Bluebird Bio nears moment of truth as FDA evaluates its gene therapies

The two-day meeting could determine the future of the struggling company and be a bellwether for similar gene therapies

A researcher at Bluebird Bio.Pat Greenhouse/Globe Staff

Bluebird Bio will make a case to the US Food and Drug Administration and its committee of independent scientists on Thursday and Friday that two of its experimental gene therapies are safe and effective enough to warrant approval — despite cases of cancer in a few patients participating in clinical trials.

It marks a make-or-break moment for the struggling Cambridge biotech, whose stock is down nearly 98 percent over three years following a failed product launch in Europe, safety concerns surrounding its gene therapies, and a broader market slump in the biotech industry.’

At the two-day meeting, the FDA’s Cell, Tissue, and Gene Therapies Advisory Committee will hear from Bluebird and FDA scientists. Each group will present its own interpretations of the data from Bluebird’s clinical trials of two gene therapies: eli-cel for a lethal neurodegenerative disease that afflicts young children, and beti-cel for the rare blood disease beta-thalassemia.

At the end of each day, the advisory committee will vote to recommend whether the drugs should be approved or rejected. The FDA often, but not always, sides with advisory panel recommendations. That decision is due by mid-August for beti-cel and by mid-September for eli-cel, which targets cerebral adrenoleukodystrophy, a genetic disease depicted in the 1992 film “Lorenzo’s Oil.”

With only enough cash to last into the first half of 2023, the firm will likely not survive if both therapies are rejected.

“We’re all rooting for them and hoping for [two] approvals here,” Nicole Paulk, an assistant professor of gene therapy at the University of California, San Francisco, said in an e-mail. “I’d be shocked, truly shocked, if beti-cel wasn’t approved, so for me the bigger question is if eli-cel gets a nod as well.”

Each treatment starts by collecting a patient’s blood stem cells, which carry a defective copy of the gene that causes their disease. Scientists use an engineered virus called a lentiviral vector to deliver a healthy copy of a gene into those cells. Patients then undergo chemotherapy to clear out space in their bone marrow for the engineered stem cells to engraft.

For nearly three decades, Bluebird — originally founded as Genetix Pharmaceuticals — has worked to make lentiviral gene therapies a reality. Although lentiviral vectors are used to make FDA-approved cell therapies for treating cancer, beti-cel and eli-cel could become the first products based on the technology for treating genetic diseases in the US.

“Bluebird Bio has been a pioneer in lentiviral gene therapy from the start. They bet on lentiviral gene therapy in the early days when it was really hard to find a path to commercial success,” said Gwen Binder, president of science and technology at Cabaletta Bio, a company using lentiviral to make cell therapies for cancer. “If any company deserves to succeed with these approvals in the US, it is Bluebird Bio.”

Lentiviruses have the advantage of inserting that gene directly into a person’s DNA, a permanent change that promises to make the gene therapy a one-and-done treatment. But that permanency also carries risks.

If the gene is haphazardly inserted into an important stretch of DNA, it can disrupt mechanisms that protect cells from dividing uncontrollably, potentially leading to cancer. In fact, a few people in Bluebird’s trials developed blood cancers. Through genetic sleuthing, the firm said that some, but not all, of the cases were in fact related to the gene therapy. The chemotherapy that patients must undergo before getting the gene therapy can cause cancer, too.

The advisory committee is expected to discuss the safety risks of the gene therapies in detail. For cerebral adrenoleukodystrophy, a lethal childhood disease with few options for treatment, the committee and the FDA will have to weigh the risks of the therapy against the disease itself. Whichever way the committee and agency lean could be a bellwether for other companies developing lentiviral gene therapies.

Paulk said that the FDA decision “should largely only have implications for other lentivirally-edited cell therapies,” and not the gene therapy field at large. Many gene therapy firms use a different engineered virus — the adeno-associated virus — which delivers a therapeutic gene that sits alongside a person’s DNA, but is not directly integrated into it.

The FDA’s briefing documents posted online ahead of the meeting indicate that about 90 percent of beta-thalassemia patients who received Bluebird’s beti-cel went two or three years without needing the usual blood transfusions they require for maintaining healthy levels of blood cells. The FDA said that this transfusion independence “represents a clinically meaningful benefit for patients,” but that the benefit-risk profile of the treatment “is not completely characterized.”

The FDA’s analysis for eli-cel was less rosy. Although Bluebird’s study suggested that its therapy improved survival in children with cerebral adrenoleukodystrophy, the agency said that issues with the study “make the results difficult to interpret.” Three cases of blood cancer among the 67 patients treated with eli-cel also raise questions about the therapy’s safety, the agency said.

Binder anticipates that approval of either Bluebird therapy would come with the requirement for “significant post-approval monitoring,” and thinks it is unlikely that the agency would reject the treatments outright. The fact that beti-cel and eli-cel are both approved in Europe bodes well for Bluebird, she added. “European regulators are usually highly stringent.”

Beti-cel won European approval in June 2019. But European payers balked at the one-time therapy’s eye-popping price tag of about $1.8 million. With no takers for the drug, Bluebird began closing its sales operations there last August.

The firm is hoping to have more luck in the US, where Roche sells an $850,000 gene therapy for a genetic form of blindness and Novartis sells a $2.1 million gene therapy for a rare childhood neurodegenerative disease.

In fact, the Institute for Clinical and Economic Review, a Boston drug pricing watchdog, recently said that a cumulative $2.1 million price tag for beti-cel could be justified if the costs were paid over several years and prorated based on the therapy’s effectiveness in an individual.

Even if the drug launches in the US, it could face competition from other companies developing one-and-done treatments for beta-thalassemia. CRISPR Therapeutics and Vertex Pharmaceuticals are jointly developing a single gene editing treatment for both beta-thalassemia and sickle cell disease, which the firms expect to submit to regulators by the end of the year.