Sickle cell disease (SCD) is a serious and life-threatening inherited blood disorder. Sickle cell disease affects millions of people worldwide and is very common in certain areas of Africa. In Kenya alone, approximately 14,000 children are born with sickle cell disease each year and 21 out of 100 children in Kisumu are born with Sickle cell trait. This chronic disease touches numerous regions within Kenya, with Western, Nyanza, and Coastal areas particularly burdened, affecting 17 counties. Moreover, the phenomenon of migration and intermarriage has led to an increasing prevalence of the condition in other regions of the country.

Although there are advances in the medical management of patients with sickle cell disease, patients continue to suffer significantly from the disease which is characterized by severe intense pain also called vaso-occlusive crisis (VOCs) that progresses into acute disease, organ failure and untimely death. Previous studies have shown that pain rate increases from early childhood to young adulthood and patients with SCD who experience multiple documented painful crises and anaemia are at risk for early death. The current study seeks to establish the how successful and how well a drug called crizanlizumab works by assessing the yearly rate of occurrence of painful crises that are attended to by healthcare professionals (HCP) over the planned 52-week treatment period in SCD patients aged 12 years and older with a history of frequent VOCs.

The study will be conducted by Victoria Biomedical Research Institute (VIBRI) at the Kisumu County Referral Hospital and Rachuonyo County Hospital. The study will enroll participants aged 12 years and older with confirmed diagnosis of SCD who have experienced at least 4-12 painful crises (VOCs) that are attended to by HCP (including VOCs leading to management at a health care facility or those managed via remote consultation) within the 12 months prior to the screening visit. A total of 315 participants who qualify for the study after consenting to participate and undergoing screening will be enrolled to receive the study drug and they will be monitored over a one-year period to ensure their safety and determine how successful the drug is. The VIBRI site plans to enrol about 60 SCD patients into the study as participants out of the total number required worldwide.

The results of this study will be used to determine how to use this drug in future among patients with sickle cell disease.

Trial Design:

This is a Phase III multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of crizanlizumab 5 mg/kg versus placebo, with or without concurrent HU/HC therapy in patients with SCD who experience frequent VOCs (4-12 events in the 12 months prior to the screening visit).

Purpose of the study:

The main purpose of this study is to determine whether crizanlizumab may reduce the number of VOCs when compared to placebo, with or without standard of care medications in adolescent and adult SCD patients with frequent VOCs leading to healthcare visits. The study duration will be approximately 2 years.

Study Rationale:

Crizanlizumab was first approved in the USA (BLA 761128) under the trade name Adakveo® on 15-Nov-2019. This BLA approval was based on the results from the Phase II Study CSEG101A2201 (SUSTAIN), a 52-week, randomized, placebo-controlled study (N=198) of crizanlizumab 2.5 and 5 mg/kg. In Study A2201, a vasoocclusive crises (VOC) was defined as an acute episode of pain with no other cause than a vasoocclusion, which required a visit to a medical facility and treatment with oral or parenteral opioids or parenteral non-steroidal anti-inflammatory drugs (NSAIDs). This included both uncomplicated VOCs as well as complicated VOCs such as acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism. These visits required a visit to a medical facility. An uncomplicated crisis was defined as a VOC that was not classified as acute chest syndrome, hepatic sequestration, splenic sequestration, priapism, and which did not lead to death.

Treatment with crizanlizumab 5 mg/kg in Study A2201 resulted in a median annual rate of VOCs leading to a healthcare visit that was 45.3% lower than the median annual rate with placebo, which was statistically significant (p=0.010). The

median annual rate of uncomplicated crises and median number of days hospitalized were 62.9% and 41.8% lower than in the placebo group, respectively. These constitute meaningful reductions in the frequency of VOCs and hospitalizations that can be expected to have a significant impact on quality of life (QoL), morbidity and mortality in patients with SCD.

Study CSEG101A2301 is an ongoing Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in adolescent and adult patients with SCD. VOC was defined the same way as previously noted in the SUSTAIN trial.

In Dec-2022, the results of the primary analysis of Study CSEG101A2301 did not show evidence of superiority of either dose of crizanlizumab (5 mg/kg or 7.5 mg/kg) over placebo on the primary or key secondary endpoints, and therefore are not consistent with the results from Study CSEG101A2201.

While the endpoint of VOC leading to a healthcare visit reflects a key aim of treatment in SCD, i.e., prevention/reduction of VOCs, it is important to note that it is dependent on patients making the decision to go or not go to the hospital. The different results in Study CSEG101A2301 compared with Study CSEG101A2201 could be due to various factors/differences between the studies, including but not limited to:

• The impact of the COVID-19 global pandemic, which may have caused a masking effect/reduction in reporting of VOCs as well as a potential reduction in triggers for VOCs in Study CSEG101A2301.

• Differences in the geographic location of participating patients, thereby factoring in the differences in healthcare utilization: patients were located primarily in the USA in Study CSEG101A2201 vs. globally dispersed in Study CSEG101A2301.

Thus, while the initial randomized, placebo-controlled trial (Study CSEG101A2201), the open label studies (Study SEG101A2202, Study SEG101B2201 and Study SEG101AUS05) and real-world data (MAP data and registries) have all demonstrated clinical benefit with crizanlizumab, the second, randomized, placebo-controlled Study CSEG101A2301 did not.

The current study (Study CSEG101A2303; hereafter referred to as Study A2303), a randomized, placebo-controlled Phase III study, was developed to overcome the uncertainties raised by the conflicting results of Studies CSEG101A2301 and CSEG101A2201. The purpose of this study is to compare the efficacy of crizanlizumab (5 mg/kg) versus placebo, with or without HU/HC in adolescent and adult SCD patients with frequent VOCs (4 to 12 per year) that are Health care practitioner-managed (including VOCs leading to management at a health care facility or those managed via remote consultation).

Data from this study will be used to evaluate the effect of crizanlizumab versus placebo, with or without concurrent HU/HC therapy, on VOC rate in SCD patients aged 12 years and older who experience frequent VOCs.

Study Population:

The study will include participants aged 12 years and older with confirmed diagnosis of SCD (all genotypes are eligible) who have experienced at least 4-12 VOCs that are HCP-managed (including VOCs leading to management at a health care facility or those managed via remote consultation) within the 12 months prior to the screening visit. Participants may receive HU/HC as a standard of care.

This study plans to enroll 315 participants. Participants will be randomized in a 2:1 ratio to the crizanlizumab 5 mg/kg or placebo treatment arm (see Section 9.9 of the Protocol v00 for more details on sample size determination).