Wells Fargo Biotech Cell and Gene Therapy Companion o Newsletter. This week's themes include: continued fund-raising for cell and gene therapy; regulatory actions including first BCMA CAR-T product approval, a first CAR-T filing for adult acute lymphoblastic leukemia, IND approval for pre-loaded NK cells, Orphan Drug designation in TTR-amyloidosis; optimization of cell therapy including point-of-care, reversal of exhaustion; further exoneration of AVV as a driver of cancer, but caution over long-term toxicity from AAV9-SMN in mice with spinal muscular atrophy; funding of an academic CRISPR trial in sickle cell disease and pre-clinical data for a gene therapy addressing hemophilia A & B.
Highlights of the week include: 1) Applied Genetic Technologies Corporation (AGTC) partner, Bionic Sight disclosing positive data for BS01 in retinitis pigmentosa. 2) Emergence of potential point-of-care cell therapy competitor, Avalon GloboCare - relevant for Precigen (PEGN) and Ziopharm (ZIOP). 3) Gracell Biotechnologies (GRCL) agreement with Lonza to manufacture dual CD19/BCMA FasCAR-T, GC-012F.4) Announcement by uniQure (QURE) that independent investigation finds it highly unlikely that the case of hepatocellular carcinoma was caused by AAV. 5) Publication with senior author Guangping Gao that natural AAV sequences in tumors and adjacent tissue are not different from each other - relevant for QURE and Sangamo Therapeutics (SGMO). 6) IND approval for Affimed's (AFMD) first IND for pre-loaded NK cell therapy. 7) Autolus Therapeutic's (AUTL) obe-cel received PRIME designation for relapsed/refractory acute lymphoblastic leukemia (ALL). (8) Filing of an sBLA by Gilead for TECARTUS in adult ALL highlights obe-cel's superior safety profile. 9) FDA approved bluebird bio (BLUE) and BMY's BCMA CAR-T, ABECMA in a more restricted patient population than studied - relevant for AUTL, Cellectis (CLLS), Celyad Oncology (CYAD), Fate Therapeutics (FATE), GRCL. 9) Intellia Therapeutics (NTLA) received Orphan Drug designation in Europe for NTLA-2001 in TTR-amyloidosis. 10) CIRM will fund a CRISPR gene therapy trial in sickle cell disease at 3 University of California institutions - relevant for Beam Therapeutics (BEAM), BLUE, CRISPR Therapeutics (CRSP) & SGMO. 11) UCLA publishes pre-clinical data supporting clinical development of CD4 CAR-T for HIV; NIH publishes less encouraging data [this is science]. 12) Clinical vignette from Chinese glioblastoma patient treated with a B7H3 CAR-T published - relevant for FATE. 13) Columbia University publish pre-clinical data suggesting gain of toxic function data in mice receiving AAV9 SMN treatment for spinal muscular atrophy - relevant for Ionis Pharmaceuticals (IONS) if there is read through to NVS's ZOLGENSMA. 14) Pre-clinical gene therapy with a platelet restricted factor Xa is effective in hemophilia A & B - relevant to QURE/SGMO. 15) CAR-T exhaustion can be reversed in pre-clinical models with a single dose of dasatinib - relevant for all companies developing CAR-T using a high affinity/avidity scFv.
Notable Corporate Events
AGTC partner Bionic Sight reported initial data from a phase 1/2 study of BS01 in advanced stage retinitis pigmentosa (RP). The data demonstrated that all four patients, who were complete or near-completely blind, can now see light and motion. Additionally, 2/4 patients can now detect the direction of motion. Bionic expects to report additional data later in 2021. Recall, AGTC has the option to pick up the program when the phase 1/2 data are available.
Avalon GloboCare Corp and strategic partner Arbele, are collaborating with the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center to advance the clinical development of point of care RNA-based autologous cell therapies using FLASH CAR technology. Avalon’s first FLASH CAR product candidate, AVA-011 targets CD19 and CD22 is on track to initiate a clinical study in B-cell leukemia and non-Hodgkin’s lymphoma – relevant for PEGN and ZIOP who use on-site point of care CAR-T manufacture leveraging Sleeping Beauty. PEGN and ZIOP use conventional DNA-CARs which integrate into the T cell genome while Avalon is using an RNA CAR which may be episomal and shorter lived.
GRCL signed an agreement with Lonza to manufacture FasTCAR products to support IND filing of dual BCMA/CD19 FasTCAR, GC-012F. Separately, GRCL announced enrollment of the first acute lymphoblastic leukemia patient into the registration-directed trial of GC007g in China. GC007g is an HLA-matched donor-derived allogeneic CD19 CAR-T product.
