Medical Policy

Policy Num:      05.003.002
Policy Name:    Gene Therapies for Sickle Cell Disease
Policy ID:          [05.003.002]  [Ac / B / M+ / P+]  [5.01.48]

Last Review:      February 20, 2025
Next Review:      April 20, 2025
 

Related Policies:

05.003.001 - Gene Therapies for Thalassemia

Gene Therapies for Sickle Cell Disease

Summary

Description

Sickle cell disease is a genetic hemoglobinopathy that results from a genetic variant in the HBB gene resulting in the production of dysfunctional hemoglobin which forms polymers in the red blood cells of individuals. The sickled red blood cells have a shorter life span and do not move as freely as normal, round, red blood cells resulting in anemia and vascular obstruction. Recurrent acute pain crises, or vaso-occlusive crises are the most prevalent manifestation of sickle cell disease. It is estimated that there are 100,000 individuals living with sickle cell disease in the United States. Two gene therapies have been approved by the U.S. Food and Drug Administration. Lovotibeglogene autotemcel adds functional copies of a modified βA-globin gene (βA-T87Q-globin) into an individual's hematopoietic stem cell through transduction of autologous CD34+ cells with BB305 lentiviral vector. After infusion, the transduced CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate to produce red blood cells containing β^A-T87Q gene that will produce HbA^T87Q protein (functional gene therapy-derived hemoglobin). Exagamglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ hematopoietic stem cells edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells. After infusion, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and fetal hemoglobin protein production in erythroid cells.

Summary of Evidence

For individuals who are 12 years and older with sickle cell disease who receive lovotibeglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality and treatment-related morbidity. In the pivotal HGB-206 (Group-C) trial, a total of 36 participants received a single intravenous infusion of lovotibeglogene autotemcel. Of the 36 total participants, 32 were evaluable for the endpoints of complete resolution of vaso-occlusive events (VOEs) and severe VOEs (sVOEs) in the 6 to 18 months post-infusion. Severe VOEs were eliminated for 94% (30/32) and all VOEs were eliminated for 88% (28/32) of evaluable study participants between 6- and 18- months post-infusion. Safety data included 54 study participants who initiated stem cell collection. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time period. After the primary evaluation period to last follow-up, 4 of the 28 trial participants who achieved complete resolution of VOE (VOE-CR) experienced VOEs. After the primary evaluation period up to 24 months, 17 of 35 (49%) trial participants were prescribed opioids for sickle cell and non-sickle cell-related pain. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that lovotibeglogene autotemcel will frequently be successful in treating sickle cell disease in at least the short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are 12 years and older with sickle cell disease who receive exagamglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality, and treatment-related morbidity. In the pivotal single-arm study CLIMB-121, a total of 44 study participants received a single intravenous infusion of exagamglogene autotemcel. Of the 44 total participants, 31 were evaluable for the primary endpoint. The primary endpoint of proportion of study participants who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion was achieved by 29 of 31 or 93.5% study participants. The key secondary endpoint of proportion of study participants who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants. Safety data includes 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of study participants. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. After the primary evaluation period to last follow-up, one of the 29 study participants who achieved primary endpoint experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that exagamglogene autotemcel will frequently be successful in treating sickle cell disease in at least short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether use of exagamglogene autotemcel and lovotibeglogene autotemcel improve the net health outcome in individuals with sickle cell disease.

Policy Statements

Exagamglogene autotemcel and lovotibeglogene autotemcel

Exagamglogene autotemcel and lovotibeglogene autotemcel are considered medically necessary for individuals if they meet criteria 1 through 6:

1. Are at least 12 years of age.

2. Diagnosis of sickle cell disease confirmed by genetic testing demonstrating the following:

   1. Homozygous sickle cell disease (e.g., HbSS) OR

   2. Heterozygous sickle cell disease (e.g., HbSC, HbSβ⁺, HbSβ⁰, HbSD, HbSOArab, HbSE)

3. Documented history of one of the following clinical signs or symptoms in the last 12 months in the setting of appropriate supportive care measures for sickle cell disease (e.g., pain management plan):

