[Updated, 12/13/17, 1:50 p.m. ET. See below.] The annual American Society of Hematology meeting is nearly over. For now, we’ve chosen updates from three disease areas to highlight, plus the more notable market movements. No surprise, there’s a lot about the genetically engineered cell therapy known as CAR-T. Gene therapy and more standard forms of care are up for discussion, too. If you’re not ASH-saturated by now, stay tuned: We’ll have more hematology coverage later this week.
[Note: Ben Fidler co-authored this report.]
The first competition in the CAR-T field will be in adult non-Hodgkin lymphoma. Kite Pharma, now part of Gilead Sciences (NASDAQ: GILD), already has approval for axicabtagene ciloleucel (Yescarta). It has set a price tag of $337,000. Novartis (NYSE: NVS) asked the FDA in October to approve its tisagenlecleucel (Kymriah). And Juno Therapeutics (NASDAQ: JUNO), lagging behind by a year or more, hopes to convince that its JCAR017—now named lisocabtagene maraleucel, or liso-cel—will be safer and more effective than its rivals.
Each competitor wants to show that their cancer-killing cells persist beyond the first few months. If not, cancers could come roaring back and insurers might balk at paying hundreds of thousands of dollars for an ephemeral treatment. To that effect, Gilead’s Kite team reported over the weekend that patients, after more than a year (median 15.4 months), still showed some response to Yescarta 42 percent of the time. Most of those patients—40 percent—were in complete remission, or cancer-free. Those figures remain steady from Kite’s earlier snapshots.
Neither Novartis nor Juno has reported data as far out as one year from their key trials, so far. Cross-trial comparisons come with many caveats, but it’s instructive to see how results within each trial change over time. Novartis filled in more details for Kymriah patients at the six-month mark. Total responses were 37 percent, with 30 percent in complete remission, roughly on par with its three-month data.
Juno weighed in with more interim data from a trial called TRANSCEND. Juno is pinning hopes for its first FDA approval on the final results, due next year. Juno is splitting TRANSCEND into subgroups, however, and only the sickest patients—those at higher risk of death and receiving a double dose of cells—are the ones whose results will matter for FDA approval. Of the 91 patients total in TRANSCEND so far, 29 are part of this “pivotal” group. Thirteen of the 19 evaluable at three months were in complete remission. After six months, seven of 14 were in complete remission. When Juno presents data to the FDA, it will be for 75 of these high-dose, high-risk patients, evaluated six months after they receive their cells, says spokesman Chris Williams. Overall response will be the primary endpoint; complete response the secondary endpoint. “There’s no ambiguity in what we are submitting to the FDA; the FDA, though, ultimately determines the label,” says Williams, referring to the type of patient eligible for the drug.
Six-month data for all of TRANSCEND’s 91 patients, including lower-risk patients, showed lower response rates than the pivotal group, which continued a trend from the three-month cutoff. As liso-cel advances, it’s possible the FDA will want to see the full pool of data—at least to assess the treatment’s safety risks. [Updated with data from Juno’s Dec. 11 presentation and its spokesman’s comments.]
Cell therapy is also rapidly advancing as a potential treatment for multiple myeloma, a nasty, persistent cancer of the bone marrow. There are many treatment options, including injectable antibody drugs, chemotherapy, pills, and stem cell transplants, but all patients eventually relapse.
That would make them candidates for CAR-T treatment. Multiple programs that engineer immune cells to attack cells with the B-cell maturation antigen (BCMA) protein on their surface are in clinical studies or starting soon. Early returns continue to impress, led by a treatment from Bluebird Bio (NASDAQ: BLUE) and Celgene (NASDAQ: CELG) called bb2121 that first produced data a year ago.
Bluebird reported at ASH that 17 of 18 evaluable patients have responded to treatment with bb2121, and 10 of them have no trace of myeloma in their blood. Three patients progressed after initially responding. The percentages of patients whose cancer had not progressed after six and nine months remained high. Jefferies analyst Brian Abrahams noted that safety was encouraging but still bears watching. Bluebird reported one case of severe neurotoxicity, and another patient died of myelodysplastic syndrome. Bluebird will begin a pivotal study of bb2121, “KarMMA,” in 2018.
A rival therapy from Novartis and the University of Pennsylvania also advanced at ASH. Again, caveats apply for cross-trial comparison. The Novartis numbers, while encouraging, included lower response rates and more frequent incidences of cytokine release syndrome and neurotoxicity.
The BCMA race is only getting more competitive. Juno will begin a trial of its own BCMA CAR-T next year. And GlaxoSmithKline presented early results of an antibody drug conjugate, which links a tumor-killing toxin to a targeting antibody. In an early study, 21 out of 35 patients responded, with responses lasting a median of eight months.
