Companies and Themes to Watch at ASH 2021
By Kyle O’Neil with Peter Bak, PhD, Back Bay Life Science Advisors
A Brighter Close to 2021?
With biotechnology markets in flux, investors are looking to see if the 2021 American Society of Hematology (ASH) annual meeting inspires a bounce across the sector. However, abstracts released November 4th ahead of the meeting starting on December 11th did not lead to a rally that many were hoping for across companies developing therapies in the fields of hematology-oncology and benign hematology. Back Bay Life Science Advisors selected key abstracts that highlight new areas of interest in oncology and compelling data readouts in hematology to watch with broader implications to the sector at ASH 2021 (Figure 1).
Figure 1: Selected key themes and companies to watch at ASH 2021
Emerging Targets and Therapeutic Classes in Oncology
Theme #1: CD79b as an emerging target for B-Cell Malignancies
Though CD19 and CD20 are well validated targets that are homogenously expressed in B-Cell malignancies, there is always interest in new target-based approaches. This is particularly important in the cell therapy landscape, where more than 40 CAR-modified therapies are in development targeting CD19 and CD20 with limited differentiation. While 2020 saw an influx of data surrounding the target ROR1 presented by VelosBio and NBE Therapeutics, emerging trends point towards CD79b as a differentiated target to watch at ASH 2021. CD79b is critical for mature B cell function and has high expression restricted to the B cell lineage.
Multiple presentations on Phase 3 studies of Roche and Chugai’s recently approved Polivy (Polatuzumab vedotin-piiq), a CD79b antibody-drug conjugate (ADC), are expected, with sales expected to reach $1.5B by 2026 according to Evaluate. A late-breaking abstract in 1L Diffuse-Large B-Cell Lymphoma (DLBCL) showed a 2-year progression free survival (PFS) of ~77% for pola-R-CHP versus a ~70% 2-year PFS for standard 1L treatment R-CHOP* (#LBA-1). Perhaps more importantly, Roche/Genentech is presenting multiple studies on Polivy combinations with its CD20xCD3 bispecific antibodies mosunetuzumab and glofitamab to potentially differentiate from other CD20xCD3 bispecific antibodies we profiled for ASH last year that have continued to see BD activity (#533, #525).
Theme #2: Innate immune system therapies
Fate Therapeutics’ CD19-targeted CAR-NK data in 20 patients is worth watching given long standing interest in this cell type as an allogenic alternative to traditional CAR-T therapies, despite the questions remaining regarding durability of the therapy (#823). With multiple other CD19-targeted cell therapies including “first-generation” (Yescarta #2, Breyzani #91) and “second-generation” (Novartis’ YTB323 #740, Precision’s PBCAR0191 #650) technologies presenting at the conference, investors are watching to see if Fate can establish superior efficacy or safety data along with long-term complete responses. Given the barriers to commercialization are high with large players in the space, indication selection and clinical differentiation are critical. This likely inspired Blackstone’s recent investment in Autolus, who is also expected to present data at the conference despite an abstract focused on manufacturing (#477).
While Fate is developing a cell-based NK product to target B-Cell malignancies, other companies are employing a bispecific strategy to harness a patient’s existing NK cell population. Recent results from Affimed further spurred interest in this approach and broadly in utilizing innate immune cells in oncology, which we profiled in 2020. Though Affimed already announced a 100% objective response rate with a 42% complete response rate in 12 patients in CD30+ lymphomas for cord blood-derived natural killer (cbNK) cells pre-complexed with innate cell engager AFM13, additional data may be presented at the conference (#3992).
Chronic and One-Time Therapies in Rare Hematology
Theme #1: Fitusiran (RNAi) and Gene Replacement Therapies for Hemophilia A/B
Sanofi is looking to shake up the ~$10B Hemophilia market with fitusiran, a subcutaneously administered siRNA therapy applicable to both Hemophilia A and B in-licensed from Alnylam. Fitusiran targets the SERPINC1 gene, which codes for antithrombin and is upstream of the coagulation factors gene therapies attempt to replace. Preliminary Phase 3 data released in 57 patients with contraindications to factor replacement therapy showed statistical significance on primary and secondary endpoints, including a ~90% reduction in annualized bleeding rate (ABR). However, safety, particularly thrombosis (blood clotting), is a known concern with Sanofi testing a lower dose that has delayed filing until 2024, with ~90% of patients in the fitusiran arm of the trial experiencing at least 1 treatment emergent adverse event (#4).
Meanwhile, late-stage gene replacement therapies are proceeding towards market in both Hemophilia A and Hemophilia B. In Hemophilia A, BioMarin expects to resubmit a BLA for valoctocogene roxaparvovec in 2Q 2022 after receiving a Complete Response Letter (CRL) in August 2020 requiring 2-year data on ABR. Updated data from January 2021 showed a reduction in ABR of ~84%. In Hemophilia B, CSL Behring and uniQure closed their commercialization and license agreement and have announced an updated regulatory plan and new data. The data showed a ~65% reduction in ABR at 18 months, a decrease from the 52 week data, with a BLA filing expected 1Q 2022.
Theme #2: GBT021601 and Gene Replacement/Editing Therapies in Sickle Cell Disease
With the sickle cell disease commercial landscape rapidly becoming more competitive, early-stage data from Global Blood Therapeutics’ 2nd-generation small molecule sickle hemoglobin polymerization inhibitor GBT021601 moved the stock down ~10% when abstracts were initially released. Though the stock rebounded, initial data from healthy patients did not reach a level of hemoglobin modification/target engagement of ~30%, which may be sufficient to revert patients to a more normal phenotype (#3099). For reference, Oxybrata (voxelotor) has shown hemoglobin modification of ~26% and is expected to achieve >$1B in sales by 2025 according to Evaluate. Investors will be watching for additional data from 6 sickle cell disease patients at the conference.
On the other side of the fence is the Bluebird’s gene therapy Zynteglo and Vertex’s/CRIPSR Therapeutics’ gene editing therapy CTX001, potential market leading gene therapies in an indication expected to provide broader proof-of-concept for cell and gene therapy platform technologies. Both require intensive induction therapy ahead of treatment infusion, the opposite of Global Blood’s convenient small molecule dosing. Neither is presenting data at the conference following CRISPR’s stock moving disclosure at ASH 2020 that showed 7 patients with transfusion-independence from β-thalassemia across 3 to 18 months and 3 patients free of sickle cell disease vaso-occlusive crises with 3 to 15 months of follow-up.
Looking Ahead
With ample cash in the market, valuations falling and the extensive capabilities required for commercialization in the competitive hematology-oncology and benign hematology spaces, market leaders are likely to strongly consider significant M&A activities in 2022 for therapies differentiated from scientific, clinical or commercial perspectives. This year’s emerging data at ASH may lead to transactions similar to the M&A observed regarding ROR1 last year, when on the heels of 2020 ASH data Merck and Boehringer Ingelheim purchased VelosBio (~$2.8B) and NBE Therapeutics (~$1.5B), respectively, after VelosBio disclosed promising ROR1 ADC results in MCL/DLBCL at ASH.
*Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone