news feature Credit: Science Lab / Alamy Stock Photo Refreshing the biologic pipeline 2020 In the absence of face-to-face meetings, FDA and industry implemented regulatory workarounds to maintain drug and biologics approvals. These could be here to stay. John Hodgson OVID-19 might have been expected since 1996) — a small miracle in itself “COVID-19 confronted us with the need to severely impair drug approvals (Fig. 1 and Table 1). to better triage sponsors’ questions,” says Cin 2020. In the event, however, To the usual crop of rare disease and Peter Marks, the director of the Center for industry and regulators delivered a small genetic-niche cancer treatments, 2020 Biologics Evaluation and Research (CBER) miracle. They found workarounds and also added a chimeric antigen receptor at the FDA. “That was perhaps the single surrogate methods of engagement. Starting (CAR)-T cell therapy with a cleaner biggest takeaway from the pandemic related in January 2020, when the outbreak veered manufacturing process and the first to product applications.” Marks says that it westward, the number of face-to face approved blockbuster indication for a became very apparent with some COVID- meetings declined rapidly; by March, small-interfering RNA (siRNA) — the 19-related files that resolving a single they were replaced by Webex and Teams. European Medicines Agency’s (EMA) issue can help a sponsor enormously and (Secure Zoom meeting are to be added registration of the RNA interference accelerate the development cycle. Before this year.) And remarkably, by 31 December, (RNAi) therapy Leqvio (inclisiran) for COVID-19, it was conceivable that a small the US Food and Drug Administration cardiovascular disease. Not to mention company would have to wait 75 days — the (FDA) had approved nearly as many the rapid approvals and Emergency Use standard schedule for a type C meeting — drugs and biologics in 2020 as it had Authorizations (Box 1) for drugs against even for relatively minor advice on whether in 2019 (itself the second highest year COVID-19. one aspect of a manufacturing process or NATURE BIOTECHNOLOGY | VOL 39 | FEBRUARY 2021 | 135–143 | www.nature.com/naturebiotechnology 135 news feature 45 NME 50 Biologic 41 40 % biologics 43 45 41 35 38 38 40 35 34 32 33 36 31 31 30 35 30 31 28 31 % biologics 27 29 29 29 28 30 24 24 25 23 24 21 24 21 25 21 20 19 20 19 20 18 18 18 19 17 22 18 20 Number of approvals 16 17 15 14 15 14 13 13 13 12 15 11 11 10 9 10 7 8 7 10 7 6 6 6 6 5 5 4 5 3 3 5 2 2 2 0 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Year Fig. 1 | FDA approvals 2020. The regulatory agency seemingly did not miss a beat in 2020, despite the pandemic. control was better than another, or whether their territories. Project Orbis, in effect, is a over current therapy as demonstrated in an animal model was appropriate. “It’s a long corridor of assessment that opens multiple cleanly designed trials. The FDA may now time to wait,” says Marks. “Going forward, doors of similar and near-simultaneous be considering expansion of the real-time we would like to find ways of increasing approvals, but it does not enforce a uniform review program to indications outside interactions so that sponsors’ issues regulatory position. oncology. don’t fester.” The Project Orbis process began in The Brazilian Health Regulatory Agency Another regulatory adjustment that September 2019 as the FDA, with its (ANVISA) was also involved in some accelerated the assessments of COVID-19 Australian and Canadian counterparts, Project Orbis approvals during 2020. In products was that clinical and approved a combination of two marketed October, the UK Medicines and Healthcare manufacturing aspects were examined drugs, in advanced endometrial carcinoma: Products Regulatory Agency, faced with fully in parallel. Looking forward to the the small-molecule multi-tyrosine-kinase Brexit-related distancing from the EMA, post-pandemic period, Marks says that, inhibitor Lenvima (lenvatinib) from decided to join not only Project Orbis but particularly in the area of vaccines and Eisai (Tokyo) and Merck’s Keytruda also the Access Consortium. Originally gene therapies, there is the potential “to (pembrolizumab), a humanized IgG4 named for its regulatory membership significantly shorten the cycle times” monoclonal antibody (mAb) against from Australia, Canada, Switzerland both through advancing manufacturing programmed cell death receptor 1 (PD1). and Singapore, the Access Consortium technologies and through advisory processes In 2020, regulatory bodies from Singapore undertakes joint assessments of drugs on non-clinical and clinical programs (its Health Sciences Authority) and beyond those in oncology, as well as of characterized by an increased number