   1. Acute pain event requiring a visit to a medical facility and administration of pain medications (e.g., oral or intravenous opioids or intravenous non-steroidal anti-inflammatory drugs), hydration therapy, or red blood cell transfusions

   2. Acute chest syndrome

   3. Acute hepatic sequestration

   4. Acute splenic sequestration

   5. Priapism lasting > 2 hours and requiring a visit to a medical facility.

4. Meet the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see Policy Guidelines). These requirements may include:

   1. Adequate Karnofsky performance status or Lansky performance status;

   2. Absence of advanced liver disease;

   3. Adequate estimate glomerular filtration rate (eGFR);

   4. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO);

   5. Adequate left ventricular ejection fraction (LVEF);

   6. Absence of clinically significant active infection(s).

5. Have not received a previous allogenic hematopoietic stem cell transplant.

6. Have not received any gene therapy or are under consideration for treatment for another gene therapy for sickle cell disease.

Exagamglogene autotemcel and lovotibeglogene autotemcel are considered investigational when the above criteria are not met.

Lovotibeglogene autotemcel is considered investigational for all other indications.

Repeat treatment with exagamglogene autotemcel or lovotibeglogene autotemcel is considered investigational.

Policy Guidelines

Recommended Dose

Minimum dose is 3 × 10⁶ CD34⁺ cells/kg.

Dosing Limits

1 injection per lifetime.

Clinical Requirements for a Stem Cell Transplant

The requirement for eligibility for a stem cell transplant varied between the pivotal trial for exagamglogene autotemcel and lovotibeglogene autotemcel. These requirements are summarized below:

• Adequate cell counts defined as WBC < 3 × 10⁹/L, ANC < 1 × 10⁹/L (< 0.5 × 10⁹/L for those on hydroxyurea treatment), or platelets < 50 to 100 × 10⁹/L
• Adequate hear function defined as LVEF < 45% or cardiac T2* < 10 ms
• Advanced liver disease as defined as ALT > 3x ULN, direct bilirubin value > 2x ULN, PT INR > 1.5x ULN, history of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy
• Adequate lung function defined as DLCO < 50% of predicted value and baseline oxygen saturation < 90% without supplemental oxygen
• Adequate performance status defined as Karnofsky performance status > 60 (≥ 16 years of age) or Lansky performance status > 60 (< 16 years of age)
• Adequate kidney function as defined as eGFR < 60 to 70 mL/min/1.73 m²

Other Considerations

There is a boxed warning for hematologic malignancy for lovotibeglogene autotemcel. Hematologic malignancy has occurred in patients treated with lovotibeglogene autotemcel. It is recommended to monitor treated individuals closely for evidence of malignancy through complete blood counts at least every 6 months for at least 15 years after treatment and through integration site analysis at months 6, 12, and as warranted.

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. Some iron chelators are myelosuppressive. It is recommended to avoid use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after the infusion of exagamglogene autotemcel or lovotibeglogene autotemcel. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration (FDA) approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Sickle Cell Disease

Sickle cell disease is a genetic disorder characterized by the presence of hemoglobin S (HbS) that includes, either from homozygosity for the sickle variant in the beta globin chain of hemoglobin (β^S/β^S) or from compound heterozygosity of a sickle beta globin mutation with another beta globin mutation (eg, sickle-beta thalassemia such as β^S/β⁰ or β^S/β⁺ genotype). The homozygous from (β^S/β^S) accounts for 60% to 70% of sickle cell disease in the United States.^1,

Production of hemoglobin with dysfunctional hemoglobin S forms polymers in the red blood cells of patients. Among healthy individuals, red blood cells are flexible and round allowing them to move easily through blood vessels. With sickle cell disease, those red blood cells are sickled or shaped like crescent moons causing them to slow down or cause blockage as blood flows through the blood vessels. This results in vascular obstruction and ischemia; a shortened lifespan of the red blood cells leading to both intravascular and extravascular hemolysis, and a sticky red blood cells surface increases adherence to the vascular endothelium which can result in vascular obstruction and can contribute to vascular proliferative lesions.^2, Recurrent acute pain crises, or vaso-occlusive crises, are the most prevalent manifestations of sickle cell disease.^3, Patients also experience acute complications including serious infections and non-infectious complications such as stroke, renal necrosis, and priapism.^4, Acute chest syndrome is a potentially life-threatening complication that can involve chest pain and shortness of breath among other symptoms.^5, Chronic complications can emerge across multiple organs and include delayed puberty, avascular necrosis, skin ulcers, chronic pain, neurocognitive impairment, chronic kidney injury, pulmonary hypertension, cardiovascular disease, and can result in early mortality.^4,

