Only a couple of years since the first sickle cell disease (SCD) gene therapies gained U.S. FDA approval, researchers are working to expand access for younger children, and to improve manufacturing and commercialization to reach patients faster.

While expensive – wholesale acquisition costs (WAC) of Vertex Pharmaceuticals Inc.’s Casgevy (exagamglogene autotemcel, exa-cel) and Genetix Biotherapeutics Inc.’s Lyfgenia (lovotibeglogene autotemcel, lovo-cel), upon their December 2023 approvals, were set at $2.2 million and $3.1 million, respectively – the one-time therapies are life-changing for patients previously facing severe pain, anemia, repeated transfusions and a shorter lifespan. While chronic treatment with hydroxyurea, or hematopoietic stem cell transplantation (HSCT), along with transfusions, are currently available therapies, gene therapies still command the headlines.

“It is not that long ago that there was public speculation about whether gene therapies for these diseases would ever be available for patients,” said Joanne Lager, chief medical officer of Somerville, Mass.-based Genetix, formerly Bluebird Bio Inc., which also gained FDA approval of Zynteglo (betibeglogene autotemcel) for adult and pediatric patients with beta-thalassemia in 2022, setting a $2.8 million WAC for the one-time intravenous infusion.

Lager participated in a briefing Dec. 3 previewing oral presentations scheduled for the American Society of Hematology’s (ASH) 67th annual meeting in Orlando, Fla., Dec. 6-9. Her talk on Dec. 8 will focus on what her company learned from creating a commercial gene therapy operation, with Lyfgenia benefitting from infrastructure already put into place for Zynteglo. Another gene therapy presentation set for Dec. 6 will roll out results of exa-cel, the first and only approved CRISPR/Cas9 gene editing therapy, in pediatric patients with both transfusion-dependent beta-thalassemia (TDT) or SCD with recurrent severe vaso-occlusive crises. Both SCD gene therapies are approved only for those 12 and older.

Based on the pediatric results, “exa-cel has the potential to provide a one-time functional cure for children aged 5 to 11 years with TDT or sickle cell disease and has potential for greater benefit by treatment before they develop chronic end organ damage,” said Haydar Frangoul, the director of the pediatric stem cell transplant program at Tristar Centennial Children’s Hospital’s Sarah Cannon Research Institute.

In the Climb Thal-141 phase III trial in TDT, 100% (6 of 6) of evaluable pediatric patients achieved transfusion independence for at least 12 months, while maintaining a weighted average hemoglobin of at least 9 g/dL. The mean duration of transfusion independence was 19.8 months (14 to 22 months). Twelve of 13 participants were able to stop red blood cell transfusion at the mean of 1.3 months, with a transfusion-free duration ranging from 2.3 months to 22.5 months.

In the Climb SCD-151 phase III trial, 100% (4 of 4) of those evaluable achieved vaso-occlusive crisis (VOC) independence for at least 12 consecutive months, and they were also hospitalization-free, with a duration of follow-up ranging from 3.2 months to 24.1 months. “Pediatric and adolescent participants have fewer VOC events after exa-cel than adult participants, consistent with the treatment prior to the onset of chronic organ damage including chronic pain,” Frangoul said.

For both trials, there were also durable increases in pancellular fetal hemoglobin levels, and the safety profile was consistent with myeloablative busulfan and autologous HSCT.

Nearly half of the 13 enrolled TDT patients had the most severe genotype of SCD, β0/β0 or β0/β0-like, and the mean age was 7, with 12 out of 13 patients having an intact spleen and patients receiving blood transfusion of about 232 ml/kg per year. The mean age was 8 for the 11 enrolled SCD patients, all of whom had the severe genotype βS/βS, and historically severe VOC events of about three on average per year, with an average of two hospitalizations a year.

The safety profile is “consistent with what we would expect from high-dose busulfan chemotherapy and autologous stem cell transplant,” Frangoul said, and similar to that seen among those ages 12 to 35. In the TDT trial, 15.4% (2/13) of those ages 5-11 developed vaso-occlusive disease of the liver, compared to 12.5% in older patients (7/56).

