Drug pipeline 3Q21—mixed news for genetic therapies

Drug pipeline 3Q21—mixed news for genetic therapies

Zydus Cadila Healthcare’s COVID-19 vaccine– the world’s very first DNA vaccine authorized for human beings– got approval in the type of an Emergency Use Authorization from India’s Central Drugs Standard Control Organisation. Regeneron’s monoclonal antibody (mAb) mixed drink Ronapreve continued to shine in medical trials, with the most recent research study reporting it secures individuals exposed to SARS-CoV-2. The European Medicines Agency (EMA) got out ahead of the United States Food and Drug Administration (FDA) with registrations of the very first drug for achondroplasia (BioMarin’s Voxzogo), the very first bispecific mAb for psoriasis (UCB’s Bimzelx), and the very first gene treatment for cerebral adrenoleukodystrophy (Bluebird Bio’s lentiviral item Skysona). All was not plain cruising for Bluebird, nevertheless, with the FDA putting a scientific hang on the program due to issues over possible insertional mutagenesis causing myelodysplastic syndrome. Preclinical liver tumorigenicity issues contributed to previous hepatotoxicity, thrombotic microangiopathy and neurotoxicity concerns related to adeno-associated viral (AAV) vector gene treatments, as the FDA positioned a medical hang on BioMarin’s AAV-5 gene treatment for phenylketonuria. A stage 1/2 trial of Arrowhead’s cystic fibrosis siRNA drug Aro-ENAC was likewise stopped due to a preclinical signal of lung swelling.

FDA approvals by drug type

Approvals for the very first 3 quarters practically equate to the overall for all of in 2015.

Partial year to 30 June.

Notable drug approvals (3Q21)

Drug/company. Sign. Drug info.
Opzelura (ruxolitinib)/ Incyte. Atopic dermatitis. 9/21/2921 FDA authorizes this small-molecule JAK/STAT inhibitor created as a cream.
Tivdak (tisotumab vedotin tftv)/ Seagen. Cervical cancer. 9/20/2021 FDA grants sped up approval to this human tissue aspect IgG1κ mAb targeting tissue aspect conjugated to MMAE by means of a protease-cleavable linker.
Exkivity (mobocertinib)/ Takeda. Non-small-cell lung cancer. 9/15/2021 FDA grants sped up 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 authorizes this supported 39- residue analog of C-type natriuretic peptide consisting of 17 additional amino acids (PGQEHPNARKYKGANKK) added to the native hormonal agent’s N terminus.
Bimzelx (bimekizumab)/ UCB. Psoriasis. 8/24/2021 EMA authorized this humanized bispecific IgG1 mAb that reduces the effects of both IL-17 A and IL-17 F.
Korsuva (difelikefalin)/ Cara Therapeutics. Pruritus. 8/23/2021 FDA authorizes this small-molecule κ-opioid receptor agonist.
Evrenzo (roxadustat)/ AstraZeneca. Anemia due to persistent kidney failure. 8/19/2021 EMA authorizes this second-generation hypoxia-inducible aspect prolyl hydroxylase inhibitor.
Nexviazyme (avalglucosidase alfa-ngpt)/ Sanofi. Pompe illness. 8/6/2021 FDA authorizes this α-glucosidase enzyme replacement treatment targeting mannose-6-phophate receptor to assist in cellular uptake.
Saphnelo (anifrolumab- fnia)/ AstraZeneca. Systemic lupus erythematosus. 7/30/2021 FDA authorizes this totally human IgG1 mAb targeting interferon-α receptor 1.
Skysona (Lenti-D, (elivaldogene autotemcel)/ Bluebird Bio. Cerebral adrenoleukodystrophy. 7/21/2021 EMA authorizes these autologous hematopoietic CD34 stem cells transduced with a lentiviral vector encoding human ABCD1 cDNA under the control of a customized enhancer/promoter of myeloproliferative sarcoma infection.
Bylvay (odevixibat)/ Albireo Pharma. Progressive familial intrahepatic cholestasis. 7/20/2021, 7/19/2021 FDA and EMA authorize this small-molecule inhibitor of ileal bile acid transporter.
Rezurock (belumosudil)/ Kadmon Holdings. Graft versus host illness treatment. 7/16/2021 FDA authorizes under its real-time approval evaluation procedure this small-molecule selective oral inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) associated with inflammatory reactions.
Zy-CoV-D/ Zydus Cadila. COVID-19 avoidance. 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 provided intradermally through the PharmaJet Tropis ID fluid-stream injection gadget.
  1. ABCD gene, ATP-binding cassette D; EGFR, skin development aspect receptor; EUA, Emergency Use Authorization; IgE, immunoglobulin E; IL, interleukin; MMAE, monomethyl auristatin E. Source: BioMedTracker, a service of Sagient Research ( http://www.biomedtracker.com)

Upcoming drivers (1Q22)

