A Phase III, Multicenter, Randomized, Placebo Controlled, Double-blind Study to Assess Efficacy and Safety of Crizanlizumab (5 mg/kg) Versus Placebo, With or Without Hydroxyurea/Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Frequent Vaso-Occlusive Crises

A phase III, multi-center, randomized, placebo-controlled, double-blind study to assess efficacy and safety of crizanlizumab (5 mg/kg) versus placebo, with or without hydroxyurea/hydroxycarbamide therapy, in adolescent and adult Sickle Cell Disease patients with frequent vaso-occlusive crises.

Start Date01 Oct 2024

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT05469828 / Not yet recruitingPhase 1/2IIT

Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia

Hypothesis
Efficient unloading of oxygen to regions of high metabolic demand requires a healthy microvasculature to sense local oxygen tension and regulate flow, accordingly. In sickle cell disease patients, the investigators have demonstrated oxygen supply-demand mismatch, or SDM, in proportion to anemia severity. SDM occurs in both the peripheral circulation and the brain, and four characteristics: 1) Hyperemia beyond expected for the level of anemia, 2) Corresponding loss of vascular dilatory reserve, 3) Impaired oxygen unloading to the tissues, and 4) Tissue hypoxia. In sickle cell disease, red blood cell (RBC) and white blood cell (WBC) adhere to vascular endothelium triggering transient or irreversible microvascular damage as well as releasing vasoactive substances that contribute to microvascular dysregulation. The investigators postulate that ongoing microvascular damage/dysregulation in the setting of increased total blood flow contributes to SDM. The investigators believe SEG101, by lowering RBC and WBC adhesion to the microvasculature, will improve SDM and tissue oxygenation.
Objectives
Primary - The investigators will test whether SEG101 improves SDM in patients with sickle cell anemia by measuring the change in tissue oxygenation measured by near infrared spectroscopy (NIRS).
Secondary/Exploratory - The investigators will identify end-organ disease and whether improvement of SDM by SEG101 occurs in patients with sickle cell anemia.

Start Date01 Jul 2024

Sponsor / Collaborator

Children's Hospital Los Angeles

[+1]

NCT05020873 / TerminatedNot Applicable

Prospective, Observational Study in Sickle Cell Disease Patients on Crizanlizumab Treatment in Middle East Countries and India (SPOTLIGHT)

This is a multicenter, prospective, single-arm observational non-interventional study (NIS), which will be conducted in various countries in the Middle East and India.

Start Date04 Nov 2021

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Crizanlizumab-TMCA

100 Translational Medicine associated with Crizanlizumab-TMCA

100 Patents (Medical) associated with Crizanlizumab-TMCA

100

Literatures (Medical) associated with Crizanlizumab-TMCA

01 Oct 2024·JOURNAL OF PHARMACY TECHNOLOGY

Gene Therapies for Sickle Cell Disease

Review

Author: Singh, Divita ; Weaver, Salome Bwayo ; Wilson, Kierra M.

Background: Sickle cell disease (SCD) is a prevalent autosomal recessive hemoglobinopathy affecting millions worldwide, particularly individuals of African ancestry. Sickle cell disease is a lifelong condition associated with a negative impact on quality of life and mortality, causing complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, long-term anemia, and end-organ damage. Currently, there are 4 U.S. Food and Drug Administration (FDA)-approved drugs, including hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, which work to alleviate symptoms and prevent complications associated with SCD, albeit without addressing the underlying cause of SCD. Allogeneic hematopoietic stem cell transplant (HSCT) has shown promise as a curative approach to SCD but is limited by donor availability and associated complications. This paper aims to review the efficacy and safety of exagamglogene autotemcel and lovotibeglogene autotemcel for managing patients with SCD, including their place in therapy, cost, and accessibility in clinical care. Data Sources: The authors searched PubMed and Medline from 2017 to 2024, for primary literature on both exagamglogene autotemcel and lovotibeglogene autotemcel. Results: The authors identified relevant studies and summarized the data on the two gene therapies. Conclusion: Exagamglogene autotemcel and lovotibeglogene autotemcel are two management strategies that address the underlying cause of SCD and provide curative potential for patients with SCD.