Incidence and prevalence of sickle cell disease vary considerably by geography with the highest rates in equatorial Africa, Brazil, Saudi Arabia and central India populations.^6, It is estimated that there are approximately 100,000 individuals living with sickle cell disease in the United States.^7,

As of 2008, screening for sickle cell disease in newborns is mandated in all 50 states of the United States and the District of Columbia, regardless of birth setting.^8, The diagnostic methods used after birth are those that separate hemoglobin species according to amino acid composition (hemoglobin electrophoresis or thin layer isoelectric focusing), solubility testing, and examination of the peripheral blood smear.^1,

Current Treatment

Specific interventions for sickle cell disease include stem cell transplantation, chronic transfusion with packed red blood cells, and hydroxyurea. While stem cell transplant can be curative, the degree of myeloablation required and lack of availability of matched donors limit its use. Chronic transfusion is generally used for primary or secondary stroke prevention. Hydroxyurea is used to reduce the number of acute pain crises in those with frequent or severe crises, and in those with a history of acute chest syndrome or severe anemia.^3, Hydroxyurea improves blood flow by decreasing sickling of red blood cells and altering the adhesion of red blood cells to endothelium. Also, it increases red blood cells survival and decreases white blood cell, reticulocyte and platelet counts.^1, Acute pain crisis may be managed with pain medications including opioids, and may require additional inpatient or outpatient treatments including hydration, transfusion, supplemental oxygen, and a variety of other treatments.^3,

In recent years, multiple specific disease-modifying treatments have been approved by the FDA for treatment of complications resulting from sickle cell disease. L-glutamine supplementation is used to decrease the frequency of acute pain crises.^9, It was approved by the FDA on July 7, 2017 to reduce the acute complications of sickle cell disease in adult and pediatric individuals 5 years of age and older. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin.^10, It was approved by the FDA on November 15, 2019 to reduce the frequency of vaso-occlusive crises in adults and pediatric individuals aged 16 years and older with sickle cell disease. It is administered intravenously in 2 loading doses 2 weeks apart and then every 4 weeks thereafter. Voxelotor is an HbS polymerization inhibitor that reversibly binds to hemoglobin to stabilize the oxygenated hemoglobin state, thus shifting the oxyhemoglobin dissociation curve.^11, Voxelotor was approved by the FDA on November 25, 2019 for the treatment of sickle cell disease in adults and pediatric individuals 12 years of age and older.

Regulatory Status

On December 8, 2023, lovotibeglogene autotemcel (Lyfgenia) was approved by the FDA for the treatment of sickle cell disease in patients 12 years or older and a history of vaso-occlusive events.

On December 8, 2023, exagamglogene autotemcel (Casgevy) was approved by the FDA for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises. On January 16, 2024, the FDA expanded the approved indication to include treatment of patients age 12 years and older with transfusion-dependent β-thalassemia.

Rationale

This evidence review was created in January 2024 with a search of the PubMed database. The most recent literature update was performed through April 10, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Sickle Cell Disease

Clinical Context and Therapy Purpose

The purpose of gene therapies in individuals with severe sickle cell disease is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this one-time therapy may include the following:

• Reduced complexity of one-time treatment.

• Novel mechanism of action or approach may allow successful treatment of patients for whom other available treatments have failed.

• Successful treatment may reduce the potential for disease and standard treatment-related morbidity and mortality and improve quality of life.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals who are 12 years and older with severe sickle cell disease.

Interventions

The therapy being considered is lovotibeglogene autotemcel and exagamglogene autotemcel. Both are intended to be one-time gene therapies. However, the mechanism of action is different. Lovotibeglogene autotemcel adds functional copies of a modified βA-globin gene (βA-T87Q-globin) into patients’ hematopoietic stem cells through transduction of autologous CD34+ cells with BB305 lentiviral vector. After infusion, the transduced CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate to produce red blood cells containing β^A-T87Q gene that will produce HbA^T87Q protein (functional gene therapy-derived hemoglobin). Exagamglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ hematopoietic stem cells edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells. After infusion, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and HbF protein production in erythroid cells.

