Adakveo (crizanlizumab-tmca) / Novartis - LARVOL DELTA

Evidence and gaps in clinical outcomes of novel pharmacologic therapies for sickle cell disease: A systematic literature review highlighting insights from clinical trials and real-world studies. (PubMed, Blood Rev) - "This systematic review aims to summarise the clinical outcomes of l-glutamine, crizanlizumab, and voxelotor in the treatment of sickle cell disease (SCD) based on clinical trials and real-world data and to identify any gaps in the observations. While some real-world studies have reported a decrease in VOCs and hospitalizations, the results are inconsistent and not conclusive. Further studies are needed to assess the impact of these novel therapies on end-organ-specific complications of SCD."

Clinical data • Journal • Real-world evidence • Review • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Prescribing Trends of Disease-Modifying Medications in Texas Medicaid Enrollees with Sickle Cell Disease (ISPOR 2025) - "Hydroxyurea remains the dominant DMT prescribed. The number of monthly users of L-glutamine, voxelotor, and crizanlizumab increased gradually; however, that number remains low."

Medicaid • Reimbursement • US reimbursement • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Patient Characteristics Associated with the Use of Newly Approved Disease-Modifying Therapy (DMT) for Sickle Cell Disease in Texas Medicaid (ISPOR 2025) - "Age and greater healthcare utilization (i.e., more outpatient visits, more VOC events, and previous use of hydroxyurea) indicating severe conditions were associated with use of newly approved DMTs."

Clinical • Medicaid • Reimbursement • US reimbursement • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Unlocking Prognostic Potential: Biomarker Predictors of Admission and Length of Stay in Pediatric Sickle Cell Vaso-Occlusive Pain Crisis (PAS 2025) - "Data collected included demographical information (age, gender, race/ethnicity), clinical characteristics (sickle cell disease genotype), disease modifying therapies (hydroxyurea, chronic PRBC transfusions, Adakveo), vital signs obtained from the ED (oxygen saturation and blood pressure), laboratory investigations obtained from most recent outpatient hematology clinic visit and ED (particularly white blood cell count, hemoglobin, platelet count, absolute neutrophil count, reticulocyte count), and total length of hospital stay. A total of 100 patients were included in the study. There was a significant relationship (r = .242, p = .015) between systolic blood pressure at admission and length of stay. There was a significant negative correlation (r = - .217, p = .031) between admission hemoglobin and length of stay when controlling for steady state hemoglobin."

Biomarker • Clinical • Genetic Disorders • Hematological Disorders • Mood Disorders • Pain • Pediatrics • Sickle Cell Disease

Impact of Different Definitions of Vaso-Occlusion on Efficacy Assessments in Sickle Cell Disease Clinical Trials. (PubMed, Adv Ther) - "Differences exist in definitions of vaso-occlusion and pain events used in SCD clinical trials. Severe VOCs (exa-cel), VOC (voxelotor), and SCPCs (crizanlizumab and L-glutamine) were more broadly inclusive than severe VOEs (lovo-cel and reni-cel) or painful crisis (hydroxyurea). Clinically, these differences resulted in differing numbers of patients being considered free from vaso-occlusion pain events, underscoring the challenge in comparing frequencies of pain events across SCD clinical trials."

Journal • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Clinically relevant clot resolution via a thromboinflammation-on-a-chip. (PubMed, Nature) - "Specifically, we observed that, in thromboinflammation, (1) early tissue plasminogen activator administration within 3 h directly improves endothelial barrier function; (2) prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms; and (3) combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease. These data introduce a paradigm in investigating the underlying mechanisms of thromboinflammatory clot resolution and conducting drug discovery thereof."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • Thrombosis • ELANE

Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial. (PubMed, Lancet Haematol) - P3 | "The STAND study supports the safety and tolerability of crizanlizumab in the treatment of sickle cell disease. The primary analysis showed no significant difference in efficacy between crizanlizumab and placebo. Factors including the COVID-19 pandemic, global enrolment with varied patterns of health-care use and vaso-occlusive crisis management as well as the commercial availability of crizanlizumab might have influenced these results. The safety profile of crizanlizumab was consistent with that in previous reports, without new safety concerns."

