Innovations in hemophilia, sickle cell disease, and thalassemia at Penn Medicine

Penn Medicine has made substantial contributions to the development of therapies for hemophilia and the hemoglobinopathies, often in partnership with colleagues at the Children’s Hospital of Philadelphia. These advances have occurred either through direct involvement in the development of these treatments, or by their early adoption as they emerge in the field. The introduction of these transformative therapies at Penn Medicine precedes their wider use regionally in the general medical community, and brings these innovations to patients in need.

Leaders in hemophilia research

The first mice with hemophilia B engineered using gene-targeting techniques to disrupt the coagulation factor IX gene were developed by a research team at the Transgenic and Chimeric Mouse Facility at the University of Pennsylvania in the mid-1990s. Within five years, Penn researchers were among the first to determine that adenoviral vectors expressing human factor IX could correct the bleeding diathesis of hemophilia B.

Factor IX (FIX) is an essential clotting factor, and its deficiency (hemophilia B) is the second most common genetic coagulation factor deficiency in human beings. FIX deficiency disrupts the clotting cascade and is the cause of increased bleeding in Hemophilia B.

Several FIX prophylactic replacement therapies are available, including recombinant and plasma-derived concentrates; but individuals using these agents are known to have the potential to develop neutralizing antibodies (inhibitors). In addition, says Adam Cuker, MD, MS, Director of the Penn Comprehensive Hemophilia and Thrombosis Program, patients need to infuse FIX replacement products on a regular basis throughout their lives to prevent and treat bleeds.

Infusions aren’t the only imposition for individuals on FIX replacement therapy, Dr Cuker notes.“These patients have to refrain from high-risk activities that might trigger bleeds,” he says. “They worry about what to do if they have a breakthrough bleed while traveling. They worry about insurance coverage for therapy should they have to stop working.”

Etranacogene dezaparvovec-drlb, the first gene therapy for hemophilia B

Etranacogene dezaparvovec-drlb (Hemgenix®), the first FDA-approved single-use gene therapy, is approved for adults >18 years of age with severe hemophilia B who currently use factor IX replacement therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

Dr. Cuker was the principal investigator of the BENEGENE-2 clinical trial that prompted the FDA-approval of the second available gene therapy for hemophilia B, fidanacogene elaparvovecgene. The findings of this trial were reported in the New England Journal of Medicine in September 2024, several months after fidanacogene elaparvovecgene was approved for the treatment of adults with severe and moderately severe hemophilia B.

Hemgenix at Penn

Dr. Cuker, who has been administering Hemgenix since October 2024, observes that gene therapy has been life-changing for his patients with hemophilia B.

“After receiving gene therapy, their bodies are making factor IX for the first time in their lives,” he says. “Now they no longer needed regular infusions. They no longer bleed. And they’re able to participate in activities and travel in ways they could never have dreamed of before.”

Hemgenix treats the underlying cause of hemophilia B by restoring the native hepatic production of factor IX proteinve by delivering a functional copy of the factor IX gene into liver cells via an adeno-associated virus vector carrier.

Hemgenix was approved on the basis of the HOPE B clinical trial, an ongoing, multinational, open-label, single-arm study. HOPE B demonstrated that Hemgenix resulted in a mean factor IX activity of 39% at six months and 36.7% percent at 24 months post infusion. Seven to 18 months post-infusion, the mean adjusted annualized bleeding rate for all bleeds was reduced by 54% compared to the six-month lead-in period, during which patients received factor IX prophylactic replacement therapy. Importantly, 94% of patients treated with Hemgenix discontinued use of prophylaxis and remained free of previous continuous routine prophylaxis therapy.

In Pennsylvania, Hemgenix is available only at the Penn Comprehensive Hemophilia and Thrombosis Program (PCHP) and the Children’s Hospital of Pennsylvania. The PCHP is a part of the Penn Blood Disorders Center at Penn Medicine, and collaborates with CHOP to offer specialized care for bleeding disorders.

Firsts in Hemoglobinopathies: Innovation in SCD & Thalassemia at Penn

In 1989, a group of researchers at the University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP) were able to synthesize, for the first time, functional human hemoglobin in transgenic mice. The result, they reported in a pioneering article in Science, “provides a foundation for production of mouse models of human hemoglobinopathies such as sickle cell disease.”

In the years since, the treatment of the hemoglobinopathies has been hastened by innovations in gene transfer techniques, stem cell engineering, and other advances in personalized medicine, both at Penn Medicine and elsewhere.

Beti-cel: first gene therapy for transfusion-dependent beta-thalassemia

Betibeglogene autotemcel, (beti-cel), is the first FDA-approved gene therapy for the treatment of transfusion-dependent beta-thalassemia.