At ASH, gene therapy results brought the field closer to what could be a one-time, long-lasting treatment for hemophilia. Treatments for hemophilia A and the less common hemophilia B continue to advance without safety problems or signs that their effects might wane, although markets registered some discontent.
Candidates from Spark Therapeutics (NASDAQ: ONCE) for hemophilia B and BioMarin Pharmaceutical (NASDAQ: BMRN) for hemophilia A were featured in the New England Journal of Medicine the past week. Both seem to address hemophilia’s main two problems, by raising the level of the blood clotting factors patients lack and preventing bleeds as well.
Six of seven severe hemophilia A patients on a high dose of BioMarin’s valoctocogene roxaparvovec went from factor VIII levels of less than 1 percent to “normal” levels, meaning at least 50 percent, with effects lasting as long as 78 weeks. The patients had a median of 16 bleeding events per year before treatment, and a median of just 1 per year after. BioMarin will begin enrolling patients this month in the first of two Phase 3 studies.
The first 10 hemophilia B patients taking Spark’s SPK-9001 are producing an average of 34 percent of normal Factor IX levels anywhere from 28 to 78 weeks after treatment. Patients with an average of 11.1 bleeding events per year before treatment have had an average of 0.4 bleeds per year since.
The BioMarin and Spark studies “are leading the way to a cure for hemophilia,” Marijke van den Berg, an associate professor at the Julius Center in the Netherlands, wrote in an NEJM editorial.
Investors were less enthusiastic, however, about Spark’s hemophilia A data published Monday morning, sending shares down 35 percent. Leerink Partners analyst Joseph Schwartz said results from the first four patients in Spark’s study were “surprisingly low and inconsistent,” which included an “early plateauing effect and/or week-to-week variability.”
The reaction highlights an important caveat about hemophilia gene therapy. Companies still can’t predict how a person will respond to treatment. It’s also still unclear how long gene therapy’s effects will last, or whether someone would be eligible for a second treatment if the first one wears off. No safety flags have emerged other than mild immune responses that a short course of steroids can reverse, but side effects from previous generations of gene therapy will likely make investors more skittish than for more established types of medicine.
Significant improvements in more standard types of treatment could also undercut the medical and financial arguments for an expensive, one-time cure. For example, Roche’s Genentech division last month won FDA approval of emicizumab (Hemlibra) for hemophilia A patients whose immune systems reject other medicines—about 20 percent of the hemophilia A population.
Emicizumab could soon be approved for the rest of the hemophilia A population, as well. emicizumab is easier to take, via a subcutaneous injection, than other drugs that require intravenous injection or infusion. And it might work with only one dose a month, compared with standard treatments that require multiple times a week.
Stock Gainers and Losers
The ASH meeting is always a volatile time for biotech stocks. Here are some of the biggest winners and losers coming out of the weekend.
—Spark shares fell 35 percent on the update to its hemophilia A program, as noted above, while BioMarin shares climbed almost 7.5 percent.
—A major question hanging over Bluebird Bio (NASDAQ: BLUE) is whether changes to its manufacturing process would lead to better results in beta-thalassemia and sickle cell disease. So far, so good. At ASH, Bluebird reported early results in a handful of patients suggesting the improvements might be helping. Between its updates in myeloma and other blood diseases, Bluebird shares climbed 18 percent Monday.
—Shares of Blueprint Medicines (NASDAQ: BPMC) climbed almost 23 percent on updates from two Phase 1 studies. At ASH, the company presented data from a study of BLU-285 (avapritinib) in advanced systemic mastocytosis, an abnormal buildup of mast cells, in which 13 of 18 evaluable patients have responded so far. At a separate scientific meeting in Hawaii, Blueprint updated a stomach cancer study in which 5 out of 18 patients responded to BLU-285.
—Seattle Genetics (NASDAQ: SGEN) reported full Phase 3 data for its flagship drug brentuximab vedotin (Adcetris) in first-line classical Hodgkin lymphoma. Investors initially sent the firm’s stock down 10.5 percent Monday amid worries that the generally positive data hid problems in certain key subgroups of patients. Sea-Gen also updated early-stage data from a combination of Adcetris and nivolumab (Opdivo) from Novartis, with a 62 percent complete response rate in 62 patients. The partners have already launched a Phase 3 study in HL patients who have relapsed or haven’t responded to other treatments. Sea-Gen shares closed down more than 6.5 percent Monday.
—Shares of Syros Pharmaceuticals (NASDAQ: SYRS) initially fell almost 50 percent on disappointing data from a Phase 2 trial of experimental SY-1425. Syros has been developing the drug for a genetic subset of patients with acute myeloid leukemia or myelodysplastic syndrome anticipated to be likely to respond to treatment. But just one out of 48 evaluable patients have responded so far. Syros shares regained less than half their losses by market close Monday.
[Updated with end-of-day stock prices.]