An Open-label, Single-arm, Multicenter Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Multiple Doses of ELA026 in Participants with Secondary Hemophagocytic Lymphohistiocytosis (sHLH).

HLH is a rare and life-threatening inflammatory syndrome characterized by
dysregulated immune function. HLH is classically divided into 2 types, primary
HLH (pHLH) and secondary HLH (sHLH),

sHLH is a rare and life threatening inflammatory syndrome characterized by
dysregulated immune function. The disease is associated with a massive systemic
inflammatory response for which patients require immediate and aggressive
treatment with intensive care

There are no approved therapies available for sHLH. But currently ELA026 is
also under safety evaluation in healthy volunteers which is ongoing in Austria.

The proposed clinical study is a Phase 1b, open-label, multicenter study to
investigate the safety, efficacy, PK, and PD of ELA026 following multiple dose
levels administration in participants with treatment naïve or
relapsed/refractory sHLH.

The proposed study will be conducted in up to 24 patients diagnosed with sHLH
>=16 years. Based on the scientific rationale supporting the utility of ELA026
in sHLH, the significant unmet need and the potential benefit/risk profile, the
Sponso is proposing to initiate development in sHLH.

Primary Objectives:

• To determine the safety of ELA026 administered IV and SC to participants
with sHLH.
• To identify the RP3D and schedule for ELA026.

Secondary Objectives:

• To characterize the pharmacokinetic (PK) profile of ELA026 administered IV
and SC to participants with sHLH.
• To determine the efficacy of ELA026 administered IV and SC to participants
with sHLH.
• To characterize the pharmacodynamic (PD) effect of ELA026 administered IV and
SC to participants with sHLH.
• To assess the immunogenicity of ELA026 administered IV and SC to
participants with sHLH.

This is a Phase 1b, open-label, multicenter study to investigate the safety,
efficacy, PK, and PD of ELA026 following multiple dose level administration in
participants with treatment naïve or relapsed/refractory sHLH. As of DMC
recommendation (issued 01Dec2023), participants with treatment-naïve or early
refractory sHLH are eligible for this study. Early refractory is defined as a
participant receiving approximately <1 week of any HLH-directed therapy with
insufficient clinical or laboratory response judged by Investigator at
screening.After signing an informed consent form, participants will be screened
for study eligibility. Participants will receive dexamethasone as background
therapy for sHLH and prophylaxis for bacterial, viral, and fungal/pneumocystis
infections according to local institutional standards.
The study consists of a Screening period, a 12-week Treatment period (>=6 years
of age), a Safety Follow-up period, an optional Extension phase for
participants (>=12 years of age) exhibiting clinical benefit may be treated on a
case-by-case basis beyond the 12-week treatment period with Sponsor approval,
and a Long-term Survival Follow-up period with the overall goals of evaluating
safety and selecting a dose and dosing regimen for Phase 3 testing.
An initial 3 participant cohort will be enrolled. Up to approximately 20
participants may be enrolled into Cohort 1 in order to obtain approximately 3-6
evaluable participants .The initial starting dose will be 0.1 mg/kg.The initial
dose will be administered to the first 3 participants in the first cohort
sequentially.

Successive participants in the first cohort will not be dosed until the
preceding participant has received and tolerated at least one dose for a
minimum of 24 hours. As of protocol Version 3.8, all newly enrolled
participants in Cohort 1 will start at modified Dose Level 2 and receive a
priming dose of 0.1 mg/kg on Day 1, and 0.3 mg/kg on Days 2 and 3. The Data
Monitoring Committee (DMC) may define a new starting dose level based on
emerging data.
Dosing of any additional participants added to Cohort 1 will proceed in
parallel. Intra-participant dose escalation will be used in this first cohort
to maximize benefit/risk in these participants and to facilitate subsequent
cohorts being dosed with the appropriate starting dose.
Starting on Day 1 (Baseline), eligible Cohort 1 participants will receive
ELA026 daily IV infusions. Prophylactic therapy must be initiated prior to
administration of ELA026 and continued until completion of the first 2 doses of
ELA026 for each dose level (refer to Section 6.7.1). After an individual
participant has received 3 daily doses at a given dose level in Cohort 1 (or
the 0.1 mg/kg priming dose followed by the 0.3 mg/kg dose on Days 2 and 3), the
dose will be escalated until that participant: 1) demonstrates biomarker
evidence of improvement, 2) develops a dose-limiting toxicity, or 3) receives
the maximum allowable dose of 3 mg/kg. If dose-limiting toxicity occurs at the
starting dose, the DMC may elect to add a cohort at a lower dose. IV
administration will be over 6 hours on Day 1 and for the first dose of each new
dose level, and then over 60 minutes for subsequent doses if the first dose is
well tolerated.
In order to be enrolled into Cohort 1, eligible participants must be >= 12 years
of age. Cohort 1 participants who are tolerating drug and who have shown
biomarker evidence of improvement will continue on the same IV dose level until
they complete Week 4, at which point they can be transitioned to a SC dosing
schedule as determined by the DMC in conjunction with the Sponsor. Total
treatment duration will be up to 12 weeks. Biomarker evidence of improvement is
defined as:

• Monocyte reduction AND
• Serum ferritin reduction >=20% compared to baseline or the most recent value
prior to the next dose level dosing if baseline levels >=3000 ng/mL, OR if
baseline levels <3000 ng/mL, any decrease in ferritin levels accompanied by an
improvement in one or more of: fasting triglyceride levels, coagulation
parameters, or sIL2 receptor levels compared to baseline.