01 Aug 2024·CLINICAL DRUG INVESTIGATION

Budget Impact of Disease-Modifying Treatments and a CRISPR Gene-Edited Therapy for Sickle Cell Disease

Article

Author: Huys, Isabelle ; Simoens, Steven ; Claes, Kathleen J ; Abdallah, Khadidja

BACKGROUND AND OBJECTIVE:

Treatment of sickle cell disease (SCD) has traditionally focused on symptomatic and preventative care. Recent advances in novel therapeutic developments, likely to be orphan-designated, are anticipated to carry a substantial price tag. This study assesses the potential budget impact of adopting disease-modifying treatments, crizanlizumab and voxelotor, and pioneering CRISPR gene-edited therapy, CTX001, in the Belgian healthcare system.

METHODS:

The perspective of the Belgian healthcare payer (RIZIV-INAMI including patient copayments), a 5-year horizon with a 2-10% uptake of disease-modifying interventions, and a 2% uptake of CTX001 were considered. Data, encompassing target population, current (chronic and acute management, curative hematopoietic stem cell transplantation) and new (crizanlizumab, voxelotor, and CTX001) interventions, clinical effectiveness, adverse events, healthcare resource utilization, and associated costs, were gathered through a comprehensive literature review (first phase) and two Delphi panels involving hematologists (second phase). The cost difference between a "world with and without crizanlizumab, voxelotor, and CTX001" was calculated to obtain the budget impact. Three scenario analyses were conducted: a 5-13% and 4% uptake analysis, a 10-18% and 8% uptake analysis, respectively for disease-modifying treatments (crizanlizumab and voxelotor) and CTX001, and a 0% crizanlizumab uptake and managed entry agreements analysis . A ± 20% univariate sensitivity analysis was performed to test the robustness of the analysis.

RESULTS:

The total five-year cumulative budget impact was estimated at €30,024,968, with 91% attributed to drug acquisition costs. The largest budget impact share was for CTX001 (€25,575,150), while crizanlizumab (€2,301,095) and voxelotor (€2,148,723) was relatively small. In scenarios one and three, a two-fold increase of the cumulative budget impact to €60,731,772 and a four-fold increase to €120,846,256 from the base case was observed. In scenario three, this budget impact decreased by 63% to €11,212,766. Patient population size, number of treated patients, and drug costs influenced the analysis the most, while discontinuation, acute crisis, and adverse event rates had comparatively minimal impact.

CONCLUSIONS:

Belgian decision-makers may consider alternative financing models, such as outcome-based risk-sharing agreements or annuities, to ensure sustainable coverage of these treatments. This study adheres to recommended practices for assessing budget impact of orphan drugs, distinguishing it from earlier studies with potentially weaker methodologies.

03 Jul 2024·Hemoglobin

Sickle Cell Disease in Brazil: Current Management

Review

Author: da Silva Araújo, Aderson ; de Castro Lobo, Clarisse Lopes ; Olalla Saad, Sara Teresinha ; Menosi Gualandro, Sandra Fátima ; Cançado, Rodolfo Delfini ; Silva Pinto, Ana Cristina ; Figueiredo, Maria Stella

Sickle cell disease (SCD) comprises inherited red blood cell disorders due to a mutation in the β-globin gene (c20A > T, pGlu6Val) and is characterized by the presence of abnormal hemoglobin, hemoglobin S, hemolysis, and vaso-occlusion. This mutation, either in a homozygous configuration or in compound states with other β-globin mutations, leads to polymerization of hemoglobin S in deoxygenated conditions, causing modifications in red blood cell shape, particularly sickling. Vaso-occlusive crisis (VOC) is the hallmark of the disease, but other severe complications may arise from repeated bouts of VOCs. SCD is considered a global health problem, and its incidence has increased in some areas of the world, particularly the Americas and Africa. Management of the disease varies according to the region of the world, mainly due to local resources and socioeconomic status. This review aimed to describe more recent data on SCD regarding available treatment options, especially in Brazil. New treatment options are expected to be available to all patients, particularly crizanlizumab, which is already approved in the country.

News (Medical) associated with Crizanlizumab-TMCA

21 Oct 2024

·www.biospace.com

5 Sickle Cell Therapies to Watch Following Pfizer’s Oxbryta Exit

iStock/ YuLi4ka In the wake of Pfizer’s voluntary market withdrawal of the popular sickle cell disease therapy, BioSpace looks at five investigational drugs currently making their way through the pipeline. A recent fumble has left the sickle cell disease community reeling . Last month, Pfizer abruptly pulled Oxbryta from all global markets after new data showed a higher risk of deaths and complications in treated patients. “[Oxbryta] was one of four medications which we would describe as disease-modifying,” Clifford Takemoto, director of clinical hematology at St. Jude Children’s Research Hospital, told BioSpace . Since the approval of Bristol Myers Squibb’s hydroxyurea for sickle cell disease (SCD) in 1998, only three disease-modifying medications have entered the market, he said. Oxbryta, which won FDA accelerated approval in November 2019, was one of these. Another, Novartis’ Adakveo, has also been called into question after failing to reduce vaso-occlusive crises (VOC) in people with SCD in a Phase III trial last year. EU regulators formally revoked Adakveo’s approval in August 2023, but it remains available in the U.S. “We were optimistic that things were changing,” Takemoto said. “People had hoped that these medications would make a difference.” SCD affects more than 100,000 people in the U.S. and 8 million worldwide. With so few treatment options, it remains a seriously underserved population . Takemoto said the Oxbryta withdrawal has left some patients a “bit angry” and distrustful of new medications, and the question for the community remains: “What’s next?” For Takemoto, the ultimate hope for SCD treatment lies in next-gen transplantation and gene therapy. With the approval of bluebird bio’s Lyfgenia and Vertex and CRISPR Therapeutics’ Casgevy, the potential for gene therapies in SCD is there, even if the rollout is slow and for most, not very accessible, he said. St. Jude is developing its own gene therapy, which the research hospital hopes to move into clinical trials sometime next year. Takemoto also pointed to work being done in bone marrow transplantation intended to reduce toxicity and improve success rates. St. Jude is working on a process that will utilize a “half match,” where a parent’s bone marrow can be used instead of a sibling. These treatments could be transformative, Takemoto said. Here, BioSpace looks at five investigational therapies making their way through the SCD pipeline. Pfizer’s Inclacumab and Osivelotor Oxbryta is not the only SCD asset Pfizer brought onboard with its 2022 acquisition of Global Blood Therapeutics . Two other investigational therapies, inclacumab and osivelotor, were also part of the deal. Inclacumab, a P-selectin inhibitor, is currently being assessed in a Phase III trial to determine its safety and efficacy in reducing VOC. The drug works by binding to P-selectin, a cell adhesion molecule found on platelets. According to Pfizer, this prevents platelets from aggregating, which in turn, is expected to help maintain normal blood flow. Like Oxbryta, osivelotor is a sickle hemoglobin polymerization inhibitor, but with a next-generation design. The asset is currently being studied in a Phase II/III study slated for completion in 2028. While Pfizer has not stated whether the recent findings related to Oxbryta will impact the development of osivelotor, Leerink Partners noted that a Phase II study raised safety concerns, with treatment-emergent adverse events seen in 8 out of 35 patients. Agios Pharmaceuticals’ Mitapivat Agios Pharmaceuticals is developing mitapivat, a pyruvate kinase (PK) activator that is already approved for the treatment of hemolytic anemia in adults with PK deficiency, for SCD. Red blood cells require the PK enzyme for energy, Takemoto explained. In December 2023, the company presented positive data from the Phase II portion of its pivotal RISE UP study. The annualized rate of sickle cell pain crises for patients in the higher dose treatment arm was 0.51 compared to 1.71 for participants in the placebo arm. Takemoto said the oral medication seems to benefit red blood cell health in general and noted that the data look favorable for patients with SCD and other hemolytic anemias. But not everyone is as convinced. Leerink Partners analysts wrote last month of concerns that similar physiological effects could be seen with both Oxbryta and mitapivat. A Phase III readout is expected next year, and the company is targeting a label expansion in 2026. Novo Nordisk’s Etavopivat In 2022, Novo Nordisk paid $1.1 billion to acquire Forma Therapeutics, gaining a lead SCD asset, etavopivat, in the deal. Like mitapivat, etavopivat is also a PK activator, but Novo’s candidate comes with a potential advantage —once daily dosing, versus mitapivat’s twice daily regimen. Etavopivat is currently being studied in a Phase III trial slated for completion in 2026. Phase I data presented by Forma at the American Society of Hematology’s annual meeting in 2021 showed a “sustained increase in hemoglobin and improvement in biomarkers of hemolysis and red blood cell health.” The results, from 15 patients dosed for up to 12 weeks, also showed a trend toward decreasing VOC compared to the 12 months prior to their entering the trial. Takemoto said the candidate “looks very promising” so far but acknowledged that “there are things we don’t know about it. We may learn new side effects as it’s used.” St. Jude will serve as a site for the Phase III trial. Fulcrum Therapeutics’ Pociredir Fulcrum Therapeutics ’ pociredir, a polycomb repressive complex 2 (PRC2) inhibitor, is designed to induce expression of fetal hemoglobin to compensate for the mutated hemoglobin that occurs in SCD. The development path for pociredir has not been without bumps. In February 2023, the FDA slapped Fulcrum with a clinical hold based on previously submitted preclinical data and non-clinical and clinical evidence of hematological malignancies observed with other PRC2 inhibitors. The hold was released six months later. The small molecule, which is currently being studied in a Phase Ib trial, has been well-tolerated in people with SCD with no treatment-related adverse events reported after up to three months exposure, according to a press release announcing the lifted clinical hold.

Clinical ResultPhase 3Phase 2Drug ApprovalPhase 1

26 Sep 2024

·www.outsourcing-pharma.com

Pfizer withdraws sickle cell disease drug Oxbryta amid safety concerns

The withdrawal decision was prompted by clinical data indicating that the overall benefit of Oxbryta “no longer outweighs the risk” in its target patient population, the company said in a public release . Specifically, the trials outline an “imbalance” in vaso-occlusive crises and fatal events that the company will assess further. The move to stop clinical trials of the drug will last while Pfizer further reviews the available data and investigates the findings. Sickle cell disease is a genetic blood disorder where patients have a mutation in hemoglobin, a protein found in red blood cells. This leads the protein to clump together, causing cells to have a sickle shape that can block blood vessels and carry less oxygen, leading to acute pain and anemia. Oxbryta, whose generic name is voxelotor, is an oral small molecule drug that was first approved by the US Food and Drug Administration (FDA) for the treatment of sickle cell disease in 2019, with an EU approval granted in 2022. The drug is designed to make hemoglobin better at carrying oxygen and less prone to clumping together, making red blood cells more functional. The treatment was previously developed by the U.S. firm Global Blood Therapeutics before the company was snapped up by Pfizer for $5.4 billion in 2022 , and bagged Pfizer $328 million in revenues in 2023 . The big pharma company has notified regulators about the data and doesn’t expect the event to impact its full-year 2024 financial guidance. Nevertheless, the company’s stock price on the New York Stock Exchange slumped by more than 1% at the news yesterday (Wednesday 25th September). googletag.cmd.push(function () { googletag.display('text-ad1'); }); Emphasizing Pfizer’s focus on patient safety, chief medical officer and head of worldwide medical and safety, Aida Habtezion, said in the company release that the Pfizer’s “primary concern is for patients who suffer from SCD, which remains a very serious and difficult-to-treat disease with limited treatment options. We advise patients to contact their physicians to discuss alternative treatment while we continue to investigate the findings from our review of the data.” The global market for sickle cell disease was worth $2.25 billion in 2022 and is expected to grow by 20.1% per year to $9.84 billion by 2030. The main players in the market have included Pfizer with Oxbryta, Novartis with the antibody Adakveo (crizanlizumab) and Generex Biotechnology’s Emmaus Medical with Endari (L-glutamine). In 2017, Endari became the first branded drug for sickle cell disease in decades when it was greenlit by the U.S. FDA. Another driver for the sickle cell disease market is gene therapy, with the first cell-based gene therapies – Casgevy by Vertex Pharmaceuticals and Lyfgenia by Bluebird Bio – approved by the U.S. FDA in late 2023 .

