Researchers Report New Opportunities to Improve Quality of Life

Studies show promising new options to address unmet needs in sickle cell disease and immune thrombocytopenia

(SAN DIEGO—Dec. 7, 2024) – Researchers report significant progress toward expanding the therapeutic options available for people with non-cancerous blood conditions in five studies presented during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. The studies offer new hope for addressing unmet needs and improving quality of life among people living with sickle cell disease (SCD) and immune thrombocytopenia (ITP).

“It’s exciting that we have four terrific studies designed to benefit people with SCD, including treatments that have been available but haven’t been used in certain populations, and potential new therapies, as well,” said Charles Abrams, MD, Francis C. Wood Professor of Medicine at the University of Pennsylvania School of Medicine in Philadelphia, who moderated the press briefing, Reading Up on the Classics: Treating Not-So-Benign Hematology Conditions. “Additionally, the ITP study shows there’s a new option for a group of patients for whom there aren’t a lot of great options currently.”

The first study examines a first-in-class oral medication for the treatment of ITP, an autoimmune disorder that leads to low levels of platelets, fatigue, and a risk of uncontrolled bleeding. The drug brought a durable platelet response in about one-quarter of study participants who had not seen lasting improvements with other available treatments, suggesting it could offer a new therapeutic option for some patients.

The other four studies present new hope for individuals with SCD, an inherited disorder that causes red blood cells to become sickle-shaped, which reduces blood flow, leading to decreased oxygen delivery to the tissue. SCD can cause a wide range of symptoms and health impacts, including vaso-occlusive crises (VOCs) – episodes of severe pain caused by oxygen deprivation in tissues – and damage to tissues and organs. There are only a few available treatments for SCD, and many affected individuals lack access to these therapies, cannot tolerate available medications, or do not derive significant benefits from them. There is a tremendous need for new therapeutic options that can improve quality of life and potentially prevent long-term damage.

The first SCD study found that pain episodes were reduced by almost half in patients taking the experimental drug etavopivat. The second study reports on tolerability and potential benefits of the SCD drug hydroxyurea in people with hemoglobin SC, a less common variant of the disease; the study represents one of few prospective studies focused on this undertreated patient group. In the third study, a small retrospective analysis, researchers report that fertility preservation procedures are safe for people with SCD under appropriate expert care, underscoring the importance of ensuring access to fertility preservation as more individuals consider therapies that may raise the risk of infertility. The fourth study reports early results from a new, potentially curative gene therapy for SCD, showing both benefit and risk.

Rilzabrutinib Found Safe and Effective for Refractory Immune Thrombocytopenia
5: Efficacy and Safety of Oral Bruton Tyrosine Kinase Inhibitor (BTKi) Rilzabrutinib in Adults with Previously Treated Immune Thrombocytopenia (ITP): A Phase 3, Placebo-Controlled, Parallel-Group, Multicenter Study (LUNA 3)

The experimental drug rilzabrutinib was well tolerated and generated an increase in platelet counts among some adults with immune thrombocytopenia (ITP) who had not experienced lasting improvements with other available ITP treatments, according to the results of a phase III trial. The trial’s primary endpoint of durable platelet response was achieved in about one-quarter of patients taking the drug and none of those taking a placebo and continued to improve with longer follow-up. Even among those who did not meet the threshold for the primary endpoint, many patients taking rilzabrutinib experienced secondary benefits including improvements in platelet count, bleeding, and fatigue.

“The drug is highly active in a highly refractory group of patients,” said the study’s lead author, David J. Kuter, MD, DPhil, program director of hematology at Massachusetts General Hospital and professor of medicine at Harvard Medical School in Boston. “In addition to raising platelet counts, bleeding events decreased significantly and quality of life improved. The drug also worked really fast – within 15 days – and those who responded maintained a durable response for a long time.”

ITP leads to low levels of platelets, a blood cell that is important for clotting. In children, it can resolve on its own, but in adults, it is typically chronic. Several medications are available to help raise platelet counts, but people who cannot tolerate or do not respond to available medications can suffer from uncontrolled bleeding and chronic fatigue.

