At Hematological Meeting, More Than Just Biotech Data Runs Blood Red

Xconomy National — 

[Editor’s note: Deputy Biotechnology Editor Ben Fidler co-wrote this story.] The annual American Society for Hematology meeting, held this year in Orlando, FL, ends today. The meeting is a showcase for new data, drugs, and approaches to treat cancers like leukemia, rare genetic diseases, and other maladies that originate in or otherwise affect blood.

But ASH also highlights lessons in investor psychology. Last year, at the conference in San Francisco, strong early data in new treatments for blood cancers and beta thalassemia helped buoy an already bullish market for biotech.

This year, biotech markets are depressed, and investors are in no mood to see glasses half full, punishing companies for not meeting unrealistic expectations, or, it seems, for just being biotech companies. On Monday, the biotech indices fell two to three percent, before recovering a bit this morning.

One problem: programs that showed great early data in 2014 are a year older, with more patients to deepen the sample size. Inevitably, some of those programs would come back to Earth—the same way a baseball player who has a hit in every two April at-bats isn’t going to stay at .500 all year.

In this roundup, we highlight the big ASH moments of the past three days and provide context for new developments regarding some of the most important technologies and blood diseases.

CAR-T immunotherapy

A huge driver for biotech enthusiasm in 2014 and much of this year were early results in new therapies called CAR-T—chimeric antigen receptor T cell—that use modified T cells to attack a patient’s cancer.

One month ago, an ASH abstract revealed that a CAR-T therapy helped beat back the leukemia of a British infant who was at death’s door. The intervention came as a special request by the parents, not as part of a clinical trial, but the therapy, UCART19, developed by French firm Cellectis (NASDAQ: CLLS), should enter testing soon in the hands of Cellectis’s bigger partners Servier and Pfizer.

(The doctors who gave UCART19 to the young girl were scheduled to present their case study at ASH Saturday, but there was no news coverage.)

UCART19 is an allogeneic or “off the shelf” T cell therapy, which means the T cells were extracted from donors, modified in a lab, and given to the patient. To avoid an immune mismatch, which could kill the recipient, and add other functions, UCART19 includes T cells whose DNA is edited three different ways, the first use of a gene edited cell to treat cancer.

But most of the past year’s good news for CAR-T came in Phase 1 trials from autologous, or personalized programs in which the T cells are collected directly from a patient. They were run by or licensed to Kite Pharma (NASDAQ: KITE), Novartis (NYSE: NVS), and Juno Therapeutics (NASDAQ: JUNO). In a trial run by Juno’s partner Seattle Children’s Hospital, for instance, 20 of 22 children had their acute lymphoblastic leukemia go into complete remission.

That was the spring. Monday, despite releasing fairly positive news, Juno shares took a tumble of more than 7 percent, or $3.79, even though its academic collaborators continued to show large majorities of patients with desperate cancers having positive responses to its modified T cell therapies.

The big difference between ASH 2015 and 2014 for Juno: a declaration from the company that patients with blood-borne cancers would get a powerful combination of chemotherapy drugs to bash the cancer—“preconditioning” is the medical term—before unleashing Juno’s cancer-killing T cells. Preconditioning has been studied for a while with T cell therapy; this small American-Swedish joint study drew some attention earlier this year.

But Phase 1 trials, run by Juno collaborator Cameron Turtle of the Fred Hutchinson Cancer Research Center in Seattle, showed patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia fared better when receiving fludarabine and cyclophosphamide, two chemotherapy drugs, before the JCAR014 T cell therapy.

Juno chief financial officer Steve Harr told Xconomy the double dose of chemo would be applied “broadly across our portfolio, at least in [hematological] malignancies.”

“I do not want to minimize the chemo, but it is generally a single course and well tolerated,” Harr wrote in an e-mail. “It is something that we want to work to eliminate over time, but [we] do not see it limiting us, at least in the patients we are treating today.”

Harr said Juno is also evaluating the impact of the chemo combination on patients in the 90-person Phase 2 trial it recently began with JCAR015, another one of its cell therapies, in adults with acute lymphoblastic leukemia. Juno hopes to use that JCAR015 trial data to ask the FDA for marketing approval.

The only CAR-T program ahead of Juno’s JCAR015 is from Novartis, which nabbed the University of Pennsylvania as its exclusive partner in 2012 and touched off the stampede into the area. At this year’s ASH, Novartis became the first to report Phase 2 CAR-T data, from its CTL019 treatment for patients with certain relapsed or refractory non-Hodgkins lymphoma (NHL). Three months after treatment, 15 of 26 patients across two subtypes of NHL showed some kind of response. Six of them had a partial response that became a complete response—no sign of cancer—at the six-month mark. Two other patients went backwards, with their lymphoma returning months later. Overall, for patients with the relapsed or refractory diffuse large B-cell lymphoma subtype of NHL, the median time the Novartis therapy stopped the disease from spreading—what’s known as progression free survival—was 3 months. It was 11.9 months for patients with follicular lymphoma, another NHL subtype.

Novartis also addressed a different question looming over the CAR-T space: How will companies handle the complicated logistics of autologous therapies, which can take weeks to produce at a high cost. In an ASH presentation, Novartis claimed it had made a successful transition of the manufacturing know-how from the UPenn academic labs to its own industry facility in New Jersey.

Gene therapy

Gene therapy—a method of sending genetic instructions into the body to produce a long-lasting, if not permanent therapeutic effect—is closer today than it’s ever been to impacting healthcare. Spark Therapeutics (NASDAQ: ONCE), after all, could have an FDA-approved gene therapy for a rare form of blindness by this time next year.

