news DGEATA PA Drug pipeline 1Q21—the old and the new The US Food and Drug Administration (FDA) continues to approve products at a rapid clip, with 17 new molecular entity (NME) and biologic approvals in the quarter. Over 40 years after the first monoclonal antibody (mAb) was approved—muromonab (Ortho Kung/ OKT3), an anti-CD3 murine mAb for use in graft-versus-host disease—FDA will consider a humanized version of the drug for type 1 diabetes. Elsewhere, CRISPR Therapeutics published promising one-year results on its CRISPR–Cas9 therapy against the BCL111A erythroid-specific enhancer in transfusion-dependent β-thalassemia and sickle cell disease. Bristol Myers Squibb (BMS) and bluebird bio’s Abecma (idecabtagene vicleucel) became the first chimeric antigen receptor (CAR)-T cell therapy to be approved for multiple myeloma and the first directed against an antigen other than CD19. Regeneron’s Evkeeza (evinacumab-dgnb) is the first mAb approved for familial hypercholesterolemia that targets the angiopoietin-like 3 protein. A double dose of bad news came in Huntington’s disease, with clinical setbacks for two antisense oligonucleotide (ASO) therapies: Ionis/Roche’s tominersen and Wave’s WVE-120102. Lilly reported positive trial results for its Alzheimer’s disease therapy mAb donanemab; by next quarter’s end, Biogen might finally get an answer from regulators on its controversial anti–Alzheimer’s disease mAb, aducanumab. Historic US regulatory approvals by drug class Notable clinical trials for COVID-19 products A healthy crop of new approvals in quarter 1, skewed toward small Drug/company Indication Drug information molecules. Immcetz/Creative Medical COVID-19 acute 1/7/2021 In a double-blind, Holdings respiratory distress placebo-controlled phase 2a 70 Vaccine syndrome (ARDS) trial for COVID-19 with ARDS, patients treated with two infusions Cell therapy of umbilical-cord-derived 60 New molecular entity* mesenchymal stem cells had a Biologic significant decrease in cytokines 50 and improved survival (91% versus 42%) Stem Cells Transl. Med. https://doi.org/10.1002/sctm. 40 20-0472, 2021) Etesevimab plus bamlanivimab/ COVID-19 1/21/2021 In a phase 2 randomized 30 Eli Lilly trial of bamlanivimab, a fully human IgG1κ mAb targeting an epitope on the receptor-binding Number of approvals 20 domain (RBD) of SARS-CoV-2 spike (S) protein, no effect was 10 seen on viral load in unhospitalized patients with mild-to-moderate COVID-19; the addition of etesevimab 0 (another fully human IgG1κ mAb 199519961997199819992000200120022003200420052006200720082009201020112012201320142015201620172018201920202021** that targets a different S protein Year RBD epitope), however, did result in significant reduction (J. Am. Med. Assoc. 325, 632–644, *New molecular entity (NME) class includes mainly small-molecule drugs, but 2021) also steroid, synthetic peptide and mixed compounds, excluding non-NME and Peginterferon lambda/Eiger COVID-19 2/5/2021 In a double-blind, new formulation. **Partial year to March 31. Source: BioMedTracker, a service BioPharmaceuticals placebo-controlled trial, this PEGylated interferon-λ accelerated of Sagient Research (http://www.biomedtracker.com). the decline in SARS-CoV-2 viral load from 3 days onward (Lancet Resp. Med. https:// doi.org/10.1016/S2213- Notable drug approvals (1Q21) 2600(20)30566-X, 2021) Drug/company Indication Drug information Actemra (tocilizumab)/Roche COVID-19 2/25/2021 In a phase 3 trials with hospitalized patients, this Lupkynis Lupus nephritis 1/22/2021 FDA approved this small-molecule humanized IgG1κ mAb targeting (voclosporin)/ calcineurin phosphatase inhibitor, the first oral drug interleukin-6 receptor (IL-6R) Aurinia for lupus nephritis did not improve clinical status at 28 days (N. Engl. J. Med. Breyanzi Diffuse large B cell 2/5/2021 FDA approved autologous CAR-T cells, https://doi.org/10.1056/ (lisocabtagene lymphoma expanded in culture, expressing CD19 and a truncated NEJMoa2028700, 2020) maraleucel)/BMS epidermal growth factor receptor (EGFR) Tocilizumab and sarilumab/ COVID-19 2/25/2021 In an adaptive trial Ukoniq* Marginal zone 2/5/2021 FDA granted accelerated approval to this Roche of this humanized IgG1 mAb (umbralisib)/TG lymphoma; indolent small molecule targeting phosphatidylinositol 3-OH κ targeting IL-6R (toclizumab) Therapeutics non-Hodgkin’s kinase (PI3K)- and casein kinase 1 (CK1)- . δ ε and human IgG1 mAb targeting lymphoma IL-6Rα (sarilumab), the group Evkeeza Dyslipidemia/ 2/11/2021 FDA approved this fully human IgG4 mAb receiving both drugs showed (evinacumab-dgnb)/ hypercholes- against angiopoietin-like 3 that has a stabilizing improved survival at 90 days Regeneron terolemia mutation in the hinge. (N. Engl. J. Med. https://doi. org/10.1056/NEJMoa2100433, Amondys 