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Drug pipeline 3Q21—mixed news for genetic therapies

Zydus Cadila Healthcare’s COVID-19 vaccine—the world’s first DNA vaccine approved for humans—got the nod in the form of an Emergency Use Authorization from India’s Central Drugs Standard Control Organisation. Regeneron’s monoclonal antibody (mAb) cocktail Ronapreve continued to shine in clinical trials, with the latest study reporting it protects people exposed to SARS-CoV-2. Meanwhile, the European Medicines Agency (EMA) got out ahead of the US Food and Drug Administration (FDA) with registrations of the first drug for achondroplasia (BioMarin’s Voxzogo), the first bispecific mAb for psoriasis (UCB’s Bimzelx), and the first gene therapy for cerebral adrenoleukodystrophy (Bluebird Bio’s lentiviral product Skysona). All was not plain sailing for Bluebird, however, with the FDA putting a clinical hold on the program due to concerns over possible insertional mutagenesis leading to myelodysplastic syndrome. Preclinical liver tumorigenicity concerns added to previous hepatotoxicity, thrombotic microangiopathy and neurotoxicity issues associated with adeno-associated viral (AAV) vector gene therapies, as the FDA placed a clinical hold on BioMarin’s AAV-5 gene therapy for phenylketonuria. A phase 1/2 trial of Arrowhead’s cystic fibrosis siRNA drug Aro-ENAC was also halted due to a preclinical signal of lung inflammation.

FDA approvals by drug type

Approvals for the first three quarters almost equal the total for all of last year.

*Partial year to 30 June.

Notable drug approvals (3Q21)

Drug/company Indication Drug information
Opzelura (ruxolitinib) / Incyte Atopic dermatitis 9/21/2921 FDA approves this small-molecule JAK/STAT inhibitor formulated as a cream
Tivdak (tisotumab vedotin-tftv) / Seagen Cervical cancer 9/20/2021 FDA grants accelerated approval to this human tissue factor IgG1κ mAb targeting tissue factor conjugated to MMAE via a protease-cleavable linker
Exkivity (mobocertinib) / Takeda Non-small-cell lung cancer 9/15/2021 FDA grants accelerated approval to this small-molecule selective tyrosine kinase inhibitor targeting EGFR and human EGFR2 exon insertion 2
Voxzogo (vosoritide) / BioMarin Achondroplasia 8/27/2021 EMA approves this stabilized 39-residue analog of C-type natriuretic peptide containing 17 extra amino acids (PGQEHPNARKYKGANKK) appended to the native hormone’s N terminus
Bimzelx (bimekizumab) / UCB Psoriasis 8/24/2021 EMA approved this humanized bispecific IgG1 mAb that neutralizes both IL-17A and IL-17F
Korsuva (difelikefalin) / Cara Therapeutics Pruritus 8/23/2021 FDA approves this small-molecule κ-opioid receptor agonist
Evrenzo (roxadustat) / AstraZeneca Anemia due to chronic renal failure 8/19/2021 EMA approves this second-generation hypoxia-inducible factor prolyl hydroxylase inhibitor
Nexviazyme (avalglucosidase alfa-ngpt) / Sanofi Pompe disease 8/6/2021 FDA approves this α-glucosidase enzyme replacement therapy targeting mannose-6-phophate receptor to facilitate cellular uptake
Saphnelo (anifrolumab- fnia) / AstraZeneca Systemic lupus erythematosus 7/30/2021 FDA approves this fully human IgG1 mAb targeting interferon-α receptor 1
Skysona (Lenti-D, (elivaldogene autotemcel) / Bluebird Bio Cerebral adrenoleukodystrophy 7/21/2021 EMA approves these autologous hematopoietic CD34+ stem cells transduced with a lentiviral vector encoding human ABCD1 cDNA under the control of a modified enhancer/promoter of myeloproliferative sarcoma virus
Bylvay (odevixibat) / Albireo Pharma Progressive familial intrahepatic cholestasis 7/20/2021, 7/19/2021 FDA and EMA approve this small-molecule inhibitor of ileal bile acid transporter
Rezurock (belumosudil) / Kadmon Holdings Graft versus host disease treatment 7/16/2021 FDA approves under its real-time approval review process this small-molecule selective oral inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) involved in inflammatory responses
Zy-CoV-D / Zydus Cadila COVID-19 prevention 8/20/2021 India’s Drugs Controller General grants an EUA to this DNA vaccine encoding the spike glycoprotein of SARS-CoV-2 and IgE signal peptide delivered intradermally via the PharmaJet Tropis ID fluid-stream injection device
  1. ABCD gene, ATP-binding cassette D; EGFR, epidermal growth factor receptor; EUA, Emergency Use Authorization; IgE, immunoglobulin E; IL, interleukin; MMAE, monomethyl auristatin E. Source: BioMedTracker, a service of Sagient Research (

Upcoming catalysts (1Q22)

