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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 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 treatments, 2020 Biologics Evaluation and Research (CBER) miracle. They found workarounds and also added a chimeric receptor at the FDA. “That was perhaps the single surrogate methods of engagement. Starting (CAR)- 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 — 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

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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 () 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 , there is the potential “to (), a humanized IgG4 named for its regulatory membership significantly shorten the cycle times” (mAb) against from Australia, Canada, 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 (), 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 () and Xeloda ecteinascidin from marine tunicates that development and the internationalization (capecitabine) for unresectable or metastatic promotes by selectively inhibiting of regulation. HER2-positive . 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 , 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

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Table 1 | FDA biologics approvals in 2020 Drug name Generic name Indication Molecule type Blenrepa -blmf Multiple myeloma Humanized anti-BCMA IgG1 mAb conjugated to auristatin F via a non-cleavable linker Danyelzaa -gqgk Neuroendocrine tumors Humanized IgG3 mAb targeting ganglioside GD2 and cluster of differentiation 3 Darzalex Faspro /hyaluronidase-fihj Multiple myeloma Fully IgG1 anti-CD38 mAb Ebanga -zykl Fully human IgG1 mAb isolated from a survivor of the 1995 outbreak. Enspryng Satralizumab-mwge Neuromyelitis optica (Devic’s Humanized IgG2 anti--6 receptor mAb syndrome) Imcivree Setmelanotide Metabolic syndrome Small peptide agonist with specificity for melanocortin-4 receptor Inmazeb //-ebgn Ebola virus infection Cocktail of three human IgG1 mAbs directed against three Ebola Margenza -cmkb Breast cancer Fc optimized chimeric IgG1 anti-epidermal receptor (EGFR) mAb Monjuvia -cxix Diffuse large B-cell Fc optimized humanized IgG1 anti-CD19 mAb Phesgo Trastuzumab/ Breast cancer Fixed dose combination of Herceptin and Perjeta (pertuzumab), two anti-EGFR humanized IgG1 mAbs Sarclisa -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 -trbw Thyroid eye disease IgG1 mAb that targets -like growth factor 1 receptor Trodelvya -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 -jjmr Migraine and other Humanized IgG1 anti-CGRP mAb Notable new molecular entities Oxlumo Lumasiran Hyperoxaluria siRNA oligonucleotide Viltepso Duchenne muscular dystrophy Phosphorodiamidate ASO

aAccelerated approval. mAb, monoclonal antibody; ASO, antisense oligonucleotide.

over,” says Peter Marks. Regulatory practice example; the oral availability of the type 1 in November 2020. But Leqvio might evolves with exposure to sponsors’ projects, combination avoids the need for parenteral take siRNA into a new dimension. and the relative newness and rarity of gene administration of decitabine. Several others Targeted at the proprotein convertase and cell therapy projects may mean that the joined it in 2020. subtilisin kexin 9 (PCSK9) transcript, evolution of regulations in different places The European approval of ’s Leqvio competes in the cholesterol-lowering is divergent. But there is a strong desire for Leqvio (inclisiran) as the first siRNA market with anti-PCSK9 mAbs, such as alignment among the FDA, EMA and Japan’s drug for elevated low-density lipoprotein Sanofi’s Praluent (, a human IgG1 Pharmaceuticals and Medical Devices cholesterol (LDL-C) could mark one mAb) and ’s Repatha (evolucumab, Agency, says Peter Marks. “For small patient of the most fundamental shifts in the a human IgG2 mAb) — drugs that populations, having divergent regulatory pharmaceutical market for decades. Thus were launched with a fanfare but have approaches is anti-innovation …. We would far, siRNA drugs have been prominent as performed disappointingly in the market. start with trying to get some of the technical rare disease therapies, as the FDA approvals However, even if Leqvio fails to become requirements aligned, so that sponsors could of Alnylam’s second and third products the blockbuster drug that Novartis hopes use same dossier anywhere to support the demonstrate: Givlaari (givosiran), which for and investors demand, 2021 will mark same product.” targets 5-aminolevulinate synthase 1 the year that siRNA as a technology joined inhibitor mRNA, was approved for acute mAbs in making the transition from orphan Going patient-centric hepatic porphyria in November 2019, niche to pharma mainstream (Fig. 2). Convenience is a watchword in drug and Oxlumo (lumasiran), which targets Another move toward patient approvals, both for patients and for hydroxyacid oxidase 1 modulator mRNA, convenience came with the August approval the healthcare system. Inqovi is one was approved for primary hyperoxaluria for a once-weekly self-injection human

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Box 1 | Lessons from Emergency Use Authorizations