Journal • P3 data • Genetic Disorders • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Sickle Cell Disease

Now where do we STAND with crizanlizumab? (PubMed, Lancet Haematol) - No abstract available

Journal

Accelerated Drug Approvals and Patient Trust: Impact of Voxelotor & Crizanlizumab for Sickle Cell Disease. (PubMed, Blood Adv) - "Crizanlizumab and voxelotor were several of the first drugs to receive FDA approval for sickle cell disease (SCD) since the approval of hydroxyurea in 1998. In addition, the impact of these events, without transparent messaging, potentially threatened the fragile trust that providers have more recently been able to build with the SCD population regarding the medical system and research. While there is a need for new therapies in SCD, we must prioritize both safety and efficacy, and maintain trust in this population."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial (Lancet Haematol) - P3 | N=258 | STAND (NCT03814746) | Sponsor: Novartis Pharmaceuticals | "Between July 26, 2019, and Aug 31, 2022, 252 patients were enrolled and treated. The primary analysis showed an adjusted annualised rate of vaso-occlusive crises of 2·49 (95% CI 1·90–3·26) in the crizanlizumab 5·0 mg/kg group, 2·04 (1·56–2·65) in the 7·5 mg/kg group, and 2·30 (1·75–3·01) in the placebo group. Ratios of adjusted annualised rates of vaso-occlusive crises leading to health-care visits were 1·08 (95% CI 0·76–1·55, p>0·999) for 5·0 mg/kg and 0·89 (0·62–1·27, p>0·999) for 7·5 mg/kg vs placebo. The incidence of adverse events was similar across treatment groups."

P3 data • Sickle Cell Disease

A critique review of fetal hemoglobin modulators through targeting epigenetic regulators for the treatment of sickle cell disease. (PubMed, Life Sci) - "Notably, pharmaceutical approaches like hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, in addition to therapeutic techniques like gene therapies like Casgevy and Lyfgenia, signify noteworthy advancements in the management of issues connected to SCD. It has been demonstrated that inhibiting these targets can prevent the silencing of the gene encoding for the formation of γ-chains and, in turn, increase the synthesis of HbF, providing a possible treatment option for SCD symptoms. These approaches could pave the way for innovative, mechanism-driven therapies that address the unmet medical needs of SCD patients."

Journal • Review • Gene Therapies • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Sickle Cell Disease • HIF1A • ZBTB7A

A review on disease modifying pharmacologic therapies for sickle cell disease. (PubMed, Ann Hematol) - "Despite slow progress towards novel therapeutic strategies for SCD and hydroxyurea being the sole medication that is shown to reduce vaso-occlusive events and mortality for almost 20 years, several pharmacological agents targeting different mechanisms have been examined in clinical trials and recently US- US-FDA-approved, including L-glutamine and crizanlizumab. Voxelotor was previously US-FDA-approved but has been voluntarily withdrawn from the market as the overall benefit did not outweigh the risks...However, excessive costs are a barrier to widespread use. Nonetheless, there is still a large area of unmet needs for patients with SCD, and further research towards better care is warranted."

Journal • Review • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

ACTIV-4: Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (clinicaltrials.gov) - P4 | N=3591 | Completed | Sponsor: Matthew Neal MD | Active, not recruiting ➔ Completed | Trial completion date: Jun 2024 ➔ Jan 2024

Trial completion • Trial completion date • Infectious Disease • Novel Coronavirus Disease

Cereblon-Based Compounds for Induction of HbF (ASH 2024) - "Nowadays there are only four drugs approved by the FDA for SCD treatment : Hydroxyurea, voxelotor, L-glutamine and crizanlizumab, while the search for new effective and safe treatments are scarce. Furthermore, the ability to significantly induce HBG1/2 expression in HUDEP-2 cells was superior to the one seen for the standard SCD treatment, HU, with levels of HBG1/2 expression 2.6-fold higher (500nM, 72h), at a concentration 200-fold lower. These findings support that ARP-49 shows promising potential for further pre-clinical studies for increasing the production of HbF."

Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Targeted Protein Degradation • CRBN • HBG1 • HDAC2

Screening Brain MRI in Sickle Cell Patients: An Insufficiently Implemented Intervention with Critical Importance (ASH 2024) - "Of those, 53% (n=49) used hydroxyurea, 14% (n=13) used voxelotor, 5% (n=5) used crizanlizumab, and 2% (n=2) were on L-glutamine. Therefore, screening MRI is of paramount importance in all SCD patients, especially in the sicker population. This study is ongoing; with a plan to screen 1000 patients in our center, we intend to implement a strategy of one-time screening MRI for all adult SCD patients with subsequent formal referral for neurocognitive testing."

Clinical • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Genetic Disorders • Hematological Disorders • Ischemic stroke • Sickle Cell Disease • Vascular Neurology

Targeting P-selectin and interleukin-1β in mice with sickle cell disease: effects on vaso-occlusion, liver injury and organ iron deposition. (PubMed, Haematologica) - "Continuous vaso-occlusive and inflammatory processes cause extensive end-organ damage in adults with sickle cell disease (SCD), and there is little evidence that longterm hydroxyurea therapy prevents this. In initial trials, P-selectin blockade with crizanlizumab reduced SCD vaso-occlusive crisis frequency, and interleukin (IL)-1β inhibition in SCD patients, using canakinumab, lowered inflammatory markers...Our findings suggest that the attenuation of inflammation, as well as of vaso-occlusive processes, may be crucial for mitigating organ damage in SCD. Future trials should explore the ability of cytokine blockade to prevent multiorgan damage in patients with SCD, beyond evaluating vaso-occlusive crisis frequency."

IO biomarker • Journal • Preclinical • Fibrosis • Genetic Disorders • Hematological Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Respiratory Diseases • Sickle Cell Disease • IL1B • TNFA

Infusion Immediate Care: Improving Hematology/Oncology Practice Quality through Expanded and Timely Access to Infusion Care (ASH 2024) - "Standard operating procedures were established by clinical experts in hematology, oncology, supportive oncology, and Sickle Cell Disease (SCD) for the delivery of same-day supportive care, including blood products, electrolytes, fluids, growth factors, intravenous medications for symptom management, workup and initial management of neutropenic fever, and dedicated SCD services, including crizanlizumab, that were previously limited in the outpatient setting...Increasing access to outpatient infusion services has decreased inpatient admissions and duration of stay. With a creative and inclusive approach to previous care barriers, there has been a demonstrable improvement in the quality of care for our pts due to the implementation of the IIC, observed most especially in pts with myeloid neoplasms."

Acute Myelogenous Leukemia • Febrile Neutropenia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Pain • Sickle Cell Disease

Pharmacokinetics/Pharmacodynamics, Safety, and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease Aged 6 to <12 Years: 2-Year Data from the Phase 2 Solace-Kids Study (ASH 2024) - P2 | "Patients received crizanlizumab with or without hydroxyurea on Day 1, Day 15, and every 4 weeks up to 2 years. Both 5.0 and 8.5 mg/kg doses showed a reduction in VOCs, resulting in decreased healthcare visits per year. Crizanlizumab was safe and well tolerated with no new/unexpected safety concerns in this patient group, consistent with the established profile of crizanlizumab in adults."

Clinical • P2 data • PK/PD data • Anemia • Back Pain • Genetic Disorders • Hematological Disorders • Musculoskeletal Pain • Pain • Pediatrics • Sickle Cell Disease

Use of Chronic Blood Transfusion Therapies and Pharmaceutical Disease Modifying Treatments in Sickle Cell Disease: A Retrospective Cohort Analysis (2014-2021) (ASH 2024) - "pDMT use was defined as at least 1 prescription fill for hydroxyurea, crizanlizumab, l-glutamine, or voxelotor. Our study points to the importance of continuing to address disease modifying treatment use in SCD as substantial concerns remain about their utilization, particularly in relation to ongoing health disparities. *Please note that the claims data for 2021 only include information up to September."

Retrospective data • Cardiovascular • Genetic Disorders • Hematological Disorders • Infectious Disease • Nephrology • Novel Coronavirus Disease • Pediatrics • Renal Disease • Sickle Cell Disease • Thrombosis

Maternal Outcomes in Pregnant Women Admitted with Sickle Cell Disease: A Retrospective Study Involving the National Inpatient Sample (NIS 2016-2021) Database (ASH 2024) - "Background : During the past five decades, there have been significant improvements in supportive care for sickle cell disease (SCD), followed by the development of disease modifying therapies such as hydroxyurea (HU) in the 1990s, and L-glutamine, voxelotor and crizanlizumab more recently. Pregnant patients with HBSS had the highest odds of developing pulmonary hypertension. HBSS and HBSC had significantly lower odds of preterm labor."