Drug / company Indication Drug information
Tezepelumab / Amgen Asthma 1/10/2022 FDA PDUFA date for this human IgG2κ mAb against thymic stromal lymphopoietin
Maribavir / Takeda Cytomegalovirus infection 1/21/2021 FDA PDUFA date for this selective ATP competitor of viral DNA polymerase
Oteseconazole / Mycovia Pharmaceuticals Non-systemic fungal infections 1/27/2022 FDA PDUFA date for this small-molecule inhibitor of lanosterol demethylase (CYP51), an enzyme involved in the synthesis of fungal cell wall sterols
Mavacamten / Bristol Myers Squibb Hypertrophic cardiomyopathy 1/28/2022 FDA PDUFA date for this first-in-class small-molecule allosteric modulator of cardiac myosin
Faricimab / Roche Diabetic macular edema/wet age-related macular degeneration 1/31/2022 FDA PDUFA date for this IgG1 bispecific mAb against vascular endothelial growth factor A and angiopoietin-2
Mitapivat / Agios Pyruvate kinase deficiency 2/17/2022 FDA PDUFA date for this first-in-class small-molecule allosteric activator of wild-type and mutated pyruvate kinase
Bardoxolone methyl / Reata Pharmaceuticals Alport syndrome 2/25/2022 FDA PDUFA date for this small-molecule (synthetic triterpenoid) activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which suppresses NF-κB- and STAT3-mediated inflammation
Roctavian (valoctocogene roxaparvovec) / BioMarin Hemophilia A 12/31/2021 EMA’s CHMP opinion due date for this AAV-8 vector encoding a factor VIII gene therapy
  1. PDUFA, Prescription Drug User Fee Act; CHMP, Committee for Medicinal Products for Human Use (Europe); IgG, immunoglobulin G. Source: BioMedTracker, a service of Sagient Research (

Notable regulatory setbacks (3Q21)

Drug / company Indication Drug information
ARO-ENaC / Arrowhead Pharmaceuticals Cystic fibrosis 7/2/2021 Company voluntarily halts phase 2 clinical trial of this inhaled nebulized solution of a small interfering (si)RNA targeting SCNN1A mRNA, encoding the epithelial sodium channel α-subunit (aENaC), encapsulated in peptide E (K16GACSERSMNFCG)-targeted DOTMA:DOPE liposomes, after a toxicology study in rats showed local lung inflammation
Teplizumab / Provention Bio Diabetes mellitus, type I 7/2/2021 FDA issues a complete response letter for this humanized IgG1 mAb with an Fc engineered with leucine-to-alanine substitutions at residues 234 and 235 (in the CH2 region) to abolish Fc receptor binding directed against the CD3 ε-chain expressed on mature T lymphocytes
Lenti-D (elivaldogene autotemcel) / Bluebird Bio Adrenoleukodystrophy 8/9/2021 FDA puts a clinical hold on this autologous hematopoietic CD34+ stem cells transduced with a lentiviral vector encoding human ABCD1 cDNA due to myelodysplastic syndrome potentially mediated by vector insertion
Verdiperstat / Biohaven Pharmaceuticals Multiple system atrophy 9/27/2021 Company announces suspension of its phase 3 trial of this oral, small-molecule, brain-penetrant, irreversible inhibitor of myeloperoxidase due to lack of statistically significant improvement
BMN 307 / BioMarin Phenylketonuria 9/6/2021 FDA puts a clinical hold on this an AAV-5-vectored gene therapy containing the gene for phenylalanine hydroxylase after mice developed liver tumors in a preclinical study
Ad26.Mos4.HIV vaccine / Johnson & Johnson HIV 8/31/2021 Company announced that this tetravalent recombinant replication-deficient adenovirus 26 (Ad26) vectored vaccine comprising two Ad26 vectors containing a mosaic insert of the HIV envelope (Env) sequence and two Ad26 vectors containing mosaic inserts of Gag and Pol sequences, along with a booster dose of the trimeric clade C glycoprotein 140, achieved only 25.2% efficacy in a phase 2 trial
Ultomiris (ravulizumab-cwvz) / AstraZeneca Amyotrophic lateral sclerosis 8/20/2021 Company discontinues phase 3 trial of this long-acting humanized IgG2/IgG4 anti-C5 mAb with an Fc engineered for increased human FcRn affinity (Xtend technology) due to lack of efficacy
Vicineum (oportuzumab monatox-qqrs) / Sesen Bio Bladder cancer 8/16/2021 FDA issues a complete response letter for this fusion of anti-EpCAM humanized single-chain variable fragment (scFv) linked to a truncated form of Pseudomonas exotoxin A, requesting additional clinical and statistical data and analyses and citing chemistry, manufacturing and control issues
Aduhelm (aducanumab) / Biogen Alzheimer’s disease 8/11/2022 The US Department of Veterans Affairs announces it will not include in its formulary this fully human IgG1 mAb against a conformational epitope on β-amyloid plaques
COVID vaccine / Sanofi COVID-19 prevention 9/29/2021 Company halts testing of this mRNA-based vaccine comprising the stabilized pre-fusion form of the SARS-CoV-2 spike glycoprotein delivered by a lipid nanoparticle comprising ionizable lipid, phosphatidylethanolamine, cholesterol and polyethylene glycol-lipid
  1. DOTMA, 1,2-di-O-octadecenyl-3-trimethylammonium propane; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; IgG, immunoglobulin G; Fc, immunoglobulin constant fragment; FcRn, neonatal Fc receptor; C5, complement protein 5; EpCAM, epithelial cell adhesion molecule. Source: BioMedTracker, a service of Sagient Research ( and company press releases

