Lovo-cel Testing on Children, Teens With SCD Resumes After Stoppage

Holdup stemmed from teen who developed persistent anemia after treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

Share this article:

Share article via email
An illustration of a repeating thumbs-up icon is shown.

Bluebird bio will resume its study of lovotibeglogene autotemcel (lovo-cel) in children and adolescents with sickle cell disease (SCD) following the U.S. Food and Drug Administration’s (FDA’s) lifting of its yearlong partial clinical hold for patients under age 18.

The temporary holdup stemmed from an investigation into an adolescent who developed persistent anemia after treatment with the experimental gene therapy.

The investigation revealed the adolescent carried two deletion mutations, called -alpha3.7/-alpha3.7, in a gene containing instructions to make the protein alpha-globin. The faulty gene causes alpha-thalassemia trait, which results in unusually small red blood cells and mild anemia. The same two deletion mutations were identified in an adult patient who also developed persistent anemia following lovo-cel treatment.

While these were the only patients in the study with this specific gene combination, -alpha3.7/-alpha3.7 deletion mutations will now be part of the list of exclusion criteria for ongoing lovo-cel studies.

Recommended Reading
Endari | Sickle Cell Disease News | Treatments | Illustration of medical professional with patient

Nula-cel (GPH101) Gene Therapy Phase 1/2 Trial Doses 1st Patient

“We are very pleased to have addressed the FDA’s questions and resolved the partial clinical hold,” said Richard Colvin, MD, PhD, Bluebird’s chief medical officer, in a press release. “We are working closely with study investigators and clinical trial sites to resume enrollment and treatment of pediatric and adolescent patients in the first quarter of next year.”

With the study unlocked for patients under 18, the company remains on track to file a biologics license application for the FDA to approve lovo-cel for SCD in the first quarter of 2023.

Results of lovo-cel investigation

Results from the investigation were shared in an oral presentation at this year’s American Society of Hematology (ASH) Annual Meeting, Dec. 10–13 virtually and onsite in New Orleans, Louisiana. It was titled, “Lovo-cel (bb1111) Gene Therapy for Sickle Cell Disease: Updated Clinical Results and Investigations into Two Cases of Anemia from Group C of the Phase 1/2 HGB-206 Study.”

People with SCD produce a faulty version of hemoglobin, known as hemoglobin S, that results from mutations in the HBB gene. Hemoglobin is a protein in red blood cells that transports oxygen and the HBB gene provides instructions for making a part of it.

Hemoglobin S causes red blood cells to acquire a sickle-like shape that makes them fragile and die prematurely, causing anemia. They also become more sticky and are prone to blocking small blood vessels, causing severe pain and damage to internal organs. This is called a vaso-occlusive episode (VOE).

Lovo-cel, previously known as bb1111 or LentiGlobin, is a one-time treatment designed to add working copies of a modified version of the HBB gene into a patient’s own blood stem cells, which are then infused back into the patient.

Once HbAT87Q — the protein coded by the modified version of the HBB gene — begins to be produced, the proportion of hemoglobin S decreases. This is expected to ease symptoms.

HGB-206 (NCT02140554) is an ongoing Phase 1/2 study that’s evaluating the safety and effectiveness of lovo-cel in up to 50 people, ages 12 to 50, with a diagnosis of SCD. The study includes three treatment groups — A, B, and C.

All 35 patients in Group C received lovo-cel, after which they were followed for a median of 20.9 months.

Treatment also requires the use of busulfan, a medication used before a stem cell transplant to destroy a patient’s existing blood-making cells. After the transplant, modified stem cells begin to “engraft,” or start to grow and produce normal blood cells, rebuilding the immune system.

Engraftment of neutrophils, a type of white blood cells, occurred on day 20; engraftment of platelets, which help form blood clots to slow or stop bleeding, occurred on day 36.

Median level of HbAT87Q reached 5 grams per deciliter (g/dL) of blood at six months post-treatment and remained stable thereafter. It made up at least 40% of all hemoglobin in the blood.

Of the 29 patients who could be evaluated, 28 had no severe VOEs in the two years after treatment. In the two years before enrolling, these patients had 3.5 VOEs a year.

“One-time treatment with lovo-cel resulted in sustained production of HbAT87Q and near-complete resolution of severe VOEs,” the researchers wrote.

Of all 35 patients, 15 (43%) had at least one serious side effect after treatment. The most common were abdominal pain, drug withdrawal syndrome from opiates, nausea, vomiting, and dehydration.

Both patients with the -alpha3.7/-alpha3.7 deletion mutations had persistent anemia despite adequately producing HbAT87Q. One maintained a total hemoglobin level of 9.8 g/dL at 1.5 years and the other required chronic transfusions to maintain a level of 10.3 g/dL, with otherwise normal complete blood counts.

They also had dyserythropoiesis, or abnormal production of red blood cells in the bone marrow (the spongy tissue found inside most bones). There were no symptoms of blood cancer and no cancer-driving mutations or chromosome abnormalities.

Both had a reduction or resolution of severe VOEs after lovo-cel treatment.