45* Duchenne muscular 2/25/2021 FDA gave accelerated approval to this 2020) (casimersen)/ dystrophy 22-residue exon-45-skipping phosophorodiamidate Sarepta Therapeutics ASO. PegiHep (PEGylated interferon COVID-19 3/10/2021 In a phase 2 alpha-2b)/Zydus Cadila randomized, open-label trial Nulibry Molybdenum 2/28/2021 FDA approved cyclic pyranopterin of PEGylated interferon- 2b, (fosdenopterin)/ cofactor deficiency monophosphate, an intermediate in the synthesis of α 95% of SARS-CoV-2–positive BridegeBio Pharma molybdenum cofactor patients with moderate Abecma Multiple myeloma 3/29.2021 FDA approved this CAR-T cell therapy with symptoms had achieved clinical (idecabtagene anti-B-cell maturation antigen (BCMA) single-chain improvement on day 15 compared vicleucel/BMS variable fragment (scFv) fused to the CD137 (4-1BB) with 68% subjects in standard co-stimulatory and CD3ζ signaling domains of care (Int. J. Infect. Dis. 105, 516–521, 2021) * Accelerated approval. Source: BioMedTracker, a service of Sagient Research (http://www. biomedtracker.com) Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com) 536 NATURE BiotECHNOLOGY | VOL 39 | MAY 2021 | 529–539 | www.nature.com/naturebiotechnology news Upcoming catalysts (3Q21) Notable clinical trial results (1Q21) Drug/company Indication Drug information Drug/company Indication Drug information Aducanumab/Biogen Alzheimer’s disease 6/7/2021, 7/1/2021 FDA and European Lumevoq/GenSight Leber’s 1/13/2021 In a phase 1/2a open-label, dose-escalation Medicines Agency Committee for hereditary optic trial of this AAV-2 gene therapy encoding wild-type Medicinal Products for Human Use neuropathy NADH dehydrogenase 4 gene (ND4), patients decisions for this this fully human IgG1 mAb achieved improvement in visual acuity over the against a conformational epitope 5-year study period (BioDrugs 35, 201–214, 2021) on -amyloid plaques β Engensis/Helixmith Diabetic 1/19/2021 In a phase 3 double-blind, Leukotac (inolimomab)/ Graft-versus-host 06/30/2021 FDA PDUFA date for this peripheral placebo-controlled trial, two isoforms of ElsaLys Biotech disease murine IgG1κ mAb that targets the neuropathy angiogenesis-promoting hepatocyte growth factor, interleukin-2 receptor-α HGF728 and HGF723, delivered into leg muscle via a DNA plasmid vector (pCK) comprising Teplizumab/Provention Bio Diabetes mellitus, 07/02/2021 FDA PDUFA date for cytomegalovirus 5 untranslated region upstream type 1 this humanized IgG1 mAb against the ′ and full-length immediate-early promoter, reduced CD3 chain expressed on mature T ε pain at up to 12 months (Clin. Transl. Sci. https://doi. lymphocytes org/10.1111/cts.12977, 2021) Anifrolumab/AstraZeneca Systemic lupus 07/05/2021 FDA PDUFA date for this fully Ublituximab/TG Chronic 2/21/2021 In a phase 3 trial, a combination of erythematosus human IgG1 mAb against subunit 1 of the κ Therapeutics lymphocytic ibrutinib plus this chimeric anti-CD20 IgG1mAb type I interferon receptor leukemia, with a low-fructose Fc region for enhanced Narsoplimab/Omeros Transplant-associated 7/16/2021 FDA PDUFA date for small-cell antibody-dependent cell-mediated cytotoxicity via thrombotic this human IgG4 mAb targeting lymphocytic CD16A (FcγRIIIa) binding resulted in a statistically microangiopathy mannan-binding lectin-associated lymphoma significant overall response rate as compared serine protease-2 with ibrutinib monotherapy (Lancet Haematol. 8, Amivantamab/Johnson & Non-small-cell lung 8/3/2021 FDA PDUFA date for this e254–e266, 2021) Johnson cancer Fc- enhanced bispecific mAb targeting EGFR Donanemab Alzheimer’s 3/15/2021 In a randomized, placebo- controlled, and cMET (LY3002813)/Eli Lilly disease double-blind phase 2 trial of this humanized IgG1 mAb AMG 510/Amgen Non-small-cell lung 8/16/2021 FDA PDUFA date for this targeting amyloid-βp3–42, the N-terminally truncated cancer first-in-class small-molecule inhibitor of pyroglutamate-3 isoform, patients with early disease mutated KRAS (G12C) showed significantly less decline at 76 weeks than those on placebo (N. Engl. J. Med. https://doi. Vicineum (oportuzumab Bladder cancer 08/18/2021 FDA PDUFA date for this org/10.1056/NEJMoa2100708, 2021) monatox)/Sesen Bio antibody–drug conjugate epithelial cell adhesion molecule–specific scFv fused to CTX001/CRISPR Transfusion- 1/21/2021 In a phase 1/2 trial, more than a year after Pseudomonas exotoxin A, a protein synthesis Therapeutics dependent one person with TDT and one with SCD received + inhibitor β-thalassemia autologous CD34 hematopoietic stem and progenitor (TDT) and sickle cells electroporated ex vivo with CRISPR–Cas9 Belumosudil/Kadmon Graft-versus-host 8/30/2021 FDA PDUFA date for this cell disease and gRNA targeting the BCL111A erythroid-specific Holdings disease small-molecule