Notable clinical trial results (3Q21)

Drug / company Indication Drug information
Tebentafusp / Immunocore Uveal melanoma 9/22/2021 In a phase 3 open-label trial, patients receiving this soluble bispecific fusion of a high-affinity monoclonal T-cell receptor (mTCR) specific for gp100 (melanocytic protein) in the context of HLA-A*0201 and an anti-CD3 scFv fragment had 73% overall survival at one year compared with 59% in control group (N. Engl. J. Med 385, 1196–1206, 2021)
Uproleselan / Glycomimetics Acute myelogenous leukemia 9/20/2021 In a phase 2/3 study of this synthetic glycomimetic small-molecule E-selectin antagonist, which sensitizes leukemic cells to the chemotherapeutic cytarabine by mobilizing them from their protective bone marrow niche, patients showed increased remission rates and improved survival (Blood, 2021)
Ensartinib / Xcovery Non-small cell lung cancer 9/2/2021 In a phase 3 open label randomized trial of this aminopyridazine-based small-molecule ALK inhibitor, the drug doubled progression-free survival compared with that seen with the small-molecule kinase inhibitor crizotinib (JAMA Oncol., 2021)
Lumevoq / GenSight Leber’s hereditary optic neuropathy 8/31/2021 In a long-term follow up study of this AAV-2 gene therapy encoding the wild-type NADH dehydrogenase 4 gene (ND4), treated patients showed progressive and sustained improvement of best-corrected visual acuity up to 52 months (J. Neuroophthalmol. 41, 309–315, 2021)
Balstilimab / Agenus Cervical cancer 8/25/2021 In a phase 2 study of this fully human IgG4 mAb targeting programmed death 1 receptor (PD-1), treated patients had a 20% response rate with median duration not reached at 14.6 months (Gynecologic Oncol., 2021)
Apabetalone / Resverlogix Cardiovascular disease 8/24/2021 In a randomized trial with patients at risk for a cardiovascular event, patients with low baseline scores receiving this small-molecule bromodomain and extraterminal domain (BET) inhibitor that reduces vascular inflammation and calcification scored better on cognitive tests (J. Alzheimers Dis., 2021)
Miplyffa (arimoclomol) / CytRx Niemann-Pick disease 8/21/2021 In a randomized, placebo-controlled trial, patients receiving this small-molecule co-inducer of heat shock protein HSF1 had a 65% relative reduction in annual progression (J. Inherit. Metab. Dis., 2021)
RVT-802 / Enzyvant Therapeutics DiGeorge syndrome 8/4/2021 In ten single-arm, open-label studies in which 105 patients were treated with allogeneic cultured decapsulated thymic tissue, 77% survived one year (J. Allergy Clin. Immunol., 2021)
Rinvoq (upadacitinib) / AbbVie Atopic dermatitis 8/4/2020 In a phase 3 randomized comparator controlled study, this small-molecule inhibitor of Janus kinase 1 (JAK1) showed superiority to dupilumab (JAMA Dermatol., 2021)
Masitinib / AB Science Amyotrophic lateral sclerosis 7/19/2021 In a randomized, placebo-controlled trial, this oral, small-molecule inhibitor of wild-type and mutated forms of c-Kit (stem cell factor receptor), Lyn and platelet-derived growth factor receptor kinases prolonged survival by over two years provided treatment was begun before severe impairment (Ther. Adv. Neurol. Dis., 2021)
Kineret (anakinra) / Swedish Orphan Biovitrum COVID-19 treatment 9/3/2021 In phase 3 randomized, placebo-controlled trial of patients at risk for severe disease, this recombinant, non-glycosylated form of human interleukin-1 receptor antagonist reduced the odds of worse outcome to 0.36 at day 28 (Nat. Med., 2021)
Ronapreve (casirivimab imdevimab) / Regeneron COVID-19 prevention 8/4/2021 In a phase 3 trial of people exposed in the home to COVID-19, this cocktail of two neutralizing human IgG1 mAbs targeting SARS-CoV-2 spike glycoprotein epitopes reduced the incidence of systemic infection by 77% (N. Engl. J. Med., 2021)
  1. ALK, anaplastic lymphoma kinase. Source: BioMedTracker, a service of Sagient Research (

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DeFrancesco, L. Drug pipeline 3Q21—mixed news for genetic therapies. Nat Biotechnol 39, 1326–1328 (2021).

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