ASH 2020 snapshot: efficacy data in hot emerging areas
A roundup of clinical trial readouts for CD47 blockers, allogeneic CAR T cells and sickle cell disease
A roundup of clinical trial readouts for CD47 blockers, allogeneic CAR T cells and therapies addressing the root cause of sickle cell disease.
By Karen Tkach Tuzman, Associate Editor
November 14, 2020 2:08 AM UTC
This year’s ASH meeting provides an opportunity to take stock of clinical progress in hot target, modality and disease areas: CD47 inhibitors, allogeneic CAR T cells and sickle cell disease.
Abstracts released ahead of the virtual 2020 American Society of Hematology (ASH) meeting, to be held Dec. 5-8, show positive early signals for all three areas.
In some presentations, companies that had already amassed clinical data for their candidates have begun spotlighting the indications, patient subsets and manufacturing processes they plan to advance to the next stage of clinical development or to a regulatory filing. Other abstracts feature promising early signals for newer agents.
Abstracts from the Society for Immunotherapy of Cancer (SITC) meeting, taking place Nov. 9-14, provide additional glimpses into the early clinical performance of some CD47 candidates, as well as preclinical updates on the next wave of CD47 and allogeneic CAR T cell candidates in the pipeline.
Eat this
Abstracts at ASH and SITC are providing more data points on the efficacy of CD47 inhibitors, and the evidence suggests the target may hold promise in solid as well as liquid tumors.
Known as a “don’t eat me” signal, CD47 is a cell surface protein upregulated by tumor cells to avoid phagocytosis by macrophages. As companies developing anti-CD47 mAbs overcome the initial safety challenges of on-target, off-tumor toxicity, they are adding to the evidence base for the efficacy of this closely watched class of myeloid checkpoint inhibitors.
In its SITC presentation, ALX Oncology is highlighting data for the solid tumor patient populations and quadruplet therapy combinations it plans to pursue in Phase II trials. The company, which raised a $105 million series C round in March, is developing a fusion protein with an inactive Fc domain to minimize toxicity. As a result, the compound must be co-delivered with a tumor-targeting mAb whose Fc domain stimulates myeloid cell activity, such as Herceptin trastuzumab, Keytruda pembrolizumab or Rituxan rituximab.
Gilead is presenting updated data for the IgG4 mAb magrolimab plus azacitidine in acute myelogenous leukemia (AML), the next-most advanced indication for the compound after myelodysplastic syndrome (MDS), where the compound substantially out-performed standard of care. The ASH abstract, which includes a TP53-mutant patient subpopulation, comes eight months after the company’s $4.9 billion takeout of Forty Seven Inc.
I-Mab, fresh off its September licensing deal with AbbVie Inc. (NYSE:ABBV), is presenting the first efficacy results for monotherapy lemzoparlimab, an IgG4 mAb that binds a specific epitope on CD47 that is more accessible on tumor cells than red blood cells. The Chinese biotech received $180 million up front and a $20 million milestone payment from AbbVie for ex-China rights to the compound, and is eligible for a total of $1.7 billion in milestones. I-Mab is recruiting patients for a dose escalation study combining lemzoparlimab with pembrolizumab or rituximab.
Trillium is presenting clinical data for two compounds, the IgG1 mAb TTI-621 and the IgG4 mAb TTI-622. Because IgG4 Fc domains stimulate myeloid cells less potently than IgG1 Fc domains, the company believes it will be able to deliver higher doses of TTI-622 to achieve more CD47 blockade while mitigating toxicity. While IgG4 mAbs have been largely thought to be less capable of single-agent activity than IgG1 mAbs, the company reported single-agent activity for TTI-622.
Additionally at SITC, Innovent Biologics Inc. (HKEX:1801) is presenting safety and PK data for its anti-CD47 mAb IBI188, and Akeso Biopharma Inc. is presenting its first-in-human clinical trial design for AK117.