Drug ApprovalGene Therapy

14 Jun 2024

·www.biospace.com

Vertex Presents Positive Long-Term Data On CASGEVY™ (exagamglogene autotemcel) at the 2024 Annual European Hematology Association (EHA) Congress

Results from CLIMB-111, -121 and -131 accepted for oral presentation Data from these trials, with the longest follow-up of more than five years, demonstrate transformative, consistent and durable benefit of CASGEVY™ Safety pro with busulfan conditioning and autologous hematopoietic stem cell transplant BOSTON--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced longer-term data for CASGEVY™ (exagamglogene autotemcel [exa-cel]) from global clinical trials in people with severe sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT). The results, presented at the annual European Hematology Association (EHA) Congress, confirm the transformative, consistent and durable clinical benefits of CASGEVY over time. CASGEVY is the first and only approved CRISPR-based gene-editing therapy. The data being presented are from more than 100 patients (46 SCD; 56 TDT) treated with exa-cel in clinical trials, with the longest follow-up now extending more than 5 years. The efficacy results are consistent with the previously reported primary and key secondary endpoints analyses from these exa-cel studies and continue to demonstrate transformative clinical benefit with durable and stable levels of fetal hemoglobin (HbF) and allelic editing. “The transformative benefit seen in patients with sickle cell disease in the trial is impressive given the significant and cumulative burden of disease faced by people living with this blood disorder,” said Haydar Frangoul, M.D., M.S., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute and HCA Healthcare’s TriStar Centennial Children’s Hospital. “I am eager to offer this therapy and the opportunity of a potential functional cure to my eligible patients.” “The comprehensive data set presented today for adult and adolescent TDT patients adds to the growing body of evidence for CASGEVY, and it is important to now ensure the availability of this innovative treatment to patients in the real world as soon as possible,” said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Catholic University of the Sacred Heart of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. “With the longest follow up now more than five years, alongside stable editing and sustained fetal hemoglobin levels, I have conviction in the durable benefit to the patients treated with CASGEVY.” New data presented from CASGEVY pivotal trials In SCD 36/39 (92.3%) evaluable patients (those with at least 16 months of follow-up) were free from vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12), consistent with the previously reported primary endpoint data. Mean duration of VOC-free was 27.9 months, with a maximum of 54.8 months. 38/39 (97.4%) patients with at least 16 months of follow-up were free from hospitalizations related to VOCs for at least 12 consecutive months (HF12), consistent with the previously reported key secondary endpoint data. In TDT 49/52 (94.2%) evaluable patients (those with at least 16 months of follow-up) were transfusion-independent for at least 12 consecutive months with a mean weighted hemoglobin of at least 9 g/dL (TI12), consistent with the previously reported primary endpoint data. Mean duration of transfusion independence was 31.0 months, with a maximum of 59.4 months. All TDT patients dosed with at least 16 months of follow up are transfusion free. Two of the three patients who did not achieve TI12 in CLIMB-111 achieved TI12 in the long-term follow-up study, CLIMB-131, and have been transfusion independent for over one year. The third has been transfusion free for 3.4 months. Both SCD and TDT patients reported sustained and clinically meaningful improvements in their quality of life, including physical, emotional, social/family and functional well-being, and overall health status. In both SCD and TDT patients, edited levels of BCL11A alleles were stable over time in bone marrow and peripheral blood indicating successful editing in the long-term hematopoietic stem cells. All patients engrafted neutrophils and platelets after exa-cel infusion. The safety pro exa-cel was generally consistent with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. These longer-term data for CASGEVY from the CLIMB clinical trials will be shared as outlined below: Abstracts S273 and S274 will be oral presentations entitled “Exagamglogene Autotemcel For Severe Sickle Cell Disease,” and “Exagamglogene Autotemcel For Transfusion-Dependent Beta-Thalassemia,” on Sunday, June 16 at 12:15 CEST and 12:30 CEST, respectively. Abstracts P1493 and P1525 will be poster presentations entitled “Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Severe Sickle Cell Disease,” and “Health-Related Quality Of Life Improvements After Exagamglogene Autotemcel In Patients With Transfusion-Dependent Βeta-Thalassemia,” on Friday, June 14 at 18:00 CEST. These presentations will include updated pivotal trial data from patients treated with CASGEVY in CLIMB-111 and CLIMB-121 and followed