[Note: Ben Fidler co-authored this report.] This weekend, San Diego will host the annual American Society of Hematology conference, the largest U.S. medical gathering to get the latest on blood diseases, and a venue for updates on some of the most cutting-edge biotechnologies that only a few years ago seemed like science fiction.
Using the previews of major studies that were released earlier this month, we’ll dive into five of the disease areas under scrutiny at ASH this year—leukemia/lymphoma, multiple myeloma, beta-thalassemia, hemophilia, and sickle cell disease—and give you plenty of background in case you haven’t been following each one closely.
LEUKEMIA AND LYMPHOMA
Of the 1.7 million new cancer cases and 610,000 cancer deaths in the U.S. this year, leukemia and lymphoma will account for nearly 10 percent. There are many types of each, often with different treatments and levels of success. Here’s a brief look at the major types and their expected updates at ASH.
Ninety percent of all new lymphoma cases are some form of non-Hodgkin lymphoma (NHL).
Two engineered therapies made from a patient’s own immune cells, known as CAR-T, have been approved for adults with desperate cases of NHL. But difficult logistics and high prices have kept CAR-T from making more inroads.
Novartis’s (NYSE: NVS]) tisagenlecleucel (Kymriah), one of the two approved CAR-T products, for instance, generated just $20 million in the third quarter. There’s another potential obstacle: Doctors at big cancer centers are reporting that real-world outcomes for the other approved CAR-T, axicabtagene ciloleucel (Yescarta), aren’t matching what its developer Kite Pharma, now owned by Gilead Sciences (NASDAQ: GILD), reported in clinical trials.
While meant to approximate what might await in the real world, clinical trials are always more carefully cultivated, so a falloff is not surprising, especially with CAR-T—a new kind of therapy with dangerous side effects that require special training to handle—says Lee Greenberger, the chief scientific officer of the Leukemia & Lymphoma Society in Rye Brook, NY. Training could be uneven, patients could be sicker; bottom line, says Greenberger, is that “we’re only in the first chapter. We’ve gotten [CAR-T] to work and gotten it approved. But combination approaches will be necessary. There will be patients who fail these therapies.”
The dream with CAR-T, as with most new cancer therapies, is to prove over time that it can be used ever earlier—not just for patients who have failed all other treatments. NHL will be a high hurdle, however, as an ASH paper lays out; a lot of younger people do quite well on standard chemo-based regimens.
New CAR-T flavors—CAR-T 2.0, if you will—are moving into clinical studies, such as this “armored” CAR-T at Memorial Sloan Kettering Cancer Center, hoping to address some of the first generation’s shortcomings, like severe side effects that overheat the patient’s immune system.
Beyond CAR-T, the other big immunotherapy class—antibody drugs known as checkpoint inhibitors—has been approved for some types of Hodgkin and non-Hodgkin lymphoma. Here’s an ASH update on the checkpoint drug pembrolizumab’s (Keytruda, from Merck) success in one form of NHL.
At ASH, investigators are also asking whether lymphoma patients who haven’t benefited from checkpoint treatment might go on to have success with other treatments, a clue for those thinking about combination therapies.
For chronic lymphocytic leukemia, the most prevalent type of leukemia, the big drug-related headlines are unrelated to immunotherapy. The story is ibrutinib (Imbruvica), a pill at the center of a stunning $21 billion buyout by AbbVie (NYSE: ABBV) three years ago, which has quickly become the standard of care for newly-diagnosed patients.
Whether alone or in combination, ibrutinib is “dramatically” changing the way CLL is treated, says Greenberger, potentially leaving chemotherapy behind for some patients. At ASH, investigators will detail ibrutinib’s clear superiority over the standard of care for patients 65 and older; its superiority, with the drug rituximab (Rituxan), over chemotherapy plus rituximab for previously untreated younger patients, which has “immediate practice-changing implications,” according to the study authors; and its increased power in combination with another approved CLL drug, venetoclax (Venclexta).
Ibrutinib targets the protein Bruton’s tyrosine kinase (BTK), which plays a key role in the expansion of CLL. “Imbruvica, in its various regimens and combinations, has won every time, and the only risk it faces is the host of other BTK inhibitors coming over the horizon with slightly different safety and tolerability profiles,” Leerink analyst Geoffrey Porges wrote in a note to investors last week.
