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News & analysis News https://doi.org/10.1038/d41573-024-00001-x 2023 FDA approvals By Asher Mullard The FDA approved 55 novel therapeutics in 2023, the second highest count in the past 30 years. nature reviews drug discovery for drugs that could confer ‘substantial improvements’ over available thera...

News & analysis News https://doi.org/10.1038/d41573-024-00001-x 2023 FDA approvals By Asher Mullard The FDA approved 55 novel therapeutics in 2023, the second highest count in the past 30 years. nature reviews drug discovery for drugs that could confer ‘substantial improvements’ over available therapies — were underrepresented in 2023, however. Just 16% of the newly approved drugs were breakthrough-designation holders, nearly half the five-year average of 30%. Boston Consulting Group (BCG) analysts estimate average peak sales of the newest CDER and CBER approvals will be US$1.0 billion, below the longer-term average forecast of $1.5 billion for new therapies. If Pfizer’s COVID-19 antiviral nirmatrelvir plus ritonavir (Paxlovid) is excluded, the average peak sales forecast for the class of 2023 drops to $760 million. The median peak sales forecast for 2023’s cohort is $500 million, in line with the historic trend. Cancer firsts, and followers The cancer community notched up a handful of first-in-class approvals. Peak sales expectations for most of these are lackluster, although such forecasts often miss the mark. AstraZeneca’s capivasertib (Truqap), for instance, is the first AKT inhibitor to secure approval. The FDA approved it in combination with the oestrogen receptor antagonist fulvestrant for hormone-receptor-positive, HER2-negative metastatic breast cancer with one or more biomarker alterations in PIK3CA, AKT1 or PTEN. AKT sits in the PI3K–AKT–mTOR signalling pathway, and PI3K and mTOR inhibitors have previously secured approval. The drug was approved alongside a companion diagnostic that evaluates PIK3CA, AKT1 and PTEN status, selecting patients that are most likely to respond but also cutting the initial market size for the drug by around half. Analysts forecast peak sales of around $690 million for the kinase inhibitor, shows data from Evaluate Pharma. Springwork’s nirogacestat (Ogsiveo) is the first γ-secretase inhibitor to make it market, for rare desmoid tumours, non-cancerous growths of the connective tissue that can put pressure on various organs. Pfizer initially developed nirogacestat for Alzheimer disease, taking on γ-secretase’s key role in the generation of the toxic amyloid-β associated with the neurodegenerative disease. Late-stage trials of γ-secretase inhibitors for Alzheimer disease failed, however, scuppered in part by the effect of these drugs on Notch signalling, which regulates cellular functions including cell growth. Notch signalling can be overactive in desmoid tumours, providing Pfizer’s spinout Springworks with an alternative development path for this small molecule. Volume 23 | February 2024 | 88–95 | 88 Credit: S.Harris/Springer Nature Limited T he FDA’s Center for Drug Evaluation and Research (CDER) approved 55 new drugs in 2023, as the small molecule and biologic pharmacopoeia continues to grow. This cohort is nearly 50% bigger than the new approval class of 2022, which fell below the approval trend line. The ten-year rolling average for new CDER approvals now stands at 46 per year, the highest it has been in over 20 years. The nadir was 2010, when this average bottomed out at 25 per year (Fig. 1; Table 1). The FDA’s Center for Biologic Evaluation and Research (CBER) kept the pace up too, approving a growing number of cell and gene therapies, vaccines and blood products in 2023. This included the first CRISPR–Cas9based gene editing product, two vaccines for respiratory syncytial virus (RSV) and a burst of gene therapies (Table 2). By therapeutic area, oncology continues to accumulate the most approvals. CDER gave a green light to 13 (24%) new cancer therapies in 2023. Neurology came in second, with 9 (16%) approvals, also in line with recent trends. Infectious diseases and haematology tied for third, with 5 (9%) apiece (Fig. 2). By modality, the medical toolbox continues to get more diverse. 2023 saw an increase in the number of nucleotide-based therapeutics, including a second RNA-aptamer product. On the antibody front, 4 T-cell-engaging bispecifics arrived (Fig. 3). The regulatory profile of these drugs was mostly in line with recent trends (Fig. 4). 