A DMC will oversee the study and review the totality of the safety and efficacy
experience for all participants. Enrollment into Cohort 1 will continue until
approximately 3-6 evaluable participants have been enrolled or the DMC decides
to initiate Cohort 2 enrollment, whichever occurs first. Enrollment may
continue (no pause) unless a safety signal is under evaluation.
All Cohort 2 participants will be enrolled at a fixed dose regimen and route of
administration (IV or SC) as determined by the DMC.
Based on the safety and efficacy experience from Cohort 2, the DMC may also add
up to 2 additional cohorts (Cohorts 3 and 4) to explore new fixed-dose regimens
and/or dose regimens for specific sHLH subtypes.

For Cohorts 2, 3, and 4, if a fixed-dose regimen is selected for further
evaluation, the DMC may expand each cohort to up to approximately 20
participants to further investigate the preliminary efficacy of the dose
regimen. As of protocol amendment 4.0, if the DMC decides to further evaluate
additional participants with the fixed-dose regimen from Cohort 2, enrollment
will only be open to participants >= 6 years of age who are treatment-naïve or
early refractory sHLH.
All participants must complete a safety follow-up visit 4 weeks after the last
dose of study drug. Long-term survival will be evaluated until study completion
(i.e., date when the last data point required for statistical analysis or death
occurs in the last participant evaluable in long-term survival follow-up,
whichever occurs first). Participants (>=12 years of age) deriving ongoing
clinical benefit may be treated on a case-by-case basis beyond the 12-week
treatment period with Sponsor approval.

At any time during the study, if, in the opinion of the investigator, the
participant*s condition is worsening, they may receive rescue treatment with
added or alternative HLH therapy, after discussion with the Medical Monitor
(when possible).

Intervention Name: ELA026

Type: Biologic

Dose Formulation: Solution for IV infusion or SC injection.

Unit Dose Strength(s): Each vial contains 150 mg of ELA026 (50 mg/mL) solution
for IV infusion/SC injection. The dosage of ELA026 will be diluted with 0.9%
normal saline for a total volume of 30 mL for IV infusions. For SC
administration, the dosage of ELA026 will be given as a bolus injection, with
dilution at lower doses only as required. Multiple SC injections may be needed
to deliver the required dosage of ELA026.

Route of Administration and Instructions:
1. Cohort 1 dose escalation phase: IV infusion over 6 hours on Day 1 of each
dose level. IV infusion over 60 minutes for Days 2 and 3 of each dose level if
first dose was well tolerated.
2. Cohort 1 Individual Fixed Dose Phase: IV infusion over 60 minutes or SC
injection.
3. Cohorts 2, 3, and 4: SC injection or IV infusion over 6 hours for the first
dose. IV infusion over 60 minutes for subsequent doses if first dose is well
tolerated.

Dosage Level(s):
Dose Level 1: 0.1 mg/kg
Dose Level 2: 0.3 mg/kg
Dose Level 3: 1 mg/kg
Dose Level 4: 3 mg/kg

Sourcing: ELA026 will be provided to the site centrally by the Sponsor or
designated representative.

Packaging and Labelling: ELA026 will be supplied as a liquid filled into a type
6R vial with a 3 mL fill volume. Label text will at a minimum include the
protocol number, lot number, storage conditions, participant identifier and
contact information.Labels comply with regulatory requirements for ELA026.

A. Non-clinical Interventions:
1. Total number of interventions/procedures to be received by each participant
as part of the research protocol.
i. Main Study Informed Consent: 1
ii. Review of Inclusion/Exclusion Criteria: 1
iii. Demographic data and medical history: 1
iv. Concomitant medications: 39
v. Adverse events: 40
vi. Prior medications: 1

2. If this intervention/procedure would be routinely given to participants as
part of their care outside the research, how many of the total would be routine?
i. Main Study Informed Consent: 0
ii. Review of Inclusion/Exclusion Criteria: 0
iii. Demographic data and medical history: 0
iv. Concomitant medications: 0
v. Adverse events: 0
vi. Prior medcations: 0

3. Average time taken per intervention/procedure (minutes, hours or days)
i. Main Study Informed Consent: 60 mins
ii. Review of Inclusion/Exclusion Criteria: 60 mins
iii. Demographic data and medical history: 30 mins
iv. Concomitant medications: 60 mins
v. Adverse events: 60 mins
vi. Prior medcations: 30 mins

