Bluebird’s Gene Therapy Quickly Halts Blood Disease in Small Study

6/14/14Follow @benthefidler

As a gene therapy company, Bluebird Bio was a surprising IPO star in 2013. After all, it’s working in a field that was kicked to the curb in the previous decade. What’s more, it made its IPO pitch on the back of the slimmest amount of data. But details from a new study released this weekend, based on upgraded technology, could reward those investors’ faith.

Today, Bluebird (NASDAQ: BLUE) is announcing that its new and improved gene therapy treatment, Lenti-Globin, has been remarkably effective in two patients with beta-thalassemia. Normally, people with the disease require monthly blood transfusions to prevent the deadly anemia caused by the faulty gene they inherit. But thanks to the correct copy of the gene inserted by Bluebird, the two patients have now gone 3.5 and 6.5 months, respectively, without needing a single transfusion, according to company officials.

“This is the first step out to show what the new product can do, and it’s about as good a step out as we ever could’ve possibly imagined,” says Bluebird CEO Nick Leschly.

These results are still very preliminary. Many daunting hurdles remain ahead on the path to turning Lenti-Globin into a viable product. But it’s rather important news for the field of gene therapy, which has been long on promise but slow to produce clinical success ever since the first human gene therapy trial 24 years ago.

“[These data are] interesting and very encouraging. Overall, these results suggest that this may well be a viable way to treat beta-thalassemia,” says Barrie Carter, the vice president who oversees gene therapy at Novato, CA-based BioMarin Pharmaceutical (NASDAQ: BMRN) and a past president of the American Society of Gene and Cell Therapy. Carter isn’t involved with the Bluebird study.

Nick Leschly, CEO of Bluebird Bio

Nick Leschly, CEO of Bluebird Bio

Bluebird, based in Cambridge, MA, is releasing the new results at the European Hematology Association’s annual meeting in Italy. The data come from the first two patients in an early-stage clinical trial in France called “HGB-205.” These patients have the most severe form of beta-thalassemia. They’ve inherited a faulty gene that codes for beta-globin, a subunit of hemoglobin, the protein in red blood cells that carries oxygen. Without the ability to make hemoglobin, these patients get severe anemia and require frequent blood transfusions to survive. They also need iron chelation therapy to deal with the iron overload those transfusions can cause (that buildup of iron is what often kills patients).

About 15,000 people in the U.S. and Europe and 280,000 worldwide are estimated to be living with the disorder, and a majority of them have beta-thalassemia major, the severe form, according to Bluebird. Although the disease can be treated with bone marrow transplants, putting in donor cells capable of making hemoglobin, just 15 to 20 percent of patients are eligible for bone marrow transplants, and the procedure carries its own significant set of risks.

The goal of Bluebird’s therapy is to genetically modify enough of the patients’ own cells so that the patients can survive without transfusions. Lenti-Globin is supposed to essentially mimic the effects of a bone marrow transplant and restart hemoglobin production, but without the donor-matching limitations and safety risks. The company takes stem cells harvested from a patient’s bone marrow. Then it uses genetically modified lentiviruses (stripped-down HIV viruses) to insert a healthy version of the beta-globin gene into them. Those cells are then grown in a culture, and infused back into the patient in a one-time procedure. They then head to the bone marrow and divide, giving rise to more cells with the correct gene—and thus, more copies of the needed protein (in this case, hemoglobin).

Bluebird expects to enroll and treat a total of seven people in the HGB-205 study, and track their progress for two years post-therapy. The data released today come from the first two patients in the trial, an 18-year-old male and a 16-year-old female who have been depending on transfusions for most of their lives, according to Leschly.

The two patients had their last transfusions 10 and 12 days, respectively, after therapy—and haven’t needed another one since. For one patient, that means as of today, it’s been 3.5 months without a transfusion. For the other, it’s 6.5 months, according to chief medical officer David Davidson.

Davidson adds that neither patient has experienced any gene therapy-related adverse events, either. Carter says the safety of the therapy “appears fine thus far,” but points out that the company will likely have to track these patients for several years to see whether the newly-introduced genes, while correcting beta-thalassemia, ended up causing other problems.

The scientific data, meanwhile, back up the clinical effect Bluebird is seeing. First, the new modified lentivirus, or vector appears to be infecting more cells than the company’s previous generation vector, as measured by a statistic called the “vector copy number.” The higher the number, the more cells the virus is inserting the new gene into. That vector copy number is 0.3 and 0.6 for two patients who got the previous vector, HPV569, several years ago. It’s 1.5 and 2.1, respectively, for the two who got Lenti-Globin.

“We did not know what the clinical result would be [of a higher vector copy number],” Leschly says. “Now we’ve been quite pleased to see, clearly, at least in these patients, more is without a doubt better.”

Those higher vector copy numbers, in turn, are translating into faster and more substantive production of hemoglobin than Bluebird saw with its old vector. Davidson says that it took the HPV569 patient who responded well a year and a half to get to peak levels of the newly produced protein, which were about 2.7 of grams of the protein per deciliter (g/dl) of blood attributed to the gene therapy (the other patient, who didn’t respond well, peaked at 0.4 g/dL of the gene therapy-created protein). The first Lenti-Globin patient, according to Davidson, got to that level in one month, and was producing 6.6 g/dL of the therapeutic globin after 4.5 months. The other patient was churning out 4.2 g/dL of the protein after two months.