56% of the newly approved therapies received priority review, a regulatory designation for therapies that the FDA expects to offer ‘significant improvements’ over the standard of care. 52% were for orphan diseases, which affect fewer than 200,000 individuals in the USA. 16% received accelerated approval, given a thumbs up on the basis of improvements on surrogate endpoints that the FDA deems as ‘reasonably likely’ to predict clinical benefit. Breakthrough designations — News & analysis nature reviews drug discovery 60 BLAs NMEs 17 6 50 Number of drugs approved Evaluate Pharma forecasts annual peak sales of around $650 million for this drug. J&J’s talquetamab (Talvey) is the first GPRC5D × CD3-targeted T-cell engager to secure accelerated approval, for heavily pretreated multiple myeloma. T-cell engagers are bispecific antibodies that bind a cancer-associated antigen with one arm and a T cell with the other, recruiting the immune cell to kill the cancerous ones. GPRC5D is enriched on multiple myeloma cells, as well as on non-malignant plasma cells and some healthy cell types. Evaluate Pharma forecasts annual peak sales of around $260 million. Previously approved T-cell engagers target CD19, CD20 and BCMA, for blood cancers, and gp100–HLA, for uveal melanoma. Pfizer’s BCMA × CD3 bispecific elranatamab (Elrexfio), Genmab and AbbVie’s CD20 × CD3 epcoritamab (Epkinly) and Roche/Genentech’s CD20 × CD3 glofitamab grow these established ranks, and bring the approval count for the modality up to 8. Epcoritamab could become the best-selling of 2023’s oncology newcomers, with annual peak sales forecasts of around $1.2 billion — making it one of only two newly approved oncology drugs with peak sales forecasts of over $1 billion. The FDA also approved two PD1-targeted monoclonal antibodies (mAbs), a class of immune checkpoint inhibitors that also unleash T cells on cancers. Incyte’s retifanlimab (Zynyz) and Cohersus’s toripalimab (Loqtorzi) bring the total PD1/PD-L1 inhibitor count up to 9. More of these immunotherapies could be up for approval in 2024. The ROS1 inhibitor class gained its fifth entrant, with the approval of BMS’s repotrectinib (Augtyro) for ROS1-positive non-smallcell lung cancer (NSCLC). BMS acquired the small molecule via its $4.1 billion purchase of Turning Point Therapeutics in 2022. The macrocyclic inhibitor is the first ROS1 inhibitor to secure an approval for patients with ROS1-positive NSCLC who have previously received a ROS1 inhibitor. Trials are ongoing in NTRK-mutated cancers, making the drug a possible future addition to the list of drugs that can be used for tissue-agnostic applications. The FDA also approved GSK’s momelotinib, a JAK1/JAK2/ACVR1 inhibitor for myelofibrosis patients with anaemia. Three other JAK inhibitors are approved for myelofibrosis. GSK expects that momelotinib’s inhibition of ACVR1 will improve iron availability, mitigating the effects of anaemia associated with this disease and with JAK inhibition. Analysts forecast peak sales of $930 million. GSK acquired momelotinib from Sierra 40 30 1 2 5 2 6 5 14 12 12 5 20 17 13 10 11 15 6 2 5 6 6 2 3 4 6 6 2 2 7 10 19 28 47 34 25 33 25 19 11 15 31 18 18 16 21 20 15 24 33 25 30 33 15 34 42 38 40 36 22 38 0 94 95 96 97 98 99 0 01 02 3 4 5 6 07 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 19 19 19 19 19 19 200 20 20 200 200 200 200 20 200 200 20 20 20 20 20 20 20 20 20 20 20 20 20 20 Year Fig. 1 | 30 years of novel FDA approvals. Annual numbers of new molecular entities (NMEs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER). See Table 1 for new approvals in 2023. Products approved by the Center for Biologics Evaluation and Research (CBER), including vaccines and gene therapies, are not included in this drug count (Table 2). Source: FDA. Oncology in 2022 for $1.9 billion. Sierra acquired it from Gilead in 2018 for $3 million upfront plus milestones. Neurology nailbiters The FDA continues to flesh out its use of regulatory flexibility in neurology, approving several new drugs on the basis of surrogate biomarkers, inconclusive evidence of clinically significant benefit or a single phase II trial. The accelerated approval of Biogen and Ionis’s tofersen (Qalsody) for SOD1-mutated amyotrophic lateral sclerosis (ALS), for example, is the first therapy to target a genetic cause of ALS. SOD1 ALS is a rare form of the neuromuscular disease, driven by a mutant and toxic SOD1 protein. Some 330 people in the US have the fatal disease. Tofersen, an antisense oligonucleotide discovered by Ionis, binds SOD1 mRNA to lower levels of toxic SOD1 in the brain. Tofersen failed to slow disease progression in patients with SOD1 ALS in the phase III trial initially intended to support full approval. But there were signs that the trial might have been too short, and the drug successfully lowered levels of both SOD1 and neurofilament light chain (NfL), a biomarker of neuronal damage. A nine-person FDA advisory panel voted unanimously that the data supports a “reasonably likely” chance that the drug helps people, based on the constellation of evidence. The ongoing phase III ATLAS trial, in asymptomatic adults with confirmed SOD1 mutations, could generate confirmatory evidence of efficacy and is assessing whether earlier use of the drug improves outcomes. The FDA granted tofersen an accelerated approval based on its effect on NfL, marking the first regulatory application of this biomarker. Drug developers hope that NfL could be useful as a biomarker in other neurological indications. “This [approval] is an important proof of principle for NfL,” said Jens Kuhle, a neurologist at University Hospital Basel. Analysts forecast peak sales of around $120 million for the rare disease drug. Eisai and Biogen’s anti-amyloid mAb lecanemab secured accelerated approval for Alzheimer disease in January, and full approval six months later. The FDA granted the accelerated approval on the basis of lecanemab’s amyloid-lowering capabilities, following the controversial regulatory precedent