Again, however, investor pessimism ruled the day for the highest-profile gene therapy program at ASH. At last year’s meeting, Bluebird Bio (NASDAQ: BLUE) debuted promising data from four beta-thalassemia patients, making the company a Wall Street darling. Those data, along with early results from the first sickle cell patient given Bluebird’s gene therapy, LentiGlobin, have been a key part of gene therapy’s renaissance the past few years.

But with Bluebird’s early success came huge expectations, rightly or wrongly, that it could cure everybody. That set up a huge fall for Bluebird, which topped out at $194 a share in June and has since lost nearly two thirds of that value. Last month, when Bluebird released the abstracts for its ASH data, the takeaway was LentiGlobin was finally bumping up against limits. Some beta thalassemia patients weren’t responding as well as others. Lo and behold, LentiGlobin wasn’t a cure-all.

As reported this weekend, that trend continued at ASH. Early data from a few more sickle cell patients weren’t nearly as good as the numbers from the first patient, and despite Bluebird’s attempts to calm investors with a Sunday night meeting—read more here at—the stock sold off in a big way. Bluebird still potentially has a viable, important treatment for sickle cell disease or beta thalassemia. For sickle cell patients, there is little else despite 100 years documenting the disease.

But it’s a reminder that despite the progress with gene therapy, there’s still a lot to be learned, patient by patient, and trial by trial.

Multiple Myeloma

The second most common blood cancer has not attracted much attention from biotechs pursuing cutting-edge cell or gene therapies. Multiple treatment options have helped improve prognosis, and more are coming. Just before ASH, the FDA approved three new products, two of which are antibodies that stimulate the patient’s immune system. They are all meant to be used in combination with previously approved drugs and chemotherapies, for patients who have not fared well with other treatments.

Much of the ASH activity centered around those three drugs— daratuzumab (Darzalex), ixazomib (Nintaro), and elotuzumab (Empliciti)—and whether they can be used in patients whose situations are less desperate.

But there was one CAR-T clinical study in myeloma at ASH. It is still underway at the National Cancer Institute, but so far, out of 12 patients, four have had at least a partial response to the treatment. One is now in complete remission, but not before getting through severe cytokine release syndrome—a dangerous side effect of T cell therapies that researchers say they are learning how to manage.

As reported, study leader James Korchenderfer of NCI told the media Saturday that CAR therapies can be powerful myeloma treatments, but also toxic, “so they will be used after other treatments and not as front line therapy in the near future.”

That has implications for Bluebird and its partner Celgene (NASDAQ: CELG), which have a deal to develop a next-gen version of the NCI treatment discussed this weekend.

The current version is called CAR-BCMA, because the patients’ T cells are modified outside their bodies to attack the BCMA protein on the surface of myeloma cells. The version licensed to Bluebird is called BB2121, which could enter the clinic in 2016.


Earlier this year we wrote about the emerging gene therapy race in hemophilia. By coaxing the body to produce the clotting factor hemophilia patients lack, gene therapy has a chance to completely change how the disease is treated. Currently, patients with the most severe forms of hemophilia get multiple injections of recombinant proteins called clotting factors every week. The allure of gene therapy is to provide one shot for a long-term, perhaps even permanent solution.

This year’s ASH meeting didn’t provide any important new clinical answers on gene therapy because of timing. Dutch firm UniQure (NASDAQ: QURE) expects its first hemophilia B results in January. Sangamo Biosciences (NASDAQ: SGMO) will begin enrolling patients in the first hemophilia B trial for its gene editing program, SB-FIX, next year.

As these gene therapies advance, it’s worth watching fitusiran, a drug from Alnylam Pharmaceuticals (NASDAQ: ALNY) that provided ASH news. It’s not gene therapy; fitusiran is meant to help hemophiliacs produce more thrombin—and normal blood clotting—through RNA interference.

Alnylam has been providing periodic updates from a Phase 1 study of fitusiran—formerly known as ALN-AT3—in dribs and drabs, with the latest coming at ASH. (See this report from the Boston Business Journal for a look at that data).

Alnylam is expected to begin late-stage testing next year. There have been encouraging signs so far, but durability will be the key question. In the BBJ report, Alnylam chief operating officer Barry Greene suggested the drug could be dosed once a month. But will that hold up in a large randomized trial? Will it curtail the need for treatment with recombinant factors, and prevent bleeds? If so, will that shrink the potential market for the gene therapy contenders?

Stock movers

If you had shorted biotech stocks prior to ASH, chances are you would have made a decent amount of money Monday. The NASDAQ Biotechnology Index (NASDAQ: IBB) fell about 2 percent on the day, lowlighted by the plummets of Bluebird Bio (37 percent) and Agios Pharmaceuticals (22.3 percent).

A number of other biotech stocks took a double-digit hit, among them Global Blood Therapeutics (17 percent), which updated an ongoing Phase 1/2 trial for its once-a-day oral treatment for sickle cell, Cellectis (14 percent), and Atara Biotherapeutics (16 percent).

The mood can perhaps best be summed up by looking at Bellicum Pharmaceuticals (NASDAQ: BLCM), a Houston-based developer of engineered T cells. The company lags behind other CAR-T players in getting cancer treatments to the clinic. But at ASH this weekend, it discussed data that showed one of its T cell lines helped kids with rare blood diseases—such as beta thalassemia and the severe immune depletion known as “bubble boy” disease—recover faster after receiving a bone marrow transplant. Small patient sample, early stage data, but in better days, enough likely to create optimism for the company’s pipeline. As of this writing, Bellicum shares are down 15 percent from their high mark Friday before the conference began.