in CLIMB-131. Vertex will also share five health economics abstracts at the EHA Congress. Abstract P1483 is entitled “Adherence, Treatment Use, and Clinical Outcomes in Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises Treated With L-Glutamine, Voxelotor, or Crizanlizumab in the United States.” Abstract P1506 is entitled “Mortality and Clinical Complications Among Patients with Sickle Cell Disease With Recurrent VOCs in Canada.” Abstract P1507 is entitled “Treatment Utilization and Clinical Complications in Patients with Sickle Cell Disease Receiving Frequent Red Blood Cell Transfusions in the United States.” Abstract P2191 is entitled “Clinical Complications and Treatment Use Among Patients With Sickle Cell Disease With Recurrent Vaso-Occlusive Crises in the Netherlands.” Abstract PB3248 is entitled “Clinical Complications Among Patients With Transfusion-Dependent Beta-Thalassemia in the Netherlands.” About Sickle Cell Disease (SCD) SCD is a debilitating, progressive, life shortening genetic disease. SCD patients report health-related quality of life scores well below the general population and significant health care resource utilization. SCD affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or “sickled” red blood cells. The clinical hallmark of SCD is vaso-occlusive crises (VOCs), which are caused by blockages of blood vessels by sickled red blood cells and result in severe and debilitating pain that can happen anywhere in the body at any time. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with SCD is around 40 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with SCD because of the lack of available donors. About Transfusion-Dependent Beta Thalassemia (TDT) TDT is a serious, life-threatening genetic disease. TDT patients report health-related quality of life scores below the general population and significant health care resource utilization. TDT requires frequent blood transfusions and iron chelation therapy throughout a person’s life. Due to anemia, patients living with TDT may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of TDT can also include an enlarged spleen, liver and/or heart, misshapen bones and delayed puberty. TDT requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life and reduced lifetime earnings and productivity. In Europe, the mean age of death for patients living with TDT is 50-55 years. Stem cell transplant from a matched donor is a potentially curative option but is only available to a small fraction of people living with TDT because of the lack of available donors. About CASGEVY™ (exagamglogene autotemcel [exa-cel]) CASGEVY™ is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. CASGEVY has been shown to reduce or eliminate VOCs for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved for certain indications in multiple jurisdictions for eligible patients. About the CLIMB Studies The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and CLIMB-121, are designed to assess the safety and efficacy of a single dose of CASGEVY in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after CASGEVY infusion. Each patient will be asked to participate in the ongoing long-term, open-label trial, CLIMB-131. CLIMB-131 is designed to evaluate the safety and efficacy of CASGEVY in patients who received CASGEVY in other CLIMB studies. The trial is designed to follow patients for up to 15 years after CASGEVY infusion. U.S. INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR CASGEVY (exagamglogene autotemcel) WHAT IS CASGEVY? CASGEVY is a one-time therapy used to treat people aged 12 years and older with: sickle cell disease (SCD) who have frequent vaso-occlusive crises or VOCs beta thalassemia (β-thalassemia) who need regular blood transfusions CASGEVY is made specifically for each patient, using the patient’s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in people with sickle cell disease and eliminate the need for regular blood transfusions in people with beta thalassemia. IMPORTANT SAFETY INFORMATION What is the most important information I should know about CASGEVY? After treatment with CASGEVY, you will have fewer blood cells for a while until CASGEVY takes hold (engrafts) into your bone marrow. This includes low levels of platelets (cells that usually help the blood to clot) and white blood cells (cells that usually fight infections). Your doctor will monitor this and give you treatment as required. The doctor will tell you when blood cell levels return to safe levels. Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of platelet cells: severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood Tell your healthcare provider right away if you experience any of the following, which could be signs of low levels of white blood cells: fever chills infections You may experience side effects associated with other medicines administered as part of the treatment regimen for CASGEVY. Talk to your physician regarding those possible side effects. Your healthcare provider may give you other medicines to treat your side effects. How will I receive CASGEVY? Your healthcare provider will give you other medicines, including a conditioning medicine, as part of your treatment with CASGEVY. It’s important to talk to your healthcare provider about the risks and benefits of all medicines involved in your treatment. After receiving the conditioning medicine, it may not be possible for you to become pregnant or father a child. You should discuss options for fertility preservation with your healthcare provider before treatment. STEP 1: Before CASGEVY treatment, a doctor will give you mobilization medicine(s). This medicine moves blood stem cells from your bone marrow into the blood stream. The blood stem cells are then collected in a machine that separates the different blood cells (this is called apheresis). This entire process may happen more than once. Each time, it can take up to one week. During this step rescue cells are also collected and stored at the hospital. These are your existing blood stem cells and are kept untreated just in case there is a problem in the treatment process. If CASGEVY cannot be given after the conditioning medicine, or if the modified blood stem cells do not take hold (engraft) in the body, these rescue cells will be given back to you. If you are given rescue cells, you will not have any treatment benefit from CASGEVY. STEP 2: After they are collected, your blood stem cells will be sent to the manufacturing site where they are used to make CASGEVY. It may take up to 6 months from the time your cells are collected to manufacture and test CASGEVY before it is sent back to your healthcare provider. STEP 3: Shortly before your stem cell transplant, your healthcare provider will give you a conditioning medicine for a few days in hospital. This will prepare you for treatment by clearing cells from the bone marrow, so they can be replaced with the modified cells in CASGEVY. After you are given this medicine, your blood cell levels will fall to very low levels. You will stay in the hospital for this step and remain in the hospital until after the infusion with CASGEVY. STEP 4: One or more vials of CASGEVY will be given into a vein (intravenous infusion) over a short period of time. After the CASGEVY infusion, you will stay in hospital so that your healthcare provider can closely monitor your recovery. This can take 4-6 weeks, but times can vary. Your healthcare provider will decide when you can go home. What should I avoid after receiving CASGEVY? Do not donate blood, organs, tissues, or cells at any time in the future What are the possible or reasonably likely side effects of CASGEVY? The most common side effects of CASGEVY include: Low levels of platelet cells, which may reduce the ability of blood to clot and may cause bleeding Low levels of white blood cells, which may make you more susceptible to infection Your healthcare provider will test your blood to check for low levels of blood cells (including platelets and white blood cells). Tell your healthcare provider right away if you get any of the following symptoms: fever chills infections severe headache abnormal bruising prolonged bleeding bleeding without injury such as nosebleeds; bleeding from gums; blood in your urine, stool, or vomit; or coughing up blood These are not all the possible side effects of CASGEVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of CASGEVY Talk to your healthcare provider about any health concerns. Please see full Prescribing Information including Patient Information for CASGEVY. About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including acute and neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes, myotonic dystrophy type 1 and alpha-1 antitrypsin deficiency. Vertex was founded in 1989 and has its global headquarters in Boston, with international headquarters in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia, Latin America and the Middle East. Vertex is consistently recognized as one of the industry's top places to work, including 14 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex's history of innovation, visit or follow us on LinkedIn, YouTube and Twitter/X. (VRTX-GEN) Vertex Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the statements by Haydar Frangoul, M.D., M.S., and Franco Locatelli, M.D., Ph.D., in this press release, and statements regarding our expectations for and the anticipated benefits of CASGEVY, our plans to share longer-term data for CASGEVY from the CLIMB clinical trials and to share health economics abstracts at the EHA Congress, and our plans for and design of the CLIMB studies. While we believe the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy, and other reasons, and other risks listed under the heading “Risk Factors” in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at and available through the company's website at . You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. View source version on businesswire.com: Contacts Vertex Pharmaceuticals Incorporated Investors: InvestorInfo@vrtx.com Media: mediainfo@vrtx.com or International: +44 20 3204 5275 or U.S.: 617-341-6992 or Heather Nichols: +1 617-839-3607 Source: Vertex Pharmaceuticals Incorporated View this news release online at:

Clinical ResultCell TherapyDrug ApprovalClinical Study

100 Deals associated with Crizanlizumab-TMCA

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KEGG	Wiki	ATC	Drug Bank
-	Crizanlizumab-TMCA	B06AX01	DB15271

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Anemia, Sickle Cell	US	Novartis Pharmaceuticals Corp.	15 Nov 2019
Vaso-occlusive crisis	US	Novartis Pharmaceuticals Corp.	15 Nov 2019

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Phase 2	US	Novartis AG	09 Jul 2020
Chronic Kidney Diseases	Phase 2	US	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	BR	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	FR	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	GR	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	IE	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	LB	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	NL	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	PA	Novartis Pharmaceuticals Corp.	10 Dec 2019
Chronic Kidney Diseases	Phase 2	ES	Novartis Pharmaceuticals Corp.	10 Dec 2019

Clinical Result

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Phase

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03264989 (CTgov)	Phase 2	Vaso-occlusive crisis \| Anemia, Sickle Cell	57	Crizanlizumab (Crizanlizumab 5.0 mg/kg)	novwsdfrtp(obrxmmqchb) = ivtbkggmzi dukjcocqqp (qwoqikxbwf, ljcoabojan - ohmrfztjbz) View more	-	23 Apr 2024
				Crizanlizumab (Crizanlizumab 7.5 mg/kg)	sryqddjzfo(hpsyhlftnt) = kkvedplbyo iwhjvrovzc (ahqqvmwulv, jrqvxqaikt - agyaeohfdl) View more
NCT03814746 (STAND, CTgov)	Phase 3	Vaso-occlusive crisis \| Anemia, Sickle Cell	253	Crizanlizumab (SEG101) (Crizanlizumab (SEG101) at 5.0 mg/kg)	ulzmmhuijf(vcmfpborjk) = yraikefopj ablylfuxoh (uytzcihtkj, ocjqnigvnu - irnrvqxcib) View more	-	08 Jan 2024
				Crizanlizumab (SEG101) (Crizanlizumab (SEG101) at 7.5 mg/kg)	ulzmmhuijf(vcmfpborjk) = koyzkboata ablylfuxoh (uytzcihtkj, mthastnnzg - fcqgyfjwto) View more
NCT03474965 (SOLACE-KIDS, EHA2023)	Phase 2	Anemia, Sickle Cell	50	Crizanlizumab 5 mg/kg	pguhehcbhf(gehdgyjdwj) = irjdhinwwx jgawvkqmqp (ntmcuckfmw ) View more	-	08 Jun 2023
NCT03264989 (Pubmed) Manual	Phase 2	Anemia, Sickle Cell	57	crizanlizumab (5.0 mg/kg)	dbbvjctqex(zwjyfgihzf) = tpdrghvtbv xxqowwugyd (dowbykxhft ) View more	Positive	10 Nov 2022
				crizanlizumab (7.5 mg/kg)	dbbvjctqex(zwjyfgihzf) = kvhbtqwavq xxqowwugyd (dowbykxhft ) View more
NCT03720626 (CSEG101A2001M, EHA2022)	Not Applicable	Vaso-occlusive crisis \| Anemia, Sickle Cell	188	Crizanlizumab	eheuzgmdei(crbzthdflg) = cgamhulbvv svkyhuqyjm (tfhovpqbgq )	-	12 May 2022
NCT04435184 (CRITICAL, Pubmed \| JACC Basic Transl Sci)	Phase 2	COVID-19	54	Crizanlizumab	ebxvcnjwuv(bjrrzjlefj) = qrbcpbyafg qptbynwxtr (ucidfrrtbr )	-	08 Dec 2021
				Placebo	npqzwmokzl(jkbawjtriy) = wtezvaqarx kukozhndid (mgclvcjfzp )
NCT04435184 (CRITICAL, CTgov)	Phase 2	COVID-19	54	Crizanlizumab (Crizanlizumab)	yfizgdpmru(ndpbgfuiwj) = zxtvtykvce spgzrfzyhb (jlfbjmqjlo, hnpcdljovz - osoizchxww) View more	-	09 Nov 2021
				0.9% saline (Placebo Saline)	yfizgdpmru(ndpbgfuiwj) = bldmvgrqki spgzrfzyhb (jlfbjmqjlo, moijliclef - lnhertyxwc) View more
NCT01895361 (SUSTAIN, CTgov)	Phase 2	Pain \| Anemia, Sickle Cell	198	SelG1 (High-dose SelG1 (Selg1 5.0 mg/kg))	fdlojznyrb(lrdhhyojeq) = yfwjfcbebb znkogiccgk (nlrgbmqqya, miozjztiqe - nbrkhpglys) View more	-	31 Jan 2020
				SelG1 (Low-dose SelG1 (Selg1 2.5 mg/kg))	fdlojznyrb(lrdhhyojeq) = qggwsnhdsd znkogiccgk (nlrgbmqqya, bfkapymgif - pukkxrkqwn) View more
NCT01895361 (SUSTAIN, Pubmed \| Br Dent J) Manual	Phase 2	Pain \| Anemia, Sickle Cell	198	Crizanlizumab	tmizftobyb(hglqadppnk) = dfqzlcbwfa nvquhfjvxc (qjmvlyahsz ) View more	Positive	02 Feb 2017
				Placebo	tmizftobyb(hglqadppnk) = zknbcvghep nvquhfjvxc (qjmvlyahsz ) View more

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