established by Biogen’s first-in-class anti-amyloid mAb aducanumab in 2021. It granted full approval based on the results of the phase III CLARITY AD trial, in which the antibody showed a 0.45-point benefit over placebo on the 18-point Clinical Dementia Rating–Sum of Boxes, after 18 months of treatment. Analysts forecast peak sales of $4.8 billion, show Evaluate Pharma data. Forecasts for aducanumab were initially even higher, but that first-in-class antibody remains a commercial flop. Volume 23 | February 2024 | 88–95 | 89 News & analysis Table 1 | CDER approvals in 2023 Drug (brand name) Sponsor Properties Indication Review Lecanemab (Leqembi) Eisai/Biogen Amyloid-β-targeted mAb Alzheimer disease P, B, A Bexagliflozin (Brenzavvy) Theracosbio SGLT2 inhibitor Glycaemic control in type 2 diabetes mellitus S a Pirtobrutinib (Jaypirca) Loxo/Eli Lilly BTK inhibitor Mantle cell lymphoma P, O, A Elacestrant (Orserdu) Stemline ER antagonist ER-positive, HER2-negative, ESR1-mutant breast cancer P Daprodustat (Jesduvroq) GSK HIF-PH inhibitor Anaemia caused by CKD for adults on dialysis S Velmanase alfa (Lamzede)a Chiesi Recombinant α-mannosidase Non-CNS manifestations of α-mannosidosis P, O Sparsentan (Filspari) Travere Endothelin and angiotensin II receptor antagonist Proteinuria in primary IgA nephropathy P, O, A Omaveloxolone (Skyclarys) Reata/Biogen Mechanism unknown, NRF2 activator Friedrich’s ataxia P, O Zavegepant (Zavzpret) Pfizer CGRP receptor antagonist Migraine S Trofinetide (Daybue) Acadia Mechanism unknown Rett syndrome P, O Retifanlimab (Zynyz)a Incyte PD1-targeted mAb Merkel cell carcinoma P, O, A Rezafungin (Rezzayo) Cidara Echinocandin antifungal Candidemia and invasive candidiasis P, O Leniolisib (Joenja) Pharming PI3Kδ inhibitor Activated PI3Kδ syndrome P, O Tofersen (Qalsody) Biogen SOD1-targeted ASO SOD1 amyotrophic lateral sclerosis P, O, A Pegunigalsidase alfa (Elfabrio)a Chiesi PEGylated recombinant α-galactosidase Α Fabry disease P Fezolinetant (Veozah) Astellas Neurokinin 3 receptor antagonist Hot flashes caused by menopause S Perfluorohexyloctane (Miebo) Bausch + Lomb Semifluorinated alkane Dry eye disease S Epcoritamab (Epkinly)a Genmab/AbbVie CD20 × CD3 T-cell engager DLBCL and high-grade B-cell lymphoma P, A Sulbactam, durlobactam (Xacduro) Entasis β-lactam antibacterial plus a β-lactamase inhibitor Hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible ABC P Nirmatrelvir, ritonavir (Paxlovid) Pfizer SARS-CoV-2 main protease inhibitor plus a CYP3A inhibitor Mild-to-moderate COVID-19 P Flotufolastat F18 (Posluma) Blue Earth Radioactive diagnostic agent PET imaging in prostate cancer S Sotagliflozin (Inpefa) Lexicon SGLT1/2 inhibitor Heart failure S Glofitamab (Columvi)a Genentech CD20 × CD3 T-cell engager DLBCL or large B-cell lymphoma P, A Ritlecitinib (Litfulo) Pfizer JAK3 inhibitor Alopecia areata S Rozanolixizumab (Rystiggo)a UCB FcRn-targeted mAb AChR- or MuSK-antibody-positive gMG P, O Somatrogon (Ngenla)a Pfizer Human growth hormone analogue Growth hormone deficiency S, O Nirsevimab (Beyfortus)a AstraZeneca RSV F protein-targeted mAb RSV lower respiratory tract disease S Quizartinib (Vanflyta) Daiichi Sankyo FLT3 kinase inhibitor AML P, O Lotilaner (Xdemvy) Tarsus Ectoparasiticide Demodex blepharitis S Zuranolone (Zurzuvae) Sage GABAA receptor PAM Postpartum depression P Avacincaptad pegol (Izervay) Iveric/Astellas C5-targeted aptamer Geographic atrophy secondary to AMD P, B Talquetamab (Talvey)a Janssen GPRC5D × CD3 T-cell engager Multiple myeloma P, O, B, A Elranatamab (Elrexfio)a Pfizer BCMA × CD3 T-cell engager Multiple myeloma P, O, B, A Palovarotene (Sohonos) Ipsen Retinoic acid receptor agonist Fibrodysplasia ossificans progressiva P, O Pozelimab (Veopoz)a Regeneron C5-targeted mAb CHAPLE disease P, O Motixafortide (Aphexda) Biolinerx CXCR4 inhibitor Haematopoietic stem cell mobilization for autologous transplantation in multiple myeloma S, O Momelotinib (Ojjaara) GSK JAK1/2, ALK2 inhibitor Myelofibrosis in adults with anaemia S, O Gepirone (Exxua) Fabre-Kramer 5HT1A receptor agonist Major depressive disorder S Cipaglucosidase alfa (Pombiliti)a Amicus Recombinant α-glucosidase Pompe disease S, O, B Nedosiran (Rivfloza) Novo Nordisk LDHA-targeted siRNA Primary hyperoxaluria type 1 S, O, B nature reviews drug discovery Volume 23 | February 2024 | 88–95 | 90 News & analysis Table 1 (continued) | CDER approvals in 2023 Drug (brand name) Sponsor Properties Indication Review Etrasimod (Velsipity) Pfizer S1P receptor modulator Ulcerative colitis S Zilucoplan (Zilbrysq) UCB Complement C5 inhibitor AChR-antibody positive gMG S, O Bimekizumab (Bimzelx)a UCB IL-17A/F-targeted mAb Plaque psoriasis S S, O Vamorolone (Agamree) Santhera Corticosteroid Duchenne muscular dystrophy Mirikizumab (Omvoh)a Eli Lilly IL-23-targeted mAb Ulcerative colitis S Toripalimab (Loqtorzi)a Coherus PD1-targeted mAb Nasopharyngeal carcinoma P, O, B Fruquintinib (Fruzaqla) Takeda VEGFR1/2/3 kinase inhibitor Colorectal cancer P Taurolidine, heparin (Defencath) Cormedix Thiadiazinane antimicrobial plus an anticoagulant Incidence of catheter-related bloodstream infections P Repotrectinib (Augtyro) Bristol Myers Squibb ROS1 and TRK kinase inhibitor ROS1-positive NSCLC P, O Efbemalenograstim