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The BCMA bonanza A long and growing list of anti-BCMA​ candidates — including chimeric antigen receptor-T​ cell therapies, antibody–drug conjugates and bispecific antibodies — are contending to transform multiple myeloma treatment.

Asher Mullard belantamab mafodotin, previously known as University of Pennsylvania. Other historically GSK2857916, by the end of the year. Also out hot targets like PCSK9 for cardiovascular Great targets are scarce, and so researchers in front, Celgene and Bluebird Bio are disease and immune checkpoint PD1/PDL1 across the biopharmaceutical industry anticipating regulatory approval in 2020 for blockers for oncology hold promise for large tend to pile in when they come along. their chimeric antigen receptor (CAR)-T cell populations, but the BCMA activity is all And when the biology is just right, such therapy idecabtagene vicleucel, previously the more impressive for its focus only on targets promise not just new therapeutic known as bb2121. But a long list of other multiple myeloma. options and commercial opportunities, ADCs, bispecifics, CAR-Ts​ and naked Interest here is driven in part by the but also rare chances to explore emerging monoclonal antibodies are marching to and clinical challenges of multiple myeloma, drug modalities. BCMA, for the treatment through the clinic (Table 1). Indeed, BCMA the second most common haematological of multiple myeloma, is the latest case is the second most popular defined target in malignancy after non-Hodgkin​ lymphoma. in point. the global cell therapy pipeline, surpassed Despite big advances in recent years with Leaders in this space are set to submit only by CD19. chemotherapy, proteasome inhibitors, first-​in-class candidates for regulatory “If you think about all the [CAR-Ts],​ immunomodulating thalidomide derivatives approval shortly. GlaxoSmithKline ADCs and bispecifics that are going after this and CD38-targeted antibodies, nearly all (GSK) is working to finalize the dossier one target, it’s pretty remarkable,” says Alfred patients still eventually relapse. A dire need for its antibody–drug conjugate (ADC) Garfall, a haematologist at the hospital of the for new drugs remains, and a market exists

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Table 1 | Select list of anti-BCMA​ candidates Drug name Sponsor Properties Status CAR-​T Idecabtagene vicleucel (bb2121) Celgene/Bluebird Bio CAR-​T Phase III, approval anticipated in 2020 JNJ-4528/LCAR-B38M Johnson & Johnson/Nanjing CAR-​T Phase II Legend Biotech P-​BCMA-101 Poseida Therapeutics CAR-​T, with safety switch Phase II, filing anticipated in 2020 bb21217 Celgene/Bluebird Bio CAR-​T, enriched for memory T cells Phase I JCARH125 Celgene/Juno Therapeutics CAR-​T Phase I/II ALLO-715 Allogene Allogeneic CAR-T,​ with an off switch IND approved Antibody–drug conjugate Belantamab mafodotin (GSK2857916) GlaxoSmithKline Afucosylated antibody conjugated Phase II, filing anticipated to monomethyl auristatin F in 2019 MEDI2228 AstraZeneca Antibody conjugated to Phase I pyrrolobenzodiazepine CC-99712 Celgene/Sutro Biopharma Undisclosed IND approved Bispecific format AMG 420 Amgen BiTE Phase I/II AMG 701 Amgen Half-life​ extended BiTE Phase I CC-93269 Celgene Bispecific antibody Phase I REGN5458 Regeneron Bispecific antibody Phase I/II JNJ-64007957 Johnson & Johnson Bispecific antibody Phase I PF-06863135 Pfizer Bispecific antibody Phase I Monoclonal antibody SEA-​BCMA Seattle Genetics Afucosylated monoclonal antibody Phase I BiTE, bispecific T cell engager ; CAR-​T, chimeric antigen receptor-​T cell; IND, investigational new drug. to support this. Multiple myeloma drugs “When one looks at antibody–drug that bound BCMA and killed cancer cells, achieved sales of nearly US$14 billion conjugates, bispecifics and CAR-Ts,​ we do but early development work with these in 2017, and are forecast to reach nearly envision a world where all these therapies stalled. For as yet undetermined reasons, $29 billion in sales by 2027. are going to coexist, and that they will have early candidates just didn’t drive sufficiently The BCMA target is also so clean different profiles that will be dependent strong efficacy signals to push the field in its expression profile that it provides on the patient populations and the targets,” forward. And at the same time, the multiple an irresistible testing ground for novel adds Greg Friberg, head of oncology myeloma community was so focused on modalities. “This is a good opportunity development at Amgen, a company that the development of proteasome inhibitors, to really explore different platforms, works on all three modalities. “The reality thalidomide derivatives and CD38 blockers without worrying about the target itself. is we’re going to have to wait and see how that BCMA fell by the wayside, says And hopefully, this will help us to better that plays out.” Yu-​Tzu Tai, who studies multiple myeloma examine different targets in the future,” at