Comparators

The following therapies are currently being used to make treat sickle cell disease. Specific interventions for sickle cell disease include stem cell transplantation, chronic transfusion with packed red blood cells, and hydroxyurea. Disease-modifying treatments approved by the FDA for treatment of complications resulting from sickle cell disease include L-glutamine, crizanlizumab and voxelotor.

Outcomes

The general outcomes of interest are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality, and treatment-related morbidity (Table 1).

Table 1. Health Outcome Measures Relevant to Sickle Cell Disease

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Lovotibeglogene autotemcel

The clinical development program is summarized in Table 2. HGB-206 (referenced as Study 1-C in the prescribing label) was the basis for FDA approval. While HGB-206 was initiated as a phase 1 study to evaluate the safety, preliminary efficacy, and pharmacokinetics, it was subsequently updated to a phase 1/2 registrational study to evaluate efficacy endpoints. Using learnings from the early results to optimize benefit–risk profile, the treatment process evolved over time. This led to retrospective designation of 3 sequential cohorts: Groups A, B, and C with each cohort determined by the specific treatment process used at that time. In Group A (n=7), the median peripheral blood vector copy number and HbA^T87Q levels were inadequate for substantial clinical effect. These improved subsequently in Group B (n=2) including improvements to cell collection and generated improved biologic and clinical efficacy including higher total hemoglobin and decreased hemolysis. Finally, Group C (n=36) demonstrated the sustained production of HbA^T87Q in 85% of RBCs and was the basis for FDA approval. Data from group C is reviewed in detail.

Table 2. Summary of the Clinical Development Program for Lovotibeglogene Autotemcel

   SCD: sickle cell disease; TDT: transfusion-dependent thalassemia. a Each participant serves as his/her own control by contributing a primary size-matched wound pair to be randomized to receive weekly topical application of either gene therapy or the placebo (excipient gel).

Pivotal Study

Study characteristics, baseline patient characteristics, and results are summarized in Tables 3 to 5, respectively. The pivotal HGB-206 was a single-arm, 24-month, open-label, multicenter phase 1/2 study. In the study, 43 study participants underwent apheresis after mobilization with plerixafor of which 36 patients received myeloablative busulfan conditioning. Seven did not proceed to conditioning; 2 discontinued due to apheresis-related issues and 5 discontinued at participant and/or physician discretion. Thirty-six study participants received the intravenous infusion of lovotibeglogene autotemcel. The transplant population for efficacy outcomes included patients with a history of at least 4 vaso-occlusive events (VOEs) in the 24 months prior to informed consent. The efficacy outcomes were complete resolution of VOEs (VOE-CR) and severe VOEs (sVOE-CR) between 6 months and 18 months after infusion of lovotibeglogene autotemcel. Severe VOEs were eliminated for 94% (30/32) of evaluable patients and all VOEs were eliminated for 88% (28/32) of evaluable patients between 6- and 18-months post-infusion.

Safety data includes data from 54 study participants who initiated stem cell collection. Lovotibeglogene autotemcel was approved with a boxed warning due to potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with lovotibeglogene autotemcel. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. Two study participants who were treated with an earlier version of lovotibeglogene autotemcel using a different manufacturing process and transplant procedure (Group A) died from acute myeloid leukemia. One study participant with α-thalassemia trait (Group C) was diagnosed with myelodysplastic syndrome. The hematopoietic stress associated with mobilization, conditioning, and infusion of lovotibeglogene autotemcel, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. Mobilization and apheresis triggered serious adverse events of sickle cell crisis in 6 (14%, 6/44) study participants who initiated mobilization. All study participants who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning. Most conditioning-attributed events were non-serious and were consistent with the known effects of alkylating agents. Thirty-three (73%, 33/45) study participants who received lovotibeglogene autotemcel experienced at least one serious adverse event.

