A RANDOMIZED DOUBLE-BLIND PHASE IIA STUDY EVALUATING THE EFFICACY, SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF CROVALIMAB AS ADJUNCT TREATMENT IN PREVENTION OF VASO-OCCLUSIVE EPISODES (VOE) IN SICKLE CELL DISEASE (SCD)

The available data from patients with SCD, and in vitro and in vivo nonclinical
models indicate that complement is activated in patients with SCD and suggest a
role in its pathophysiology in multiple domains. Complement activation is
detected in patients at steady state in SCD and has also been described in
association with acute VOE. In vitro and in vivo models of complement
inhibition suggest multiple potential downstream effects of C5 inhibition in
patients with SCD that include prevention of endothelial activation by free
heme, reduction in rate of hemolysis, reduction in vaso-occlusion, improvement
in chronic inflammation, and reduction in end-organ damage.

Published evidence supports exploratory trials of complement inhibition in
patients with SCD, which may address the unmet medical need in this disease,
employing a mechanism that does not overlap with current therapies. Crovalimab
induces rapid and complete inhibition of the terminal complement pathway by
targeting C5, making it a suitable candidate for exploration of the role of
targeting complement in treatment for
SCD.

Please also refer to chapter 1.1, 1.2 and 1.3.1 of the protocol.

This study has been transitioned to CTIS with ID 2022-502542-28-00 check the CTIS register for the current data.

This study will evaluate the efficacy, safety, pharmacokinetics, and
pharmacodynamics of crovalimab compared with placebo as adjunct treatment for
the prevention of vaso-occlusive episodes (VOEs) in patients with sickle cell
disease (SCD).

The study will enroll approximately 90 patients at approximately 30 sites
globally. The screening period of the study will be up to 28 days in length.
Patients who do not meet the criteria for participation in this study (screen
failure) may qualify for two rescreening opportunities (for a total of three
screenings per patient) at the investigator*s discretion.

This study has three parts:
1. Screening to assess the eligibility for the study (up to 28 days)
2. Treatment (48 weeks)
3. Follow-up to check on patients after treatment is finished

Eligible patients will be randomized 1:1 to receive either crovalimab or
placebo in addition to their current SCD therapy. Patients in both treatment
arms will receive standard treatment for SCD as guided by the treating
physician and/or institutional guidelines, including but not limited to
treatments currently approved for SCD within each country participating in this
study.

After completing 48 weeks of study treatment, or, if patients stopped study
treatment at any time, they will return to the clinic for a safety follow-up
visit 24 weeks after the final dose of the study treatment. Also, a safety
follow-up telephone call will be conducted at 46 weeks after the last dose of
study treatment.

The investigational medicinal products (IMPs) for this study are crovalimab and
placebo.

The first dose of the study drug will be given as an IV infusion (into the
vein) and will last approximately 1 hour (at W1D1). All other doses after this
will be given as an injection under the skin. For subcutaneous injection, the
crovalimab solution is used undiluted. For IV infusion, the crovalimab
solution (2 mL or 340 mg (nominal) crovalimab) is diluted in 0.9% (w/v).
Patients in placebo group will receive the same volume as weight-based
crovalimab by IV infusion and injection under the skin.

Patients in this study will receive crovalimab according to a weight-based
tiered dosing approach schedule for 48 weeks:

The first dose of the study drug (crovalimab or placebo) according to a
weight-based dosing approach:
-1000 mg IV( 60 ± 10 minutes) for patients whose weight is >= 40 kg to < 100 kg
and,
-1500 mg IV (90 ± 10 minutes) for patients whose weight is >= 100 kg

Afterwards, they will get one injection (2 mL) under the skin on W1D2, W2,W3
and W4. At Week 5 and every 4 weeks onwards the dose will be:
- Two injections of 2 mL each (4 mL total) under the skin for patients whose
weight is >= 40kg to <100kg and,
- Three injections of 2 mL each (6 mL total) under the skin for patients >=
100kg.

Published evidence supports exploratory trials of complement inhibition in
patients with SCD, which may address the unmet medical need in this disease,
employing a mechanism that does not overlap with current therapies. Crovalimab
induces rapid and complete inhibition of the terminal complement pathway by
targeting C5, making it a suitable candidate for exploration of the role of
targeting complement in treatment for SCD.

Nonclinical findings and published evidence for safety of C5 inhibition in
asplenic patients (described above) support the use of crovalimab in patients
with SCD, with a preliminary safety profile of crovalimab assessed in the Phase
I/II clinical study in PNH. The safety risk is considered to be manageable with
patient selection, prevention by immunization and use of prophylactic
antibiotics where indicated, long-term safety monitoring, strict guidance for
early evaluation and intervention, and ongoing patient education measures. In
addition, early mandatory reporting of sentinel events and ongoing safety
assessments will provide an ongoing assessment of the risk and allow for
optimization of the risk minimization approach where, or, if needed.
Hence, the benefit-risk profile to participants in this study is considered
acceptable.

Please refer to Section 1.3.1 and 1.3.2. protocol: Study rational and
benefit-risk assessment of the protocol for further details.