Drug/ business. Sign. Drug details.
Tezepelumab/ Amgen. Asthma. 1/10/2022 FDA PDUFA date for this human IgG2κ mAb versus thymic stromal lymphopoietin.
Maribavir/ Takeda. Cytomegalovirus infection. 1/21/2021 FDA PDUFA date for this selective ATP rival 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 associated with 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 heart myosin.
Faricimab/ Roche. Diabetic macular edema/wet age-related macular degeneration. 1/31/2022 FDA PDUFA date for this IgG1 bispecific mAb versus vascular endothelial development element A and angiopoietin-2.
Mitapivat/ Agios. Pyruvate kinase shortage. 2/17/2022 FDA PDUFA date for this first-in-class small-molecule allosteric activator of wild-type and altered pyruvate kinase.
Bardoxolone methyl/ Reata Pharmaceuticals. Alport syndrome. 2/25/2022 FDA PDUFA date for this small-molecule (artificial triterpenoid) activator of nuclear element erythroid 2-related element 2 (Nrf2), which reduces NF-κB- and STAT3-mediated swelling.
Roctavian (valoctocogene roxaparvovec)/ BioMarin. Hemophilia A. 12/31/2021 EMA’s CHMP viewpoint due date for this AAV-8 vector encoding an aspect VIII gene treatment.
  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 ( http://www.biomedtracker.com)

Notable regulative problems (3Q21)

Drug/ business. Sign. Drug details.
ARO-ENaC/ Arrowhead Pharmaceuticals. Cystic fibrosis. 7/2/2021 Company willingly stops stage 2 scientific trial of this breathed in nebulized service of a little interfering (si) RNA targeting SCNN1A mRNA, encoding the epithelial salt channel α-subunit (aENaC), encapsulated in peptide E (K16 GACSERSMNFCG)- targeted DOTMA: DOPE liposomes, after a toxicology research study in rats revealed regional lung swelling.
Teplizumab/ Provention Bio. Diabetes mellitus, type I. 7/2/2021 FDA concerns a total action letter for this humanized IgG1 mAb with an Fc crafted with leucine-to-alanine replacements at residues 234 and 235 (in the CH2 area) to eliminate Fc receptor binding directed versus the CD3 ε-chain revealed on fully grown T lymphocytes.
Lenti-D (elivaldogene autotemcel)/ Bluebird Bio. Adrenoleukodystrophy. 8/9/2021 FDA puts a medical hang on this autologous hematopoietic CD34 stem cells transduced with a lentiviral vector encoding human ABCD1 cDNA due to myelodysplastic syndrome possibly moderated by vector insertion.
Verdiperstat/ Biohaven Pharmaceuticals. Several system atrophy. 9/27/2021 Company reveals suspension of its stage 3 trial of this oral, small-molecule, brain-penetrant, permanent inhibitor of myeloperoxidase due to absence of statistically considerable enhancement.
BMN 307/ BioMarin. Phenylketonuria. 9/6/2021 FDA puts a medical hang on this an AAV-5-vectored gene treatment including the gene for phenylalanine hydroxylase after mice established liver growths in a preclinical research study.
Advertisement26 Mos4.HIV vaccine/ Johnson & Johnson. HIV. 8/31/2021 Company revealed that this tetravalent recombinant replication-deficient adenovirus 26 (Advertisement26) vectored vaccine making up 2 Advertisement26 vectors including a mosaic insert of the HIV envelope (Env) series and 2 Advertisement26 vectors including mosaic inserts of Gag and Pol series, together with a booster dosage of the trimeric clade C glycoprotein 140, attained just 25.2?fectiveness in a stage 2 trial.
Ultomiris (ravulizumab-cwvz)/ AstraZeneca. Amyotrophic lateral sclerosis. 8/20/2021 Company stops stage 3 trial of this long-acting humanized IgG2/IgG4 anti-C5 mAb with an Fc crafted for increased human FcRn affinity (Xtend innovation) due to absence of effectiveness.
Vicineum (oportuzumab monatox-qqrs)/ Sesen Bio. Bladder cancer. 8/16/2021 FDA problems a total reaction letter for this blend of anti-EpCAM humanized single-chain variable piece (scFv) connected to a truncated kind of Pseudomonas exotoxin A, asking for extra medical and analytical information and analyses and mentioning chemistry, production and control problems.
Aduhelm (aducanumab)/ Biogen. Alzheimer’s illness. 8/11/2022 The United States Department of Veterans Affairs reveals it will not consist of in its formulary this totally human IgG1 mAb versus a conformational epitope on β-amyloid plaques.
COVID vaccine/ Sanofi. COVID-19 avoidance. 9/29/2021 Company stops screening of this mRNA-based vaccine consisting of the supported pre-fusion kind of the SARS-CoV-2 spike glycoprotein provided by a lipid nanoparticle consisting of ionizable lipid, phosphatidylethanolamine, cholesterol and polyethylene glycol-lipid.
  1. DOTMA, 1,2-di- O– octadecenyl-3-trimethylammonium gas; DOPE, 1,2-dioleoyl- sn– glycero-3-phosphoethanolamine; IgG, immunoglobulin G; Fc, immunoglobulin consistent piece; FcRn, neonatal Fc receptor; C5, enhance protein 5; EpCAM, epithelial cell adhesion particle. Source: BioMedTracker, a service of Sagient Research ( http://www.biomedtracker.com) and business news release