alfa (Ryzneuta)a Evive Recombinant leukocyte growth factor Neutropenia S Capivasertib (Truqap) AstraZeneca AKT kinase inhibitor Breast cancer P Nirogacestat (Ogsiveo) Springworks γ-secretase inhibitor Desmoid tumours P, O, B Iptacopan (Fabhalta) Novartis Complement factor B inhibitor Paroxysmal nocturnal haemoglobinuria S, O, B Birch triterpenes (Filsuvez) Chiesi Mechanism unknown Epidermolysis bullosa P, O Eplontersen (Wainua) Ionis/AstraZeneca TTR-targeted ASO hATTR with polyneuropathy S, O Biologic approval. A, accelerated; ABC, Acinetobacter baumannii-calcoaceticus complex; AChR, anti-acetylcholine receptor; AMD, age-related macular degeneration; AML, acute myelogenous leukaemia; ASO, antisense oligonucleotide; B, breakthrough; CGRP, calcitonin gene-related peptide; CKD, chronic kidney disease; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; ESR1, estrogen receptor 1; ER, estrogen receptor; FcRn, neonatal Fc receptor; gMG, generalized myasthenia gravis; hATTR, hereditary TTR amyloidosis; HER2, human epidermal growth factor receptor 2; HIF-PH, hypoxia-inducible factor prolyl hydroxylase; IgA, immunoglobulin A; LDHA, lactate dehydrogenase; mAb, monoclonal antibody; MuSK, musclespecific tyrosine kinase; NSCLC, non-small-cell lung cancer; O, orphan; P, priority; PAM, positive allosteric modulator; PD1, programmed death receptor 1; RSV; respiratory syncytial virus; S, standard; S1P, sphingosine 1-phosphate; siRNA, small interfering RNA; TTR, transthyretin. Source: Drugs@FDA. a Eli Lilly’s donenemab, by contrast, was denied accelerated approval in January (Table 3). It too lowers amyloid levels, but Lilly said in January that the FDA rejected it because too few patients had 12 months of drug exposure. Whereas aducanumab and lecanemab are dosed continuously, donenemab is discontinued once amyloid plaques have been cleared from the brain. This drug-sparing trial design reduced the amount of patient-exposure data the company collected in its phase II trial. Donenemab could yet achieve full approval on the basis of the phase III Trailblazer-ALZ 2 trial, which showed a 3.25-point benefit for the mAb over placebo on the 146-point Alzheimer Disease Rating Scale (iADRS) score after 18 months. A decision for this mAb is due in 2024. Neurologists remain divided over whether these amyloid-lowering antibodies provide a clinically meaningful benefit to patients. The FDA also approved Reata’s omaveloxolone (Skyclarys) for Friedreich’s ataxia, a rare inherited disease that progressively damages the nervous system. Omaveloxolone’s mechanism of therapeutic action is unknown, but it activates the NRF2 pathway, dampening oxidative stress and potentially protecting neurons. The phase II trial for this drug met its nature reviews drug discovery primary endpoint, after the company changed this endpoint mid-trial. At 48 weeks of treatment, it provided a 2.4-point benefit over placebo on the modified Friedreich’s Ataxia Rating Scale (mFARS) score, a 99-point measure of physical function, in a “full-analysis population”. Reata said in 2020 that the FDA had requested a second trial to confirm these results. It instead submitted additional analyses to support an approval. A recently published post hoc analysis of an open-label extension trial showed that patients who continued on the drug for up to three years performed ~3.6 points better on the mFARS than did matched, untreated patients from a natural history study. The FDA had planned to discuss omaveloxolone at an advisory committee meeting, but it delayed and then cancelled this session. Analysts forecast peak sales of $1.1 billion. Biogen acquired Reata for $7.3 billion in 2023. CBER, rather than CDER, used the accelerated approval pathway to greenlight Sarepta’s gene therapy delandistrogene moxeparvovec (Elevidys) for Duchenne muscular dystrophy (DMD). This rare, fatal neuromuscular disease is caused by mutations in the dystrophin gene. Delandistrogene moxeparvovec uses an adeno-associated virus (AAV) vector to deliver a transgene that encodes a shortened version of the full-length protein, in an attempt to preserve muscle function. Sarepta’s phase II data show that ‘micro-dystrophin’ production increases with treatment, but the 48-week trial did not show a statistically significant benefit over placebo on the North Star Ambulatory Assessment (NSAA) total score, a measure of ambulatory function. At an FDA advisory meeting, panellists asked about whether micro-dystrophin mimics the function of the natural protein and noted concerns about the efficacy signal. They voted 8 to 6 in favour of approval. “It’s a vote for hope,” panellist Donald Kohn, a stem-cell researcher at the University of California Los Angeles, told Nature. He voted to approve the gene therapy. “From a statistical standpoint, [Sarepta] haven’t pled their case,” he said. The FDA approved the gene therapy for patients aged 4–5 years, based on a subgroup analysis suggesting that this age group might have had the most benefit. Sarepta priced its gene therapy at $3.2 million, making it the second most expensive therapy now on the market (behind CSL Behring/ uniQure’s $3.5 million etranacogene dezaparvovec (Hemgenix)). Analysts forecast peak sales of $3.1 billion for this gene therapy. Volume 