Beti-cel is currently available at Penn Medicine at the Penn Comprehensive Adult Thalassemia Program, directed by Scott Alan Peslak, MD, PhD, an Assistant Professor of Medicine and Gene Therapy at the Hospital of the University of Pennsylvania (HUP).

“We’re excited to be able to provide this innovative treatment option to the thalassemia community and continue cutting-edge research here at UPenn,” Dr. Peslak says, adding that in collaboration with the Cell Therapy and Transplant program at HUP, over the past year the first two patients were successfully treated with beti-cel and both are now transfusion-independent.

Beta-thalassemia is an inherited red cell disorder caused by mutations in the beta-globin gene that lead to a reduction or absence of hemoglobin. The major complications of beta-thalassemia are due primarily to severe anemia and ineffective red cell production in the bone marrow.

For many patients, treatment for beta-thalassemia includes regular red cell transfusions to allow for normal growth and development and for prevention of complications including bone deformities, enlarged spleen and liver, and decreased bone mineral density. However, transfusions can also lead to progressive iron overload, which can cause iron accumulation in the liver, heart, and endocrine organs if not properly treated with chelation therapy.

Beti-cel was approved in August 2022 as a one-time cellular gene therapy for the treatment of transfusion-dependent beta-thalassemia. Treatment involves mobilizing and collecting a patient’s stem cells and genetically modifying these cells to produce functional beta-globin. Following collection and manufacturing, patients receive busulfan (a form of chemotherapy) to make room in the bone marrow for the new gene-modified stem cells, which are reinfused as a single-dose autologous stem cell transplant.

The safety and effectiveness of beti-cel in transfusion-dependent thalassemia was established in a pair of multicenter clinical trials, with effectiveness based on achievement of transfusion independence for a period of at least 12 months. Of 41 patients receiving beti-cel, 90 percent achieved transfusion independence.

Beti-cel is available at the Penn Comprehensive Adult Thalassemia Program, which is housed at the Hospital of the University of Pennsylvania and the Perelman Center for Advanced Medicine, serving as one of the few of its kind in the nation exclusively focused on the unique needs of adults with thalassemia.

Lovo-cel: transformative gene therapy for sickle cell disease

Lovo-cel is among the first FDA-approved gene-modifying agents for the treatment of adults with sickle cell disease (SCD).

SCD is an inherited blood disorder caused by a single mutation in the beta-globin gene, which results in the formation of stiff, crescent-shaped red blood cells that cause the blockage of small blood vessels (vaso-occlusion) and increased breakdown of red cells (hemolysis). These changes lead to anemia and decreased oxygen delivery to the body, causing severe pain and organ damage.

To decrease the frequency of pain and improve outcomes, patients with sickle cell disease are treated with a variety of disease-modifying therapies, including hydroxyurea, to increase the protective fetal form of hemoglobin or red blood cell transfusions to reduce the amount of sickled red blood cells and prevent organ damage. However, this treatment requires lifelong continuous therapy.

Scott Peslak, MD, the gene therapy lead for the HUP Comprehensive Sickle Cell Program, notes that it has been a 25-year journey to bring gene therapy-based approaches to patients with SCD. Among the gene therapies now available, he adds, is lovo‑cel, a one-time gene addition therapy for patients with sickle cell disease.

“In partnership with the Cell Therapy and Transplant program, this transformative cellular therapy is now available at Penn to help prevent painful vaso-occlusive episodes, or VOEs, and enable patients living with sickle cell disease to thrive in the community,” Dr. Peslak said in a recent interview.

Approved in December 2023 to reduce the frequency of VOEs in patients with SCD, lyfgenia treatment involves mobilizing and collecting a patient’s stem cells and genetically modifying them to produce an anti-sickling form of hemoglobin. As with Zynteglo, following collection and manufacturing, patients receive busulfan to make room in the bone marrow for the new gene-modified stem cells, which are reinfused as a single-dose autologous stem cell transplant.

The FDA approval of lovo-cel was based on the single-arm, 24-month multicenter lovo-cel study which enrolled SCD patients with a history of VOE between the ages of 12 and 50 years of age. Effectiveness was evaluated based on complete resolution of VOEs between 6 and 18 months after infusion with lovo-cel. During this time period, 88 percent of patients achieved complete resolution of VOEs.

Lovo-cel is available at the Penn Comprehensive Sickle Cell Program. Housed at the Hospital of the University of Pennsylvania and the Perelman Center for Advanced Medicine, it offers subspecialized, multidisciplinary, evidence-based care for adult SCD patients.

Referrals and consultations

To get a second opinion or consultation from a Penn hematologist, please call 877-937-7366 or refer a patient online. The Sickle Cell Program at Penn Medicine can be reached directly at 215-615-6555.