Rilzabrutinib is a first-in-class oral Bruton tyrosine kinase inhibitor designed to boost platelet counts by simultaneously reducing the production of platelet-targeting autoantibodies, reducing the destruction of platelets by macrophages, and inhibiting B cell activation and inflammatory pathways. While other drugs increase the rate of platelet production, the mechanism of action for rilzabrutinib is unique in its multifaceted approach to ITP.

For this phase III trial, researchers enrolled 202 adults with persistent/chronic ITP that was not sufficiently managed with standard-of-care therapies. Participants had seen no lasting benefit from a median of four prior therapies before enrolling in the trial. Two-thirds of the participants were randomly assigned to take rilzabrutinib and one-third took a placebo for a 24-week double-blind period. After the first 12 weeks, 64% of patients on rilzabrutinib and 32% on placebo achieved a platelet response (platelet count ≥50×109/L or ≥30–<50×109/L and doubled from baseline) and continued on the blinded study; those with no platelet response had the option of discontinuing the study or taking rilzabrutinib open label. After 24 weeks, all participants had the option to take rilzabrutinib open label.

The study’s primary endpoint was a durable platelet response, defined as platelet counts of 50x109/L or higher for eight or more of the last 12 weeks of the 24-week blinded period without taking any additional ITP rescue therapies. This endpoint was met in 23% of patients randomized to take rilzabrutinib (29% when including initially non-responding rilzabrutinib patients at week 12 who crossed over to open label rilzabrutinib) and zero patients taking placebo.

Secondary endpoints revealed that participants treated with rilzabrutinib showed improvements in platelet counts, fatigue, and bleeding, and a reduced need for ITP rescue therapies compared with those in the control group.

“The fatigue scores got much better among those taking the drug, and that happened whether the platelet count rose or not,” said Dr. Kuter. “This suggests there are other aspects of ITP that affect fatigue besides platelet count.” For example, he suggested that the anti-inflammatory action of rilzabrutinib could help to reduce fatigue even without improvements in platelet counts.

Previous research has suggested that patients who started rilzabrutinib earlier in their ITP course, had taken fewer prior therapies, and had shorter disease duration saw the greatest improvements in durable platelet response.

Dr. Kuter reported that rilzabrutinib was safe and well tolerated, with comparable rates of adverse events among both study arms. The most common treatment-related adverse events were diarrhea, nausea, headache, and abdominal pain, mostly low grade.

The researchers will continue to follow responding patients in the open-label portion for an additional 28 weeks and long-term extension for at least one year to assess the durability of the platelet response and long-term safety profile. In addition, results from a parallel phase III study in children are anticipated to be reported next year. Dr. Kuter added that future studies could help to determine whether rilzabrutinib might be suitable for use earlier in the course of ITP treatment and whether it could be helpful in treating other autoimmune conditions.

This study was funded by Sanofi, maker of rilzabrutinib.

David Kuter, MD, DPhil, of Massachusetts General Hospital and Harvard Medical School, will present this study in a plenary session on Sunday, December 8, 2024, at 2:00 p.m. Pacific time in Hall B in the San Diego Convention Center.

Etavopivat Decreases Sickle Cell Pain Episode Frequency by Nearly Half
179: Etavopivat Reduces Incidence of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: HIBISCUS Trial Phase II Results through 52 Weeks

The experimental drug etavopivat resulted in a significant reduction in VOCs and improved other markers of hemolysis in SCD, according to new findings from a phase II clinical trial. Researchers also report that the drug was well tolerated at both higher and lower doses, showing promise as a potential safe and effective new therapy to address unmet treatment needs among people living with SCD.

“The results are very encouraging,” said site principal investigator, Julie Kanter, MD, professor of medicine and pediatrics and director of the adult sickle cell program at the University of Alabama at Birmingham. “We see a reduction in VOCs, an improvement in overall hemoglobin, and a decrease in hemolysis, as well as some early improvements in important patient-reported outcomes like fatigue. This suggests the drug may be beneficial for people with SCD and warrants further investigation in the ongoing phase III trial as well as a planned multi-national phase III trial.”

Etavopivat is a daily oral medication that is designed to improve the health of red blood cells by boosting an enzymatic process that improves energy dynamics and allows the cells to retain oxygen longer. For the phase II trial, researchers enrolled 60 teens and adults (ages 12-65 years) with SCD. The average age of participants was 33.5 years, and participants had suffered an average of more than three VOCs in the year before joining the study.

Participants were randomly divided into three groups and assigned to take etavopivat at a dose of 200 mg/day, etavopivat at a dose of 400 mg/day, or a placebo for 52 weeks. Among all study participants, those assigned to take etavopivat had significantly fewer VOCs over the course of the year, one of the study’s co-primary endpoints. Participants taking etavopivat at either dose had an average number of one VOC over the course of the year, while those taking just the placebo had an average of just under two VOCs, showing that taking the drug cut the rate of VOCs nearly in half. In addition, taking etavopivat extended the median time to the first VOC from about 17 weeks in the control group to 34 weeks in the etavopivat group.

Participants taking etavopivat were also more likely to see a marked improvement in hemoglobin (a protein that allows red blood cells to carry oxygen), the study’s second primary endpoint, with an increase in hemoglobin by over 1 g/dL from baseline to week 24 occurring in 38% of those taking the 200 mg dose of etavopivat, 25% of those taking the 400 mg dose, and 11% of those taking the placebo. The differences among the two primary endpoints were even more pronounced among the subset of participants who strictly adhered to all study protocols.

Participants taking etavopivat also showed a reduction in hemolysis biomarkers (an indicator of the breakdown of red blood cells) and improvements in patient-reported fatigue scores.

Adverse events related to etavopivat were generally mild to moderate, with the most common side effects being headaches, stomach discomfort, and elevated liver enzymes. None required cessation of the drug, and most were resolved without intervention.

SCD is a highly heterogeneous condition, meaning that it can manifest differently in different individuals. Thus, not all treatments will work the same in everyone, making it even more important to understand which groups of patients may benefit most from a given treatment. Because etavopivat works through a different mechanism of action than existing therapies – by enhancing natural processes that are already present in the red blood cell – researchers suggest that it could fill a gap where other SCD treatments fall short.

“This is a very exciting mechanism of action and could offer great benefit,” said Dr. Kanter. “It’s not going to be for everyone, so we need to see who it’s going to be best for and how it can be used in combination with other therapies, but it’s absolutely a step in the right direction.”

A phase III trial is underway now in the United States, and a second phase III trial will be conducted in a more diverse global population. In addition to confirming that etavopivat reduces VOCs and improves the health of red blood cells and their ability to carry oxygen, Dr. Kanter said that future studies could help to determine whether the drug can also help to prevent long-term organ damage.

The study was funded by Novo Nordisk, maker of etavopivat.

Sophia Delicou, MD, of Hippokrateio General Hospital, will present this study during an oral presentation on Saturday, December 7, 2024, at 3:00 p.m. Pacific time in Hall B in the San Diego Convention Center.

Hydroxyurea Shows Benefits for Managing HbSC Form of Sickle Cell Disease
3: Double-Blind, Placebo-Controlled Randomized Trial of Hydroxyurea for HbSC: Results of the Prospective Identification of Variables as Outcomes for Treatment (PIVOT) Trial

Hydroxyurea was generally well tolerated and beneficial for people with the hemoglobin SC (HbSC) variant of SCD, according to results from PIVOT, a phase II clinical trial conducted in Ghana. The study is the first double-blind, placebo-controlled, randomized trial to assess the use of hydroxyurea — the current standard of care for the more common hemoglobin SS (HbSS) variant of SCD — in patients with HbSC. Although PIVOT did not meet its primary study endpoint, researchers say the trial provides important information about the morbidity of HbSC disease and how hydroxyurea may function as an effective disease-modifying therapy.

“Hydroxyurea was well tolerated by most patients with HbSC, with hematologic dose-limiting toxicities that were typically mild and transient. We also observed laboratory and clinical benefits, including fewer VOCs and hospitalizations,” said the study’s lead author, Yvonne Dei-Adomakoh, MBBS, hematologist at the University of Ghana Medical School Korle Bu Teaching Hospital in Accra, Ghana. “Since our phase II study was focused primarily on safety and dosing, it is now essential to carry out a phase III trial to look specifically at clinical efficacy.”