Te FDA has issued many Emergency 19-related products, at least, regulators two-antibody cocktail of casirivimab Use Authorizations (EUAs) during the responded to the need for speed, and imdevimab. In October, full FDA pandemic, mostly for in vitro diagnostics considering regulatory steps in parallel approval was granted to another passive and personal protective equipment, but rather than sequentially. immunization therapy, Regeneron’s also for a few therapeutics and vaccines Inmazeb, a three-monoclonal cocktail for (see table). EUAs are not approvals. Tey Lesson 2. Not every EUA will be given the treatment of . remain in efect only for the duration of full approval, even when backed by high the emergency and the reviews are less authority. US President Donald Trump’s Lesson 4. Most small molecules are rigorous. Whereas regular FDA approvals forceful espousal of the antimalarial blunt tools for combatting a highly will refer to “substantial evidence” of safety generic hydroxychloroquine was one infectious viral respiratory pathogen, and efcacy, EUAs are issued on the basis factor that led to its EUA at the end of but in the absence of alternatives, of reasonable belief that products may be March. Insufcient evidence of efcacy ballpark activity can be enough. Gilead safe and efective. Although some lessons against SARS-CoV-2 led to Science’s Veklury (remdesivir) was not learned by regulators and drug developers revocation less than three months later. designed for SARS-CoV-2. It is an may only apply to pandemic responses, Tis is a clear reminder that although inhibitor of viral RNA-dependent RNA other may be pointers for the future of regulatory outcomes may combine elements polymerase with broad in vitro antiviral . of science, patient need and political action against a range of animal and human context, evidence ultimately triumphs. pathogens from many virus families. Lesson 1. Te regulatory process fexes It got a US EUA on the basis that it according to prevailing pressures (a lesson Lesson 3. Human plasma is a good appeared to shorten recovery times that actually applies to both EUAs and full starting point for anti-infective drug with SARS-Cov-2 if used early enough. approvals). It turns out, for instance, that development programs. Passive Similarly, Lilly’s Olumiant (), a face-to-face meetings with regulators are immunization has been known to be small-molecule inhibitor of less important than the opportunity to an efective fx for infectious diseases (JAK) originally approved for rheumatoid exchange information on a regular basis, as since the beginning of the twentieth arthritis, found a role in damping the long as security challenges are met. Te way century, and so it proved with SARS-CoV-2. cytokine storms that claimed many lives regulators adjusted during the COVID-19 Tree EUAs have been issued for passive in COVID-19’s frst wave. pandemic is a particular reminder for immunization: the collection and use executives in smaller companies that the of convalescent plasma; Eli Lilly’s single Lesson 5. For EUAs, the needs of the many authorities are best regarded as enablers monoclonal antibody ; outweigh those of the few. Innovation rather than gatekeepers. For COVID- and Regeneron Pharmaceuticals’ serves everybody.

FDA Emergency Use Authorizations for combatting COVID-19 Intervention Company EUA date Comments Chloroquine, hydroxychloroquine – 28 March EUA revoked 15 June Veklury (remdesivir) 30 April Antiviral, full approval 22 October COVID-19 convalescent plasma – 23 August Passive immunotherapy Bamlanivimab Eli Lilly 9 November Passive immunotherapy Olumiant (baricitinib) with remdesivir Eli Lilly and Gilead Sciences 19 November Immune storm reduction, antiviral Casirivimab and imdevimab Regeneron 20 November Passive immunotherapy COVID-19 vaccine and BioNTech 11 December mRNA vaccine COVID-19 vaccine Therapeutics 17 December mRNA vaccine

EUA, emergency use authorization. Source: US FDA, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#covidtherap eutics

growth hormone (hGH) formulation, Novo which albumin can attach, extending the Tikva, Israel) and GlaxoSmithKline have Nordisk’s Sogroya (somapacitan-beco), circulatory half-life from around 3–4 hours halted the development of their albuminated coming a mere 35 years after the approval to 2–3 days. granulocyte colony stimulating factor of ’s recombinant human growth A number of albumin-linked protein (GCSF) products (Egranli (balugrastim) hormone, Protropin, which requires daily fusion drugs have been produced over the and Albugranin, respectively). Merrimack injections. Novo borrowed the technical key past decade, but not all have made the grade. Pharmaceuticals’ HER2–HER3–HSA to Sogroya from the development of insulin The FDA approved CSL Behring’s Idelvion (human serum albumin) bispecific fusion detemir, the company’s long-acting insulin (albutrepenonacog alfa), a recombinant product floundered as the company ceased analog: substituting cysteine for leucine at albumin–human coagulation factor IX, in operational business. Having acquired position 101 of hGH yields a molecule to 2016. But both Teva Pharmaceuticals (Petah Principia Pharmaceutical in 2000 for