Arch Oncology Inc., ImmuneOncia Therapeutics Inc., Invenra Inc. and Kahr Medical Ltd. are presenting preclinical data on CD47-targeting compounds at the meetings.
Allogeneic advances
Promising efficacy data from China’s Bioheng are among the allogeneic CAR T cell updates at ASH this year.
The past year has seen a growing number of clinical readouts for off-the-shelf allogeneic chimeric antigen receptor (CAR) T cells, which stand to cut the cost, variability and lag time of autologous CAR T cell therapies individually manufactured for each patient.
Recent data suggests the gene editing and knock down strategies used to stop expression of the cells’ endogenous TCRs are succeeding in preventing graft-versus-host disease (GvHD), the modality’s primary safety risk. Yet allogeneic CAR T cells are showing they carry other safety risks including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), similarly to autologous CAR T cells.
A key question is whether allogeneic CAR T cells will be able to match or out-perform their autologous counterparts. Abstracts released ahead of the 2020 ASH meeting present a mixed picture.
In addition to Nanjing Bioheng Biotech Co. Ltd., two other companies have disclosed clinical efficacy data in ASH abstracts: Allogene Therapeutics Inc. (NASDAQ:ALLO) and Cellectis S.A. (NASDAQ:CLLS; Euronext:ALCLS). A fourth, Celyad S.A. (NASDAQ:CYAD; Euronext:CYAD), published an abstract that said it would disclose clinical data at the virtual meeting.
In multiple myeloma (MM), Allogene’s early data for ALLO-715 suggest the allogeneic candidate may be at an efficacy disadvantage compared with autologous BCMA-targeting CAR T cells, many of which are showing overall response rates (ORRs) of over 90% at ASH.
However, data released earlier this year from Allogene’s Phase I ALPHA trial in non-Hodgkin lymphoma (NHL) suggest the company’s CD19-targeting ALLO-501 could be on equal footing with marketed autologous CD19 CAR T cells.
Investors responded positively to Cellectis’ data showing early evidence that its allogeneic CD22-targeted CAR T cell therapy UCART22 could treat B cell acute lymphoblastic leukemia (ALL) without triggering GvHD, although two of the five patients experienced serious treatment-emergent adverse events. The company gained 10% to $18.13 on the news.
Bioheng’s early data stood out for the 83% ORR achieved by its CD19- and CD22-targeting allogeneic CAR T cell, CTA101, in B cell ALL. In September, Autolus Therapeutics plc (NASDAQ:AUTL) reported an ORR of 71% for the highest dose of AUTO3, its autologous CAR T cell against the same targets.
Bioheng — which was founded in 2017 and focuses on immunotherapy, gene therapy and CRO services — uses CRISPR/Cas9 to disrupt the allogeneic cells’ TRAC locus, which encodes part of the endogenous TCRα chain, and CD52, a cell surface marker expressed on immune cells.
The TRAC disruption stops endogenous TCR signaling by allogeneic cells, while the CD52 knock out enables them to withstand concurrent delivery of a lympodepleting anti-CD52 mAb, which promotes engraftment and prevents rejection.
Allogene and Cellectis are disrupting those same two genes using TALEN-mediated editing. Celyad’s CYAD-211 uses shRNA knock down of the CD3z chain to stop TCR signaling, and does not alter CD52 expression.
All three companies reported no instances of GvHD or ICANS.
At SITC, there were preclinical allogeneic CAR T cell presentations from cell therapy companies Atara Biotherapeutics Inc. (NASDAQ:ATRA) and Poseida Therapeutics Inc. (NASDAQ:PSTX), as well as the base editing company Beam Therapeutics Inc. (NASDAQ:BEAM).
Red cell rally
The move toward sickle cell disease therapies that address the pathology’s root causes is reflected in promising early-stage readouts at ASH, which include changes in both disease event rates and red blood cell biology.