Over time, CAR-T could become a factor in CLL, especially for people who aren’t helped by ibrutinib or venetoclax; results at ASH are from early CLL trials at the Fred Hutchinson Cancer Research Center, City of Hope (using Juno Therapeutics’ experimental JCAR017), and at Memorial Sloan Kettering Cancer Center.
For acute myeloid leukemia (AML), we’ll highlight a few studies. The first isn’t technically AML, it’s the rare blood disorder myelodysplastic syndrome, or MDS, in which mutations arise in the patient’s blood stem cells. It can be a precursor to AML, with about 30 percent of MDS patients converting, typically those whose cells have a higher number of mutations. (AML is a tough cancer to treat because of its wide range of genetic subtypes.)
But MDS can be deadly without converting to AML, leading to severe, even deadly anemia. Partners Celgene (NASDAQ: CELG) and Acceleron Pharmaceuticals (NASDAQ: XLRN) have brought the drug luspatercept—also in development for beta-thalassemia—through Phase 3 for MDS, with results that indicate the drug can significantly reduce the number of blood transfusions that MDS patients require to avoid anemia. Celgene and Acceleron will discuss the details of that study, MEDALIST, at ASH.
There are also promising data for newly diagnosed AML patients who aren’t eligible for chemotherapy, and a multi-arm trial, sponsored by the Leukemia & Lymphoma Society, which assigns patients with various genotypes to different arms and get them on treatment within seven days.
For the roughly 20 percent of AML patients with IDH mutations, two drugs from Agios Therapeutics (NASDAQ: AGIO) will produce updates at ASH. Ivosidenib (Tibsovo) alone has promise in previously untreated IDH1-mutation patients, based on interim Phase 1 data;
and, when combined with chemotherapy, ivosidenib and enasidenib (Idhifa, for IDH2 mutations) have shown enough in newly diagnosed patients to warrant moving into Phase 3, according to investigators.
Acute lymphoblastic leukemia, or ALL, is a rare leukemia, with less than 6,000 estimated new U.S. cases in 2018. But it’s a nasty disease and a difficult proving ground for new therapies. The first-ever CAR-T approval was for kids and young adults with ALL based on data that showed that 36 percent of patients who initially did well relapsed after 12 months. (These are patients who had already failed to respond to many other treatments, including bone marrow transplant.)
Another CAR-T, from Juno Therapeutics, was pulled from ALL trials after several patients died during the course of treatment. Juno, now owned by Celgene, is now working on pediatric ALL with a different experimental CAR-T product (no ASH update, however), and Gilead’s Kite division hopes that updated Phase 1 data at ASH builds momentum for its Yescarta to gain approval in ALL.
Efforts to broaden the attack on ALL by hitting the cancer from two directions are advancing as well. The first generation of CAR-Ts all go after the common protein CD19; at least three groups are reporting progress at ASH—here, here, and here—in going after a second protein, CD22, also often present on ALL cells.
Meanwhile, researchers at the University of Pennsylvania are working on CAR-T plus a checkpoint inhibitor.
All of those CAR-T programs require engineering a patient’s own cells, a complicated and expensive proposition. Another technique, using “off the shelf” cells, could prove cheaper and more straightforward, but it’s not as far along in development. Updated Phase 1 data for the most advanced of these treatments, called UCART19 and developed by Allogene Therapeutics (NASDAQ: ALLO) and Servier, will be discussed at ASH.
It’s not all CAR-T all the time for ALL, to be sure. Amgen (NASDAQ: AMGN) first received approval to treat one genetic type of ALL with its antibody drug blinantumumab (Blincyto) in 2014 and has since been cleared to treat a broader group of patients.
At ASH, European investigators will discuss the survival rates of adults receiving blinatumumab, and clinicians in the U.S. will step through a Phase 1 study of the drug combined with two checkpoint inhibitors.
Next year is shaping up as a big one for patients with beta-thalassemia, a rare, crippling blood disease that affects about 15,000 people in the U.S. and Europe. Two new medicines could be approved, and both would upend current treatments.
