There were 15 novel large molecule drugs approved in 2020, an increase over the 12 large molecule drugs approved in 2019. Here’s a visual list of the FDA’s 2020 large molecule drug approvals, with more scientific details and references below. There is no significance to the order in which molecules are presented.
This summary is intended for drug discovery research scientists and is for educational purposes only. This is not intended for medical advice, diagnosis, or treatment.
Short Summaries
Blenrep | Danyelza | Sogroya | Viltepso | Margenza | Monjuvi | Oxlumo
Tepezza | Ebanga | Inmazeb | Trodelvy | Sarclisa | Vyepti | Uplizna
1. Blenrep (belantamab mafodotin-blmf)
Monomethyl auristatin F (MMAF) is a microtubule disruptor, derived from the natural product dolastatin, originally identified from the “sea hare” or Dolabella auricularia (Newman 2019). MMAF was conjugated using a protease-resistant link to an anti-B-cell maturation antigen (BCMA) antibody developed by GlaxoSmithKline, J6M0 (Tai 2014). Not only is the ADC targeted to BCMA and internalized to release its drug payload in MM cells, the antibody was designed with an afucosylated Fc domain, enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) compared to native Fc (Tai 2014). Patients with relapsed or triple-class refractory MM (refractory to a monoclonal antibody, proteasome inhibitor, and immunomodulatory agent) have poor prognosis with limited treatment alternatives (Mikhael 2019). The recent approval of Blenrep offers an additional option for MM patients who have had at least four prior treatments (FDA).
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2. Danyelza® (naxitamab-gqgk)
The ganglioside, GD2, is a major adhesion molecule highly expressed on neuroblastoma (NB) cells (Sait 2017). The mAb targeting GD2 was discovered using the hybridoma approach, in which B-cells from mice immunized with human neuroblastoma cells were fused to myeloma cell lines (Cheung 1985). Concerns of human anti-mouse antibody responses prompted researchers to engineer a humanized version, hu3F8, with enhanced antibody-dependent cell-mediated cytotoxic (ADCC) activity (Cheung 2012). The humanization was successful as hu3F8 exhibited potent cytotoxic effects on several cancer cell lines compared to the murine mAb (Cheung 2012). Given the on-target CNS toxicities including neuropathic pain observed with this mechanism due to GD2 expression in healthy nerve cells (Richman, 2017), opioids and gabapentin are given in combination with this drug class. While the approval of GD2-targeted drugs such as Danyelza dinutuximab offer the first new mechanisms approved for neuroblastoma in decades, there is still a long way to go for patients with this horrible pediatric disease.
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3. Sogroya® (somapacitan-beco)
Patient non-compliance in hormone replacement therapy for growth hormone deficiency (GHD) is common and partially due to the discomfort of daily injections (Rosenfeld 2008). In an effort to increase the half-life of GH and reduce the frequency of therapy, researchers at Novo Nordisk engineered a GH analog containing a fatty acid-modified side chain with albumin-binding abilities (Rasmussen 2014). Clinical trials revealed that patient outcomes with weekly administration of the GH analog were comparable to daily GH administration (Rasmussen 2014, Johannsson 2020). With the FDA’s approval of Sogroya (FDA), there is potential for the GH analog to replace daily hormone therapies in GHD adults.
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4. Viltepso® (viltolarsen)
Duchenne Muscular Dystrophy (DMD) is a genetic disease caused by out-of-frame mutations in the dystrophin gene leading to premature stop codons and severely reduced dystrophin production (Gao 2015). However, because dystrophin is the largest known human gene spanning >2200 kb, or 0.1% of the whole genome, it is hard to restore using viral gene therapy due to the large size of the cDNA and limited capacity of adenoviruses. Truncated mini- and micro-dystrophin proteins appeared to be enough to partially restore dystrophin deficiency in animal models, supporting the development of an exon skipping antisense oligonucleotide (ASO) approach (Gao 2015). The exon 53-skipping phosphorodiamidate morpholino antisense oligonucleotide (ASO) NS-065/NCNP-01, alters the mutant dystrophin gene splicing process, bypassing premature stop codons, allowing production of a shorter transcript encoding a partially functional dystrophin (Komaki 2018). Viltepso is the second ASO approved for DMD, after the exon 51-skipping Exondys 51 (Eteplirsen) in 2016 (FDA). Viltepso is expected to be used for 8 to 10% of DMD patients susceptible to exon 53 skipping (Komaki 2018, FDA).