After they receive the therapy, the children will be followed for 15 years. “We want to make sure this is durable,” he said, adding that those in the 12 to 35 age group have been followed for more than seven years. “There have been no malignancies in our program in the older patients,” he said, adding that they will also monitor to see if the gene therapy can prevent long-term organ damage. “We have every reason to believe that this is going to be the case because what we have seen in the older patient is that this is durable, but we need to continue to do due diligence in the younger population.”

Costs, commercial demand

Acknowledging that cost is a factor with gene therapies, Frangoul said that an analysis comparing HSCT and its associated complications, such as graft-vs.-host disease (GVHD), with the price of gene therapies has not been done. “The big advantage of gene therapy,” he said, “[is] it’s a one-time therapy. There is no risk of graft failure, for example … and there is no risk of graft-vs.-host disease, which can also affect the overall cost over many years of allogeneic transplantation. … I am looking forward in the future for researchers to actually do these analyses and figure out the economics of all of this. But I am very glad that these therapies are currently available for our patients that don’t have a naturally identical sibling.”

Lager said her company’s real-world analysis of the Zynteglo and Lyfgenia launches highlights the commercial demand for gene therapies to treat SCD and thalassemia, as well as the need for scalability. The experience at Genetix “sets a benchmark” for delivery and reinforces the value, she said.

While the number of patients treated with the company’s gene therapies is not widely known, Lager disclosed that 369 patients are currently enrolled to receive either Zynteglo (173) or Lyfgenia (196), with collection initiated for 122 and 94 of them, respectively. Of those, 78 have been treated with Zynteglo and 37 were treated with Lyfgenia, for a total of 115 patients.

“The startup was [about two times] faster for Lyfgenia vs. Zynteglo,” she said, “which we attribute to experience and having infrastructure in place at the time of the Lyfgenia launch.” Genetix is now expanding its manufacturing capacity to move quickly when patients are ready, and is enhancing its mobilization and collection efforts so that only one collection needs to be done, in an effort to try “to improve timelines for patients,” she said.

Hydroxyurea, adherence and HSCT

Other ASH presentations of note in the SCD space include one evaluating pregnancy outcomes in those treated with hydroxyurea, indicating 0% mortality and no specific adverse effects in mothers or newborns, based on a study presented by a scientist from France’s Henri-Mondor University Hospital; plus another focused on timeliness of pain medication administration, based on ASH and National Heart, Lung and Blood Institute guidelines, in hospital emergency departments. The latter study found significant variations based on patient demographics and facilities. Looking at 398,895 emergency visits for uncomplicated sickle cell pain at 233 sites between 2019 and 2024, the study presented by a Nemour’s Children’s Health scientist, found 30% guideline adherence for those older than 19 vs. 52% for those 19 and younger; 29% for females vs. 37% for males; and 65% for pediatric sites vs. 30% for general sites.

And a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis looked at the long-term survival and late effects of HSCT, finding that outcomes were superior in patients undergoing the therapy at a younger age, using bone marrow from a matched sibling, as opposed to an alternative donor, and in those who remain GVHD-free. The analysis included data from 1,013 patients, with a median age of 12, who had received HSCT from 1996 to 2022. Nearly three-quarters of the cohort experienced no late effects, while the others reported noninfectious liver toxicity or pulmonary toxicity, as well as diabetes, gonadal dysfunction and avascular necrosis. Two percent developed a malignancy post-transplant, and 9% (80 patients) died of organ failure, infection, GVHD or SCD itself. Overall survival was 95% at one year and 90% at seven years, while rejection-free survival was 89% at one year and 83% at seven years. Among those with severe GVHD, rejection-free survival was 68% at one year and 83% at seven years.

Whether patients choose hydroxyurea, transfusions, gene therapies or HSCT, “I think there’s a real need to compare the long-term outcomes from all of these therapies, which are still relatively new and really require decades of follow-up in a large number of patients to really adequately compare, so I think our analysis sets the stage in a registry-based cohort what those late effects look like with our median follow-up of 60 months,” said Elizabeth Stenger, an associate professor of pediatrics at Emory University School of Medicine’s Aflac Cancer and Blood Disorders Center.