The momentum generated by last year’s approvals of sickle cell therapies from Novartis AG (NYSE:NVS; SIX:NOVN) and Global Blood Therapeutics Inc. (NASDAQ:GBT) continues via the progress made by next-wave candidates exploiting new modalities and candidates.
While Novartis’ Adakveo crizanlizumab, an anti-P-selectin mAb, reduces the frequency of vaso-occlusive crises (VOCs) by stopping sickled red blood cells (RBCs) from sticking to blood vessels, Global Blood’s Oxbryta voxelotor is geared to prevent sickling in the first place by modulating the oxygen affinity of mutant hemoglobin so that it doesn’t polymerize into rods that deform RBCs. That mechanism of action led Global Blood to pioneer the surrogate endpoint of increased blood hemoglobin levels.
Companies presenting clinical data for next-generation sickle cell disease candidates at the 2020 ASH meeting are similarly reporting readouts showing biochemical improvements in RBC health, including levels of different types of hemoglobin, sickling propensity, and metabolic markers such as ATP and 2,3-DPG.
bluebird bio Inc. (NASDAQ:BLUE) is presenting data from a subgroup of its Phase I/II HGB-206 study of the ex-vivo gene therapy LentiGlobin, in which patients received a version of the therapy made using an optimized manufacturing process and cell harvesting protocol.
The company, which also has a Phase III HGB-210 trial of LentiGlobin ongoing for sickle cell disease, had to make cuts in R&D spending due to the COVID-19 pandemic, including indefinitely pausing its HGB-211 trial of LentiGlobin to treat sickle cell disease in patients at high risk of stroke.
On Nov. 5, bluebird lost $9.72 (17%) to $48.83 on the news that its BLA submission for LentiGlobin to treat sickle cell disease will be delayed to late 2022 from 2H21; the BLA application will be based on data from the HGB-206 subgroup highlighted at ASH.
Aruvant Sciences Inc. also has an ex vivo gene therapy in Phase I/II testing. Both Aruvant and bluebird are transducing patients’ hematopoietic cells with lentiviral vectors encoding modified versions of hemoglobin subunits.
CRISPR Therapeutics AG (NASDAQ:CRSP) will present long-term durability data for its ex vivo CRISPR-edited hematopoietic stem and progenitor cell (HSCP) therapy CTX-001 in sickle cell disease, with one patient remaining free of VOCs for over a year. By editing the enhancer region of the transcription factor BCL11A, CTX-001 upregulates expression of fetal hemoglobin.
Agios Pharmaceuticals Inc. (NASDAQ:AGIO) and Forma Therapeutics Inc. (NASDAQ:FMTX) are each presenting data on Phase I studies of their PKR allosteric activators, which improves the metabolic health of RBCs.
Sickle cell disease candidates with preclinical data at ASH include a fetal hemoglobin-inducing small molecule from Fulcrum Therapeutics Inc. (NASDAQ:FULC), a SLC40A1 inhibitor from Vifor Pharma Ltd. (SIX:VIFN), a gene edited cell therapy candidate from Editas Medicine Inc. (NASDAQ:EDIT), and a base editing strategy from Beam.
TARGETS BCMA (TNFRSF17; CD269) – Tumor necrosis factor (TNF) receptor superfamily member 17 CD22 (SIGLEC2) CD3z (CD247) – CD3zeta p53 (TP53) PKR - Pyruvate kinase isoenzyme R SLC40A1(SLC11A3; ferroportin) - Solute carrier family 40 iron-regulated transporter member 1 TCR - T cell receptor TRAC - T cell receptor alpha constant
BioCentury & Getty Images
This year’s ASH meeting provides an opportunity to take stock of clinical progress in hot target, modality and disease areas: CD47 inhibitors, allogeneic CAR T cells and sickle cell disease.
Abstracts released ahead of the virtual 2020 American Society of Hematology (ASH) meeting, to be held Dec. 5-8, show positive early signals for all three areas...