The purpose of the study limitations table (Table 6) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. The median (range) duration of follow-up in HGB-206 was 38 (12, 61) months. After the primary evaluation period to last follow-up, 4 of 32 patients who achieved VOE-CR experienced VOEs while maintaining globin response. After the primary evaluation period up to 24 months, 17 of 35 (49%) patients were prescribed opioids for sickle cell and non-sickle cell-related pain. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. Three cases of hematologic malignancies were reported. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice.

Table 3. Summary of Key Pivotal Trial

   a VOEs were defined as any of the following events requiring evaluation at a medical facility: 1) an episode of acute pain with no medically determined cause other than vaso-occlusion, lasting more than 2 hours; 2) acute chest syndrome; 3) acute hepatic sequestration; 4) acute splenic sequestration.  b sVOEs were defined as either of the following events: 1) VOE requiring a hospitalization or multiple visits to an emergency department/urgent care over 72 hours and receiving intravenous medications at each visit; 2) priapism requiring any level of medical attention. c Globin response was defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion: weighted average hemoglobin AT87Q percentage of non-transfused total Hb ≥30% AND weighted average non-transfused total Hb (HbS+HbF+HbA2+HbAT87Q) increase of ≥3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb ≥10 g/dL.  CR: complete resolution; sVOE: severe vaso-occlusive events; VOE: vaso-occlusive events.

Table 4. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Trial

   a Two study participants developed anemia following treatment with lovotibeglogene autotemcel; one continues to require monthly packed red blood cell transfusions. The other has been diagnosed with myelodysplastic syndrome. Both individuals had α-thalassemia trait (-α3.7 /-α3.7). b Study participants with a history of stroke were included in early inclusion criteria.

Table 5. Summary of Key Results in Pivotal Trial

   a VOEs were defined as any of the following events requiring evaluation at a medical facility: 1) an episode of acute pain with no medically determined cause other than vaso-occlusion, lasting more than 2 hours; 2) acute chest syndrome; 3) acute hepatic sequestration; 4) acute splenic sequestration.  b sVOE were defined as either of the following events: 1) VOE requiring a hospitalization or multiple visits to an emergency department/urgent care over 72 hours and receiving intravenous medications at each visit; 2) priapism requiring any level of medical attention. c Globin response was defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion: weighted average hemoglobin AT87Q percentage of non-transfused total Hb ≥30% AND weighted average non-transfused total Hb (HbS+HbF+HbA2+HbAT87Q) increase of ≥3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb ≥10 g/dL.  Note: Efficacy outcomes were complete resolution of VOE-CR and sVOE-CR between 6 months and 18 months after infusion of lovotibeglogene autotemcel. 

Table 6. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Section Summary: Lovotibeglogene autotemcel

In the pivotal HGB-206 (Group-C) study, a total of 36 study participants received a single intravenous infusion of lovotibeglogene autotemcel. Of the 36 total participants, 32 study participants were evaluable for the endpoints of complete resolution of VOEs and sVOEs in the 6 to 18 months post-infusion including 8 adolescent study participants. Severe VOEs were eliminated for 94% (30/32) of evaluable study participants and all VOEs were eliminated for 88% (28/32) of evaluable study participants between 6- and 18-months post-infusion. Safety data includes data from 54 study participants who initiated stem cell collection. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time period. After the primary evaluation period to last follow-up, 4 of 32 study participants who achieved VOE-CR experienced VOEs while maintaining globin response. After the primary evaluation period up to 24 months, 17 of 35 (49%) study participants were prescribed opioids for sickle cell and non-sickle cell-related pain. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as side effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice.

Summary of Evidence

For individuals who are 12 years and older with sickle cell disease who receive lovotibeglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality and treatment-related morbidity. In the pivotal HGB-206 (Group-C) trial, a total of 36 participants received a single intravenous infusion of lovotibeglogene autotemcel. Of the 36 total participants, 32 were evaluable for the endpoints of complete resolution of vaso-occlusive events (VOEs) and severe VOEs (sVOEs) in the 6 to 18 months post-infusion. Severe VOEs were eliminated for 94% (30/32) and all VOEs were eliminated for 88% (28/32) of evaluable study participants between 6- and 18- months post-infusion. Safety data included 54 study participants who initiated stem cell collection. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time period. After the primary evaluation period to last follow-up, 4 of the 28 trial participants who achieved complete resolution of VOE (VOE-CR) experienced VOEs. After the primary evaluation period up to 24 months, 17 of 35 (49%) trial participants were prescribed opioids for sickle cell and non-sickle cell-related pain. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that lovotibeglogene autotemcel will frequently be successful in treating sickle cell disease in at least the short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Exagamglogene autotemcel

The clinical development program is summarized in Table 7. CLIMB-121 (referenced as Trial 1 in the prescribing label) was the basis for FDA approval and is reviewed in detail.