Hydroxyurea is a daily oral medication that can reduce SCD symptoms by helping red blood cells maintain a healthy shape.

HbSS and HbSC are distinguished by the genes a person inherits from their parents to cause SCD. HbSS is the most common variant and tends to be more severe. In the U.S., about 60-65% of people with SCD have HbSS, and about 25-30% have HbSC. Some people with HbSC experience fewer symptoms, and this has led to a perception that HbSC is a milder form of the disease, but many people with HbSC experience debilitating VOCs and long-term health impacts, Dr. Adomakoh explained.

“There is a general perception that people who have HbSC disease have a mild phenotype, and it important to dispel this myth among both the public and health care workers,” she said. “Many people with HbSC disease are not receiving long-term care or disease-modifying treatment for their condition as they are felt not to have the ‘real’ SCD. Hydroxyurea is the current standard of care for people with HbSS, and we thought that it’s possible that patients with HbSC may also benefit from hydroxyurea, but there have been very few prospective studies so far.”

The PIVOT trial was conducted in Ghana, where HbSC is highly prevalent, comprising about 50% of the population with SCD. Researchers enrolled and randomized 212 eligible patients with HbSC at two SCD clinics. Half of the participants were children and half were adults. Prior to the trial, 95% had been hospitalized for complications related to their SCD, 86% experienced VOCs, and 20% had previously received at least one blood transfusion.

Participants were randomly assigned to receive either oral hydroxyurea or a placebo at 20 mg/kg/day for 12 months. For the primary endpoint, focused on the drug’s safety and tolerability, researchers assessed the frequency of side effects related to blood health — specifically, abnormally low blood cell counts or elevated hemoglobin — that were severe enough to cause physicians to pause or lower the dose.

These hematologic toxicities occurred in 33% of participants taking hydroxyurea and 11% of those taking placebo. Since this 22% difference was more than the expected 15%, the study did not meet its formal primary endpoint. However, researchers noted that these toxicities were mostly mild and transient, similar to what has been seen in trials with patients who have the HbSS variant of SCD, reflecting an overall favorable safety profile for hydroxyurea in this setting.

Participants taking hydroxyurea experienced significant improvements in several laboratory measures of SCD severity, including higher mean corpuscular volume (larger red blood cells, which are less likely to become sickle-shaped) and higher fetal hemoglobin levels (which result in an improved ability to produce healthy red blood cells), as well as lower leukocyte and neutrophil counts. Participants on hydroxyurea also experienced reductions in the rate of VOCs and hospitalizations compared to those on placebo. These improvements were seen consistently in both children and adults. Additional data collected on organ function and quality of life are still being analyzed.

Based on these findings, the researchers concluded that the PIVOT trial offers promising evidence that hydroxyurea is well tolerated and could significantly improve the health and quality of life of millions of people living with the HbSC variant of SCD around the world.

“Hydroxyurea comes at a low cost; in Ghana it’s on our national health insurance,” said Dr. Dei-Adomakoh. “If we see safety and efficacy in a multicenter phase III trial, I think that countries should push for it to be on their national health insurance and be readily available at very low cost to patients with SCD.”

Theravia provided financial support and donated hydroxyurea and matching placebo, but had no role in the trial design, conduct, data collection, data analysis, manuscript preparation, or submission.

Yvonne Dei-Adomakoh, MBBS, will present this study in a plenary session on Sunday, December 8, 2024, at 2:00 p.m. Pacific time in Hall B in the San Diego Convention Center.

Study Sheds Light on Access and Safety Issues for Fertility Preservation Before Curative Sickle Cell Therapies
802: Fertility Preservation Outcomes for People with Ovaries and Sickle Cell Anemia: A Multi-Center Study

A small retrospective study of fertility preservation procedures in people with SCD – who can face diminished egg supply and infertility related to their condition and its treatments – found that these interventions are safe under the care of SCD experts and reproductive endocrinology experts. While study participants faced more complications than the general population who undergo similar procedures, complications were manageable. According to researchers, the results underscore the importance of ensuring access to fertility preservation among people living with SCD, especially as more individuals consider undergoing curative therapies that heighten the risk of infertility.

