1.1. Sickle Cell Disease Sickle cell disease (SCD) is an autosomal recessive disease characterized by chronic hemolysis and inflammation, vaso-occlusion presenting as recurrent pain episodes (variously termed sickle cell-related pain crises or vaso-occlusive crises [VOCs]), multiorgan dysfunction, and early death (Kato, 2018). Vaso-occlusion in SCD is driven by a series of complex and often redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged endothelium and exposed sub-endothelium. Extensive research demonstrates that P-selectin mediated cellular interactions with sickled red blood cells (sRBCs), leukocytes, and platelets (PLTs) play a crucial role in the pathophysiology of vaso-occlusion in SCD. By contrast, blocking P-selectin-mediated cellular interactions or reducing the levels of P-selectin reduces or eliminates vaso-occlusion in animal models. Taken together, these data led to the hypothesis that blocking P-selectin could reduce the risk of VOCs in SCD patients. Results from a randomized, placebo-controlled Phase 2b trial of crizanlizumab, a humanized monoclonal antibody, in SCD bolstered the hypothesis that blocking the interaction of P-selectin with its receptors could prevent vaso-occlusion and VOCs (Ataga, 2017). 1.2. Current Therapy for Sickle Cell Anemia Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for SCD. HSCT in children with SCD is associated with overall and event-free survival rates of 95% and 92%, respectively. However, HSCT use is limited by the paucity of suitable donors, the risk of graft-versus-host-disease, infections, infertility, and other long-term transplant-related complications. Moreover, HSCT is generally available only in high-income countries and not commonly used in older patients with significant morbidity (Kassim, 2017). Three therapies, hydroxyurea (HU [DROXIA®, 2017]; also known as hydroxycarbamide), L-glutamine (ENDARI, 2017) and crizanlizumab (ADAKVEO®, 2019), have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to reduce VOCs in patients with SCD (Niihara, 2018; Ataga, 2017; Charache, 1995). However, the effectiveness of HU is impaired by low compliance rates and frequent treatment discontinuation (Shah, 2019). Moreover, while L-glutamine is also approved to reduce the frequency of VOCs in patients with SCD but provides a modest 25% reduction in annual VOC rates (Niihara, 2018). Crizanlizumab, a monoclonal antibody directed against human P-selectin, can be used alone and in combination with HU to reduce the frequency of VOCs in patients with SCD. However, patients are required to travel to an infusion center for drug administration once every 4 weeks, a potentially limiting factor in continued adherence to a life-long therapy. Treatment adherence is essential for quality care and non-adherence leads to poor health outcomes and increased healthcare costs, especially among patients with chronic conditions (Roebuck, 2011; Simpson, 2006; Osterberg, 2005). Furthermore, medications with less frequent dosing result in Global Blood Therapeutics, Inc. Protocol Amendment 3 GBT2104-131 CONFIDENTIAL 20 better adherence (Saini, 2009; Richter, 2003). Patient preference for less frequent dosing has been established across many chronic conditions including inflammatory diseases such as rheumatoid arthritis and hematological diseases such as hemophilia and paroxysmal nocturnal hemoglobinuria (PNH) (Kaiser, 2020; Wells, 2019; Tkacz, 2015). Frequent intravenous (IV) infusions also extract a cost on patient and caregiver productivity because of the substantial time commitments and work absence required from both for such infusions. One recent study demonstrated that PNH patients receiving eculizumab every 2 weeks had three times higher productivity losses compared to PNH patients treated every 8 weeks with ravulizumab solely due to more frequent dosing (Levy, 2019). Moreover, patients report that therapies with less frequent dosing regimens enable them to feel independent, better plan future activities, and lead more active lives, all important considerations in developing treatments for SCD, which is a debilitating disease characterized by idiosyncratic and unpredictable exacerbations (Kaiser, 2020; Wells, 2019). In summary, despite the recent availability of new options to treat VOCs, an unmet medical need exists to further reduce the frequency of VOCs while reducing patient burden and enhancing patient adherence to therapy. 