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100% Spinraza in the United States (but not in the rest of the world) were down 9% in the

90% second quarter of 2020 and down 23% in the third versus the corresponding quarters in 2019. 80% Rare disease, common approval

70% Regulatory systems around the world now strongly incentivize drug development for rare diseases. However, although orphan 60% exclusivities can offer financial incentives for drug developers, low patient numbers 50% pose their own conundrum — namely, whether it is ethical or practical to recruit patients with severe inherited disease 40% without recourse to other treatments into a arm of a trial. Other 30% The FDA and other regulators have Metabolic shown sympathy for this position, allowing Cardiovascular the control arms of clinical studies to 20% Endocrine Ophthalmology be based on historical data on disease progression. One of the trials underpinning 10% Respiratory Evrysdi’s approval examined how the drug Infectious disease slowed the loss of babies’ abilities to sit or Autoimmunity/immunology breathe unaided, compared with the course Oncology 0% of untreated SMA. 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 At the far end of the rare disease spectrum is Hutchinson–Gilford progeria syndrome, a form of premature aging Fig. 2 | Monoclonal antibody approvals over time by disease group. Oncology and immunity and that affects only 1 in 18 million people. autoimmunity predominate, but other disease groups are slowly getting traction. Symptoms show up in the first few months of life, and affected individuals die by their early teens, often from a stroke or a heart attack. In November, the its albumin fusion technology, Human product, Evrysdi (). This drug FDA approved the first treatment, Eiger Genome Sciences developed Albuferon was approved in August for treating spinal BioPharmaceuticals’ Zokinvy (lonafarnib), (albinterferon-alfa-2b) as a competitor to muscular atrophy (SMA) and is the first an oral small-molecule farnesyltransferase Roche’s PEGylated α-interferon Pegasys small-molecule exon-skipping drug, a inhibitor, on the basis of data that showed (peginterferon alfa-2a), as well as a selective splice modulator of survival of the drug extended the lifespan of treated long-lasting hGH, Albutropin. The half-lives motor neuron 2 (SMN2) mRNA originally patients by an average of 2.5 years compared of both were extended substantially. developed at PTC Therapeutics. Evrysdi with untreated ones. However, Human Genome Sciences stopped is the third drug approved for SMA, and Neurofibromatosis type 1 (NF1) affects development of Albuferon-alfa in 2010 like ’s Spinraza (), a around 1 in 3,000 people. Yet the approval after an FDA ruling that it was no more 2′-O-2-methoxyethyl phosphorothioate in April of Cambridge, UK, AstraZeneca’s effective than Pegasys. Albutropin is still in antisense oligonucleotide developed Koselugo () for treating development at Teva. originally by Ionis and approved in plexiform neurofibromas in NF1 also drew Other new approvals will allow patients 2016, and Novartis’s gene therapy upon natural history data. AstraZeneca’s to avoid hospital-based treatment, a Zolgensma (), data showed that the median reduction in particularly desirable quality in the midst a recombinant adeno-associated the volume of painful, disfiguring tumors in of COVID-19. Adding recombinant virus serotype 9 vector containing an nerve sheaths was 28% in children treated human hyaluronidase from Halozyme SMN2 transgene under the control of a with selumetinib1 compared with a volume Therapeutics to a fixed-dose combination of cytomegalovirus enhancer/chicken-β-actin increase of at least 20% in age-matched Hoffmann-La Roche (, Switzerland)/ hybrid promoter, approved in 2019, controls from the US National Cancer Genentech humanized IgG1 anti-HER2 it works by increasing the amounts of Institute’s natural history study of NF1. mAbs trastuzumab and pertuzumab led to full-length SMN2 mRNA and functional One of the effects of orphan drugs the development of Phesgo (pertuzumab/ protein. Unlike Spinraza and Zolgensma, legislation is that multiple drugs are trastuzumab/hyaluronidase-zzfx). Because which are administered intrathecally and approved for the same rare indication Phesgo is administered as a subcutaneous intravenously, respectively, and which both within a short period of time. Neuromyelitis injection, its approval last June means that require hospitalization, Evrysdi comes as a optica spectrum disorder (NMOSD) is an patients with HER2-positive breast strawberry-flavored drink formulated for autoimmune disease that affects the optic can now be treated outside infusion centers. infants that can be given at home. It is too nerves and spinal cord in around 1–2 per Safety considerations during COVID- early to say definitively how COVID-19 100,000 white people and around 5–10 19 may have provided a more rapid and the launch of Evrysdi altered the SMA per 100,000 Black people worldwide. It route to market share for a second Roche market, but its noteworthy that sales of had no approved treatments before 2019.

