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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 (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 . 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 receptor (CAR)- therapy to be approved for and the first directed against an antigen other than CD19. Regeneron’s Evkeeza (-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 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 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 -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 ()/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 ()/ phosphatase inhibitor, the first oral drug -6 receptor (IL-6R) Aurinia for lupus nephritis did not improve clinical status at 28 days (N. Engl. J. Med. Breyanzi Diffuse large 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 receptor (EGFR) Tocilizumab and / 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)

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Upcoming catalysts (3Q21) Notable 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 - β Engensis/Helixmith Diabetic 1/19/2021 In a phase 3 double-blind, Leukotac ()/ 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 /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) /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 inhibitor of Rho-associated (SCD) enhancer, high levels of allelic editing were detected coiled-coil kinase 2 (ROCK2) in marrow and blood, with pancellular fetal Belzutifan/Merck Renal cell cancer 09/15/2021 FDA PDUFA date for this hemoglobin distribution, transfusion independence, small-molecule antagonist of hypoxia-induced and (for SCD) elimination of vaso-occlusive episodes (N. Engl. J. Med. 384, 252–260, 2021) factor 2-α Abecma (idecabtagene Multiple 2/24/2021 In a phase 2 pivotal trial, of patients PDUFA, User Fee Act. Source: BioMedTracker, a service of Sagient Research vicleucel)/BMS myeloma receiving this CAR-T cell therapy with anti-BCMA (http://www.biomedtracker.com) scFv fused to 4-1BB co-stimulatory and CD3ζ signaling domains, 73% overall responded and 33% had a complete response or better (N. Engl. J. Med. 384, 705–716, 2021) Notable regulatory setbacks (1Q21) Teplizumab/ Diabetes 3/3/2021 In a phase 2 trial of at-risk people, one Provention Bio mellitus, type 1 injection of this humanized IgG1 mAb against Drug/company Indication Drug information the CD3ε chain (developed by grafting six complementarity-determining regions from OKT3 into Ultomiris COVID-19 1/13/2021 Data monitoring committee recommended a human framework containing leucine-to-alanine ()/ pausing enrollment of this anti-C5 humanized IgG2/ substitutions at residues 234 and 235 in the CH2 Alexion IgG4 chimeric mAb (comprising human light chain κ region to abolish binding) delayed onset; constant region, a IgG2 heavy-chain CH1 domain and onset averaged 5 years compared with 2 years hinge region, a hybrid IgG2/IgG4 CH2 domain and for untreated individuals (Sci. Transl. Med. 13, an IgG4 CH3 domain) due to lack of efficacy over eabc8980, 2021) standard of care Sotatercept/Acceleron Pulmonary 4/1/2021 In a phase 2 randomized double-blind, Ropeginterferon Polycythemia vera 3/14/2021 FDA issued a complete response letter arterial placebo-controlled trial of this glycosylated, dimeric alfa-2b/ for this PEGylated proline-interferon- 2b, requesting α hypertension comprising the extracellular domain Pharmaessentia more information on the prefilled syringes, owing to and pulmonary of the human activin receptor type IIA and the Fc delay in inspection of site in Taiwan hypertension region of human IgG1, patients receiving the drug had WVE-120102/ Huntington’s disease 3/29/2021 The company stopped clinical statistically significant reduction in vascular resistance Wave Life Sciences development of this stereopure phosphorothioate (N. Engl. J. Med. 384, 1204–1215, 2021) ASO due to lack of statistically significant reduction in Vigil 3/11/2021 In a phase 2b placebo-controlled trial, this mutant huntingtin (gemogenovatucel-T)/­ autologous tumor cell product transduced ex vivo with Tominersen/Roche Huntington’s disease 3/22/2021 Company discontinued phase 3 trial Gradalis a DNA plasmid encoding short-hairpin RNA against of this chimeric 2′-O-(2-methoxyethyl)-modified furin (which blocks immunosuppressive transforming gapmer ASO conjugated to an mAb targeting growth factor-β1 and β2) and recombinant human transferrin receptor on basis of review of risk/benefit granulocyte macrophage colony stimulating factor ratio by IDMC (which activates T cells) extended overall survival and recurrence-free survival as compared with Tesetaxel/Odonate Metastatic breast, 3/23/2021 Company discontinued trials of this oral placebo (Gynecol. Oncol. https://doi.org/10.1016/ Therapeutics colorectal, solid synthetic taxane after FDA indicated the data are j.ygyno.2021.03.009, 2021) tumors unlikely to support approval RG6356/Sarepta Duchenne muscular 1/7/2021 Phase 2 study of this adeno-associated /Allakos Gastroenteritis 10/22/2020 In a phase 2 randomized, Therapeutics dystrophy virus (AAV) serotype rh74 containing the human placebo-controlled trial, this anti–Siglec-8 IgG1 mAb microdystrophin gene under an muscle-specific reduced gastrointestinal (N. Engl. J. Med. MHCK7 promoter failed to show statistical 383, 1624–1634, 2020). improvement in function compared with placebo, Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com) although it did meet primary biological endpoint (protein level) OV101 (gaboxadol)/ Angelman’s 12/2/2020 Company discontinued trial on this Ovid Therapeutics syndrome extrasynaptic δ-selective γ-amino butryric acid A Laura DeFrancesco (GABAA) receptor agonist as it missed the primary Senior Editor, Nature Biotechnology. endpoint in pivotal phase 3 trial IDMC, independent data monitoring committee. Source: BioMedTracker, a service of Sagient Research Published online: 12 May 2021 (http://www.biomedtracker.com) https://doi.org/10.1038/s41587-021-00917-4

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