and statistically significant weight
loss, setmelanotide has demonstrated clinically meaningful and statistically
significant decreases in hunger. Both the decreased hunger and the weight loss
continued over 52 weeks of treatment and are maintained with continued
setmelanotide treatment. Furthermore, following the significant weight loss
with setmelanotide treatment, there were improvements in lipids and other
parameters, as well as body composition with decreased fat mass and decreased
waist circumference. These weight loss changes were accompanied by improvements
in quality of life.
Setmelanotide is well tolerated. Side effects of setmelanotide are predictable,
well understood, and do not present significant safety concerns. Collectively,
safety data obtained to date show that adverse events (AEs) commonly associated
with setmelanotide include injection site reactions (ISRs) and skin
hyperpigmentation. Less commonly, nausea and vomiting were reported and rarely,
sexual AEs have been observed. Potential mechanistic-based events such as
hypertension have been assessed throughout the setmelanotide clinical
development program and have not been observed. Events associated with severe
obesity such as depression and suicidal ideation occurred infrequently and were
assessed as not related to setmelanotide.
Specifically, regarding children less than 12 years old, the AEs reported in
this population were consistent with those reported in other studies of
setmelanotide. Adverse events reported as related to setmelanotide treatment
were consistent with the known safety profile. No evidence for concern
regarding bone development has been observed. Three of the 4 patients showed
progression into puberty.
Daily injection of setmelanotide is technically challenging for pediatric
patients and patients with poor coordination/vision or other physical
challenges, thus, the Sponsor is developing the weekly formulation to improve
compliance and to address user limitations, with the assumption that safety and
efficacy between the two formulations will be comparable.
In summary, setmelanotide has a positive benefit-risk profile in patients with
genetic defects upstream of the MC4R and the QW formulation may have the added
advantage of a more convenient dosing regimen.
More detailed information about the known and expected benefits and risks and
reasonably expected AEs of setmelanotide may be found in the Investigator*s
Brochure.
The PI and staff (and other covering clinicians) will be available at all times
to study participants in the event of a clinical emergency; both this
availability and how to reach the investigator in an emergency will be clearly
communicated orally and in writing to the study participants. All study
interventions will be provided free of cost.
Berkeley Street, Suite 1200 222
Boston MA 02116
US
Berkeley Street, Suite 1200 222
Boston MA 02116
US
Listed location countries
Age
Inclusion criteria
1. All patients must have met the criteria for diagnosis of a gene defect in
the MC4R pathway (BBS, biallelic PPL, heterozygous PPL), for which they are
being treated with QD setmelanotide.
2. Patients must be >=6 years old at screening.
3. Patients must have been taking the setmelanotide QD formulation for at least
6 months in the LTE trial with acceptable safety and tolerability, and the dose
level must have been stable at 2, 2.5 or 3 mg of setmelanotide for at least the
last 3 months prior to starting the Run-in Period.
4. Patient and/or parent or guardian is able to communicate well with the
Investigator, to understand and comply with the requirements of the trial and
is able to understand and sign the written informed consent/assent.
5. Patient must meet one of the following requirements:
Female participants of childbearing potential, defined as fertile, following
menarche and until becoming post-menopausal unless permanently sterile
(hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be
confirmed non-pregnant and agree to use a highly effective form of
contraception throughout the trial and for 90 days following the trial. Highly
effective forms of contraception are detailed below and in Section 8.8.7:
- Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, or transdermal)
- Progestin-only hormonal contraception associated with inhibition of ovulation
(oral, implantable, or injectable)
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomy/vasectomized partner (provided that the vasectomized partner is the
sole sexual partner of the female participant, and the vasectomized partner has
received medical assessment of surgical success)
- Sexual abstinence, only if it is the preferred and usual lifestyle of the
patient
Female participants of non-childbearing potential, defined as: permanently
sterile (status post hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy), or post-menopausal for at least 12 months (and confirmed with a
screening follicle-stimulating hormone (FSH) level in the post-menopausal lab
range) do not require contraception during the trial.
Younger female patients who have not achieved sexual maturity at study entry
will be assessed for Tanner staging and required to comply with contraception
requirements at first menarche.
Male participants with female partners of childbearing potential must agree to
use a highly effective method of contraception if they become sexually active
during the trial or within 90 days following their participation in the study.
Male patients must also not donate sperm during and for 90 days following their
participation in the trial.
Exclusion criteria
1. HbA1C >9.0% at screening.
2. Has taken a medication that is approved to treat obesity (e.g., orlistat,
lorcaserin, phentermine-topiramate, naltrexone-bupropion) within 3 months prior
to starting the Run-in Period. Glucagon-like peptide-1 (GLP) -1) receptor
agonists being prescribed for the treatment of obesity are not allowed.
3. History of significant liver disease or liver injury, or a current liver
assessment due to abnormal liver tests for an etiology other than nonalcoholic
fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD,
including diagnosed nonalcoholic steatohepatitis (NASH), other causes of
hepatitis, or history of hepatic cirrhosis is exclusionary, but the presence of
NAFLD is not exclusionary.
4. Moderate to severe renal dysfunction as defined by a glomerular filtration
rate <30 mL/min. (based upon the Chronic Kidney Disease Epidemiology
Collaboration [CKD-EPI] creatinine equation 2021 from the National Kidney
Foundation). In patients <18 years of age the Bedside Schwartz Equation should
be used to calculate estimated glomerular filtration rate (eGFR).
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin
lesions (excluding non-invasive basal or squamous cell lesion), determined as
part of comprehensive skin evaluation performed by the Investigator during
screening. Any concerning lesions identified during the Screening Period will
be biopsied and results must be known to be benign prior to enrollment. If the
pretreatment biopsy results are of concern, the patient should be excluded from
the trial.
6. Diagnosis of schizophrenia, bipolar disorder, personality disorder, or other
psychiatric disorders that the Investigator believes will interfere
significantly with trial compliance. Neurocognitive disorders affecting ability
to consent will not be disqualifying as long as an appropriate guardian able to
give consent has been appointed.
7. Clinically significant depression or suicidality as defined by: any suicidal
ideation of type 4 or 5 on the C SSRS, any lifetime history of a suicide
attempt, or any suicidal behavior in the last month or a Patient Health
Questionnaire-9 (PHQ-9) score of >=15 during Screening in patients with no
significant neurocognitive deficits.
8. Patient is not suitable, in the opinion of the Investigator, to participate
in the trial.
9. Hypersensitivity to the active substance or to any of the excipients of the
investigational products (active or placebo).
10. Inability to comply with the QW and QD injection regimens.
11. Participation in any clinical trial with an investigational drug/device
within 3 months prior to the first day of dosing, with the exception of a
setmelanotide clinical trial.
12. Legally protected persons per local regulations (e.g., those that fall
under the L1121-6 article of the Public Health code in France) or other
applicable local laws.
13. The patient or a relative of the patient is the investigator or a sub
investigator, research assistant, pharmacist, trial coordinator, or other
staff directly involved with the conduct of the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-004597-65-NL |
| ClinicalTrials.gov | NCT05194124 |
| CCMO | NL80213.078.22 |