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Now it has three, all mAb therapies. The A reckoning for exon-skipping drugs in products. This is because they not only first was Alexion’s Soliris (eculizumab), DMD may be approaching. It is four years improve the performance or convenience of a humanized monoclonal IgG2/4κ mAb since the approval of Sarepta’s Exondys 51 a drug, but also build intellectual property against complement protein C5 approved () in 2016, and the company has a protection for the originating company. for NMOSD in 2019. The second arrived in third compound, , due before the Halozyme’s recombinant hyaluronidase June 2020 as the AstraZeneca autoimmunity FDA in February. platform, Enhanze, helps reposition and inflammation spin-off Viela Bio As yet, none of these data have been biological drugs from specialist centers brought its first product to market: Uplizna published, but it all may become moot in (such as hospitals or infusion centers) (inebilizumab-cdon), a CD19-directed the light of potential progress in DMD gene towards doctors’ offices or home settings. humanized afucosylated IgG1 mAb. The therapies and also next-generation exon Recombinant human hyaluronidase is third, Enspryng (satralizumab-mwge), a skippers. Paul Matteis, a biotechnology an that acts as a permeabilizer, humanized IgG2 mAb against the human analyst at Stifel, says that although the breaking down the subcutaneous interleukin-6 receptor developed by delivery of microdystrophin through polysaccharide found in the extracellular Hoffmann-La Roche, followed swiftly, with gene therapy is “unlikely to be curative,” matrix of the skin and subcutaneous tissue FDA approval in August. Competition it could still be “a huge win for patients and thus facilitating loading, dispersion between the three products in this indication and a big revenue generator.” Matteis says and absorption of biologics. In effect, is likely to be intense, with only an estimated that mechanistic synergies mean that the hyaluronidase allows biological drugs to be 4,000–8,000 people with NMOSD in future of DMD could lie in combinations given through subcutaneous injection rather the United States. Other products might of microdystrophin gene therapy and than through infusion. join the throng soon: Alexion’s longer next-generation exon skippers. Sarepta will Two more ‘Enhanze-inside’ mAb acting (once every eight weeks) Soliris have results of a placebo-controlled trial on products were approved in 2020: Janssen follow-up Ultomiris (ravulizumab-cwvz), DMD gene therapy in 2021. Pharmaceutica’s (Beerse, Belgium) Darzalex a C5-targeting IgG2/4κ mAb containing Faspro (a mixture of daratumumab, a an Fc engineered for reduced neonatal Optimizing adoptive cell therapy human IgG1κ mAb targeting CD38, and Fc receptor binding, is in a phase 3 study In July, the FDA approved Gilead Sciences’ hyaluronidase-fihj) for the treatment (NCT04201262). Tecartus (brexucabtagene autoleucel), of light-chain amyloidosis and Roche/ Similar product competition is seen in autologous T cells engineered retrovirally Genentech’s Phesgo. These bring the number gene therapy for rare diseases, says Difei Yang, ex vivo to express a CAR comprising a of approved products containing Halozyme’s a senior biotech analyst at Mizuho Securities mouse anti-CD19 single-chain variable technology to six: the other three were USA. She estimates, for example, that fragment (scFv) linked to CD28 and CD3ζ Baxalta’s HyQvia (hyaluronidase and a 10% Duchenne muscular dystrophy (DMD) gene co-stimulatory domains, for the treatment infusion of human polyclonal immune therapies from both and of advanced mantle cell lymphoma. This globulin) in 2014, Roche/Genentech’s Pfizer are likely be ready for Biologics License was the second product stemming from Rituxan Hycela (hyaluronidase and Application (BLA) submission within 6–12 Gilead’s 2017 $11.9 billion acquisition chimeric anti-CD-20 IgG1κ mAb) in 2017, months of each other. This alignment erodes of Kite Pharma. Compared with that of and Herceptin Hylecta (trastuzumab and any first-to-market advantage, something that Gilead’s first approved CAR-T therapy, hyaluronidase-oysk) in 2019. Halozyme’s is particularly relevant in the one-shot world Yescarta (axicabtagene ciloleucel) for collaborative pipeline now includes Pfizer, of gene therapy. “Competition eventually large B cell non-, the , Alexion and Eli Lilly, leads to better and more choices for patients manufacturing process for Tecartus has an as well as Roche and Janssen. and physicians,” says Yang, “And can be extra T cell enrichment step that reduces the expected to put a lid on the high price tag of expansion of CD19-expressing tumor cells Antibody–drug conjugates loosen up novel therapies.” in the autologous cell preparation. In effect, Another antibody adjunct that features Viltepso (viltolarsen) became the third Tecartus is a ‘cleaner’ CAR-T product. prominently among 2020 drug approvals is approved exon-skipping drug for DMD Notwithstanding the greater product Seagen’s antibody-directed conjugate when Japan’s Ministry of Health, Labour purity, the administration of Tecartus to (ADC) technology. The first came in April and Welfare gave it the nod in March, nearly patients remains burdensome, requiring with the approval of Immunomedics’ five months in advance of FDA’s approval in treatment centers that are certified by the Trodelvy (sacituzumab govitecan-hziy, a August. Viltepso is a phosphorodiamidate FDA and staffed by medical personnel humanized IgG1κ mAb targeting Trop-2 morpholino antisense oligonucleotide that trained to spot the treatment’s severe side (trophoblast cell-surface antigen-2) binds exon 53 of dystrophin pre-mRNA. effects. At this point in development, conjugated to the topoisomerase inhibitor It was developed by Nippon Shinyaku adoptive cell therapy remains a last-ditch drug SN-38 via a hydrolysable CL2A linker) (Kyoto, Japan) and covers the same patient cancer treatment: patients in the trial on for third-line metastatic triple-negative subgroup as Vyondys 53 () from which the approval of Tecartus was based breast cancer. The second Seagen ADC Sarepta: the 8% of patients with confirmed had all previously failed to respond not only project to market in 2020 came in August dystrophin mutations susceptible to to but also to treatment with with the approval of GlaxoSmithKline’s exon 53 skipping. a CD20 antibody (mAbs like , Blenrep (belantamab mafodotin-blmf, All four approvals so far in this class , , or an afucosylated humanized IgG1 mAb (including that for Viltepso) have accepted ) or a Bruton covalently linked to the microtubule increased dystrophin production as a inhibitor (small molecules like , inhibitor via a surrogate marker for efficacy but have or ). protease-resistant maleimidocaproyl linker) required sponsors to demonstrate clinical for multiple myeloma. benefit in postmarketing studies. Viltepso Getting under the skin For Trodelvy, the path to market was far raises dystrophin levels to a greater extent Big pharma appreciates incremental from smooth. The roots of the compound go (around five times more) than Vyondys 53. technical improvements for its antibody back at least to 2004, when Immunomedics