23 | February 2024 | 88–95 | 91 News & analysis Sarepta is using its phase III EMBARK trial to provide confirmatory evidence of benefit for the gene therapy. Just five months after the accelerated approval, this trial also failed to show a statistically significant benefit on the NSAA primary endpoint. Sarepta has also yet to provide confirmatory evidence of benefit for its eteplirsen (Exondys 51), a first-in-class exon-skipping antisense oligonucleotide that secured accelerated approval in 2016 for DMD based on its ability to boost dystrophin production. Data from this confirmatory trial could be due in 2024. The FDA’s oncology team has been tackling “dangling accelerated approvals”, increasing the regulatory transparency for products that are still on the market after the failure of confirmatory trials. It remains to be seen how the rest of the FDA will handle such cases. The RSV three Several new infectious disease products pack big commercial punches. AstraZeneca’s nirsevimab (Beyfortus), for the prevention of RSV in newborns and infants born during or entering their first RSV season, is the latest pathogen-targeted mAb to hit the market. The mAb is a follow-on to the company’s first-in-class RSV prophylactic palivizumab (Synagis), developed by MedImmune and approved by the FDA in 1998. Both palivizumab and nirsevimab provide passive immunity against the RSV by binding the fusion (F) glycoprotein on the virus’s surface, blocking its ability to enter host cells and thereby reducing RSV-associated disease. Whereas palivizumab is dosed monthly, a single shot of nirsevimab provides protection for at least five months, the length of a typical RSV season. Peak sales forecasts are around $1.9 billion. A commercial success could increase interest in mAbs targeting viral proteins. Two RSV vaccines also secured FDA approval, from CBER. GSK’s Arexvy is approved for prevention of lower respiratory tract disease caused by RSV in adults aged over 60, and Pfizer’s Abrysvo is approved for both over 60s and for pregnant women to pass antibody protection onto their newborns. RSV has long eluded vaccine developers. Both the newcomers are stabilized prefusion F subunit vaccines, enabled a decade ago by insights into the crystal structure of this viral surface protein. “It’s an example of how one little insight can open up a whole new set of possibilities,” said Barney Graham, an immuno­ logist and virologist at Morehouse School of Medicine who made this discovery. Both of these vaccines could achieve blockbuster status. GSK’s Arexvy is currently in the lead, with a peak sales forecast of nearly $3.2 billion. The FDA also granted full approval to Pfizer’s COVID-19 combination product nirmatrelvir plus ritonavir. This antiviral, discovered and developed at Pfizer at record speed during the height of the pandemic, secured an Emergency Use Authorization in 2021. It racked up $18.9 billion in sales in its first year on the market, but these have since fallen dramatically. Complementary competition The FDA granted full approval to four inhibitors of the complement system, with the newcomers spanning therapeutic modalities and indications. Three of these drugs target the complement protein C5, a key node in the innate immune Table 2 | Selected CBER approvals in 2023 Biologic name (brand) Sponsor Properties Indication Fc-vwf-xten fusion protein (Altuviiio) Bioverativ Recombinant antihaemophilic factor Haemophilia A Omidubicel (Omisirge) Gamida Cell Nicotinamide modified allogeneic haematopoietic progenitor cell therapy Neutrophil recovery in patients with haematologic malignancies Fecal microbiota spores, live (Vowst) Seres Bacterial spore suspension in capsules for oral administration C. difficile recurrence RSV vaccine, adjuvanted (Arexvy) GSK Stabilized prefusion F subunit vaccine RSV prevention, in over 60s Beremagene geperpavec (Vyjuvek) Krystal HSV-based gene therapy with COL7A1 transgene Skin wounds in COL7A1-mutated DEB RSV vaccine (Abrysvo) Pfizer Bivalent stabilized prefusion F subunit vaccine RSV prevention, in over 60s and pregnant women Delandistrogene moxeparvovec (Elevidys) Sarepta AAV-based gene therapy with a micro-dystrophin transgene DMD patients aged 4–5 Donislecel (Lantidra) Celltrans Allogeneic pancreatic islets Type 1 diabetes patients unable to approach target HbA1c Valoctocogene roxaparvovec (Roctavian) Biomarin AAV-based gene therapy with modified factor VIII transgene Haemophilia A Anthrax vaccine adsorbed, adjuvanted (Cyfendus) Emergent Protective antigen protein-based vaccine Post-exposure prophylaxis Prothrombin complex concentrate, human (Balfaxar) Octapharma Prothrombin complex concentrate containing factor II, VII, IX and X, and proteins C and S Urgent warfarin reversal Meningococcal groups A, B, C, W, and Y vaccine (Penbraya) Pfizer Conjugate and recombinant protein vaccine, pentivalent Meningococcal disease prevention Chikungunya vaccine, live (Ixchiq) Valneva Live, attenuated chikungunya virus vaccine Chikungunya virus prevention ADAMTS13, recombinant (Adzynma) Takeda Recombinant rADAMTS13 cTTP Exagamglogene autotemcel (Casgevy) Vertex/CRISPR CRISPR–Cas9-based BCL11a-gene-editing therapy Sickle cell disease Lovotibeglogene autotemcel (Lyfgenia) Bluebird Lentivirus-based