Retrospective data • Beta-Thalassemia • Bone Marrow Transplantation • Cardiovascular • Developmental Disorders • Gene Therapies • Genetic Disorders • Gynecology • Hematological Disorders • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Sickle Cell Disease • Venous Thromboembolism

Evaluating High-Sensitivity Troponin Levels in Patients with Sickle Cell Disease Presenting to the Emergency Department (ASH 2024) - "There were no differences between groups 1 and 2 in hydroxyurea use (85% in group 1 and 83% in group 2), crizanlizumab (30% and 28%), or voxelotor (3% and 4%) use. A longitudinal prospective study is needed to assess whether high sensitivity troponin may indicate vaso-occlusion in SCD or predict subclinical cardiac findings. Research should explore integrating troponin measurement with other biomarkers and imaging for comprehensive cardiac health assessment in SCD."

Clinical • Acute Coronary Syndrome • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Hematological Disorders • Myocardial Infarction • Pain • Sickle Cell Disease • TNNI3

A contemporary review of the management strategies for sickle cell disease related ischaemic and stuttering priapism. (PubMed, Int J Impot Res) - "Finally, we review treatments utilised to treat the underlying sickle cell disease with contemporary options such as hydroxyurea to more novel therapies such as crizanlizumab and voxelotor. The role of potentially curative techniques such as gene therapy and stem cell transplantation are also reviewed and summarised."

Journal • Review • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation

Buprenorphine Is Associated with Lower Home Opioid Use and Acute Care Utilization in Sickle Cell Disease (ASH 2024) - "While hydroxyurea can reduce vaso-occlusive episodes and lower home opioid use and newer disease modifying agents like crizanlizumab, and l-glutamine reduce pain crises, and voxelotor increases hemoglobin and reduce hemolysis, none effectively modify SCD chronic pain...Another patient with SCD and OUD had 41 acute care visits pre-buprenorphine induction and 19 visits post-buprenorphine, and morphine MME usage decreased by nearly 50% from 392 MME pre-buprenorphine induction to 192 MME post-buprenorphine induction during the treatment period...This study confirms that buprenorphine is acceptable for SCD chronic pain with and without OUD when full-agonist opioid therapy is not satisfactory. The complex and heterogeneous nature of chronic SCD pain necessitates better phenotyping to understand which subphenotypes benefit most from buprenorphine treatment."

Gastroenterology • Genetic Disorders • Hematological Disorders • Hepatology • Neuralgia • Pain • Sickle Cell Disease • Substance Abuse

Low Uptake of FDA-Approved Medications for Sickle Cell Disease Amongst the Adult Medicaid Population in North Carolina (ASH 2024) - "Introduction After decades in which hydroxyurea (HU) was the only FDA-approved medication for sickle cell disease (SCD), there has been a remarkable expansion of therapies, with FDA approval of L-glutamine (2017), crizanlizumab (2019) and voxelotor (2019). This contrasts with the two-fold higher uptake of opioid analgesics, which treat symptoms of SCD but do not alter comorbidity trajectory. Among the subset of people with SCD who saw a hematologist, uptake rates were markedly higher, and this increase was more pronounced for FDA-approved therapies than for opioids."

Clinical • Medicaid • Reimbursement • US reimbursement • Anemia • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Do Jehovah's Witnesses with Sickle Cell Disease Avoid the Healthcare System? (ASH 2024) - "Different modalities were reportedly used to try to avoid sickle cell crisis : 79% see a physician regularly, 39% see a dentist, 61% get their immunization, and 85.6% report taking their medications regularly : 68% hydroxyurea, 14% voxelotor, 3.6% crizanlizumab, and 0% glutamine. Although this was a very limited sample size, it suggests that awareness of treatment options is fairly high in the Jehovah's Witness population with SCD. The results continues to reinforce the need to improve general access to care and healthcare delivery for SCD."

Genetic Disorders • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Pain • Sickle Cell Disease