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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

A healthy crop of new approvals in quarter 1, skewed toward small molecules.

*New molecular entity (NME) class includes mainly small-molecule drugs, but also steroid, synthetic peptide and mixed compounds, excluding non-NME and new formulation. **Partial year to March 31. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com).

Notable drug approvals (1Q21)

Drug/company Indication Drug information
Lupkynis (voclosporin)/Aurinia Lupus nephritis 1/22/2021 FDA approved this small-molecule calcineurin phosphatase inhibitor, the first oral drug for lupus nephritis
Breyanzi (lisocabtagene maraleucel)/BMS Diffuse large B cell lymphoma 2/5/2021 FDA approved autologous CAR-T cells, expanded in culture, expressing CD19 and a truncated epidermal growth factor receptor (EGFR)
Ukoniq* (umbralisib)/TG Therapeutics Marginal zone lymphoma; indolent non-Hodgkin’s lymphoma 2/5/2021 FDA granted accelerated approval to this small molecule targeting phosphatidylinositol 3-OH kinase (PI3K)-δ and casein kinase 1 (CK1)-ε.
Evkeeza (evinacumab-dgnb)/Regeneron Dyslipidemia/hypercholesterolemia 2/11/2021 FDA approved this fully human IgG4 mAb against angiopoietin-like 3 that has a stabilizing mutation in the hinge.
Amondys 45* (casimersen)/Sarepta Therapeutics Duchenne muscular dystrophy 2/25/2021 FDA gave accelerated approval to this 22-residue exon-45-skipping phosophorodiamidate ASO.
Nulibry (fosdenopterin)/BridegeBio Pharma Molybdenum cofactor deficiency 2/28/2021 FDA approved cyclic pyranopterin monophosphate, an intermediate in the synthesis of molybdenum cofactor
Abecma (idecabtagene vicleucel/BMS Multiple myeloma 3/29.2021 FDA approved this CAR-T cell therapy with anti-B-cell maturation antigen (BCMA) single-chain variable fragment (scFv) fused to the CD137 (4-1BB) co-stimulatory and CD3ζ signaling domains
  1. *Accelerated approval. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Notable clinical trials for COVID-19 products

Drug/company Indication Drug information
Immcetz/Creative Medical Holdings COVID-19 acute respiratory distress syndrome (ARDS) 1/7/2021 In a double-blind, placebo-controlled phase 2a trial for COVID-19 with ARDS, patients treated with two infusions of umbilical-cord-derived mesenchymal stem cells had a significant decrease in cytokines and improved survival (91% versus 42%) Stem Cells Transl. Med. https://doi.org/10.1002/sctm.20-0472, 2021)
Etesevimab plus bamlanivimab/Eli Lilly COVID-19 1/21/2021 In a phase 2 randomized trial of bamlanivimab, a fully human IgG1κ mAb targeting an epitope on the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein, no effect was seen on viral load in unhospitalized patients with mild-to-moderate COVID-19; the addition of etesevimab (another fully human IgG1κ mAb that targets a different S protein RBD epitope), however, did result in significant reduction (J. Am. Med. Assoc. 325, 632–644, 2021)
Peginterferon lambda/Eiger BioPharmaceuticals COVID-19 2/5/2021 In a double-blind, placebo-controlled trial, this PEGylated interferon-λ accelerated the decline in SARS-CoV-2 viral load from 3 days onward (Lancet Resp. Med. https://doi.org/10.1016/S2213-2600(20)30566-X, 2021)
Actemra (tocilizumab)/Roche COVID-19 2/25/2021 In a phase 3 trials with hospitalized patients, this humanized IgG1κ mAb targeting interleukin-6 receptor (IL-6R) did not improve clinical status at 28 days (N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2028700, 2020)
Tocilizumab and sarilumab/Roche COVID-19 2/25/2021 In an adaptive trial of this humanized IgG1κ mAb targeting IL-6R (toclizumab) and human IgG1 mAb targeting IL-6Rα (sarilumab), the group receiving both drugs showed improved survival at 90 days (N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2100433, 2020)
PegiHep (PEGylated interferon alpha-2b)/Zydus Cadila COVID-19 3/10/2021 In a phase 2 randomized, open-label trial of PEGylated interferon-α2b, 95% of SARS-CoV-2–positive patients with moderate symptoms had achieved clinical improvement on day 15 compared with 68% subjects in standard of care (Int. J. Infect. Dis. 105, 516–521, 2021)
  1. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Upcoming catalysts (3Q21)