gene therapy with HbAT87Q transgene Sickle cell disease AAV, adeno-associated virus; C. difficile, Clostridioides difficile; cTTP, congenital thrombotic thrombocytopenic purpura; DEB, dystrophic epidermolysis bullosa; DMD, Duchenne muscular dystrophy; HbA1c; glycated haemoglobin; HSV, herpes simplex virus; RSV, respiratory syncytial virus. Source: FDA. nature reviews drug discovery Volume 23 | February 2024 | 88–95 | 92 News & analysis nature reviews drug discovery 30 Proportion of approvals (%) pathway. Two C5-targeted antibodies were already approved, including Alexion’s (now AstraZeneca’s) first-in-class mAb eculizumab (Soliris). The FDA first approved this mAb in 2007, for the rare blood disorder paroxysmal nocturnal haemoglobinuria (PNH). By 2010 it was the world’s most expensive drug, at $410,000 per year. Iveric Bio and Astellas’s avacincaptad pegol (Izervay) for geographic atrophy secondary to age-related macular degeneration now offers a first complement protein C5 inhibitor for an ocular disease. The newcomer is an RNA aptamer, an oligonucleotide with antibody-like ability to bind and block a target. Avacincaptad pegol, a 39-nucleotide pegylated molecule, binds the C5 protein to prevent its cleavage and resulting inflammatory signalling. It is the second RNA aptamer to market, following 19 years after Eyetech and Pfizer’s VEGFtargeted aptamer pegaptanib (Macugen). “The eye remains a great opportunity for aptamers,” said SomaLogic’s Nebojsa Janjic and Larry Gold, who helped pioneer the modality. Analysts forecast peak sales of just under $520 million for the drug. Astellas paid $5.9 billion to acquire Iveric Bio in 2023. The drug is competing with Apellis’s intravitreal pegcetacoplan (Syfovre), a C3-targeted pegylated cyclic peptide that also modulates complement signalling. The approval of Regeneron’s C5-targeted mAb pozelimab (Veopoz) expands this class into another rare inherited immune disease called CD55-deficient protein-losing enteropathy or CHAPLE disease. UCB’s zilucoplan (Zilbrysq) is a 15-aminoacid macrocyclic peptide that also inhibits C5. It was discovered by Ra Pharmaceuticals, who were acquired by UCB in 2019 for $2.1 billion. The FDA approved this drug for generalized myasthenia gravis in anti-acetylcholine receptor antibody-positive adults. Analysts forecast peak sales of around $730 million. The older C5-targeted mAbs are also approved for this indication. The FDA also approved Novartis’s iptacopan (Fabhalta), a small-molecule inhibitor of the serine protease factor B. Factor B interacts with C3 to initiate the complement-signalling cascade. Iptacopan is the first oral monotherapy for adults with PNH. Analysts forecast peak sales of $920 million. The agency also granted an Emergency Use Authorization to InflaRx’s C5a-targeted mAb vilobelimab (Gohibic) for COVID-19 in hospitalized adults within 48 hours of going on artificial life support. The NIH’s COVID19 Treatment Guidelines Panel says there is 5-year average 2023 20 10 0 r s s y y y y y y y e try gic ary ing tiv og og ula olog log log log rolog ase ase hia ag on uc olo rol tol co no ise ise asc at hro yc Im eu rod cri ulm ma nte On alm iov sd Ps ep ed rm N o p P e e r h u d e N a e t d r o a r D R n H tio str Ca Op cs/ ec &e Ga eti Inf sm en oli lg b a ta dic Me Me Therapeutic area Fig. 2 | CDER approvals by therapeutic area. Indications that span multiple therapeutic areas are classified under only one, based on which FDA office and division reviewed the approval application. Sources: Nature Reviews Drug Discovery, FDA. Other firsts insufficient evidence to recommend either for or against the mAb, however. If converted into a full approval, vilobelimab will be the first mAb to target C5a, a cleavage product of activated C5. More complement competition could be coming in 2024, including a first-in-class inhibitor of the serine protease factor D. With the approval of Astellas’s fezolinetant (Veozah) for hot flashes caused by menopause, the FDA expanded the women’s health medicine box. Many menopausal women either do not or cannot take the hormone therapy that is the standard of care for hot flashes. Fezolinetant targets the neurokinin Oligonucleotides Approvals by modality RNA aptamer 4 1 1 siRNA 17 2 Small molecules Proteins Hormone Fusion protein Enzyme Bispecific Antisense 1 3 34 1 Radiolabelled Peptide 2 Small molecule 1 8 4 mAb 31 Fig. 3 | CDER approvals by modality. Small molecules, including peptides of up to 40 amino acids in length, and oligonucleotides are approved as new molecular entities (NMEs). Protein-based candidates are approved through biologics license applications (BLAs). mAb, monoclonal antibody; siRNA, small interfering RNA. Source: Nature Reviews Drug Discovery. Volume 23 | February 2024 | 88–95 | 93 News & analysis 80 Proportion of approvals (%) 5-year average 2023 60 40 20 0 ty ori Pri an gh ed ph rat rou Or ele kth c a Ac Bre Designation Fig. 4 | CDER approvals by regulatory designation. Source: Nature Reviews Drug Discovery, FDA. 3 receptor, which initially attracted interest as a target for next-generation antipsychotics and was later implicated in hormone-mediated thermoregulation. Analysts forecast sales of $1.7 billion, show Evaluate Pharma data. Sage and Biogen’s zuranolone (Zurzuvae) now provides a first FDA-approved oral option for women with postpartum depression (PPD). Zuranolone is a rapid-acting positive allosteric modulator of GABAA receptors — acting on both synaptic and extrasynaptic GABAA receptors in a way that may differentiate it from related agents. In 2019, the FDA approved Sage’s brexanolone (Zulresso), another positive allosteric modulator of GABAA receptors, as a first FDA-approved, infused option for PPD. Biogen paid $1.5 billion upfront, plus milestones and equity investments, to Sage in 2020 to partner on zuranolone. Analysts forecast peak sales of $645 million. Sage and Biogen also applied to get the drug approved for major depressive disorder, but the FDA rejected its use in this indication. Dicerna’s nedosiran (Rivfloza) was approved for primary hyperoxaluria type 1 (PH1), a rare metabolic disorder. Nedosiran is an siRNA oligonucleotide that harnesses the RNAi pathway to silence the expression of the lactate dehydrogenase (LDH) enzyme, which produces the oxalate metabolite that drives the disease. Alnylam’s previously approved siRNA lumasiran (Oxlumo) silences the glycolate oxidase enzyme, which acts upstream of LDH, to treat PH1. Lumasiran does not have activity in patients with PH2 and PH3, related forms of the genetic disease, but nedosiran is in trials in these settings. Novo Nordisk acquired Dicerna for $3.3 billion in 2021. Analysts forecast peak annual sales of under $100 million. The FDA has now approved six siRNA drugs. Nedosiran is the only one of these that was discovered by a company other than Alnylam. GSK’s daprodustat ( Jesduvroq) is the first hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor to secure FDA approval, for anaemia caused by chronic kidney disease for adults on dialysis. HIF-PH regulates the cell’s response to oxygen, and inhibition of this enzyme stabilizes HIF to drive erythropoiesis. The FDA previously rejected two other HIF-PH inhibitors (Fibrogen’s roxadustat and Akebia’s vadustat) due to safety concerns. An FDA advisory panel recommended an approval for daprodustat for use in dialysis-dependent adults, but recommended against approval Table 3 | Selected rejected drugs of 2023 Drug Sponsor Properties Indication Donanemab Eli Lilly Amyloid-β-targeted mAb Alzheimer disease Omecamtiv mecarbil Cytokinetics Myosin activator Chronic heart failure Inbakicept ImmunityBio IL-15 agonist fusion protein Bladder cancer Concizumab Novo Nordisk TFPI-targeted mAb Haemophilia A and B Obeticholic acid (Ocaliva)a Alfasigma Farnesoid X receptor agonist NASH Zuranolone (Zurzuvae) Sage GABAA receptor PAM MDD Avasopasem manganese Galera Superoxide dismutase mimetic Mucositis Lebrikizumab Eli Lilly IL-13-targeted mAb Atopic dermatitis Gefapixant Merck & Co. P2X3 receptor antagonist Chronic cough b Approved in 2016 for primary biliary cholangitis. bApproved in 2023 for postpartum depression. mAb, monoclonal antibody; MDD, major depressive disorder; NASH, nonalcoholic steatohepatitis; PAM, positive allosteric modulator; TFPI, tissue factor pathway inhibitor. Source: BioMedTracker. a nature reviews drug discovery in adults who are not dependent on dialysis. The FDA followed suit. CRISPR, gene therapy and more CBER also ushered in first-in-class products, and a first-in-modality one. Vertex and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; Casgevy) especially is the first CRISPR–Cas9-based gene editor to secure a green light from the FDA, winning an approval for sickle cell disease (SCD). Exa-cel is an ex vivo gene-edited cell therapy: blood cells are harvested from patients, genetically modified at the BCL11a transcription factor to re-enable fetal haemoglobin production, and then re-infused into patients. The therapeutically upregulated fetal haemoglobin compensates for the defects in β-haemoglobin that cause the diseases. Clinical data shows that the gene therapy has curative potential, although longer-term data are needed to assess the durability of the effect. When Harvard Medical School and HHMI’s Stuart Orkin and colleagues discovered the role of BCL11a in fetal haemoglobin production in 2008, it was unclear how to drug the transcription factor. The arrival of the CRISPR–Cas9 gene-editing system in 2012 provided a path forward for haemoglobinopathies. The development of the programme was “remarkably fast”, said Orkin. “It is a perfect example of how the ecosystem can work.” Vertex and CRISPR have priced the one-off treatment at $2.2 million. It also requires a harsh preconditioning chemotherapy regimen, to make room for the edited cells. The therapy will consequently remain out of reach for many patients. “This is not the end game,” says Orkin, who has his eye on next-generation gene editors and small molecules that might be more accessible. Bluebird bio also scored an approval for its SCD gene therapy lovotibeglogene autotemcel (lovo-cel; Lyfgenia). Cells are harvested from patients and then engineered with a lentiviral vector system to insert a transgene that encodes the non-sickling haemoglobin HbAT87Q. This therapy also offers curative potential, but carries a black box warning noting the risk of blood cancers. It also requires pre-treatment chemotherapy, and is priced at $3.1 million — making it the