Drug pipeline 3Q22 — rare disease and Alzheimer’s treatments

With only nine approvals in 3Q, 2022 looks likely to be numerically the worst year for FDA approvals since 2016, with few small molecules approved and monoclonals down, too. Even so, six biologics for rare diseases were approved either by the US Food and Drug Administration (FDA) or by the European Medicines Agency (EMA). Bluebird bio received FDA approval for two gene therapies within weeks of each other: Zynteglo for β-thalassemia and Skysona for adrenoleukodystrophy, a rare genetic disease (both previously approved in Europe, but subsequently withdrawn from the market due to pricing concerns). The enzyme replacement therapy Xenpozyme for acid sphingomyelinase deficiency, originating in Sanofi’s Genzyme arm, was approved, as was Boehringer’s anti-interleukin-36 receptor monoclonal antibody, Spevigo, the first drug for generalized pustular psoriasis. The EMA approved two adeno-associated virus (AAV)-vectored gene therapies, BioMarin’s Roctavian for hemophilia A and PTC Therapeutics’ Upstaza for aromatic l-amino acid decarboxylase deficiency. The fourth quarter will bring two FDA decisions on monoclonal antibodies targeting different molecular species in the β-amyloid pathway as treatments for Alzheimer’s disease: Eisai/Biogen’s lecanemab, originating at the Swedish neuroscience company BioArctic, is an early pathway intervention that targets soluble Aβ protofibrils and aims to prevent plaque accumulation, while Lilly’s donanemab targets a pyroglutamate form of Aβ and aims to clear existing plaques. The FDA is taking a cautious approach to new base-editing approaches, holding up Beam Therapeutics’ Investigational New Drug application for an ex vivo C-to-T base-edited CAR-T cell therapy for acute lymphoblastic leukemia. Potentially sparking another controversy over accelerated approvals, in late September the FDA approved a (non-new molecular entity) drug combination for amyotrophic lateral sclerosis, Amylyx’s Relyvrio (sodium phenylbutyrate and taurursodiol), after the advisory committee voted first against and then for approval.

FDA approvals by drug type

Small-molecule and antibody approvals are down on most recent years.

*Partial year to 30 September. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com).

Notable drug approvals (3Q22)

Drug/company	Indication	Drug information
Zynteglo (betibeglogene autotemcel)/bluebird bio	β-thalassemia	8/17/2022 FDA approves this autologous CD34+ cell therapy, transduced ex vivo with a lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein G carrying the HBBA-T87Q β-globin gene under the control of the β-globin enhancer and locus control region
Xenpozyme (olipudase alfa)/Sanofi	Acid sphingomyelinase deficiency	8/31/2022, 5/20/2022 FDA and EMA approve this first-in-class treatment, a hydrolytic lysosomal sphingomyelin-specific enzyme of 570 amino acids produced in a CHO cell line
Spevigo (spesolimab-sbzo)/Boehringer Ingelheim	Psoriasis	9/1/2022 FDA approved this humanized IgG1 mAb against human IL-36R produced in a CHO cell line
Terlivaz (terlipressin)/Mallinckrodt	Hepatorenal syndrome	9/14/2022 FDA approves this vasopressin analog peptide for improving kidney function in adults with hepatorenal syndrome.
Skysona (elivaldogene autotemcel)/bluebird bio	Adrenoleukodystrophy	9/16/2022 FDA grants accelerated approval to 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
Tecvayli (teclistamab)/Janssen	Multiple myeloma	8/24/2022 EMA grants conditional approval to this humanized BCMA × CD3 DuoBody IgG4 mAb
Sunlenca (lenacapavir)/Gilead Sciences	HIV/AIDS	8/22/2022 EMA approves this HIV capsid inhibitor that acts by binding to a conserved site at the interface of two monomers
Upstaza (eladocagene exuparvovec)/PTC Therapeutics	AADC deficiency	7/20/2022 EMA approved this AAV delivering the human aromatic l-amino acid decarboxylase (DDC) gene
Roctavian (valoctocogene roxaparvovec)/BioMarin	Hemophilia A	8/24/2022 EMA approves this AAV vector carrying a factor VIII gene under the control of a liver-specific promoter.

1. CHO, Chinese hamster ovary cell; IgG, immunoglobulin G; mAb, monoclonal antibody; IL-36R, interleukin-36 receptor; RET, ret proto-oncogene mutation; BCMA, B cell maturation antigen; AADC, aromatic l-amino acid decarboxylase; AAV, adeno-associated virus. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Upcoming catalysts (1Q23)

Drug/company	Indication	Drug information
Lecanemab/Eisai, Biogen	Alzheimer’s disease	1/6/2023 FDA PDUFA date for this humanized IgG1 mAb against large soluble amyloid-β protofibrils
Tofersen (IONIS-SOD1Rx)/Biogen, Ionis	Amyotrophic lateral sclerosis	1/25/2023 FDA PDUFA date for this oligonucleotide (caggatacat ttctacagcu) targeting SOD1
Omidubicel/Gamida Cell	Bone marrow transplant and stem cell transplant	1/30/2023 FDA PDUFA date for this umbilical cord blood–derived ex vivo expanded stem and progenitor cell therapy
Donanemab/Eli Lilly	Alzheimer’s disease	1/20/2023 FDA PDUFA date for this humanized IgG1 mAb targeting amyloid-βp3–42, the N-terminally truncated pyroglutamate-3 isoform
Vyjuvek (beremagene geperpavec)/Krystal Biotech	Epidermolysis bullosa	2/17/2023 FDA PDUFA date for this non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein targeted to deliver human COL7A1 genes to skin cells
Evusheld (tixagevimab and cilgavimab)/AstraZeneca	COVID-19	3/1/2023 FDA PDUFA date for this combination therapy of two IgG1κ mAbs, each of which acts as a SARS-CoV-2 spike protein attachment inhibitor
HPC-cord blood/StemCyte	Ischemic stroke	1/1/2023 FDA PDUFA date for this umbilical cord blood hematopoietic stem cell product intended for unrelated-donor hematopoietic progenitor cell transplantation