Drug/company Indication Drug information
Aducanumab/Biogen Alzheimer’s disease 6/7/2021, 7/1/2021 FDA and European Medicines Agency Committee for Medicinal Products for Human Use decisions for this this fully human IgG1 mAb against a conformational epitope on β-amyloid plaques
Leukotac (inolimomab)/ElsaLys Biotech Graft-versus-host disease 06/30/2021 FDA PDUFA date for this murine IgG1κ mAb that targets the interleukin-2 receptor-α
Teplizumab/Provention Bio Diabetes mellitus, type 1 07/02/2021 FDA PDUFA date for this humanized IgG1 mAb against the CD3ε chain expressed on mature T lymphocytes
Anifrolumab/AstraZeneca Systemic lupus erythematosus 07/05/2021 FDA PDUFA date for this fully human IgG1κ mAb against subunit 1 of the type I interferon receptor
Narsoplimab/Omeros Transplant-associated thrombotic microangiopathy 7/16/2021 FDA PDUFA date for this human IgG4 mAb targeting mannan-binding lectin-associated serine protease-2
Amivantamab/Johnson & Johnson Non-small-cell lung cancer 8/3/2021 FDA PDUFA date for this Fc- enhanced bispecific mAb targeting EGFR and cMET
AMG 510/Amgen Non-small-cell lung cancer 8/16/2021 FDA PDUFA date for this first-in-class small-molecule inhibitor of mutated KRAS (G12C)
Vicineum (oportuzumab monatox)/Sesen Bio Bladder cancer 08/18/2021 FDA PDUFA date for this antibody–drug conjugate epithelial cell adhesion molecule–specific scFv fused to Pseudomonas exotoxin A, a protein synthesis inhibitor
Belumosudil/Kadmon Holdings Graft-versus-host disease 8/30/2021 FDA PDUFA date for this small-molecule inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2)
Belzutifan/Merck Renal cell cancer 09/15/2021 FDA PDUFA date for this small-molecule antagonist of hypoxia-induced factor 2-α
  1. PDUFA, Prescription Drug User Fee Act. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Notable regulatory setbacks (1Q21)

Drug/company Indication Drug information
Ultomiris (ravulizumab)/Alexion COVID-19 1/13/2021 Data monitoring committee recommended pausing enrollment of this anti-C5 humanized IgG2/IgG4 chimeric mAb (comprising human κ light chain constant region, a IgG2 heavy-chain CH1 domain and hinge region, a hybrid IgG2/IgG4 CH2 domain and an IgG4 CH3 domain) due to lack of efficacy over standard of care
Ropeginterferon alfa-2b/Pharmaessentia Polycythemia vera 3/14/2021 FDA issued a complete response letter for this PEGylated proline-interferon-α2b, requesting more information on the prefilled syringes, owing to delay in inspection of site in Taiwan
WVE-120102/Wave Life Sciences Huntington’s disease 3/29/2021 The company stopped clinical development of this stereopure phosphorothioate ASO due to lack of statistically significant reduction in mutant huntingtin
Tominersen/Roche Huntington’s disease 3/22/2021 Company discontinued phase 3 trial of this chimeric 2′-O-(2-methoxyethyl)-modified gapmer ASO conjugated to an mAb targeting transferrin receptor on basis of review of risk/benefit ratio by IDMC
Tesetaxel/Odonate Therapeutics Metastatic breast, colorectal, solid tumors 3/23/2021 Company discontinued trials of this oral synthetic taxane after FDA indicated the data are unlikely to support approval
RG6356/Sarepta Therapeutics Duchenne muscular dystrophy 1/7/2021 Phase 2 study of this adeno-associated virus (AAV) serotype rh74 containing the human microdystrophin gene under an muscle-specific MHCK7 promoter failed to show statistical improvement in function compared with placebo, although it did meet primary biological endpoint (protein level)
OV101 (gaboxadol)/Ovid Therapeutics Angelman’s syndrome 12/2/2020 Company discontinued trial on this extrasynaptic δ-selective γ-amino butryric acid A (GABAA) receptor agonist as it missed the primary endpoint in pivotal phase 3 trial
  1. IDMC, independent data monitoring committee. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Notable clinical trial results (1Q21)