140 Nature Biotechnology | VOL 39 | February 2021 | 135–143 | www.nature.com/naturebiotechnology news feature developed a , hRS7, Fc engineering to the fore Genetically targeted drugs continue against Trop-2 (epithelial glycoprotein-1), The accelerated approval of Monjuvi march an antigen overexpressed on numerous (tafasitamab-cxix, an anti-CD19 humanized So called precision cancer drugs are one of tumor types. In 2017, the compound was to IgG1/2 mAb containing a hybrid Fc domain biotechnology’s stocks-in-trade. Six were be the cornerstone of a major collaboration with two amino acid substitutions to modify approved in 2020 (Table 2). The use of a between Immunomedics and Seagen (at the Fc-mediated functions) at the end of genetic marker enables clinical development the time called Genetics). Seattle July made it the second approved product costs to be mitigated by targeting a Genetics, which already had Adcetris for MorphoSys (Planegg, Germany) and development program to highly selected (, a chimeric IgG1 the second approved therapeutic to use small numbers of patients. The flagship mAb targeting CD30 conjugated to the Xencor’s XmAb Fc-domain-engineering product is Novartis’s Gleevec (), a microtubule inhibitor monomethyl technology. Xencor earned a $25 million small-molecule drug approved in 2001 for auristatin E via a protease-cleavable linker) regulatory milestone. The first XmAb mAb chronic myelogenous (CML) with on the market, was to assume responsibility on the market was Ultomiris (see “Rare a chromosome 9 and 22 fusion ( for manufacturing development and taking disease, common approval” above). For chromosome). Gleevec transformed the compound through the regulatory Monjuvi, XmAb engineering increased the five-year survival rates from 30% to process. Key Immunomedics shareholders level of natural killer (NK) cell-mediated around 89%. argued that the deal has been “rushed” and antibody-directed cellular cytotoxicity Gleevec pioneers Brian Druker of did not deliver value to shareholders. The (ADCC) in vitro3. Monjuvi’s initial Oregon Health & Science University complete response letter issued by FDA indication is confined to a narrow patient and Nick Lydon, then of Ciba-Geigy in January 2019 outlining concerns about subgroup (as a second-line treatment in Pharmaceuticals, went on to found aspects of Trodelvy’s submission related to relapsed or refractory diffuse large B cell Blueprint Medicines in in 2008. chemistry, manufacturing and control added lymphoma in patients who are not eligible Twelve years later, Blueprint’s first two further fuel to the fire. But ultimately, the for an autologous stem cell transplant) product approvals arrived: Ayvakit partnership was vindicated — first by the and has to be used in combination with (), a small-molecule multiple drug’s approval in April 2020 and then again, lenalidomide (Celgene’s Revlimid). tyrosine kinase inhibitor for patients in September 2020, when Gilead made its However, MorphoSys and US partner with a platelet-derived growth factor $21 billion offer for Immunomedics. hope to expand its use to a range receptor A D842V mutation in exon 18, in Trodelvy has been described by the of lymphoma indications. January 2020, and Gavreto (), company and its advisors as “a pipeline A second Fc-engineered mAb was a small-molecule multiple tyrosine kinase in a product” because it represents a approved on 16 December: MacroGenics’ inhibitor for patients with a RET gene fusion different approach to ADCs. Early ADCs Margenza (margetuximab-cmkb), a (CCDC6-RET) and V804L, V804M and (like Adcetris) bound a single, highly toxic HER2-targeting chimeric IgG1κ mAb with M918T mutations, in September. molecular payload tightly to an antibody. an Fc engineered for increased binding Most of these approvals will not have Tumor killing ensued when the complex of of activating Fcγ receptor 3A (CD16A) an impact anything like that of Gleevec. bound antibody and toxin was internalized and decreased binding to inhibitory Fcγ Whereas the cancer cells in nearly all cases and the linker proteolytically degraded. receptor 2B (CD32B). These changes lead of CML carry the Trodelvy, by contrast, puts up to eight to greater in vitro ADCC and NK cell and are likely susceptible to Gleevec, specific copies of a moderately toxic compound activation. Margenza, MacroGenics’ first genetic rearrangements account for only (SN-38) onto a single antibody. The linker approved product, outperformed Herceptin a fraction of other cancers. For instance, chemistry can be tuned so that, in addition in a head-to-head trial, particularly in the fibroblast 2 to internalization, the toxin is released patients with low-affinity CD16A genotypes, (FGFR2) fusion target for Incyte’s Pemazyre locally under the physiological conditions of the group for whom trastuzumab is (), a small-molecule kinase 2 the tumor . less effective. inhibitor targeting FGFR1, FGFR2 and

