ORLANDO, Fla. – New research being presented at the American Society of Hematology (ASH) meeting is adding to growing evidence that experimental gene therapies may improve the health of people with inherited bleeding and immune disorders, as well as some forms of blood cancer, but progress is not as even as investors would like.

Progress on multiple fronts is freeing a small group of intrepid people from dependence on repeated blood transfusions or stem cell transplant, drawing ongoing interest for companies that have made deep investments in the space.

Together, those advances are delivering on nearly 30 years of fundamental and translational research to provide what is "in almost a predictable manner, providing impressive proof of concept," said George Daley, director of the stem cell transplant program at Boston Children's Hospital, during a Saturday morning briefing. "Simply put, gene therapy works."

Updated results from proof-of-concept trial Northstar (HGB-204), Bluebird Bio Inc.'s phase I/II study of the lentiviral gene therapy Lentiglobin BB305 for beta-thalassemia major, provided one example of the progress. As of Oct. 28, 13 transfusion-dependent beta-thalassemia major patients received Lentiglobin BB305 therapy and Bluebird reported that the modified gene is in all patients and producing the corrected hemoglobin.

Of the nine patients who were treated more than six months ago, all of the five with non-β0/β0 genotypes (representing the largest group of beta-thalassemia patients) and at least six months follow-up are transfusion-free, including three patients who were treated longer than a year ago. The remaining four patients, each with two copies of a specific type of HBB gene mutation known as β0, made progress, requiring fewer transfusions, though did not achieve complete independence, news that sent company shares falling last month when first announced.

So far, the level of transfusion reduction in patients with the β0/β0 genotype ranges from 33 percent to 100 percent. Investors who noted the difference between the groups when earlier data from the study were announced last month panicked almost immediately and Bluebird's shares (NASDAQ:BLUE) fell $19.79, or 22 percent, to close at $70.36. (See BioWorld Today, Nov. 6, 2015.)

"In many patients, HbAT87Q levels have not yet plateaued, so further study with longer follow-up is needed to fully assess the impact on transfusion requirements in these patients," said David Davidson, Bluebird's chief medical officer.

Mark Walters, a doctor at UCSF Benioff Children's Hospital Oakland who worked on the study, said it offered "significant advances" in the treatment of beta-thalassemia. Compared to a bone marrow transplant, which is the only curative therapy currently available, treatment with Lentiglobin BB305 appeared to be safer, in that none of the patients have had a life-threatening complication. Furthermore, he said, because the therapy uses a patient's own stem cells, it bypasses the need to find a blood marrow donor and so should be more broadly available to patients. He told BioWorld Today that the therapy should have no problem being scaled up to accommodate greater numbers of patients in the future.

PATIENT-BY-PATIENT

Despite the progress on beta-thalassemia, concern over data from a phase I study (HGB-206) evaluating BB305 in patients with severe sickle cell disease (SCD) sunk Bluebird shares Monday, sending them down 37.5 percent to close at $52.25. The concern was that, out of three patients dosed in the study to date, just one appears to be benefiting so far. In the other two, the proportion of anti-sickling hemoglobin produced so far is less than is considered to be disease-modifying.

Evaluation of the latter two patients is early, three months post-infusion for one and six-months post-infusion for the other, and Bluebird said that longer follow up data and additional subjects will be needed to get a better picture of the treatment. But investors, and some analysts, aren't in the mood to wait. Both Bank of America/Merrill Lynch and Roth Capital Partners downgraded their ratings on company shares a notch and lowered their target prices.

JPMorgan's Cory Kasimov, who maintains an overweight rating on Bluebird shares, had a different take: "Unfortunately this seems to be the new norm in biotech: watching a product evolve patient-by-patient [both the highs and the lows]. The bottom line is we think it's way too premature to declare SCD dead (not to mention B0/B0 B-Thal)."

CHEMO-FREE

A lentiviral vector also figured into another featured study in which B-cell malignancies were treated with allogeneic hematopoietic stem cell transplantation. Donor T cells were engineered to express a chimeric antigen receptor (CAR) and then programmed to recognize CD19, a protein on the surface of most B cells, and attack the targeted cell. Uniquely, patents were not prepped with chemotherapy, as they have been in other studies, including Bluebird's Northstar trial.

Instead of unmanipulated white blood cells, the current standard treatment following stem cell transplant, researchers hypothesized that an infusion of genetically engineered donor T cells would eradicate progressive disease after stem cell transplant in patients with B-cell malignancies, which include types of leukemia and non-Hodgkin lymphoma. Eight of the 20 total patients in the study obtained remissions, including six complete remissions and two partial remissions.

Response rates were highest for patients with acute lymphocytic leukemia, with four of five patients achieving complete remission. The longest ongoing complete remission is more than 30 months in a patient with chronic lymphocytic leukemia.

James Kochenderfer, of the National Cancer Institute, presented the study and said its findings supported the hypothesis that infusing anti-CD19 donor CAR T cells is a promising method for treating B-cell malignancies that emerge after stem cell transplant. Although Kite Pharma Inc. is using the same CAR in a multicenter trial, this was solely a small academically sponsored trial.

PROGRESS ON WISKOTT-ALDRICH

Five years after another phase I/II trial sponsored first by San Raffaele Telethon Institute for Gene Therapy and later by Glaxosmithkline plc, researchers found gene therapy for the rare genetic disease Wiskott-Aldrich syndrome has held up well. With up to five years of follow-up data on hand for patients who received lentiviral hematopoietic stem cell gene therapy, patients continue to see improvement, said Francesca Ferrua, of San Raffaele Telethon Institute for Gene Therapy and San Raffaele Scientific Institute in Milan, Italy.

As of October, eight patients had been treated at a median age of 2.2 years. All patients were alive after a median follow-up of 3.3 years after treatment and there were no adverse reactions to gene therapy observed after infusion. Six patients with a follow-up period of more than two years after receiving treatment experienced "a marked reduction" in the rate of severe infections and bleeding events after treatment, as compared with before gene therapy, Ferrua said.

"Our plan with GSK is to apply for marketing authorization in, let's say, two years' time," but to treat new patients with the approach as needed under a program supporting experimental therapies on a case-by-case basis, she said.

Asked whether the clinical excitement was warranted given the very small number of patients involved, Daley, the Boston Children's Hospital doctor, pointed out that a lot of the diseases in question start out with very small numbers. "The fact that there's now really clinical proof of principle in a variety of these rare diseases is remarkably exciting."