the Dana–Farber Harvard Cancer says Yusri Elsayed, vice president of BCMA beginnings Center and who has collaborated with haematological malignancies at Janssen, The BCMA gene was identified in 1992, GSK, Amgen, AstraZeneca and Johnson a company that is exploring multiple and was found shortly after to be associated & Johnson on the preclinical validation of BCMA-targeting​ modalities. with B cell maturation and with multiple BCMA-targeted​ biologics. myeloma. Further work revealed that BCMA “This is unfortunate because it kind of is only expressed on plasma cells, that it is delayed the development of antibody formats over-expressed on multiple myeloma cells for multiple myeloma, but it is also very If you think about all and that it is dispensable for overall B cell important because clinicians now know how the [CAR-​Ts], ADCs and health and homeostasis. These characteristics to use those other drugs,” says Tai. bispecifics that are going make it a compelling target, with a rock The delay created an opening for solid disease association and limited risk of CAR-T​ developers, mainly in academia after this one target, it’s off-tissue toxicity. initially, who were working on a then-​ pretty remarkable By 2007 researchers across industry had emergent and now burgeoning modality in identified monoclonal antibodies and ADCs which T cells are extracted from patients and

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engineered ex vivo to seek out and destroy Given the small sizes of these trials could provide important lessons as to cells expressing antigens of interest. By 2014, and key differences in their designs — how to further lower the risks of systemic as GSK was just starting trials of its ADC, in terms of patient inclusion criteria, inflammatory responses. researchers at the NIH were enrolling patients average prior lines of therapy, whether “A core aim of ours is to learn and improve into a phase I trial of BCMA-targeted​ CAR-​Ts. lymphodepleting chemotherapy was used as we go along, so this is definitely a great CD19-targeted CAR-​Ts were inducing and more — the results of the various opportunity for us,” says Elsayed. “We will long-lasting​ responses in leukaemias and anti-​BCMA trials should not be compared learn from this with regard to the CAR-Ts,​ lymphomas, and haematologists hoped with one another. how to use them in the clinic, how to that this strategy would offer durable “They’re all impressive,” says Garfall, combine them with other drugs, and more.” remissions — if not cures — in multiple who was an investigator on a trial of a myeloma as well. BCMA CAR-T​ that was partially funded by With initial tweaking of the CAR-T​ Novartis. This marks an often overlooked technology, researchers started seeing breakthrough, he adds, because one of Autologous cell therapies remarkable responses. In a phase I trial of the big questions for the CAR-T​ field was have to have exceptionally Celgene and Bluebird’s idecabtagene vicleucel whether it would be possible to make these better efficacy or safety in 33 patients with relapsed or refractory therapies with any target other than CD19. multiple myeloma, who had undergone at “The one big take-home​ lesson from BCMA profiles to war-​rant the cost least 3 prior lines of therapy, 85% of patients is that CAR-T​ cells will work for other and inconvenience had an objective response with treatment targets,” he adds. and the median time to progression was And yet the durability of the CAR-T​ 11.8 months. Reporting these results in the responses, even in the patients who Antibody advances New England Journal of Medicine in May, the respond best to these treatments, has not Drug developers are also making a move with study investigators noted that this compared been as high as initially hoped. Patients enhanced antibody formats. favourably with past trials of several salvage are still relapsing at around the 1-year GSK’s ADC belantamab mafodotin, therapies in multiple myeloma, associated mark. “This is a little disappointing,” says the most advanced of these, uses a with response rates of 30% and medians of Garfall. With Novartis’s CD19 CAR-T​ BCMA-​targeted antibody to deliver a 4 months to progression. tisagenlecleucel in relapsed or refractory chemotherapeutic monomethyl auristatin F Celgene and Bluebird now anticipate diffuse large B cell lymphoma, by contrast, warhead directly to cancerous cells. an approval for their CAR-T​ in 2020, and median duration of response had not been The expression profile of BCMA is so are already working on follow-on​ CAR-​T reached after an average of 19 months clean — restricted to plasma cells and products that they hope will offer better of follow-up,​ the company reported overexpressed in myeloma — that it is the results yet. “The field of CAR-T​ cells is last December. perfect candidate for an ADC, adds Hal still in its early adolescence in terms of The biology behind the lack of Barron, CSO at GSK. “If you can find an what is the optimal way to