“It’s very exciting,” says Craig Butler, the executive director of the nonprofit Cooley’s Anemia Foundation. (Cooley’s is another name for beta-thalassemia.)
Patients with beta-thalassemia have inherited a faulty gene that codes for hemoglobin, the protein in red blood cells that carries oxygen. The effects depend upon the amount of normal hemoglobin the body manages to produce. Patients with “mild” thalassemia might not need help at all. The more severe beta-thalassemia major is potentially deadly because of severe anemia that requires a lifetime of blood transfusions, often every two to four weeks. Repeated transfusions have their own risk: a dangerous buildup of iron that, in turn, requires iron chelation therapy to prevent organ damage, heart failure, or death. (Bone marrow transplants are a potential cure, but they’re not available to everyone and carry their own risks as well.)
Transfusions and iron chelation can help people with beta-thalassemia major live until their 50s or beyond, Butler says. But there is room for improvement for patient health and for reducing healthcare costs. Transfusions are all-day affairs; patients frequently miss school or work. It’s hard to tell which iron chelation drugs will work for each patient. And the cost is daunting: a study in the 2017 journal Blood estimated the average cost at $75,000 per patient, per year. Butler estimates it typically costs the system $200,000 to $300,000 per person, per year, for all the associated costs.
Therapies with key updates at ASH could reduce if not eliminate the need for transfusions. One is a gene therapy, from Bluebird Bio (NASDAQ: BLUE). A single infusion of the treatment, called LentiGlobin, is meant to restart hemoglobin production for life, the same effect as a bone marrow transplant but without the fear of a deadly rejection of the donor’s blood. (That said, the LentiGlobin procedure still requires a chemotherapy step called myeloablative conditioning that carries certain risks, as well.)
European regulators have begun a review that could lead to approval next year; Bluebird has not yet asked the FDA to begin a review.
Luspatercept, from Acceleron and Celgene, is also meant to boost hemoglobin but requires an infusion every few weeks. Acceleron could ask for approval of the drug in both the U.S. and Europe next year.
Both therapies have limitations. Patients are excited about living a “normal life” with the help of a gene therapy, says Butler, but it’s unclear who will be eligible and how long the improvement will last. Bluebird has reported different results in different genetic subsets, and patients want “clarification whether [LentiGlobin] would theoretically work for all types of beta-thalassemia major, or whether it will have limited efficacy only for certain types,” Butler says.
It’s also unclear how insurers will deal with the variations, and what they will do if patients switch insurers. Butler also notes that the myeloablative conditioning that precedes the gene therapy might scare off patients, as well.
Butler says that luspatercept could appeal to patients who see gene therapy as too risky. Like LentiGlobin, however, it’s unclear which patients might benefit. Acceleron and Celgene reported in July that luspatercept provided at least a 33 percent reduction in the volume of blood transfusions after 13 to 24 weeks of treatment. An ASH abstract posted in November showed that 21.4 percent of luspatercept patients achieved this response, compared to 4.5 percent of placebo patients. But more details are necessary to answer big questions, and Acceleron is expected to provide them at ASH.
At ASH, Bluebird will address the durability question with data from patients who received LentiGlobin as much as 3.5 years ago, in an early study dubbed Northstar. Bluebird will also update results from a Phase 3 study called Northstar-3 to include data from a key genetic subset of patients who so far have had the toughest time responding to its treatment. That study will help form the basis of Bluebird’s approval application in the U.S.
Elsewhere, LJPC-401 from La Jolla Pharmaceutical (NASDAQ: LJPC) is in early testing and will get an ASH update. It’s a synthetic form of the hormone hepcidin, which helps the body regulate iron absorption and may prevent build-up. If, someday, both a hemoglobin booster and hepcidin were available for beta-thalassemia patients, “the combination of the two could make a really big difference,” Butler says.
SICKLE CELL DISEASE
Long bereft of pharmaceutical options, patients with sickle cell disease are well aware that several new experimental therapies are in development. Some promise long-lasting relief with a single treatment (it’s premature to use the word “cure”); some are meant to better manage the severe pain, anemia, and other debilitating symptoms of the inherited disease.