1.3. Rationale for Inclacumab in SCD Inclacumab is a recombinant, fully human, monoclonal antibody based on a human immunoglobulin 4 (IgG4)-type framework containing heavy chain VH gamma 4 and light chain VL kappa subgroup sequences. Inclacumab is directed against the human P-selectin (CD62P). The monoclonal antibody consists of two heavy chains (451 amino acid residues each) and two light chains (214 amino acid residues each) with inter- and intra-chain disulfide bonds that are typical of IgG4 antibodies. Two single-point mutations were introduced into the hinge (S228P) and Fc (L235E) region of inclacumab to prevent Fab arm exchange, an inherent feature of IgG4 antibodies, and to mitigate antibody-dependent cellular cytotoxicity (ADCC), respectively. Inclacumab binds to P-selectin, which is a cell adhesion molecule produced by endothelial cells and PLTs. Upon activation of these cells (eg, by thrombin, cytokines, complement components, hypoxia, and heme), P-selectin is translocated to the cell surface where it binds to its primary ligand P-selectin glycoprotein ligand-1 (PSGL-1) in leukocytes and mediates leukocytes recruitment by PLTs or endothelial cells. The same mechanism is also responsible for abnormal adhesion of sRBC to the endothelium, initiating acute vascular occlusion and chronically impairing microvascular blood flow in patients with SCD. Inclacumab binding of P-selectin and prevention of P-selectin binding to its ligands is the putative mechanism by which inclacumab effectively blocks interactions between endothelial cells, PLTs, sRBCs and leukocytes, thereby preventing VOCs. P-selectin inhibition has demonstrated safety and efficacy in the SCD population with the recently approved monoclonal antibody therapeutic crizanlizumab. Nonclinical studies have been conducted to characterize inclacumab include primary and secondary pharmacodynamics (PD), safety pharmacology, pharmacokinetics (PK), and toxicology. The nonclinical studies are described in detail in the inclacumab Investigator’s Brochure (IB). Global Blood Therapeutics, Inc. Protocol Amendment 3 GBT2104-131 CONFIDENTIAL 21 1.3.1. Study Design Rationale This study is a randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of inclacumab compared to placebo when administered once every 12 weeks (Q12W) (Day 1, Week 12, Week 24, and Week 36) to patients with a diagnosis of SCD who have experienced between 2 and 10 VOCs in the 12 months preceding enrollment in this study. Given the long half-life of inclacumab (terminal half-life of 21 to 28 days) at the dose to be evaluated in this study, the majority of participants receiving active study drug are expected to maintain target concentrations through Week 48. The primary endpoint of the study is the rate of VOCs occurring over a 48-week treatment period. The safety of treatment with inclacumab over the 48-week period will also be assessed. This study builds on experience from previous clinical studies in patients with SCD in reducing the incidence of VOCs. A placebo-controlled trial represents the most common and acceptable approach for determining the safety and efficacy for a therapeutic through a well-designed, controlled study. Some notable distinctions from prior studies include the definition of a VOC that allows for telemedicine in addition to the previous definitions which required a visit to a healthcare facility. This distinction has been incorporated based on the changes in treatment practices that have occurred as a result of the coronavirus disease 2019 (COVID-19) pandemic. Patients with SCD are less likely to visit a healthcare facility and are more frequently reaching out to their healthcare provider for pain medication changes/prescriptions (McFarling, 2020; Powell, 2020). Even though patients are not making as many visits to a healthcare facility for a VOC, the telemedicine visit nonetheless represents a crisis on the part of the patient that requires intervention by a healthcare practitioner. Use of a telemedicine-based VOC is therefore justified. 1.3.2. Rationale for Dose Regimen In this study, an IV dose of 30 mg/kg will be administered Q12W for a total of 4 doses over a 48-week period to reduce the frequency of VOCs in patients with SCD. More than 700 participants in prior studies (healthy or cardiovascular disease patients) have been exposed to inclacumab; a maximum tolerated dose was not identified. The maximum single dose tested, 40 mg/kg, has not demonstrated any drug-related safety or tolerability signals in a Phase 1 study in healthy participants. Chronic IV dosing of inclacumab (20 mg/kg every 4 weeks for 32 weeks) in a cohort of 142 patients with severe cardiovascular disease was shown to be safe and well tolerated with the majority of adverse events (AEs) considered