ASH 2020 Preview
By Kyle O’Neil with Peter Bak, PhD, Back Bay Life Science Advisors
With novel modalities such as cell and gene therapies creating new ways to treat disease alongside monoclonal antibodies (mAbs) and small molecules in oncology and hematology, the 2020 American Society of Hematology (ASH) annual meeting is a harbinger of future biopharmaceutical growth in the space. Abstracts released November 4th already moved markets. More data is expected at the meeting, which starts December 5th, offering investors presentations across immuno-oncology, cell therapy, and genetic and small molecule therapeutics in rare hematology.
Back Bay Life Science Advisors conducted an analysis of key abstracts and selected companies working across the four key areas to watch at ASH 2020 [Figure 1: Selected companies with key programs presenting at ASH 2020].
FIGURE ONE: Key Players at ASH 2020
IO
In immuno-oncology, a significant proportion of exciting data is on new target-based approaches or novel ways to drug established targets. At ASH 2020, a handful of companies will present their work to develop new therapeutics across both categories. The current focus of interest is on novel ways to drug CD20, which was the target of the successful first monoclonal antibody approved for the treatment of lymphoma, rituximab. Additional interest is on new target-based approaches focused on CD47, a “marker of self” checkpoint protein that binds to SIRPα.
New approaches to targeting CD20, including bispecific antibodies, novel combinations, and cell therapies will present data at ASH. Bispecific antibodies are a contested approach, with therapeutics targeting CD20 and CD3 in development from Genmab/AbbVie (epcoritamab, partnered for $750 million upfront in 2020), IGM Biosciences (IGM-2323), Roche (mosunetuzumab and glofitamab), and Regeneron (odronextamab).
Preliminary data released on epcoritamab showed a 100% objective response rate (ORR) at the high dose in diffuse large B cell lymphoma (DLBCL) (#402), while IGM-2323 disappointed investors with its first-in-human data (#1142), resulting in a ~7% share price drop.
Large players Roche and Regeneron released updated data sets for odronextamab (#400), mosunetuzumab (#401), and glofitamab (#403), respectively, disclosing ~50-60% ORRs.
In other CD20 targeting modalities, TG Therapeutics released promising Phase 3 data from Umbralisib (dual inhibitor of PI3Kδ and CK1ε) Plus Ublituximab (novel anti-CD20 mAb) in CLL (#543) while Mustang Bio announced results in 4 patients treated with a modified version of MB-106 (#1443), an autologous CD20 directed CAR-T.
The other competitive space in IO to watch at ASH 2020 is the CD47/SIRPα Axis, with Gilead Sciences (through its $4.9B acquisition of Forty Seven, Inc. in March), Trillium Therapeutics (stock up >1,000% YTD), and ALX Oncology all advancing novel therapies. Gilead’s CD47-directed mAb magrolimab led to a 65% ORR in AML (#330) while Trillium’s SIRPα targeting antibodies TTI-621 (directed to the SIRPαFc IgG1) and TTI-622 (directed to the SIRPαFc IgG4) led to a ~20% and ~30% ORR in relapsed/refractory hematologic malignancies, respectively (#646, #1191). Lastly, ALX Oncology’s ALX148, directed to mutated SIRPαFc with inert IgG1, led to dose-dependent ORRs in combination with rituximab ranging from ~40-60% (#3016).
Allogeneic Cell Therapies
In the cell therapy space, investors are watching second generation allogeneic CAR-T therapies to see if they can live up to the promise of addressing the manufacturing, logistic, and safety challenges than have limited the uptake of first-generation CAR-Ts KYMRIAH and YESCARTA.
Allogene disclosed initial results for ALLO-715, a BCMA-directed allogenic CAR-T therapy given alongside ALLO-647, a CD52-targeting mAb. To date, the ALLO-715 program has a 33% ORR in 15 patients in ≥4L multiple myeloma (#129). Four episodes of Grade ≥3 infections occurred, raising safety concerns, and sending Allogene’s stock down ~10%. With Janssen and bluebird bio, Inc./BMS disclosing >~85% ORRs for autologous CAR-Ts ciltacabtagene autoleucel (#177) and ide-cel (#131), respectively, finding a role for a BCMA-directed allogeneic CAR-T may be challenging unless data improves.