Drug/company Indication Drug information
Lumevoq/GenSight Leber’s hereditary optic neuropathy 1/13/2021 In a phase 1/2a open-label, dose-escalation trial of this AAV-2 gene therapy encoding wild-type NADH dehydrogenase 4 gene (ND4), patients achieved improvement in visual acuity over the 5-year study period (BioDrugs 35, 201–214, 2021)
Engensis/Helixmith Diabetic peripheral neuropathy 1/19/2021 In a phase 3 double-blind, placebo-controlled trial, two isoforms of angiogenesis-promoting hepatocyte growth factor, HGF728 and HGF723, delivered into leg muscle via a DNA plasmid vector (pCK) comprising cytomegalovirus 5′ untranslated region upstream and full-length immediate-early promoter, reduced pain at up to 12 months (Clin. Transl. Sci. https://doi.org/10.1111/cts.12977, 2021)
Ublituximab/TG Therapeutics Chronic lymphocytic leukemia, small-cell lymphocytic lymphoma 2/21/2021 In a phase 3 trial, a combination of ibrutinib plus this chimeric anti-CD20 IgG1mAb with a low-fructose Fc region for enhanced antibody-dependent cell-mediated cytotoxicity via CD16A (FcγRIIIa) binding resulted in a statistically significant overall response rate as compared with ibrutinib monotherapy (Lancet Haematol. 8, e254–e266, 2021)
Donanemab (LY3002813)/Eli Lilly Alzheimer’s disease 3/15/2021 In a randomized, placebo- controlled, double-blind phase 2 trial of this humanized IgG1 mAb targeting amyloid-βp3–42, the N-terminally truncated pyroglutamate-3 isoform, patients with early disease showed significantly less decline at 76 weeks than those on placebo (N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2100708, 2021)
CTX001/CRISPR Therapeutics Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) 1/21/2021 In a phase 1/2 trial, more than a year after one person with TDT and one with SCD received autologous CD34+ hematopoietic stem and progenitor cells electroporated ex vivo with CRISPR–Cas9 and gRNA targeting the BCL111A erythroid-specific enhancer, high levels of allelic editing were detected in bone marrow and blood, with pancellular fetal hemoglobin distribution, transfusion independence, and (for SCD) elimination of vaso-occlusive episodes (N. Engl. J. Med. 384, 252–260, 2021)
Abecma (idecabtagene vicleucel)/BMS Multiple myeloma 2/24/2021 In a phase 2 pivotal trial, of patients receiving this CAR-T cell therapy with anti-BCMA 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)
Teplizumab/Provention Bio Diabetes mellitus, type 1 3/3/2021 In a phase 2 trial of at-risk people, one injection of this humanized IgG1 mAb against the CD3ε chain (developed by grafting six complementarity-determining regions from OKT3 into a human framework containing leucine-to-alanine substitutions at residues 234 and 235 in the CH2 region to abolish Fc receptor binding) delayed onset; onset averaged 5 years compared with 2 years for untreated individuals (Sci. Transl. Med. 13, eabc8980, 2021)
Sotatercept/Acceleron Pulmonary arterial hypertension and pulmonary hypertension 4/1/2021 In a phase 2 randomized double-blind, placebo-controlled trial of this glycosylated, dimeric fusion protein comprising the extracellular domain of the human activin receptor type IIA and the Fc region of human IgG1, patients receiving the drug had statistically significant reduction in vascular resistance (N. Engl. J. Med. 384, 1204–1215, 2021)
Vigil (gemogenovatucel-T)/Gradalis Ovarian cancer 3/11/2021 In a phase 2b placebo-controlled trial, this autologous tumor cell product transduced ex vivo with a DNA plasmid encoding short-hairpin RNA against furin (which blocks immunosuppressive transforming growth factor-β1 and β2) and recombinant human granulocyte macrophage colony stimulating factor (which activates T cells) extended overall survival and recurrence-free survival as compared with placebo (Gynecol. Oncol. https://doi.org/10.1016/j.ygyno.2021.03.009, 2021)
Lirentelimab/Allakos Gastroenteritis 10/22/2020 In a phase 2 randomized, placebo-controlled trial, this anti–Siglec-8 IgG1 mAb reduced gastrointestinal eosinophils (N. Engl. J. Med. 383, 1624–1634, 2020).
  1. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

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DeFrancesco, L. Drug pipeline 1Q21—the old and the new. Nat Biotechnol 39, 536–537 (2021). https://doi.org/10.1038/s41587-021-00917-4

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