Sickle cell’s hallmark is abnormal crescent-shaped red blood cells that clog blood vessels and block the flow of oxygen. As with beta-thalassemia, the disease stems from a mutation in hemoglobin. Only two drugs have been approved to treat the symptoms: a repurposed chemotherapy and a version of a dietary supplement. Beyond those medicines, there are blood transfusions and plans, like helping patients avoid emergency room visits, to improve lives. Those efforts will be a big part of the sickle cell story at ASH this year.
For example, researchers will discuss a large study called ESCAPED, which shows that treating people with pain episodes (or “crises”) in infusion centers instead of in emergency rooms, where they often end up, controls their pain faster and improves care significantly, with a six-fold decrease in costly hospitalizations.
Is “cure” an appropriate description for gene-altering medicines? We don’t know yet, and ASH won’t help us divine much. Bluebird’s gene therapy LentiGlobin has been working its way through early testing for sickle cell, and the company has been tweaking the parameters of a Phase 1 trial; investigators will share an early look at a third group of patients.
Another avenue of sickle-cell gene therapy aims to switch off the faulty adult hemoglobin and revert the patient back to the healthy fetal version of hemoglobin. Bluebird’s program will get an extremely early airing at ASH.
(A sickle cell treatment that uses CRISPR-Cas9 gene editing—the first human study of its kind—is about to start any day now. Perhaps it will be one of the must-see presentations at next year’s ASH.)
For all the hope of fixing genes, sickle cell disease does in fact have a cure. But the treatment, bone marrow transplant, is rarely an option for African-Americans, who make up the majority of the roughly 100,000 U.S. patients. A gene therapy, if eventually approved, could widen that door.
That said, a paper to be presented at ASH looks back at nearly two decades of transplants for pediatric sickle cell patients in Europe. The success rate—two years of survival—was mostly in the 82 percent to 96 percent range, depending on the donor. (Best success: perfectly matched siblings.) The study authors conclude that new, expensive medicines will have a high bar to clear: “The emerging gene therapy approach will have to be compared to these well-established results.”
The most advanced new experimental drug to get an airing at ASH is voxelotor, from Global Blood Therapeutics (NASDAQ: GBT), which aims to boost a patient’s levels of hemoglobin. At ASH, doctors will dive into results from the first part of a Phase 3 voxelotor study that GBT discussed in brief earlier this year. Over 12 weeks, a higher dose of voxelotor boosted hemoglobin more than 1 gram per deciliter in 23 of 40 patients; placebo was only 4 of 44.
GBT has said it will ask the FDA for an early approval, even though plans fell through to record a more direct benefit—a reduction of pain crises. GBT will argue that the hemoglobin boost is tied to better health, similar to the correlation between lower cholesterol and better heart health. A meta-study at ASH looking at 20 years of sickle cell studies will bolster that argument. (Caveat: One of the five authors is a GBT official, and the lead author, the director of the University of Tennessee’s Center for Sickle Cell Disease, is an advisor to the company.)
Since the early 1990s, hemophiliacs have been able to treat their disease with chronic infusions of proteins, or factors, that help clot their blood. These drugs, typically infused at least once a week, have turned hemophilia into a manageable condition, but still stressful and expensive to treat. Things are changing. “We’re inching into the next generation of treatment,” says Mark Skinner, the former longtime president of the World Federation of Hemophilia, and a patient with the disease.
In the research presented at ASH this weekend, Skinner sees broad recognition that the standard of care just isn’t good enough.
Typical factor replacement therapy doesn’t give patients a steady amount of clotting protein. Levels wane through the next dose, leading to what Skinner calls “cycles of risk and protection.” That means patients with severe hemophilia have to be extra careful about “subclinical” bleeds they might not be aware are happening. Without treatment, subclinical bleeds can contribute to long-term health problems like joint damage. By preventing these bleeds, newer therapies could improve upon existing ones.
The first of the new wave is already here. Emicizumab (Hemlibra), from Roche is approved for hemophilia A and is a big advance. Patients with “inhibitors,” whose immune systems reject standard medicines, now have a new option to prevent bleeds. Emicizumab also provides a steady level of clotting protein, which may help some patients live life “relatively freely,” Skinner says.