“Patients deserve to know why fertility preservation may be warranted and what risks are involved,” said the study’s lead author, Marti Goldenberg, DO, pediatric hematology fellow physician at Johns Hopkins University School of Medicine in Baltimore. “This study speaks to access and availability issues, shows that it’s safe to do under the right setting with a multidisciplinary team of experts, and has helped us become more familiar with the complications these patients may face.”

SCD can cause diminished ovarian reserve, or a low egg supply, likely as a result of inflammation and damage to blood vessels around the ovaries. Common SCD therapies such as hydroxyurea may also affect egg supply and fertility. In recent years, curative options, including gene therapies, have become more available to people with SCD. However, infertility is a common side effect of the chemotherapy and radiation required to undergo these treatments, so counseling about fertility preservation is indicated for anyone considering these options.

Standard fertility preservation options are available after puberty for people with testes and regardless of pubertal status for people with ovaries. For people with ovaries, the process of fertility preservation involves taking medications to stimulate the production of oocytes, undergoing a procedure to extract the mature eggs, and then freezing the eggs so that they can later be used for in vitro fertilization.

To understand the benefits and risks of fertility preservation in this population, researchers retrospectively analyzed health records at five medical centers of 46 people with SCD who attempted fertility preservation between 2016-2024. Participants had a median age of 23.7 years, and most experienced frequent and serious complications from SCD despite receiving hydroxyurea, regular transfusions, or both to manage their condition, resulting in a median of four acute care visits for pain in the year before fertility preservation. Most of the patients decided to undergo fertility preservation in preparation for a curative SCD therapy.

A majority of study participants underwent one oocyte stimulation and egg extraction cycle, while six required multiple cycles, for a total of 55 cycles across 46 individuals. The procedure was successful in most cases, resulting in a median of 11 cryopreserved oocytes per patient. Complications were common, occurring in nearly half of the cycles; 11 of 46 participants experienced more than one complication. The most common complications were VOCs and unplanned transfusions; people who had three or more VOC episodes in the year before fertility preservation were most likely to experience complications.

Researchers said that awareness of the potential complications can help medical teams plan and prepare to minimize the impacts. “There is a series of sickle cell ‘landmines’ you walk through when you do fertility preservation, and when you know about them, you can manage them,” said Dr. Goldenberg. For example, the cessation of routine SCD medications during fertility preservation can increase the likelihood of VOCs or other problems, as can the elevated estrogen, steroids, and anesthesia typically involved in the oocyte stimulation and extraction processes. Medical teams can adjust some protocols to account for these factors, such as avoiding the use of steroids and considering anticoagulant medications to account for an increased risk of blood clots.

To cover the substantial health care costs associated with fertility preservation, about half of the patients in the study relied on public insurance or participation in research studies; the rest were privately insured or paid for the procedure on their own. As policymakers consider coverage decisions for curative SCD therapies, researchers said that it will be important to also consider coverage for fertility preparation ahead of those procedures. “Just like all other people, people with SCD should have the choice and the agency to have children if they want to,” said Dr. Goldenberg. “We have the technology, and we should make sure it reaches the patients.”

Researchers noted that the study is limited by its retrospective nature and relatively small sample size. In addition, the study participants had relatively severe health impacts from SCD and may face more health risks than the broader population of people who might consider fertility preservation ahead of sickle cell therapies in the future. The study did not include data on the production of embryos or live birth outcomes, which could be useful to assess in future studies to help inform decision making.

Marti Goldenberg, DO, of Johns Hopkins University School of Medicine, will present this study during an oral presentation on Monday, December 9, 2024, at 3:30 p.m. Pacific time in Room 33 in the San Diego Convention Center.

Base-Edited Gene Therapy Shows Robust Results in Early Trial
513: Initial Results from the BEACON Clinical Study: A Phase 1/2 Study Evaluating the Safety and Efficacy of a Single Dose of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) in Patients with Sickle Cell Disease with Severe Vaso-Occlusive Crises

The first seven patients to receive a new investigational gene therapy for SCD experienced a robust response with high production of fetal hemoglobin and no VOCs post-engraftment, according to initial results from an early phase clinical trial.