engineer and durability with BCMA CAR-Ts​ remains overexpressed antigen that is unique to a manufacture these products. It’s important to be resolved. Myeloma-intrinsic​ factors disease, it is really an ideal target for an ADC. to iterate and to test different concepts,” may be to blame, for instance if the nature of There may not be as many of these as we had says Kristen Hege, vice president of the myeloid cells or the microenvironments hoped, and ADCs might have been a little translational medicine for hematology/ in which they reside help diseased cells overhyped, but I think there are more cancers oncology at Celgene. With bb21217, for to hide out until after the CAR-Ts​ pass. where these antigens are overexpressed and example, Celgene and Bluebird are culturing Or, it might have to do with patient-​ can be taken advantage of.” the CAR-​T cells with a PI3K inhibitor specific factors, for instance if prior lines The antibody portion of belantamab to skew them more towards an early of therapy are compromising T cell health, mafodotin has been afucosylated, he adds, memory phenotype. with downstream consequences for the to optimize the ADC’s ability to induce collection and production of the autologous antibody-dependent​ cellular cytotoxicity cell therapies. (ADCC) and cell killing via the recruitment “The next big thing for multiple myeloma of natural killer cells. The field of CAR-​T cells is still that we need to crack is what makes a Here too phase I results have been in its early adolescence … difference in terms of durability and cure-​ encouraging. In a trial of belantamab It’s important to iterate and ability,” adds Garfall. “I would love to see mafodotin in 35 relapsed or refractory to test different concepts some focused effort on that, rather than just patients, the majority of whom had more of the same or similar BCMA CAR-Ts​ received at least 5 lines of prior therapy, being churned out.” 60% of patients achieved an overall Other firms are also enjoying But at the same time, CAR-T​ developers response, investigators reported in BCMA-targeted​ CAR-T​ successes. At the see BCMA as an invaluable opportunity Lancet Oncology last year. The median American Society of Hematology (ASH) to debug the emergent modality. First-​ progression-​free survival was 12 months, annual meeting last year Johnson & Johnson hand experience with manufacturing and they added in an update in Blood Cancer and Nanjing Legend Biotech reported an delivery bottlenecks is key to figuring Journal. The most common side effects 88% overall response rate and median out how to overcome these burdens, include corneal events, thrombocytopenia progression-​free survival of 15 months in for example. And while the potentially and anaemia, all linked to the ADC’s 57 relapsed or refractory patients who had fatal cytokine release syndrome that cytotoxic warhead. undergone on average 3 prior therapies, is associated with this modality is These results have prompted GSK to for example. manageable, the BCMA programmes double down on BCMA, launching a broad

Nature Reviews | Drug DiSCovery volume 18 | JULY 2019 | 483 News & Analysis

development plan that is already testing the although at a lower rate and lower severity induces cell death not only through its drug in more than 300 patients, with more than with CAR-T​ products. warhead but also via ADCC and immune combination trials to come. An ongoing Amgen has long been working in the effector cells, researchers speculate pivotal trial is underway and anticipated BCMA space, says Friberg, and their decision that it might act synergistically with to read out before the end of the year, with to advance a BiTE is informed by their own immune-​modulating drugs. a regulatory filing for this first-in-class​ false starts. “We’ve actually brought three Combination and sequencing strategies agent expected shortly after. And Barron different ADCs into the clinic, and in all cases are in the works for bispecifics and CAR-Ts.​ is optimistic about this ADC’s ability we were able to see responses but we just Administration profiles offer another to compete. didn’t see the depth and the durability that we level of differentiation, with implications for If the current data hold out, the ADC wanted. We think BCMA is a perfect target patient preferences, optimal combination use offers response rates and durability that for a BiTE, which we hope can unlock more and sequencing strategies. CAR-Ts,​ while are in line with the effects of CAR-Ts,​ profound activity.” onerous to make, are only administered he explains, without the risk of cytokine once. GSK doses its ADC via a 1-hour release syndrome. As an off-the-shelf​ agent, infusion, once every 3 weeks. And Amgen’s it is simple to manufacture and get to AMG 420 is delivered by continuous patients, likely translating into faster access We need to do more to infusion via a pump for 4 weeks at a time. and lower costs. It can be readily tested, under-stand​ how to best (Amgen’s AMG 701 is a