third priciest therapy on the market. Analysts currently forecast higher peak sales for exa-cel, at just over $2.6 billion. Krystal Biotech secured an approval for beremagene geperpavec for the rare genetic skin disorder dystrophic epidermolysis bullosa Volume 23 | February 2024 | 88–95 | 94 News & analysis (DEB). DEB is caused by mutations in the gene that encodes type VII collagen, resulting in fragile skin that tears and blisters easily. Krystal’s gene therapy is applied repeatedly to open wounds, enabling collagen production and speeding up wound repair. Beremagene geperpavec is the first gene therapy to be approved for topical use, in a re-dosable format, using a herpes simplex virus vector. CellTrans’s donislecel (Lantidra) — made up of donor-derived pancreatic islet cells — became the first FDA-approved cell therapy for patients with type 1 diabetes who are unable to approach target HbA1c levels. After islet cells are transfused, patients need life-long immunosuppression to keep the cells active. The Islets for US Collaborative, a group of over 50 islet and pancreas transplantation experts, argues that islet cells would be better regulated in the US through the framework that covers organ transplantation. The FDA also approved Seres Therapeutics’ and Nestlé’s Vowst for the prevention of Clostridioides difficile recurrence following antibiotics. Vowst is the first pharmaceuticalgrade orally administered faecal microbiota product, and competes with Ferring/Rebiotix’s rectally administered microbiota product Rebyota, which the FDA approved in 2022. Table 4 | Selected approvals to watch for in 2024 nature reviews drug discovery Sponsor Properties Indication Timing Zolbetuximab Astellas Claudin 18.2-targeted mAb Gastric cancer January Lifileucel Iovance Tumour-infiltrating lymphocyte therapy Melanoma February Resmetiroma Madrigal/Synta Thyroid hormone receptor β agonist NASH March Sotatercepta Merck & Co./ Acceleron Fusion protein ligand trap for TGF-β superfamily PAH March mRNA-1345a Moderna mRNA-based vaccine RSV prevention April Donanemab Eli Lilly Amyloid-β-targeted mAb Alzheimer disease Q1 EB-101a Abeona Gene therapy with COL7A2 transgene RDEB May Patritumab deruxtecana Merck & Co. HER3-targeted ADC NSCLC June Imetelstat Geron Telomerase inhibitor Transfusion-dependent anaemia with MDS June Tarlatamaba Amgen DLL3 × CD3 T-cell engager antibody SCLC June Fidanacogene elaparvoveca Pfizer/Spark AAV-based gene therapy with factor IX transgene Haemophilia B Q2 Bentracimaba Laboratoires SERB Ticagrelor-neutralizing antibody Drug toxicity 1H a A new year 2024 will offer more notable new entrants into the pharmacopeia (Table 4). Astellas’s zolbetuximab could provide a much needed if only modestly effective treatment option for metastatic gastric cancer, and heads a crowded claudin-18.2-targeted pipeline. The antibody was rejected by the FDA in January 2024, however, due to manufacturing issues, says Astellas. Madrigal’s thyroid hormone receptor β agonist resmetirom could provide a first therapy for non-alcoholic steatohepatitis (NASH), a year after Intercept’s farnesoid X receptor agonist obeticholic acid (Ocaliva) was rejected a second time for this liver disease. The non-profit Multidisciplinary Association for Psychedelic Studies (MAPS) hopes to get a green light for MDMA in post-traumatic stress disorder (PTSD), and establish a precedent for the role of hallucinogens in psychiatric indications. An approval Biologic name Crovalimaba Roche C5-targeted mAb PNH July Danicopana AstraZeneca/ Alexion Factor D inhibitor PNH July Midomafetaminea MAPS MDMA PTSD August Xanomeline plus trospium Karuna/BMS Muscarinic receptor modulators Schizophrenia September Acoramidis BridgeBio TTR stabilizer TTR amyloidosis December Marstacimab Pfizer TFPI-targeted mAb Haemophilia A and B Q4 Afamitresgene autoleucela Adaptimmune MAGE-A4-targeted autologous, engineered T cell therapy Synovial sarcoma 2024 Breakthrough designated drug. AAV, adeno-associated virus; ADC, antibody–drug conjugate; mAb, monoclonal antibody; MDS, myelodysplastic syndromes; NASH, non-alcoholic steatohepatitis; NSCLC, non-small-cell lung cancer; PAH, pulmonary arterial hypertension; PNH, paroxysmal nocturnal haemoglobinuria; PTSD, post-traumatic stress disorder; RDEB, recessive dystrophic epidermolysis bullosa; RSV, respiratory syncytial virus; SCLC, small-cell lung cancer; TFPI, tissue factor pathway inhibitor; TTR, transthyretin. Source: BioMedTracker and press releases. a for Moderna’s RSV vaccine mRNA-1345 would show that the mRNA vaccine platform has potential beyond COVID-19. Karuna’s dual M1/M4 muscarinic receptor modulator combination therapy xanomeline plus trospium (KarXT) could provide the first new treatment approach for schizophrenia in decades, and follows BMS’s $14 billion acquisition of Karuna in 2023. Iovance’s lifileucel stands to provide a first approval for a tumour-infiltrating lymphocyte (TIL) therapy, in metastatic melanoma. A regulatory win for this adoptive T cell therapy would mark a major milestone in the modality’s 35-year journey to patients. “It has taken way too long,” says NCI chief of Surgery Steven Rosenberg, who first showed the clinical potential of TILs in 1988. Volume 23 | February 2024 | 88–95 | 95