Notable medical trial outcomes (3Q21)

Drug/ business. Indicator. Drug info.
Tebentafusp/ Immunocore. Uveal cancer malignancy. 9/22/2021 In a stage 3 open-label trial, clients getting this soluble bispecific combination of a high-affinity monoclonal T-cell receptor (mTCR) particular for gp100(melanocytic protein) in the context of HLA-A *0201 and an anti-CD3 scFv piece had 73%total survival at one year compared to 59%in control group ( N. Engl. J. Med385, 1196–1206, 2021).
Uproleselan/ Glycomimetics. Intense myelogenous leukemia. 9/20/2021 In a stage 2/3 research study of this artificial glycomimetic small-molecule E-selectin villain, which sensitizes leukemic cells to the chemotherapeutic cytarabine by activating them from their protective bone marrow specific niche, clients revealed increased remission rates and enhanced survival ( Blood https://doi.org/101182/ blood.2021010721, 2021).
Ensartinib/ Xcovery. Non-small cell lung cancer. 9/2/2021 In a stage 3 open label randomized trial of this aminopyridazine-based small-molecule ALK inhibitor, the drug doubled progression-free survival compared to that seen with the small-molecule kinase inhibitor crizotinib ( JAMA Oncol https://doi.org/101001/ jamaoncol.20213523, 2021).
Lumevoq/ GenSight. Leber’s genetic optic neuropathy. 8/31/2021 In a long-lasting follow up research study of this AAV-2 gene treatment encoding the wild-type NADH dehydrogenase 4 gene ( ND4), cured clients revealed progressive and continual enhancement of best-corrected visual skill as much as 52 months ( J. Neuroophthalmol 41, 309–315, 2021).
Balstilimab/ Agenus. Cervical cancer. 8/25/2021 In a stage 2 research study of this completely human IgG4 mAb targeting configured death 1 receptor (PD-1), cured clients had a 20?tion rate with mean period not reached at 14.6 months ( Gynecologic Oncol https://doi.org/101016/ j.ygyno.202108018, 2021).
Apabetalone/ Resverlogix. Heart disease. 8/24/2021 In a randomized trial with clients at danger for a cardiovascular occasion, clients with low standard ratings getting this small-molecule bromodomain and extraterminal domain (BET) inhibitor that lowers vascular swelling and calcification scored much better on cognitive tests ( J. Alzheimers Dis. https://doi.org/103233/ JAD-210570, 2021).
Miplyffa (arimoclomol)/ CytRx. Niemann-Pick illness. 8/21/2021 In a randomized, placebo-controlled trial, clients getting this small-molecule co-inducer of heat shock protein HSF1 had a 65%relative decrease in yearly development ( J. Inherit. Metab. Dis https://doi.org/101002/ jimd.12428, 2021).
RVT-802/ Enzyvant Therapeutics. DiGeorge syndrome. 8/4/2021 In 10 single-arm, open-label research studies in which 105 clients were treated with allogeneic cultured decapsulated thymic tissue, 77%made it through one year ( J. Allergy Clin. Immunol https://doi.org/101016/ j.jaci.202106028, 2021).
Rinvoq (upadacitinib)/ AbbVie. Atopic dermatitis. 8/4/2020 In a stage 3 randomized comparator regulated research study, this small-molecule inhibitor of Janus kinase 1 (JAK1) revealed supremacy to dupilumab ( JAMA Dermatol https://doi.org/101001/ jamadermatol.20213023, 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 altered kinds of c-Kit (stem cell element receptor), Lyn and platelet-derived development element receptor kinases extended survival by over 2 years offered treatment was started prior to serious problems ( Ther. Adv. Neurol. Dis https://doi.org/101177/17562864211030365, 2021).
Kineret (anakinra)/ Swedish Orphan Biovitrum. COVID-19 treatment. 9/3/2021 In stage 3 randomized, placebo-controlled trial of clients at danger for extreme illness, this recombinant, non-glycosylated kind of human interleukin-1 receptor villain decreased the chances of even worse result to 0.36 at day 28 ( Nat. Med https://doi.org/101038/ s41591 -021-01499- z, 2021).
Ronapreve (casirivimab imdevimab)/ Regeneron. COVID-19 avoidance. 8/4/2021 In a stage 3 trial of individuals exposed in the house to COVID-19, this mixed drink of 2 reducing the effects of human IgG1 mAbs targeting SARS-CoV-2 spike glycoprotein epitopes minimized the occurrence of systemic infection by 77%(N. Engl. J. Med. https://doi.org/101056/ NEJMoa2109682, 2021).

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  1. Senior Editor, Nature Biotechnology

    Laura DeFrancesco

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