Table 7. Summary of the Clinical Development Program for Exagamglogene Autotemcel

   SCD: sickle cell disease; TDT: transfusion-dependent thalassemia. a Each participant serves as his/her own control by contributing a primary size-matched wound pair to be randomized to receive weekly topical application of either gene therapy or the placebo (excipient gel).

Pivotal Study

Study characteristics, baseline patient characteristics and results are summarized in Tables 8 to 10, respectively. The pivotal CLIMB-121 was a single-arm, 24-month, open-label, multicenter study. At the time of the interim analysis (June 2023), a total of 63 individuals enrolled in the trial, of which 58 (92%) started mobilization. A total of 44 (76%) participants received exagamglogene autotemcel infusion. Of these, 31 participants (70%) had adequate follow-up to allow evaluation of the primary efficacy endpoint and formed the primary efficacy set. The mean (SD) and median (range) number of mobilization and apheresis cycles required for the manufacture of exagamglogene autotemcel and for the back-up collection of rescue CD34+ cells were 2.3 (1.41) and 2 (1, 6), respectively. Six (10%) patients were unable to receive exagamglogene autotemcel therapy due to not achieving the minimum dose. The primary efficacy outcome was the proportion of responders defined as participants who did not experience any protocol-defined severe vaso-occlusive crises (VOCs) for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion. The proportion of patients who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was a key secondary endpoint. The primary endpoint was achieved by 29 of 31 or 93.5% participants. The key secondary endpoint of patients who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants.

Safety data includes data from 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of patients with sickle cell disease. The most common serious adverse reactions (≥2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain (upper), non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. Although not observed in healthy donors and study participants, the risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants cannot be ruled out.

The purpose of the study limitations tables is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time period. The median (range) duration of follow-up in the pivotal trial was 19.3 months. Of the 29 study participants who met the definition of responder for the primary efficacy endpoint, one study participant experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization; this study participant was reported to have a parvovirus B19 infection at the time. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as side effects. While no cases of malignancies or unintended, off-target genome editing were reported in the trial participants, off-target editing in an individual’s CD34+ cells cannot be ruled out due to genetic variants especially in the larger, real-world, population. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about off-target genome editing risk.

Table 8. Summary of Key Pivotal Trial

   a sVOCs were defined as an occurrence of at least 1 of the following: 1) acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous non-steroidal anti-inflammatory drugs) or RBC transfusions; 2) acute chest syndrome; 3) priapism lasting >2 hours and requiring a visit to a medical facility; 4) splenic sequestration. b The evaluation started 60 days after last RBC transfusion for posttransplant support or SCD management. The median (min, max) time to last RBC transfusion after infusion of exagamglogene autotemcel in the primary efficacy set was 19 (11, 52) days. HSCT; hematopoietic stem-cell transplantation; sVOCs: severe vaso-occlusive crises. 

Table 9. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Trial

   a Interim analysis conducted based on June 2023 data cut-off date. b The primary efficacy set is a subset of the full analysis set. The subset was defined as all patients who had been followed for at least 16 months after exagamglogene autotemcel infusion. Patients who had less than 16 months follow-up due to death or discontinuation due to exagamglogene autotemcel -related adverse events, or continuously received RBC transfusions for more than 10 months after exagamglogene autotemcel were also included in this set. An additional patient who had less than 16 months of follow-up but was otherwise determined to be a non-responder for the primary efficacy endpoint, was also included in the subset. VOCs: vaso-occlusive crises.