1. PDUFA, Prescription Drug User Fee Act; IgG, immunoglobulin G; mAb, monoclonal antibody; HSV, herpes simplex virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Notable regulatory setbacks (3Q22)

Drug/company	Indication	Drug information
AOC 1001/Avidity Bioscience	Muscular dystrophy	9/27/2022 FDA placed a partial hold on a phase 1/2 trial of this mAb targeting TfR1, conjugated to an siRNA directed against DMPK RNA, due to a serious adverse event in a trial participant
FHD-286/Foghorn Therapeutics	Acute myelogenous leukemia	8/23/2022 FDA placed a clinical hold on a phase 1 dose-escalation trial of this small-molecule allosteric inhibitor of BRG1 and BRM due to suspected cases of fatal differentiation syndrome
BEAM-201/Beam Therapeutics	Acute lymphoblastic leukemia	7/29/2022 FDA placed a hold on the IND application for an anti-CD7 multiplexed allogeneic CAR-T cell therapy, requesting more information on off-target editing and cytokine-independent growth assay
ION449/Ionis Pharmaceuticals	Dyslipidemia/hypercholesterolemia	9/23/2022 Company suspended development of a generation-2.5 ligand-conjugated antisense oligonucleotide against PCSK9 after phase 2b clinical trial failed to distinguish it from competitors
Gemcabene/NeuroBo	Dyslipidemia/hypercholesterolemia	8/2/2022 FDA placed a partial clinical hold on a phase 2 clinical study of this PARPα agonist that clears VLDLs and inhibits fatty acid and cholesterol production, requesting a 2-year rat and mouse carcinogenicity study

1. TfR1, transferrin receptor 1; mAb, monoclonal antibody; DMPK, dystrophy myotonic protein kinase; BRG1, Brahma-related gene 1, BRM, Brahma ATPase; IND, Investigational New Drug; CAR, chimeric antigen receptor; PSCK9, proprotein convertase subtilisin/kexin type 9; PARP, proliferation-activated receptor; VLDL, very low density lipoprotein. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)

Notable clinical trial results (3Q22)

Drug/company	Indication	Drug information
Sabizabulin/Veru	COVID-19	7/6/2022 In a phase 3 double blind, randomized, placebo-controlled clinical trial of a tubulin polymerization inhibitor, hospitalized patients with moderate to severe COVID-19 had 24.9% fewer deaths than controls (N. Engl. J. Med. 10.1056/EVIDoa2200145, 2022)
Lenzilumab/Humanigen	COVID-19	7/6/2022 In a randomized, controlled, blinded phase 3 trial, a human engineered IgG1 chimeric monoclonal antibody targeting GM-CSF demonstrated a 62% reduction in the relative risk of mechanical ventilation and death compared to placebo (Thorax 10.1136/thoraxjnl-2022-218744, 2022)
FLT180a/Freeline Therapeutics	Hemophilia B	7/21/2022 In an open-label phase 1/2 clinical trial, a single dose of FLT180a, an AAVS3 containing the Padua variant of human F9, protected people from bleeding and the need for coagulation factor IX replacement at a mean follow-up of 27 months (N. Engl. J. Med. 10.1056/NEJMoa2119913, 2022)
Litifilimab/Biogen	Systemic lupus erythematosus	7/28/2022 In a randomized, placebo-controlled trial, double blind phase 2 trial of humanized IgG1 anti-BDCA2 antibody, patients had fewer active joint counts and improved skin compared to placebo (N. Engl. J. Med. 10.1056/NEJMoa211802, 2022)
Tofersen/Ionis Pharmaceuticals	Amyotrophic lateral sclerosis	9/21/2022 In a phase 3 clinical trial of this antisense oligonucleotide (caggatacat ttctacagcu) targeting SOD1, the primary endpoint of improved activity was not achieved, but there was less SOD1 in CSF and fewer neurofilaments in plasma over 28 weeks (N. Engl. J. Med. 10.1056/NEJMoa2204705, 2022)
OP-101/Ashvattha Therapeutics	COVID-19 treatment	7/20/2022 In a phase 2a trial, N-acetylcysteine covalently coupled to a brain-penetrating dendrimer improved clinical outcomes and survival for patients with severe COVID-19 (Sci. Transl. Med. 10.1126/scitranslmed.abo2652, 2022)
Pepinemab/Vaccinex	Huntington’s disease	8/8/2022 A randomized, double blind, placebo-controlled phase 2 trial of a humanized monoclonal antibody that blocks the signaling activity of semaphorin 4D did not meet its primary endpoint of impression of change, but brain imaging showed less caudate atrophy and increase in brain activity (Nat. Med. 10.1038/s41591-022-01919-8, 2022)

1. GM-CSF, granulocyte–macrophage colony stimulating factor; BDCA, blood dendritic cell antigen; AAVS3, adeno-associated virus serotype 3; CSF, cerebrospinal fluid. Source: BioMedTracker, a service of Sagient Research (http://www.biomedtracker.com)