A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Depemokimab in Adults with Hypereosinophilic Syndrome (HES)
1. Participant must be ≥18 years of age, at the time of signing the informed consent.
Body weight
2. Participants who are ≥40 kg at Screening Visit 1.
Type of Participant and Disease Characteristics
3. Participants who have a documented diagnosis of HES prior to Visit 2. HES
diagnosis is based on:
• blood eosinophilia of >1500 eosinophils/μL on at least 2 occasions at ≥1-month
interval, without a discernible non-haematological secondary cause, and
• signs or symptoms of organ involvement and/or dysfunction that can be directly
related to eosinophilia.
4. Flare history: A history of 2 or more HES flares within the past 12 months prior to
Visit 1. Historical HES flares are defined as documented HES-related worsening of
clinical symptoms or blood eosinophil counts requiring an addition or escalation in
OCS or cytotoxic/immunosuppressive therapy. At least one HES flare within the past
12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
Sex and Contraceptive/Barrier Requirements
5. Male or female participants
• A female participant is eligible to participate if she is not pregnant or
breastfeeding, and one of the following conditions applies:
• Is a woman of non-childbearing potential (WONCBP) as defined in
Section 10.4, Appendix 4
OR
• Is a woman of childbearing potential (WOCBP) and using a contraceptive
method that is highly effective, with a failure rate of <1%, as described in,
Section 10.4, Appendix 4, from at least 14 days prior to the first dose of study
intervention until at least 30 weeks after the last administered dose of study
intervention. The Investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive serum pregnancy test at
Screening Visit 1 and a negative highly sensitive urine pregnancy test within 24
hours before the first dose of study intervention. If a urine test cannot be
confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is
required. In such cases, the participant must be excluded from participation if the
serum pregnancy result is positive. Additional requirements for pregnancy testing
during and after study intervention are located in Section 8.3.5.
• Contraceptive use by women should be consistent with local regulations regarding
the methods of contraception for those participating in clinical studies.
• The Investigator should evaluate the potential for contraceptive method failure
(e.g., non-compliance, recently initiated in relationship to the first dose of study
intervention.
• The Investigator is responsible for review of medical history, menstrual history,
and recent sexual activity to decrease the risk for inclusion of a woman with an
early undetected pregnancy.
Informed Consent
6. Capable of giving signed informed consent as described in Section 10.1, which
includes compliance with the requirements and restrictions listed in the ICF and in
this protocol.
French participants: In France, a participant will be eligible for inclusion in this
study only if either affiliated to or a beneficiary of a social security category.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. HES disease manifestations which in the opinion of the Investigator may put the
Participant at unacceptable risk from study participation or confound
interpretation of efficacy or safety data. Specific consideration should be given to the
participant’s ability to comply with protocol requirements, including the list of prohibited therapies; exclusion criteria no. 14 - 16.
2. Infection:
• Participants with chronic or ongoing active infections requiring systemic treatment.
• Participants with a pre-existing parasitic infestation within 6 months prior to
Visit 1.
3. Immunodeficiency: Participants with a known immunodeficiency (e.g., Human
Immunodeficiency Virus [HIV]), other than that explained by the use of OCS or
other therapy taken for HES.
4. Malignancy:
• Participants with a history of or current lymphoma.
• Participants with current malignancy or previous history of cancer in remission
for less than 5 years prior to Visit 1. Participants that had localized carcinoma
(i.e., basal or squamous cell) of the skin which was resected for cure will not be
excluded.
• Participants with a haematologic malignancy with hypereosinophilia in which
HES is not the primary diagnosis, e.g., chronic myeloid leukaemia,
myelodysplastic syndrome, chronic eosinophilic leukaemia-not otherwise
specified.
5. Liver disease:
• Cirrhosis or current unstable liver or biliary disease per Investigator assessment
defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice.
NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome,
asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if
participant otherwise meets entry criteria.
6. Cardiovascular: Participants who have severe or clinically significant
cardiovascular disease uncontrolled with standard treatment.
7. Vasculitis: Participants with current diagnosis of vasculitis. Participants with high
clinical suspicion of vasculitis at Screening will be evaluated and current vasculitis
must be excluded prior to randomization.
8. Eosinophilia of unknown significance: Hypereosinophila with no clinical
symptoms and/or proof of organ dysfunction.
9. Clinical diagnosis of EGPA.
10. Coronavirus disease 2019 (COVID-19): Participants that, according to the
Investigator's medical judgment, are likely to have active COVID-19 infection
should be excluded. Participants with known COVID-19 positive contacts within the
past 14 days must be excluded for at least 14 days following the exposure during
which the participant must remain symptom-free.
11. Other concurrent medical conditions that may affect the participant’s safety:
Participants who have known, pre-existing, clinically significant endocrine,
autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic,
haematological, respiratory, cardiac or any other system abnormalities that are not
associated with HES and are uncontrolled with standard treatment.
12. Hypersensitivity: Participants with an allergy/ intolerance to a monoclonal antibody
or biologic, or any of the excipients of the investigational product in Section 6.1.
13. Monoclonal antibodies (mAbs) targeting IL-5/5R: Participants who have a
previous documented failure with anti-IL-5/5R therapy.
14. mAbs: Participants who have received mAb within 30 days or 5 half-lives,
whichever is longer, prior to Visit 1. If a participant has been treated with and
responsive to biologics for HES, the participant should not stop the treatment for
study eligibility purpose.
15. Non-oral systemic corticosteroids: Participants who have received intravenous,
intramuscular, or subcutaneous corticosteroids within 4-weeks prior to Visit 2.
16. Investigational medications/clinical study:
• Participants who have received treatment with an investigational agent within
30 days or 5 drug half-lives whichever is longer, prior to Visit 1. The term
“investigational” applies to any drug not approved for sale in the country in which
it is being used or investigational formulations of marketed products.
• Participants who are currently participating in any other interventional clinical
study.
Note: Any COVID-19 vaccine approved by local government is permitted.
Experimental COVID-19 vaccines are not permitted.
Diagnostic Assessments
17. FIP1L1-PDGFRα Status: Participants who test positive for the FIP1L1-PDGFRα
fusion gene.
Blood sampling is required for all participants at Screening (Visit 1) for this test
unless the documented result is available.
18. ECG Assessment: QTcF ≥450 msec or QTcF ≥480 msec for participants with Bundle Branch Block at Screening Visit 1.
Other Exclusions
19. OCS responsiveness: Participants who are not responsive to OCS based on clinical
response or blood eosinophil counts in the opinion of the Investigator.
20. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or
substance abuse within 2 years prior to Visit 1.
21. Pregnancy: Participants who are pregnant or breastfeeding. Participants must not be
randomized if they plan to become pregnant during the time of study participation.
22. Adherence: Participants who have known evidence of lack of adherence to
controller medications and/or ability to follow physician’s recommendations.
Depemokimab in participants with hypereosinophilic syndrome, efficacy, and safety trial.