half-life-extended​ combined and sequenced with other agents manage the disease using BCMA-targeted​ BiTE that might offer more to improve efficacy further still. And it has these tools convenient delivery.) the potential to be first to market. Given all of the patient-population​ “When I think about all those things hypotheses and treatment-combination​ in aggregate, that makes me very excited Other antibody-​based agents are in earlier permutations, the multiple myeloma about [belantamab mafodotin] and its phases of development, including naked community has years of BCMA research ability to help patients,” says Barron. antibodies that are still in the running. Seattle ahead of it. “It’s one of those success “Having an agent that can be used off the Genetics advanced an afucosylated naked problems, and it’s a great problem to have,” shelf offers a big advantage over things that antibody into phase I trials late last year, says Celgene’s Hege, whose company has require plasmapheresis and reinfusion, for example. five different BCMA candidates, in three and because of that autologous cell therapies modalities, in the clinic. have to have exceptionally better efficacy Spoilt for choice But there is also a risk that the field is or safety profiles to warrant the cost and In many ways, drug developers, oncologists approaching a place of diminishing returns inconvenience,” adds Barron, who was and patients stand to benefit from having so — with a cost for patients that is hard to on the board of Juno Therapeutics and many BCMA-targeted​ agents to choose from. quantify. At the American Association for remains excited about the overall prospects “They are all powerful,” says Tai, who also Cancer Research meeting in Atlanta earlier of CAR-Ts.​ emphasizes that results from phase I trials this year, the director of the FDA’s Oncology Off-the-shelf​ bispecific formats are cannot be compared. Given unique sets of Center of Excellence Richard Pazdur called also in contention. These are designed to advantages and disadvantages, and the near out drug developers for chasing the crowd bind the BCMA antigen on myeloma cells universal relapse rate of multiple myeloma, with PD1/PDL1 blockers, to the detriment with one arm, and to bind CD3 on the more is better. “Now we need to do more to of the clinical trial system and the rest of the surface of T cells with the other, resulting understand how to best manage the disease cancer pipeline. “Do we just have too many in T cell activation, cell killing and cytokine using these tools.” of these same drugs here?”, he asked in the production. For instance, the therapeutics may session ‘PD-1 Pandemonium’. Amgen’s AMG 420, the most have different activity profiles in different BCMA, once itself passed over in favour advanced of these, belongs to a subgroup patient populations. ADCs that bring of trendier targets, could soon prompt of bispecifics called bispecific T cell chemotherapeutic warheads directly to the same questions. With so many agents engagers (BiTEs). These are smaller than cells, for instance, can induce cell death already in the clinic, are trials that dip into traditional antibodies, and consist of two even when the immune system is depleted, a limited pool of patients asking the most antibody domain fragments joined via a potentially offering activity even in the most important questions? And, are other targets linker. They are thought to offer exquisite immunocompromised patients. Bispecific falling through the cracks as a result? activity, but with shorter half-lives​ than formats that rely on the functional T cells to full-​length antibodies. kill cancerous cells, by contrast, may have In a cohort of ten patients with relapsed their place earlier in the disease when the or refractory multiple myeloma who had disease bulk is lowest and the immune system When is enough enough? been on at least two lines of prior therapy is in the best shape. That’s a hard question and who received the recommended dose of The field is also going to have to figure AMG 420, 70% achieved an overall response, out how to combine and sequence the the company reported at the ASH meeting various BCMA-​targeted agents with other “When is enough enough? That’s a last year. The median duration of response drugs to achieve the best results. GSK hard question,” says Hege. “You want to was 9 months, the company reported at already has trials ongoing to evaluate its really prosecute on outstanding targets the American Society of Clinical Oncology belantamab mafodotin in combination with as many novel strategies as you can. annual meeting in June. with current standard-of-care​ regimens, And at the same time, you can’t lose sight of Adverse events in this trial included as well as with Merck & Co.’s PD1-blocking the reality that there is probably another great infections and cytokine release syndrome, pembrolizumab. Because the ADC target out there waiting to be discovered.”

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