QURE announced the results of an independent investigation into the case of hepatocellular carcinoma (HCC) diagnosed in a patient in the HOPE-B trial. QURE noted that the independent investigation found it highly unlikely the HCC was caused by the company's AAV gene therapy etranacogene dezaparvovec (etra-dez).
Notable Regulatory/Clinical News
AFMD and partner NKMax America announced FDA IND clearance for a co-sponsored phase 1/2a dose escalation and expansion study evaluating AFMD’s EGFR/CD16A innate cell engager AFM24 in combination with NKMax America’s autologous NK-cell product SNK-01, currently in phase 1 testing, in patients with advanced/metastatic EGFR-expressing solid tumors.
AUTL announced receipt of PRIME designation for Obe-cel (AUTO1) in relapsed/refractory B-acute lymphoblastic leukemia (B-ALL) as well as recent listing of the MCARTY trial (NCT04795882) evaluating a modular CAR-T targeting BCMA alone or BCMA with CD19.
AUTL – Filing of an sBLA by GILD for TECARTUS highlights the superior safety profile of obe-cel (AUTO-1). With 1/4 and nearly 1/2 of TECARTUS-treated adult acute lymphoblastic leukemia patients suffering grade 3 or higher cytokine release syndrome (CRS) and neurotoxicity / immune cell associated neurotoxicity syndrome (ICANS) respectively at the 1M cell dose of ZUMA-3. By contrast, in 20 patients treated with obe-cel, AUTL reported no grade 3 or higher CRS and ICANS was limited to 4/20 patients, of which 3 cases were grade 1 and resolved within 24 hours.
AUTL – Chinese academics listed a phase 1 trial of a TRBC1 CAR-T in TRBC1+ve relapsed/refractory T cell leukemia. AUTL is conducting the LIbrA T1 trial of AUTO4 in TRBC1+ve T cell leukemia with interim data expected 2H21; AUTL expects to initiate clinical development of AUTO5 in TRBC2 T cell leukemia 2H21.
AUTL/CLLS/CYAD/ FATE & GRCL - we see the approved label for bluebird bio/ Bristol Myers Squibb's BCMA CAR-T, ABECMA for relapsed/refractory multiple myeloma setting a low bar for competitors. While ABECMA was studied in 4th line plus myeloma FDA gave the product a 5th line plus label. ABECMA’s blackbox warning includes hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) which occurred in 4% of patients overall increasing to 8% at the 450MM dose; approved CD19 CAR-T do not have an HLH/MAS blackbox warnings. In more recent BCMA trials, we note use of the IL-1 receptor antagonist, ANKINRA, potentially for HLH/MAS with 19% use in JNJ/Legend Biotech's cilta-cel CARTITUDE-I trial.
NTLA announced receipt of orphan drug designation from European Commission (EC) for Regeneron-partnered in vivo editing program NTLA-2001 for TTR amyloidosis (ATTR). The decision follows the initiation of the phase 1 study of NTLA-2001 in hereditary ATTR with polyneuropathy (hATTR-PN).
BEAM/BLUE/CRSP/EDIT - California Institute of Regenerative Medicine will support a phase 1 trial of CRISPR engineered SCD gene therapy to be conducted at The University of California, San Francisco (UCSF), UC Berkeley (UCB) and UC Los Angeles (UCLA).The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.
Notable Peer Reviewed Publications
FATE/CLLS – With both companies expected to announce programs outside of oncology we note UCLA scientists publish data for a 2nd generation anti-HIV1 CAR-T. UCLA’s use of engineered hematopoietic stem cells could be replaced by FATE’s induced pluripotent stem cells in our view. UCLA modified hematopoietic stem cells with a truncated CD4 CAR to target HIV envelope, that unlike the first gen CAR prevented HIV transmission as well as prevented IL-16 binding and potential non-specific CAR signaling while maintaining similar cytotoxicity against Env+ve cells. The use of 41BB as a costimulatory domain of the CAR, versus CD28 was essential for successful differentiation and improved anti-viral function. Suppression of viremia in untreated mice by the 2nd gen CAR was enhanced by combination treatment with ART which increased CAR-T persistence. The authors believe the 2nd gen CAR-T should be pursued as a clinical candidate. Separately we note an NIH manuscript describing the development of CAR-T against SIV. The studies failed to protect or gain control of viral spread. The authors identified optimal targets noting that while minimally expanded T cells were the most potent, generating large numbers was a challenge, one we note would not be an issue for an iPSC/allogeneic CAR-T. In addition, the authors observed that virus infected cells expressed Env protein for a relatively small fraction of the rapid viral lifecycle, and only towards the end when virus may be about to be released, an observation we interpret as requiring CAR-T persistence or the ability to re-dose.