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5. Margenza™ (margetuximab-cmkb)
The anti-HER-2 mAb trastuzumab (Herceptin) induces antibody-dependent cell-mediated cytotoxicity (ADCC) through its Fc-domain by activating certain Fc-receptors on NK cells/monocytes. Certain human polymorphisms in Fc-receptors were found to correlate with better trastuzumab response due to greater affinity for the Fc domain of the drug, resulting in more efficient ADCC (Musolino 2008). Scientists at MacroGenics engineered a mAb with enhanced FcγR-binding relative to trastuzumab and found it elicited greater cytotoxicity to trastuzumab-resistant tumor cells (Nordstrom 2011). In a randomized, open-label clinical trial, a statistically significant response was observed in the margetuximab-treated group compared to trastuzumab-treated (FDA, Rugo 2021). The FDA’s approval of Margenza will add another treatment option for HER2-positive breast cancer patients who have received at least two anti-HER2 therapies (FDA).
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6. Monjuvi® (tafasitamab-cxix)
Tafasitamab is a chimeric, humanized anti-CD19 mAb with an Fc-domain engineered to better induce antibody-dependent cell-mediated cytotoxicity (ADCC) against CD19-expressing lymphomas (Horton 2008, Makita 2018). Tafasitamab treatment demonstrated high cytotoxic activity of lymphocytic leukemia cell in preclinical studies (Kellner 2013) and 55% of patients with relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) were at least partially responsive in an open-label, single-arm clinical trial (FDA, Salles 2020). As few treatment options are available for rrDLBCL patients who are resistant to the standard R-CHOP regime (Wang 2020), this anti-CD19 antibody may be helpful for patients, especially for those ineligible for CD19-targeted CAR-T therapies.
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7. Oxlumo™ (lumasiran)
Primary hyperoxaluria type 1 (PH1) is a rare disease caused by a deficiency of the alanine-glyoxylate aminotransferase enzyme resulting in liver failure due to oxalate build-up (Hoppe 2012). Lumasiran is an small interfering RNA (siRNA) that targets the HAO1 gene, which encodes the enzyme that produces oxalate, glycolate oxidase (Liebow 2016). Delivery of siRNA therapeutics is commonly achieved using nanoparticles but this approach can be associated with off-target effects (Tatiparti 2017, Nair 2014). Instead of using nanoparticles, the amino sugar N-acetylgalactosamine was conjugated to the HAO1 mRNA-targeting siRNA, resulting in its targeted internalization into hepatocytes (Liebow 2017, Nair 2014). Remarkably, lumasiran reduces urinary oxalate levels to normal or near-normal levels in PH1 patients, and is the first approved treatment addressing the underlying cause of the disease (Businesswire 2020).
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8.Tepezza® (teprotumumab-trbw)
R1507 was originally identified as a potent and specific IGF-1R inhibitor by immunizing mice with recombinant IGF-1R (Schnitzer 2006, Smith 2017). It was intended to treat cancer but failed to significantly improve prognosis in patients with solid malignancies (Smith 2017, Qu 2017, Smith 2020). Because IGF-1R is involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO) (Mohyi 2018), R1507 showed promise as a treatment for thyroid eye disease. After two successful clinical trials sponsored by Horizon Therapeutics, the FDA approved Tepezza as the first drug treatment for TAO (FDA, Smith 2020, Smith 2017 NEJM, Douglas 2020) with expectations that it will replace the standard-of-care which entails symptom management or surgical intervention (Smith 2020, Smith 2020).
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9. Ebanga™ (ansuvimab-zykl)
The mAb that was to become Ebanga was discovered in an Ebola virus survivor of the 1995 Kikwit outbreak (Corti 2016). By screening this survivor’s B-cell population, scientists were able to identify and produce several glycoprotein-binding mAb candidates, of which mAb114 exhibited potent viral neutralization and antibody-dependent cell-mediated cytotoxicity (Corti 2016). The Ebola virus glycoprotein (GP) is challenging to target with a mAb because unlike other viral receptors, GP undergoes protease-mediated cleavage intracellularly in the lysosome prior to viral-host membrane fusion and host entry (Miller 2012). Thus, a mAb must bind both the GP extracellularly and remain bound intracellularly to the cleaved form of GP. Scientists found that mAb114 bound to several regions on the glycoprotein, including a region that was retained on the virus post-proteolysis (Misasi 2016), contributing in part to the potency of mAb114 observed in preclinical and clinical trials (Corti 2016a, Mulangu 2019). Approval of Ebanga, along with Inmazeb (below), offers two treatment options for a scary, treatment-sparse disease (FDA).