4. Details of who will conduct the intervention/procedure, and where it will
take place.
i. Main Study Informed Consent: The Investigator or his/her representative
will explain the nature of the study to the participant or his/her LAR and
answer all questions regarding the study.
ii. Review of Inclusion/Exclusion Criteria: The study doctor will review
the inclusion and exclusion criteria with the participant to make sure that the
participant still qualify for the study. The participant will be assessed to
determine their eligibility for the study based upon the inclusion and
exclusion criteria at site.
iii. Demographic data and medical history: By the study doctor or their
delegate.
iv. Concomitant medications: Concomitant medications necessary for the
health and well being of the participant and that do not interfere with study
assessments are permitted during the study at the Investigators discretion.
This includes the use of appropriate medications for the treatment of AEs
and/or concurrent illnesses under the direction of the Principal Investigator.
All medications must be recorded in the source and on the appropriate
electronic case report forms (eCRFs).
v. Adverse events: The investigator and any qualified designees are
responsible for detecting, documenting, and recording events that meet the
definition of an AE or SAE and remain responsible for following up AEs that are
serious, considered related to the study intervention or study procedures, or
that caused the participant to discontinue the study intervention. AEs will be
classified according to the NCI CTCAE, version 5.
vi. Prior medcations: Prior medication will be discussed and recorded
during the time of screening.


B. Clinical Interventions:
1. Total number of interventions/procedures to be received by each participant
as part of the research protocol.
i. PK blood sampling: 46
ii. PD blood sampling: 7
iii. Blood sampling for research cytokine analysis: 7
iv. Blood sampling for ADA: 2
v. Cardiac telemetry monitoring: 15
vi. Soluble CD25 analysis: 5
vii. Blood sample exploratory analysis: 5

2. If this intervention/procedure would be routinely given to participants as
part of their care outside the research, how many of the total would be routine?
i. PK blood sampling: 0
ii. PD blood sampling: 0
iii. Blood sampling for research cytokine analysis: 0
iv. Blood sampling for ADA: 0
v. Cardiac telemetry monitoring: 0
vi. Soluble CD25 analysis: 0
vii. Blood sample exploratory analysis: 0

3. Average time taken per intervention/procedure (minutes, hours or days)
i. PK blood sampling: 10 mins
ii. PD blood sampling: 10 mins
iii. Blood sampling for research cytokine analysis: 10 mins
iv. Blood sampling for ADA: 10 mins
v. Cardiac telemetry monitoring: 120 mins
vi. Soluble CD25 analysis: 10 mins
vii. Blood sample exploratory analysis: 10 mins

4. Details of who will conduct the intervention/procedure, and where it will
take place.
i. PK blood sampling: The study doctor or suitably trained delegate at site.
ii. PD blood sampling: The study doctor or suitably trained delegate at
site.
iii. Blood sampling for research cytokine analysis: The study doctor or
suitably trained delegate at site.
iv. Blood sampling for ADA: The study doctor or suitably trained delegate
at site.
v. Cardiac telemetry monitoring: The study doctor or suitably trained
delegate at site.
vi. Soluble CD25 analysis: The study doctor or suitably trained delegate at
site.
vii. Blood sample exploratory analysis: The study doctor or suitably
trained delegate at site.

The potential downsides and risks of participating in the study are that
patients will have a series of routine exams that can be inconvenient or
slightly painful. Examination procedures related to disease treatment are
performed in the hospital by a qualified nurse, doctor, or appropriately
trained health professional.

Strategies will be implemented during the course of the trial to minimize study
participant*s risk* those include close monitoring of patients' health status
through prolonged hospitalization of study participants for the treatment of
sHLH at centers with access to emergency assistance equipment.

All patients will be fully informed of all study tests and what is required of
them to take part in the study. Each patient will be asked to complete the
consent form in order to participate in the study. Patients will be asked to
provide written Informed Consent to screening assessments and also written
informed consent to undergo study specific activities.

Currently ELA026 is also under evaluation in Healthy Volunteers which is
ongoing in Austria so safety data will be collected.

Throughout the study the health of the subject will be regularly monitored and
appropriate medical intervention will be available if required. The only
information on side effects comes from studies in animals.

The study drug could cause lower white blood cell that may lead to infections.
Sometimes participants can have allergic reaction. The potential risks based on
non-clinical studies have been described in the Investigator's brochure
(section 6.9).

Risk associated with the study procedures:
Blood samples: May cause discomfort, pain and minor infection but it can be
easily treated.
Cardiac monitoring: ECG electrodes may cause local allergic reaction.
Abdominal ultrasound: There is no risk.

Measures to minimize the study participant's risk include:
- Lower dose levels, slower infusion and sequential dosing in the first cohort.
- Premedication with steroids, anti-histamines.
- Close monitoring through laboratory parameters, as well as cardiac telemetry,
pulse oximetry and blood pressure measurements prior, during and post drug
administration.
- Available interventional support.

Due to COVID, the Sponsor will continually assess whether the limitations
imposed by the COVID-19 public health emergency on protocol implementation pose
new safety risks to study participants, and whether it is feasible to mitigate
these risks by amending study processes and/or procedures.

Overall Benefit: Risk Conclusion:
Taking into account the measures taken to minimize risk to participants taking
part in this study, the potential risks associated with ELA026 are justified by
the anticipated benefits that may be afforded to participants with sHLH.