Other allogeneic cell therapies to-be-presented include first-in-human data for Fate Therapeutic’s FT596, a allogeneic CD19-directed CAR-NK (#2356) and Cellectis’ UCART22, a allogeneic CD22-directed CAR-T (#163), with a trial-in-progress paper to-be-presented on Cellectis’ UCART123. Although FT596 and UCART22 demonstrate promising results, few patients have been treated to date.
Rare Hematology
As the genetic and biological understanding of disorders such as hemophilia, sickle cell disease, and β-thalassemia has evolved in the 21st century, multiple therapeutics have advanced into clinical development, with several competitors vying to be first-to-market. This year at ASH there is broad investor interest in rare hematology clinical data from both genetic medicines and small molecule programs from first-in-human to post-approval studies.
Genetic Medicines
Gene therapies for Hemophilia A and B will be a focus at the conference for mid- and large-cap biotech and pharma companies. Recently, uniQure made waves with its late breaking abstract showing initial Phase 3 data for AAV5 etranacogene dezaparvovec (AMT-061) in Hemophilia B, sending its market cap above $2 billion. With 54 patients dosed to date, 72% reported 0 bleeds in the first 26 weeks post treatment (LBA-6). Although initial data is promising, investors will be watching for further explanation at the conference around one patient who did not respond to treatment, particularly with Pfizer also advancing Spark’s SPK-9001 in Hemophilia B pivotal studies.
Two partnered programs in Hemophilia A disclosed results at ASH. Ultragenyx Pharmaceutical and Bayer reported proof-of-concept first-in-human data using a AAVhu37 vector and are expected to release 22-month follow-up data at the conference (#1539). Similarly, Sangamo Therapeutics and Pfizer are expected to present data on the portion of 11 patients followed for 1+ year post-treatment with their AAV6 vector (#671).
In sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT), the genetic therapy battle spans modalities with Vertex’s/CRISPR Therapeutics’ early stage ex vivo CRISPR therapy, CTX001 attempting to differentiate from bluebird bio’s ex vivo lentiviral gene replacement therapy, Zynteglo.
While Zynteglo is approved for TDT in the EU based on data in ~15 patients who achieved transfusion independence, long-term follow-up in both TDT and SCD will be presented at ASH as bluebird seeks additional regulatory approvals which have been delayed by CMC challenges (#153, #677).
In contrast, investors sent CRISPR Therapeutics’ stock up 10% based on data released from seven patients treated with TDT and SCD. Five patients with TDT have been transfusion-free since ~2 months after CTX001 infusion and updated data is expected to be presented at the conference (#4).
In the less common rare hematology indications, Rocket Pharmaceuticals is presenting first-in-human data on autologous ex vivo lentiviral gene replacement therapies in two patients with Fanconi anemia and two patients with severe leukocyte adhesion deficiency-I (#674, #675).
Small Molecules
Three small molecules in SCD have shifted the conversation around a disorder where there were no new therapies approved between 1997 and 2017. Oxbryta (voxelotor), an inhibitor of deoxygenated sickle hemoglobin polymerization, was approved in 2019 based on data showing a ~51% increase in hemoglobin response rate compared to a ~6% in the placebo-treated group. While sales to date have disappointed, a 72-week analysis of the pivotal study sent the stock of Global Blood Therapeutics up ~15% due to a clearer, not significant, link between Oxbryta and vaso-occlusive crises (#1716).
Switching pathways, Agios and Forma Therapeutics are presenting data at ASH regarding two small molecule treatments involved in activating red cell pyruvate kinase. Agios’ abstract contains already disclosed positive topline data for mitapivat (#681), while Forma released target-validating first-in-human data for FT-4202 (#679) and more data is expected from both programs at the conference.
Looking Ahead
Alongside the progressing science and manufacturing of cell and gene therapies, the number of indications under consideration for their use will also increase. With antibodies and small molecules still improving the standard of care in hematology and oncology, the differentiation of modalities that becomes ever clearer at ASH will play a key role in therapeutic prioritization, the approach to clinical development, commercial strategies, and future areas of investment.
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