“If these results hold up over a longer period, as for [the better responding] subject in the first trial, then it is a good clinical result, because one problem with treating beta-thalassemia is that constant blood transfusions cause iron build up and this can be difficult to manage,” Carter says.

These results are what prompted Bluebird to share the data now, six months earlier than it originally planned, says Leschly.

“When you look at the speed and the quantity of the globin that’s expressed in these patients, it was sort of beyond our expectations,” he says. “In the first month or two, [these patients] are doing what [the original] patient basically never even achieved.”

In rare disease, a small number of patients can be instructive. But two patients is by no means proof. Bluebird will need these results to be durable, and see similar success with other beta-thalassemia patients. At this point, two other patients have been enrolled in the HGB-205 trial, and neither has been treated yet, according to Leschly. Once the trial is complete, Bluebird can begin to think about taking Lenti-Globin into a further trial, and discussing with the FDA what would be required to get the treatment approved. (The FDA has never approved a gene therapy. The only one that’s approved by regulators is sold by UniQure in Europe.)

The central challenge of gene therapy has always been inserting corrective genes into enough cells to make a difference in the disease being treated. It’s also crucial that those cells survive and divide, thus creating a self-perpetuating population of cells that make working versions of the protein that’s defective in the disease.

For years, scientists experimented with using modified adenoviruses, similar to cold viruses, to insert genes. But the efficiency of gene transfer was often low—and the adenoviral vectors could trigger immune reactions. In 1999, a severe immune reaction from an adenoviral vector killed a gene therapy patient, slowing progress in the whole field. Now, many gene therapy hopefuls use tiny adeno-associated viruses (AAVs), which are thought to be safer than adenoviruses, as their vectors of choice.

Bluebird has taken a different tack, turning to lentiviruses as the gene therapy vector. Like HIV, these viruses are able to deliver large amounts of genetic material into cells—and have the added benefit (for gene therapy) of being able to infect non-dividing cells. Lentiviruses are particularly useful for Bluebird, though, because it wants to deliver genes to the stem cells found in a patient’s bone marrow and perpetuate the genetic change when those cells divide.

The two-patient cohort seems tiny, but it was a similar small sample size that effectively saved the company. Founded as Genetix Pharmaceuticals almost 20 years ago, it was surviving on bridge loans when a study published in 2009 in Science showed that its approach to gene therapy was able to slow the progression of childhood cerebral adrenoleukodystrophy (CCALD), a crippling genetic disorder affecting the brain, in two children. Third Rock Ventures and Genzyme stepped in with existing backers like Easton Capital and TVM Capital and put $35 million into the company. Leschly, a former project leader for bortezomib (Velcade) at Millennium Pharmaceuticals, was at that point a Third Rock partner, and took over as interim president. He eventually left the firm to head Genetix, which was renamed Bluebird in September 2010.

Then, Bluebird was able to show that its older-generation lentiviral vector, HPV569, helped a single patient in France become transfusion-free after a year (a second patient who got the treatment didn’t have the same response). That, along with the CCALD results, helped fuel Bluebird’s big IPO last year.

So why is the new vector better? Without divulging specifics, Leschly calls the changes “hard core improvements in the manufacturing.” The company focused on making a purer virus that could infect more cells, meaning Bluebird could use less of it, but get the same type of results, he says.

The approach seems to be solving that central problem of gene therapy: lack of efficacy. The improved Lenti-Globin vector appears to insert the corrective gene into enough cells to make a clinical difference—at least so far, since the two new patients haven’t yet needed blood transfusions and their hemoglobin levels have remained high.

That implies that the genetically modified cells must be dividing and reproducing, repopulating the bone marrow. If the cells weren’t reproducing, hemoglobin levels would drop as the original modified cells died off over a period of weeks (as happens with cells added through a transfusion). “We’re not seeing that, certainly in the first patient,” Leschly says.

Leschly also notes that the beta-thalassemia patient who got HPV569 several years ago and responded is still producing enough hemoglobin to stay clear of transfusions, even with an earlier, presumably less potent vector.

“Obviously time will have to tell, but that’s what’s giving us a lot of promise even though the numbers are small,“ he says.

Ideally, that increased potency from the new vector is a sign of things to come in other trials with Lenti-Globin. Leschly says, for example, that the manufactured genes in Lenti-Globin have an “anti-sickling” property that could help with sickle-cell disease—along with beta-thalassemia, the two most common genetic disorders in the world—while boosting hemoglobin. Bluebird has a trial open to find out.

Other answers are on the way, as well. Bluebird has a second, larger beta-thalassemia study in the U.S. called “Northstar” that it’s hoping to share some data from in November. Six of an anticipated 15 patients have been enrolled in that study so far, according to Leschly, and one has been treated. Updated results from the HGB-205 trial are on the way as well. A Phase 2/3 trial called “Starbeam” testing its other vector, Lenti-D, for CCALD, will wrap up further down the road—Bluebird aims to complete enrollment in 2015.

“As we get more data, we’ll have the appropriate dialogue with the thought leaders and the regulatory agencies to determine what the appropriate next steps are,” Leschly says. “We don’t know those answers yet. First things first, continue to follow and treat more patients, that’s really our focus.”

Ben Fidler is Xconomy's Deputy Biotechnology Editor. You can e-mail him at bfidler@xconomy.com Follow @benthefidler

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