The trial represents the first time a gene therapy using a high-precision gene-editing approach known as base editing has been administered to patients with SCD and only the second time base-edited gene therapy has been used in humans. The therapy is designed to induce the body to make red blood cells with a higher proportion of the fetal form of hemoglobin – the protein that allows red blood cells to carry oxygen – rather than the mutated adult sickle form, which is prone to red blood cell sickling in people with SCD.

“This study uses an exciting novel method of gene therapy for induction of non-sickle hemoglobin – in particular the exchange of sickle hemoglobin reduction with increased fetal hemoglobin – to provide symptom and mechanistic resolution, representing a potentially transformative treatment for people with sickle cell disease,” said the study’s lead author, Matthew M. Heeney, MD, associate chief for hematology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and associate professor of pediatrics at Harvard Medical School.

Several therapies can reverse SCD’s side effects by inducing the body to produce red blood cells that are less prone to sickling. Such therapies include a bone marrow transplant from a matched sibling donor and two gene therapies that have been recently approved by the U.S. Food and Drug Administration. For gene therapies, a patient’s own blood stem cells are collected from the peripheral blood, genetically altered, and then infused back into the patient where they find their way back to the bone marrow and begin manufacturing healthy new blood cells.

The new gene therapy used in the BEACON trial, called BEAM-101, works through a different gene-editing technique, called base editing. Instead of making cuts across the full double helix of the DNA strand, base editing replaces a single nucleotide (in this case, adenine) with another nucleotide. This can be done at multiple points along the DNA strand without ever making a full cut of the DNA or triggering DNA repair mechanisms, making it a potentially “gentler” approach from the perspective of the stem cell.

In preclinical studies, this resulted in more efficient gene editing and a higher number of edited stem cells produced compared to other gene editing approaches. BEAM-101 targets the promoter sequence of the fetal hemoglobin genes. By base editing the promoter sequence to prevent binding of a known gene repressor, fetal hemoglobin is reactivated and the disease-causing sickle hemoglobin is silenced.

To date, seven patients have received BEAM-101 infusions as part of the trial. All study participants were adults and experienced four or more VOCs in the two years before enrolling. All patients showed successful engraftment of the infused cells in the bone marrow, increased total hemoglobin production, and stabilized or reduced breakdown of red blood cells. Analyses of the hemoglobin fractions in all patients also revealed that more than 60% of the hemoglobin was the fetal form and less than 40% was the sickling form. None of the infused patients have been reported by the investigators to have VOCs post-engraftment.

There were no serious adverse events related to the gene therapy itself. However, one patient died of respiratory failure, which was determined to be likely a result of busulfan conditioning, part of the process used to prepare the bone marrow to receive an infusion of stem cells. “This was tragic, but not completely unexpected,” Dr. Heeney noted, since busulfan, which is used for all current sickle gene therapies, is known to carry a risk of severe side effects, including lung toxicity.

The study is ongoing, and patients will be followed for 15 years to assess the durability and safety of BEAM-101. Looking forward, Dr. Heeney said that approaches are emerging to eliminate the need for busulfan or other genotoxic conditioning regimens as part of administering gene therapies that could improve safety and make these therapies accessible to more patients.

He also added that there is a continuing need for approaches to improve the outlook for people living with SCD globally. “There’s still a lot of work to be done and a lot of unmet need, especially in resource-limited settings like sub-Saharan Africa which face the highest burden of disease,” said Dr. Heeney. “We need to continue to push forward with transformational or curative therapies along with finding better disease-modifying therapies.”

This study was funded by Beam Therapeutics.

Matthew M. Heeney, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, will present this study during an oral presentation on Sunday, December 8, 2024, at 10:00 a.m. Pacific time in Room 30 in the San Diego Convention Center.

The American Society of Hematology (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. Since 1958, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.

The Blood journals (https://ashpublications.org/journals) are the premier source for basic, translational, and clinical hematological research. The Blood journals publish more peer-reviewed hematology research than any other academic journals worldwide.

Claire Whetzel, 202-629-5085
cwhetzel@hematology.org