Switzerland (Swissmedic) joined the medical devices. of informal or less formal interactions. Project Orbis approval of its first new Two other new drugs were approved Furthermore, there was clear evidence drug, Tukysa (tucatinib), a small-molecule under Project Orbis in 2020: Zepzelca during 2020 of two new and highly desirable inhibitor of HER2 developed by Seagen. (lurbinectedin) from PharmaMar (Madrid) directions in the regulation of drugs and Tukysa was approved in combination is a synthetic alkaloid derivative of an biologics: moves toward patient-centered with Herceptin (trastuzumab) and Xeloda ecteinascidin from marine tunicates that development and the internationalization (capecitabine) for unresectable or metastatic promotes apoptosis by selectively inhibiting of regulation. HER2-positive breast cancer. The US label RNA polymerase II transcription in for Tukysa includes its use in patients with small-cell lung cancer; and Otsuka’s Going global brain metastases, a growing indication Inqovi for myelodysplastic syndrome is an One global regulatory initiative is Project that stems at least partly from the orally available fixed-dose combination Orbis, an FDA-led scheme under which combination of prolonged survival due to of decitabine and cedazuridine, a select group of national regulatory directed antibody therapies (like Herceptin) small-molecule inhibitors of cytosine agencies are collaborating in assessing drug and the inability of such antibodies to cross DNA methyltransferase and cytidine applications in oncology. A single regulatory the blood–brain barrier. deaminase, respectively. submission to the FDA will be assessed Tukysa’s approval was rapid, taking just For cell and gene therapy, however, collectively by experts from various agencies, 119 days from submission to approval, a moves towards international alignment were leading, if the data are acceptable, to record for new molecular entities under one of the first casualties of COVID-19. multiple approvals. However, control of the the FDA’s Real-Time Oncology Review Regulators from the United States, Europe timing and precise nature of approvals may process that former FDA commissioner and Japan met face to face in Geneva in vary. Following a joint assessment, separate Scott Gottlieb introduced in 2018. The rapid January 2020, but discussions may not national agencies may impose different process applies only to candidate drugs that resume for another six months or more — labeling and indication requirements for show substantial top-line improvements “as soon as the COVID hurricane passes 136 NATURE BIOTECHNOLOGY | VOL 39 | FEBRUARY 2021 | 135–143 | www.nature.com/naturebiotechnology news feature Table 1 | FDA biologics approvals in 2020 Drug name Generic name Indication Molecule type Blenrepa Belantamab mafodotin-blmf Multiple myeloma Humanized anti-BCMA IgG1 mAb conjugated to auristatin F via a non-cleavable linker Danyelzaa Naxitamab-gqgk Neuroendocrine tumors Humanized IgG3 3F8 mAb targeting ganglioside GD2 and cluster of differentiation 3 Darzalex Faspro Daratumumab/hyaluronidase-fihj Multiple myeloma Fully human IgG1 anti-CD38 mAb Ebanga Ansuvimab-zykl Ebola virus infection Fully human IgG1 mAb isolated from a survivor of the 1995 outbreak. Enspryng Satralizumab-mwge Neuromyelitis optica (Devic’s Humanized IgG2 anti-interleukin-6 receptor mAb syndrome) Imcivree Setmelanotide Metabolic syndrome Small peptide agonist with specificity for melanocortin-4 receptor Inmazeb Atoltivimab/maftivimab/odesivimab-ebgn Ebola virus infection Cocktail of three human IgG1 mAbs directed against three Ebola epitopes Margenza Margetuximab-cmkb Breast cancer Fc optimized chimeric IgG1 anti-epidermal growth factor receptor (EGFR) mAb Monjuvia Tafasitamab-cxix Diffuse large B-cell lymphoma Fc optimized humanized IgG1 anti-CD19 mAb Phesgo Trastuzumab/pertuzumab Breast cancer Fixed dose combination of Herceptin and Perjeta (pertuzumab), two anti-EGFR humanized IgG1 mAbs Sarclisa Isatuximab-irfc Multiple myeloma Humanized IgG1 mAb against CD38 Sogroya Somapacitan-beco Short stature Recombinant human growth hormone analog with a single substitution in the backbone (L101C) to which an albumin is attached via a hydrophilic spacer Tecartusa Brexucabtagene autoleucel Mantle cell lymphoma CD19-directed genetically modified autologous CAR-T cell Tepezza Teprotumumab-trbw Thyroid eye disease IgG1 mAb that targets insulin-like growth factor 1 receptor Trodelvya Sacituzumab govitecan-hziy Breast cancer Humanized IgG1κ monoclonal mAb conjugated with SN-38, a topoisomerase inhibitor, using hydrolysable linker CL2A Uplizna Inebilizumab-cdon Neuromyelitis optica Humanized IgG4 anti-CD19 mAb Vyepti Eptinezumab-jjmr Migraine and other headaches