Table 2 | Gene-targeted drugs approved in 2020 Drug Generic name Indication Developer Date approved Ayvakit Avapritinib GIST harboring a PDGFRA exon 18 mutation Blueprint Medicines 9 January (FDA), 28 July (EMA) Pemazyre Pemigatinib Cholangiocarcinoma harboring an in-frame FGFR2 gene fusion (with a Incyte 17 April breakpoint within intron17/exon 18) or non-fusion rearrangement Tabrecta NSCLC harboring MET exon 14 mutations Novartis 6 May Retevmo NSCLC harboring RET mutations in the extracellular cysteine-rich Loxo Oncology/Eli Lilly 8 May region (M918T, V804M, V804L or others) Tazverik Tazemetostat Relapsed or refractory with mutations in EZH2 Epizyme/Royalty Pharma 18 June leading to loss of integrase interactor 1 Gavreto Pralsetinib NSCLC harboring RET gene fusion (CCDC6-RET) or V804L, V804M Blueprint Medicines 4 September and M918T mutations

GIST, gastrointestinal stromal tumor; FGFR2, receptor 2; NSCLC, non-small-cell lung cancer; MET, mesenchymal–epithelial transition gene; RET, the RET proto-oncogene; PDGFRA platelet-derived growth factor receptor-α; EZH2, enhancer of zeste homolog 2; CCDC6, coiled-coil domain containing 6.