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10. Inmazeb™ (atoltivimab, maftivimab, odesivimab-ebgn)
Antibody candidates are often identified first in rodents and humanized to reduce immunogenicity. Regeneron instead developed an in vivo platform, VelocImmune mice, to generate fully human mAbs directly. They applied this platform against the surface fusion glycoprotein of the Zaire ebolavirus (Pascal 2018) to identify a triple mAb cocktail. As mentioned above, the Ebola virus glycoprotein (GP) is challenging to target with a mAb because unlike other viral receptors, GP undergoes protease-mediated cleavage intracellularly in the lysosome prior to viral-host membrane fusion and host entry (Miller 2012). Thus, a mAb must bind both the GP extracellularly and remain bound intracellularly to the cleaved form of GP. Each mAb of Inmazeb binds to a different region on the target glycoprotein and contributes to both direct virus neutralization as well as antibody-dependent cell-mediated cytotoxicity of infected cells (Pascal 2018). Inmazeb is the first approved therapeutic for Zaire ebolavirus-infected patients (FDA).
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11. Trodelvy™ (sacituzumab govitecan-hziy)
After a few years of reduced industry interest in ADCs, Gilead made headlines in 2020 with its $21B acquisition of Immunomedics for its Trodelvy asset. Trodelvy is a TROP-2 targeted monoclonal antibody conjugated to SN-38, the active metabolite of the topoisomerase inhibitor irinotecan (Moon 2008, Goldenberg 2019). In contrast to other ADCs stably linked to ultratoxic agents, Trodelvy employs a lower potency compound with a less stable linked that results in complete drug release without excessive toxicity and a bystander effect, killing neighboring cancer cells. TROP-2 is a surface antigen with increased expression in several cancer cell types, including metastatic triple-negative breast cancers (mTNBC) (Goldenberg 2019). Trodelvy is expected to work well in cancers with high TROP-2 expression, but also in those with low levels of TROP-2 expression with DNA-repair deficiencies due to the mechanism of SN-38 (Cardillo 2020). The FDA approved Trodelvy for the treatment of patients who have undergone at least two prior treatments for mTNBC (FDA) due to its remarkable response rate in this difficult to treat setting (Shen 2020, Gilead press release). Presumably Gilead paid a high premium for the asset due to an expectation that the drug will work in many other settings in which TROP-2 may be expressed even at low levels.
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12. Sarclisa® (isatuximab-irfc)
The glycoprotein, CD38, is an important therapeutic target due to its expression on plasma, lymphoid, and myeloid cells and is the target of numerous heme cancer drug discovery programs (Morandi 2018). Using hydridoma technology and functional screening, the apoptosis-inducing anti-CD38 mAb, SAR650984, was identified (Deckert 2014). SAR650984 stimulates antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis (Deckert 2014). Based on clinical trial results, which showed SAR650984 improved progression-free survival, the FDA approved Sarclisa for the treatment of patients with relapsed and refractory multiple myeloma (MM) who had received two prior treatments with lenalidomide and a proteasome inhibitor (FDA).
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13. Vyepti™ (eptinezumab-jjmr)
Anticonvulsants, calcium channel blockers, and other small molecule drugs are commonly prescribed for migraine but are not always efficacious (Pellesi 2017). Research into migraine mechanisms have implicated calcitonin gene-related peptide (CGRP) as a significant contributor to migraine progression and encouraged efforts into developing CGRP-receptor antagonists and anti-CGRP mAbs (Pellesi 2017, Garcia-Martinez 2014, Baker 2017). Due to liver toxicities associated with initial oral CGRP-receptor antagonists (Pellesi 2017), mAbs took the lead clinically. Though Vyepti was approved in early 2020 and can potentially treat chronic migraine patients, the FDA is currently evaluating new safety concerns (FDA). While anti-CGRP antibodies have been transformative for many migraine patients, they will likely be displaced by recently approved oral drugsthat have finally passed the safety hurdles.
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14. Uplizna® (inebilizumab-cdon)
Neuromyelitis optica spectrum disorder (NMOSD) is a rare, B-cell mediated, autoimmune disease affecting the central nervous system with no approved therapeutics until recently (Cree 2019, FDA). MEDI-551, or inebilizumab, is a humanized, B-cell targeting anti-CD19 mAb (Herbst 2010, Cree 2019) which, like tafasitamab above, depletes B-cell lineage cells via ADCC. To enhance antibody-dependent cell-mediated cytotoxicity, the antibody was generated in an afucosylated form using a fucosyltransferase-deficient Chinese hamster ovary cell line (Herbst 2010). Uplizna and Enspryng (not shown) are the only approved NMOSD drugs to date.
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