Table 10. Summary of Key Results in Pivotal Trial

   a sVOCs were defined as an occurrence of at least 1 of the following: 1) acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous non-steroidal anti-inflammatory drugs) or RBC transfusions; 2) acute chest syndrome; 3) priapism lasting >2 hours and requiring a visit to a medical facility; 4) splenic sequestration. C; confidence interval; Hb: hemoglobin; HbF: fetal hemoglobin; SD: standard deviation; VOC: veno-occlusive crisis. 

Table 11. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Section Summary: Exagamglogene autotemcel

In the pivotal, single-arm study CLIMB-121, a total of 44 study participants received a single intravenous infusion of exagamglogene autotemcel. Of the 44 total participants, 31 were evaluable for the primary endpoint. The primary endpoint of proportion of study participants who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion was achieved by 29 of 31 or 93.5% study participants. The key secondary endpoint of proportion of study participants who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants. Safety data includes 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of study participants. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. After the primary evaluation period to last follow-up, one of the 29 study participants who achieved primary endpoint experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as side effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants.

Summary of Evidence

For individuals who are 12 years and older with sickle cell disease who receive exagamglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality, and treatment-related morbidity. In the pivotal single-arm study CLIMB-121, a total of 44 study participants received a single intravenous infusion of exagamglogene autotemcel. Of the 44 total participants, 31 were evaluable for the primary endpoint. The primary endpoint of proportion of study participants who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion was achieved by 29 of 31 or 93.5% study participants. The key secondary endpoint of proportion of study participants who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants. Safety data includes 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of study participants. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. After the primary evaluation period to last follow-up, one of the 29 study participants who achieved primary endpoint experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that exagamglogene autotemcel will frequently be successful in treating sickle cell disease in at least short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Hematology Clinical Practice Guidelines on Sickle Cell Disease:

The American Society of Hematology (ASH) in partnership with the Evidence-Based Practice Research Program at Mayo Clinic published five 2019-2021 ASH clinical practice guidelines on sickle cell disease that cover sickle cell disease-related 1) cardiopulmonary and kidney disease, 2) transfusion support, 3) cerebrovascular disease, 4) acute and chronic pain and 5) stem cell transplantation. These guidelines are available online and are updated annually. ^20, Current version of the guidelines does not mention use of lovotibeglogene autotemcel or exagamglogene autotemcel. Recommendation from the 2021 guidelines for stem cell transplantation are summarized briefly. ^21, The ASH guideline panel suggests:

• HLA-matched related HSCT rather than standard of care (hydroxyurea/transfusion) in patients with sickle cell disease who have experienced an overt stroke or have an abnormal transcranial Doppler ultrasound (conditional recommendation. very low certainty in the evidence).

• Using related matched allogeneic transplantation rather than standard of care for patients with frequent pain (conditional recommendation, very low certainty in the evidence about effects).

• Using matched related allogeneic transplantation over standard of care for patients with recurrent episodes of acute coronary syndrome (conditional recommendation, very low certainty in the evidence about effects).

• Using transplants from alternative donors in the context of a clinical trial for patients with sickle cell disease with an indication for HSCT who lack a matched sibling donor (conditional recommendation, very low certainty in the evidence about effects).

• Using allogeneic transplantation at an earlier age rather than an older age in patients with an indication eligible for HSCT (conditional recommendation, low certainty in the evidence about effects).

• Use HLA-identical sibling cord blood when available (and associated with an adequate cord blood cell dose and good viability) over bone marrow (conditional recommendation, very low certainty in the evidence about effects).

Institute for Clinical and Economic Review

The Institute for Clinical and Economic Review published a final report on gene therapies for sickle cell disease on August 21, 2023. The Report concluded that for people with severe sickle disease lovotibeglogene autotemcel to be incremental or better with moderate certainty of a small or substantial net health benefit (“B+”) versus standard of care and exagamglogene autotemcel to be comparable or better with moderate certainty of a comparable or small or substantial net health benefit (“C++”). ^22,

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

   NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

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19. Prescribing label for Casgevy (exagamglogene autotemcel) suspension for intravenous infusion. Available at https://pi.vrtx.com/files/uspi_exagamglogene_autotemcel.pdf. Accessed December 14, 2023.
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Codes

Policy History