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FGFR3 for patients with an in-frame FGFR2 of Tazverik in Japan to Royalty Pharma and rights on the basis of the results of the gene fusion (with a breakpoint in intron17/ arranged a $70 million line of credit with ARROW . exon 18) or non-fusion rearrangement, Pharmakon Advisors, a Royalty subsidiary, The synergy between biotech firms is seen in just 9–14% of patients with to fund the regulatory milestones it owes and big pharma is likely to persist, says cholangiocarcinoma. Similarly, although Eisai. US sales of Tazverik since its approval Mizuho’s Yang. “Biotech brings strengths around 70% of non-small-cell lung cancers are below $5 million per quarter. in technology innovation and an approach have a genomic mutation of some kind, For another 2020-approved precision to clinical validation that brings products only 3–4% lead to skipping of MET exon drug, Retevmo (selpercatinib), a forward in the most valuable indications or 14 (METex14), the oncogenic driver against small-molecule multikinase inhibitor disease settings. Pharma, on the other hand, which Novartis’s Tabrecta (capmatinib), a indicated for patients with RET mutations has the wherewithal to navigate complex small-molecule inhibitor of MET kinase, in the extracellular cysteine-rich region regulatory environments, invest in new is directed. (M918T, V804M V804L and others), the manufacturing technologies, and work with For Epizyme, the developer of Tazverik business story is already well advanced. payers/physicians/patients to optimally (tazemetostat), a small-molecule inhibitor Retevmo was a prominent asset in Eli Lilly’s commercialize new therapies” (Box 2). of the methyltransferase EZH2, the limited early-2019 $8 billion acquisition of patient population (the drug is approved Loxo Oncology. Another compound that Looking forward to 2021 only for patients with mutations leading to fits this category is Blueprint’s Gavreto The inauguration of Joe Biden as president loss of integrase interactor 1) means that (see above); in July 2020, Roche paid of the United States on 20 January 2021 is the company may struggle to pay back its $675 million up front plus a $100 million unlikely to impact drug approval policy, but investment in the compound. Epizyme has equity investment for non-US, non-China it may affect pricing. MassBio’s Director of assigned the royalties due from Eisai on sales co-development and co-commercialization Government Affairs, Susan Martin, says

Box 2 | Business journeys

Some of the 2020 roster of approved drugs Other drugs have travelled circuitously. for procedural sedation in adults. Tis traveled far from their origins (see Table). Tepezza (teprotumumab-trbw), a fully benzodiazepine started as a germ of an Between developer and their current owner, human IgG1 mAb targeting insulin-like asset at GlaxoSmithKline before being mAbs such as Sarclisa (isatuximab-irfc), a growth factor-1 receptor) was originally bartered in 2003 to Cambridge, UK, startup CD38-directed chimeric IgG1 mAb, and developed by Danish company , CeNeS Pharmaceuticals in exchange for Vyepti (eptinezumab-jjmr), a humanized subsequently licensed to Roche, returned a 5% stake. In 2008, the drug was sold to IgG1 mAb against calcitonin gene-related to Genmab, and developed further by River Paion (Aachen, Germany) in an all-stock peptide (CGRP) ligand, crossed the Vision (a company established solely to transaction valued at $21.7 million. Four Atlantic Ocean. Xeglyze (abametapir), develop the asset) before fnally being sold years ago, Dublin, Ireland-based Cosmo a small-molecule metalloproteinase to Horizon Pharma in 2017. Pharmaceuticals in-licensed the US rights inhibitor for treating human head But the award for the most to remimazolam and joined Paion in eforts lice, is marketed by India’s Dr Reddy’s time-consuming journey must go to to progress the candidate to registration. In Laboratories, but started life as an Byfavo (remimazolam), a short-acting July 2020, Cosmo sold the license to Acacia infestation control agent in the Australian anesthetic γ-aminobutyric acid A Pharmaceuticals, which received FDA poultry company HatchTech. (GABAA) receptor agonist that is indicated approval in October 2020.

Acquired approvals Product Current owner Previous developer Mode of acquisition Indication Sarclisa (isatuximab-irfc) Sanofi Immunogen Licensed product Third-line multiple myeloma Vyepti (eptinezumab-jjmr) Lundbeck (Valby, Denmark) Alder BioPharmaceuticals Bought Alder for Migraine prevention $1.95 billion in 2019 Tukysa (tucatinib) Seagen Array BioPharma via Cascadian Bought Cascadian for Advanced HER2-positive Therapeutics $614 million in 2018 breast cancer Tepezza Horizon Therapeutics Genmab via River Vision and Bought River Vision for Thyroid eye disease (teprotumumab-trbw) Roche $145 million in 2017 QWO (Clostridium Endo BioSpecifics Technologies Bought BioSpecifics for Cellulite histolyticum collagenase) $540 million in 2020 Zeposia (ozanimod) Bristol Myers Squibb Celgene Bought Celgene for Relapsing $74 billion in 2019 Byfavo (remimazolam) Paion (Aachen, Germany) GlaxoSmithKline via CeNeS Bought CeNeS for Procedural sedation Pharmaceuticals $22 million in 2008 Xeglyze (abametapir) Dr. Reddy’s Laboratories HatchTech Licensed product Head lice infestation Tecartus (brexucabtagene Gilead Science Kite Pharma Bought Kite for Advanced mantle cell autoleucel) $11.9 billion in 2017 lymphoma