unrelated to study drug. In a recent Phase 1 study in healthy participants, the safety and tolerability of a single IV dose of up to 40 mg/kg of inclacumab was consistent with the safety profile of previous studies with inclacumab at doses up to 20 mg/kg IV performed in healthy participants and in individuals with cardiovascular disease (refer to the current version of the IB for details). Inclacumab plasma concentrations above 10 µg/mL have been associated with maximal inhibition of ex vivo thrombin receptor activating peptide (TRAP)-induced platelet leukocyte aggregate (PLA) formation in healthy volunteers and patients with peripheral arterial disease (PAD) from prior clinical studies. Chronic dosing to maintain inclacumab plasma concentrations above 10 µg/mL is expected to be required for maximal sustained benefit. Population PK simulations project that the inclacumab dose regimen of 30 mg/kg Q12W will maintain Global Blood Therapeutics, Inc. Protocol Amendment 3 GBT2104-131 CONFIDENTIAL 22 concentrations above 10 µg/mL throughout the 48-week study period in the majority of participants, thereby maximizing the pharmacology required for effective reduction of VOC in the SCD population. 1.3.3. Use of a Placebo Control This study uses placebo as a comparator on the background of standard of care (SOC) treatment for a VOC. Placebo was chosen as the control because it is necessary to determine the safety and efficacy of inclacumab by allowing efficacy to be estimated controlling for background VOCs with SOC and safety signals to be distinguished from AEs occurring due to SCD. Treatments with stable SOC are allowed including stable doses of HU, erythropoiesisstimulating agents (ESAs), voxelotor, and L-glutamine. However, initiation of these agents during screening or after randomization and use of crizanlizumab for 90 days prior and during the study is prohibited. Crizanlizumab has a similar mechanism of action that would confound interpretation of this study. All other standard therapeutic interventions for SCD (eg, hydration, analgesia, acute transfusions) are allowed under this protocol. Randomization to placebo treatment in this study does not place study participants at increased risk, as the SOC (other than the use of crizanlizumab) for patients with VOCs will be provided during the study. Global Blood Therapeutics, Inc. Protocol Amendment 3 GBT2104-131 CONFIDENTIAL 23 2. OBJECTIVES The primary objective of this study is to evaluate the safety and efficacy of treatment every 12-week with inclacumab to reduce the incidence of VOCs in participants with SCD. Additional objectives of the study are to evaluate the PK and PD of inclacumab, the presence of anti-drug antibodies (ADAs), and changes in quality of life (QOL). Global Blood Therapeutics, Inc. Protocol Amendment 3 GBT2104-131 CONFIDENTIAL 24 3. INVESTIGATIONAL PLAN This is a Phase 3, randomized, double-blind, placebo-controlled, 2-arm, multi-center, parallel-group study. 3.1. Study Design This study will assess the safety and efficacy of inclacumab in reducing the frequency of VOCs in approximately 240 adult and adolescent participants (≥ 12 years of age) with SCD. Initial enrollment will include participants ≥ 16 years of age until the independent Data Monitoring Committee (DMC) recommends to the Sponsor that adequate safety and PK data support the enrollment of participants 12 to 15 years of age. Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as follows:  Inclacumab 30 mg/kg administered IV Q12W; or  Placebo administered IV Q12W. At the time of randomization, participants will be stratified by Baseline HU use (yes; no), number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North America; sub-Saharan Africa; Europe/rest of world). All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be recorded weekly by the participant and collected every 4 weeks, with participants contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 40, and 44. Following completion of the Week 48 Visit, eligible participants will be given the option to enroll in an open-label extension (OLE) study (under a separate protocol) to receive inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 Visit. Participants enrolling in the OLE study will not be required to return to clinic for the Week 60 Visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for participants not enrolling on the OLE study. The DMC will regularly review the totality of accumulated safety data from all ongoing inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent participants. Details are provided in the DMC Charter.