Gene therapy could arrive within the next few years for both hemophilia A and the less common hemophilia B. Drug makers BioMarin Pharmaceutical (NASDAQ: BMRN), UniQure (NASDAQ: QURE), Pfizer (NYSE: PFE), and Spark Therapeutics (NASDAQ: ONCE) are all conducting late-stage clinical studies. If they work, will the effect eventually wear off? Why do some patients respond better than others? Will patients stick with the treatments they trust? And will insurers cover what could be $1 million-plus per-patient price tags?
That said, new data from gene therapies aren’t this year’s headlines. Instead, Skinner points to research on the impact of hemophilia on a patient’s life. If a patient is worrying less about subclinical bleeds, for example, perhaps she can be more active or avoid hospital trips or surgeries.
Multiple abstracts this year focus on the prevalence of those bleeds and how they change peoples’ lives, and on understanding the outcomes that really matter to hemophilia patients. Those studies could eventually help drug makers make better cases to payers or doctors.
Skinner has his eye on another presentation. Bioverativ, the ex-hemophilia business of Biogen now owned by Sanofi, is developing a factor replacement therapy for hemophilia A that might require less frequent injections. It’s not a major step forward like gene therapy could be, but Skinner believes it could be important for patients who aren’t candidates for gene therapy or who can’t get insurance coverage for emicizumab. Or perhaps they’re just more comfortable sticking with the kind of treatment they know. “It could nicely fill a space that moves us beyond where we are, and gives patients a range of options,” Skinner says.
A cancer of the plasma cells in the bone marrow, multiple myeloma is the third most common type of blood cancer behind leukemia and lymphoma, with 30,000 new U.S. cases a year and about 12,000 deaths. The good news is there are more treatment options and better outcomes for patients than ever before.
Over more than a decade, several drugs, led by lenalidomide (Revlimid), bortezomib (Velcade), and more recently daratumumab (Darzalex), have received approval. Combined with chemotherapy, they can knock myeloma into remission for longer periods of time. But myeloma, a persistent and lethal cancer, almost always returns.
A new weapon could emerge to help people who relapse, however: therapies that target a tumor protein called BCMA (B-cell maturation antigen). Several groups are developing CAR-T cell therapies to home in on cells that produce BCMA and wipe them out. Early experimental results have shown promise in patients who are running out of options. But there’s a looming question: How long do these treatments last? So far, there’s no solid answer.
The most advanced BCMA CAR-T program is from partners Bluebird Bio and Celgene. Investigators reported in June that half the 22 patients taking the highest available dose of bb2121 had no trace of cancer; median response of any kind averaged nearly 11 months. Celgene is going to test it, at that highest dose, head-to-head against standard combination regimens for patients who have failed other treatments. There is no update scheduled at ASH.
But ASH will feature a first look at a new version called bb21217. It’s been engineered to last longer in the patient (and kill more cancer cells); development of both versions will continue. In the ongoing Phase 1 trial of bb21217, the longest any patient has been on the therapy is six months. (Caveat: As with all data plucked from the abstracts, which were published in November, there could be notable updates during the presentation.)
Chinese firm Nanjing Legend Biotech is also in the mix, and, at ASH, will discuss an ongoing Phase 1 study of its LCAR-B38M conducted in China. According to the abstract, 42 of 57 patients have had a complete response with a median duration of 22 months.
CAR-T isn’t the only new type of medicine going after BCMA. Different flavors of antibodies—ones that carry a cell-killing chemotherapy, ones that pull immune cells toward tumor cells, and more—are in early development. Amgen (NASDAQ: AMGN) will update progress on AMG-420, which grabs T cells by one receptor and myeloma cells via another.
As of May, the ongoing Phase 1 study testing a range of doses showed most promise at the 400 mg/dl dose of AMG-420. Five of six had at least partial responses, with three in total remission for at least 4.6 months. The study’s leaders will give an update at ASH. In addition to how long the drug’s benefit lasts, there’s another big question: Will anyone want to take it? One dose cycle requires being hooked up to an IV machine for four weeks straight, then two weeks off. Some patients in the study have received several cycles.