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Biden’s support for a form of international antibody in advanced clinical trials in Biogen’s aducanumab has been equivocal at pricing index for Medicare drugs and broader hypercholesterolemia indications. best. Indeed, Biogen’s own view of the drug policies that aim to keep drug prices in step In March, the FDA is expected to candidate’s performance has flip-flopped. with inflation makes the new president look at Pfizer and Eli Lilly’s , a In March 2019, the company announced “worse on drug pricing reform for the life humanized IgG2 heavy chain and κ-light aducanumab did not meet its primary sciences industry than President Trump, but chain mAb, one of two antibodies targeted endpoints of slowing cognitive decline not by much.” against (NGF) in in the ENGAGE and EMERGE phase 3 Until the northern hemisphere winter late-stage development (the other is clinical studies. But in October that year, it season for respiratory diseases has passed, Regeneron and Teva’s fully human IgG1 did an about-face, arguing that reanalyzed most of the public attention around the mAb ). The issue with anti-NGF evidence from EMERGE indicated that biotech and pharmaceutical industry agents has been that some treated patients’ high-dose aducanumab had slowed cognitive sectors will remain focused on the progress osteoarthritic disease has worsened, decline. Biogen leaked that the FDA had of COVID-19-related therapeutics and perhaps because the agents’ potent indicated to the company that it planned to vaccines. “COVID-19 has been agenda item relief has allowed patients to be more act early on aducanumab, but the responses 1, 2 and 3 for regulators everywhere,” says active. Nevertheless, this observation has from the agency’s Peripheral and Central CBER’s Marks. However, in preparing for restricted the clinical programs for both Nervous System Drugs Advisory Committee the next pandemic, Marks believes that, in tanezumab and fasinumab to the use of on 6 November 2020 were largely, if not addition to keeping abreast of biological low-dose preparations. Two earlier trials overwhelmingly, negative. innovations, it will also be important of tanezumab, in osteoarthritis of the knee In the light of the negative advisory for industry and regulators to rise to the and hip, were halted in 2009 and 2010, committee, an FDA approval of aducanumab challenge of manufacturing innovations respectively, because of worsening disease. would be “pretty controversial,” says Matteis. in huge quantities. “For antibodies, even Any approval of tanezumub is likely to be “But investors might then view FDA as for vaccines, could we see continuous or restricted to patients who are unable to more accommodating, sending positive semicontinuous manufacturing rather than use standard-of-care analgesics, such as signals to other companies working in batch processes? We need very much to be non-steroidal anti-inflammatory drugs. Alzheimer’s, where a good deal of medical working towards this in order to be better Also in March, the FDA is expected to need will remain unmet.” Across neurology, prepared for the next pandemic,” he says. pass judgment on Biogen’s controversial where clinical development is notoriously Within investor and industry circles, key strategy with the Alzheimer’s drug difficult, Matteis says that a positive decision regulatory decisions scheduled for the first aducanumab, a chimeric human IgG1 in March for aducanumab might help quarter of 2021 will help delineate the role of mAb targeting β-amyloid. The decision has reaffirm that drugs can get approved with humanized mAbs in substantial indications, much at stake, according to Stifel analyst some positive and some negative data. But such as Alzheimer’s disease, osteoarthritis Matteis. Beyond aducanumab potentially historical precedents, at least from the past and metabolic disease (Fig. 2). representing the first disease-modifying 15 years, are unpromising: “We’ve been In the last of these, increasing therapeutic Alzheimer’s drug, its success or failure unable to find a drug that’s gotten approved options for cholesterol-lowering drugs, will have a profound impact on Biogen’s after zero AdComm panelists voted in favor,” including the launch of the siRNA Leqvio, profitability. Matteis believes that the says Matteis. ❐ portend an increasingly competitive market. aducanumab decision will be an indicator Regeneron’s , a fully human of FDA flexibility in the post-Gottlieb John Hodgson IgG1 mAb against -like 3 era, both in Alzheimer’s disease and in Cambridge, UK. protein, is expected to go before the FDA neurology generally. in February 2021 and would become the No surprise, then, that before the FDA Published online: 28 January 2021 first mAb to be used for homozygous Advisory Committee for aducanumab last https://doi.org/10.1038/s41587-021-00814-w familial hypercholesterolemia. Although November, analysts at Canaccord Genuity homozygous familial hypercholesterolemia called the antibody “biopharma’s most References 1. Gross, A. M. et al. N. Engl. J. Med. 382, 1430–1442 (2020). affects only around 1,300 people in the closely-watched pipeline product” outside 2. Goldenberg, D. M. et al. Oncotarget 6, 22496–22512 (2015). United States, Regeneron also has the COVID. The evidence for the effectiveness of 3. Kellner, C. et al. Leukemia 27, 1595–1598 (2013).

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