Trial of Gene-editing Therapy for Severe SCD Now Enrolling in US

Recruitment underway for 15 patients for Phase 1/2 trial testing BEAM-101

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by Steve Bryson, PhD |

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Recruitment is now underway in BEACON, a Phase 1/2 U.S. trial testing BEAM-101, a transplant-based gene-editing cell therapy for sickle cell disease (SCD).

The interventional study, in which all participants will be given a single dose of the experimental treatment, is expected to enroll up to 15 adults with SCD, ages 18–35. All eligible patients for the gene-editing trial will have severe sickle cell disease.

Sponsored by Beam Therapeutics, the therapy’s developer, the trial will held at Boston Children’s Hospital, in Massachusetts. Interested patients may contact Stephen Huang, MD, at 603-401-2798, or via email at [email protected].

“Bringing a novel transplant-based medicine into clinical development in the U.S. has been a tremendous effort, and we are laser-focused on screening and site activation efforts to enroll our first sickle cell patient by year-end,” John Evans, Beam’s CEO, said in a press release.

“Our top priority is executing the BEACON trial for BEAM-101,” Evans added.

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BEAM-101 is part of the company’s Wave 1 strategy to rapidly advance a disease-modifying therapy for people with SCD. The genetic blood disorder is caused by mutations that lead to the production of an abnormal form of hemoglobin — the protein in red blood cells that carries oxygen.

The therapy is designed to enable the production of fetal hemoglobin (HbF) to compensate for the lack of functional adult hemoglobin.

Usually, most people stop making HbF and start producing the adult form of the protein within the first few months after birth. By activating HbF — a form of hemoglobin that is more efficient at carrying oxygen than its adult counterpart — BEAM-101 may lessen the symptoms of SCD and other inherited blood diseases caused by hemoglobin defects. This includes beta-thalassemia.

To be eligible for BEACON, patients must have severe SCD, defined by the occurrence of at least four severe and typically painful vaso-occlusive crises (VOCs) in the two years prior to study screening. Such crises will have occurred despite patients receiving hydroxyurea or other supportive therapies. In a VOC, sickled red blood cells block blood flow so severely that tissues become deprived of oxygen.

According to the BEACON trial (NCT05456880) protocol, once the first patient is enrolled, the individual will undergo a procedure to retrieve blood cell precursors, called hematopoietic stem cells (HSCs), from the bone marrow.

These cells are then gene-edited to activate HbF, creating a BEAM-101 product that is patient-specific.

After that first procedure, the patient will receive pre-transplant conditioning using a standard-of-care chemotherapy regimen to eliminate HSCs currently living in the bone marrow. This procedure ensures that only newly engineered cells can repopulate the bone marrow and make HbF.

Following a manufacturing process to increase cell numbers, edited cells are returned to the same patient, by intravenous (into-the-vein) injection, in the form of a stem cell transplant.

With successful engraftment of the first patient, treatment of a second participant can proceed.

One of BEACON’s main goals is to evaluate changes in the annualized number of severe VOCs, which will be assessed six months after treatment. In addition to safety and tolerability, other outcomes include the time until engraftment of various types of blood cells over two years, and transplant-related mortality within 100 days (3.2 months) after treatment.

Due to the current regulations covering SCD trials, Beam is working to amend the BEACON protocol to enable trial modifications that will streamline and expedite patient enrollment, and eventually seek regulatory approval on data generated from the study.

The company also is planning to finalize its manufacturing process for BEAM-101 by making the required investments.

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Beam’s Wave 2 strategy, which includes Engineered Stem Cell Antibody Paired Evasion (ESCAPE), aims to improve the conditioning regimen for patients undergoing HSC transplants.

Because current conditioning regimens use toxic chemotherapy agents, these approaches have safety risks. ESCAPE is an antibody-based method designed to eliminate HSCs from the bone marrow, while allowing engineered cells to “escape” and become established with reduced toxicity.

The company has announced its plans to present new data on ESCAPE at the upcoming American Society of Hematology (ASH) annual conference. The 64th ASH Annual Meeting and Exposition will take Dec. 10–13, virtually and in person in New Orleans, Louisiana.

Meanwhile, Beam’s Wave 3 strategy is focused on the delivery of gene editors directly to HSCs using lipid nanoparticles — tiny particles made up of fatty molecules.

As a result of all these efforts, the company has decided to postpone clinical testing of BEAM-102. That investigational gene-editing therapy directly alters an SCD-causing mutation; such an approach would create the naturally occurring version of normal adult hemoglobin, called HbG-Makassar.

Overall, the company says it has changed its strategy, and first will optimize its Makassar approach, as well as its HbF strategy, instead of asking permission from regulators to begin testing BEAM-102 in human trials.

“We are also accelerating our overall BEAM-101 development program, where we see an opportunity to potentially seek regulatory approval on data generated from the BEACON trial,” Evans said.

Thus, the company will not file an investigational new drug (IND) application in 2022 for BEAM-102.

“Instead, we will take the opportunity to streamline the BEACON trial while focusing the next phase of our investment in sickle cell disease on our Wave 2 programs for non-genotoxic conditioning, as well as our Wave 3 strategy for in vivo lipid nanoparticle delivery of base editors, continuing to leverage both HbF and Makassar editing strategies,” Evans said.