With another American Society of Hematology meeting in the books, the industry can take a minute to appreciate the notable advances seen in San Diego earlier this week. A new collection of medicines look ready to take on multiple myeloma, while CAR-T and gene therapies affirmed their emerging place in the treatment of blood illnesses.
Science doesn't break for long, though. Before they even packed up their poster presentations, researchers and drugmakers were already talking about the next steps in running better clinical trials and making more effective pharmaceuticals. Below, BioPharma Dive has identified a few major questions likely to linger as the industry heads into a new year.
Has Celgene proved its pipeline?
Biotech markets rapidly cooled over the last few months. Celgene's a preeminent example of the trend, with shares of the New Jersey-based drugmaker falling 25% in the last year and around 50% since last fall.
For a beleaguered biotech that gets nearly three-fourths of its revenue from blood cancer drugs, there's no better place to mount a turnaround than ASH. There, Celgene showcased data from more than 100 abstracts, including two of the five investigational drugs the company believes will offset impending generic challenges for its top-seller, Revlimid (lenalidomide).
One of those drugs, a fusion protein called luspatercept, was found to significantly reduce blood transfusion burden in patients with beta-thalassemia or myelodysplastic syndromes. The other, a CAR-T cell therapy called JCAR017, drove a response in 13 out of 16 patients with relapsed/refractory chronic or small lymphocytic leukemia who previously received Imbruvica (ibrutinib). Notably, seven of those responders achieved complete response.
Celgene estimates peak sales of $2 billion or more for luspatercept and $3 billion for JCAR017. When factoring in another of its closely watched CAR-T therapies, bb2121, as well as multiple sclerosis drug ozanimod and myelofibrosis treatment fedratinib, Celgene expects combined annual peak sales of $12 billion to $14 billion from the lot.
Analysts found the data presented at ASH encouraging, but conceded that Celgene needs a fairly flawless delivery of its pipeline over the next several years to hit its estimates and revitalize share price. That's been a problem for Celgene thus far, particularly with ozanimod.
"While it can take time to get back toward [the] higher part of that cycle, we think stock could work better with an improved biotech backdrop and continued execution," and no more setbacks to its five pipeline priorities, wrote Jefferies analyst Michael Yee in a Dec. 3 note.
Investors, however, appear tepid still. Celgene's stock was basically unchanged at market's close Tuesday compared to what it was before ASH kicked off.
What to do when CAR-T patients relapse?
CAR-T infusions are generally given to very sick cancer patients who already failed multiple other treatments. The first generation of these cell therapies are showing positive lasting power, yet not all patients respond. Under that scenario, researchers are still trying to parse out what's the best plan of attack.
In acute lymphoblastic leukemia, some patients' cancer cells lose their CD19 antigens — the proteins that treatments like Novartis' Kymriah (tsiagenlecleucel) rely on to deliver targeted therapy.
"Of the patients who do relapse, three-quarters of them have CD19-negative disease. The CAR-T cells are still there, they are working, but the leukemia learns to hide," said Stephan Grupp, director of the Cancer Immunotherapy Program at the Children's Hospital of Philadelphia and lead investigator of the ELIANA study of Kymriah.
Grupp said there's generally three routes available upon relapse. If the patient still registers positive for CD19, they'll be given another CAR-T infusion. From Grupp's experience, that tends to put half or more of these patients into remission. On the opposite end, there are patients who don't react at all to a second infusion. Then there's a group in the middle who has a response but its durability is in question. In that case, a bone marrow transplant is the best option.
Researchers are digging deeper into relapses in other cancers as well, including diffuse large B cell lymphoma (DLBCL) for which Kymriah and Gilead Sciences' Yescarta (axicabtagene ciloleucel) are approved.
One study presented at ASH looked at 51 patients with various lymphomas whose disease progressed after CD19-specific CAR-T therapy. Findings showed that patients who went on to receive one or more subsequent treatments, such as a second CAR-T infusion, a targeted therapy, chemotherapy or an allogeneic stem cell transplant, had a lower risk of death. Notably, the second CAR-T therapy didn't appear to improve survival over the other subsequent therapies.
Teams at the Stanford Medicine and MD Anderson aim to publish data soon on CD19-negative relapsing in DLBCL. Stanford researchers are also looking to open next year a study of CD19- and CD20-therapy for that disease and mantle cell lymphoma, with a cohort of patients who failed CAR19 therapy.
"Our hope is that we can design better agents to follow up after patients fail CD19-directed therapy, but there's definitely no standard yet," said Jay Spiegel, a second-year hematology fellow at Stanford, in an interview with BioPharma Dive.
Which technology will prove its edge in blood cancers?
Durability isn't the only concern with CAR-T. The cell therapies are incredibly pricey and difficult to manufacture, even by pharma standards.
Those drawbacks have opened the door for less personalized yet still-effective treatments to carve out a place in the blood cancer market. Two of the categories garnered considerable attention at ASH: bispecifics and antibody drug conjugates.
Amgen, Roche and Regeneron Pharmaceuticals are each working on the former. The draw with bispecifcs is they link up to both the cancer cell and the body's immune cells, bringing them within close proximity to spur a cancer-killing attack. Manufacturers in this space have also been quick to tout the "off-the-shelf" quality of bispecifics, meaning they aren't individualized on a patient-by-patient basis.
Meanwhile, GlaxoSmithKline, AstraZeneca and Seattle Genetics are leading the charge in ADCs. Seattle actually has one on the market already with Adcetris, indicated for multiple lymphomas, and is working on another targeting BCMA. GSK has been viewed as a potential player in the space because of GSK857916, an ADC that last summer showed impressive response rates among relapsed and refractory multiple myeloma patients.
Roche could play a role, too, arriving at ASH with strong data from its ADC polatuzumab vedotin in DLBCL — results it hopes will soon lead to an approval.
Bispecifics and ADCs present their own challenges, though. For instance, there are concerns antibody-based drugs will need to be given in larger doses, which could bring more harmful side effects.
Many blood cancer experts actually see all three types of therapy playing a role in the treatment of blood cancer for years to come.
Craig Hofmeister, an acting associate professor at the Emory University School of Medicine, noted to BioPharma Dive that bispecifics have become increasingly appealing to both industry and academia. Yet, they face stiff competition in the curative potential of CAR-T and the nearer-term opportunities of antibody drug conjugates.
"A truly effective cellular therapy is the long-term, and the short term is likely to be the antibody drug conjugates because they're the farthest along at the moment in comparison to the bispecifics," he said.