Peptides and Oligonucleotides) Harvest

pharmaceuticals

Review 2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

Othman Al Musaimi 1,† , Danah Al Shaer 2,† , Fernando Albericio 1,3,4,* and Beatriz G. de la Torre 2,*

1 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa; [email protected] 2 KRISP, School of Laboratory of Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa; [email protected] 3 Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 4 Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain * Correspondence: [email protected] (F.A.); [email protected] (B.G.d.l.T.); Tel.: +27-614-009-144 (F.A.); +27-614-047-528 (B.G.d.l.T.) † These authors contributed equally to this work.

Abstract: 2020 has been an extremely difﬁcult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved 53 new drug entities, six of which fall in the peptides and oligonucleotides (TIDES) category. The number of authorizations for these kinds of drugs has been similar to that of previous years, thereby reﬂecting the consolidation of the TIDES market. Here, the TIDES approved in 2020 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

Keywords: belantamab mafodotin-blmf; 64Cu-DOTATATE; drugs; FDA; 68Ga-PSMA-11; lumasiran; setmelanotide; oligonucleotides; peptides; viltolarsen Citation: Al Musaimi, O.; Al Shaer, D.; Albericio, F.; de la Torre, B.G. 2020 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals 2021, 14, 145. 1. Introduction https://doi.org/10.3390/ph14020145 In 2020, the Food and Drug Administration (FDA) has approved 53 drugs [1,2], giving a total of 228 entities (new chemical entities and biologics) authorized during the last Academic Editor: Jean Jacques 5 years (2016–2020) (Figure1)[ 2]. Of the 53 drugs accepted in 2020, six are peptides and Vanden Eynde oligonucleotides (TIDES). In this regard, the last five years have witnessed the authorization of 23 TIDES. These numbers further strengthen the TIDES market, which, in number of Received: 31 January 2021 drugs, accounts for around 10% of the total. Accepted: 9 February 2021 Although 2020 can be considered an excellent year from the perspective of both the Published: 11 February 2021 total number of drugs approved and TIDES, it has been marked by the coronavirus disease 2019 (COVID-19) pandemic. However, this unique situation has allowed confirmation Publisher’s Note: MDPI stays neutral of the robustness of all pharmaceutical industry stakeholders. Indeed, in the space of with regard to jurisdictional claims in approximately 10 months, the disease was identified and the first vaccinations were rolled published maps and institutional affil- out. From the perspective of TIDES, it is important to highlight that the three first vaccines iations. approved by the regulatory agencies could be considered first-in-class and are based on either RNA or DNA. The explosion of oligonucleotides as drugs in recent years and later as key components of vaccines has been driven by intense research and investment in these intriguing molecules by many academic and industrial groups over more than 30 years. Copyright: © 2021 by the authors. The four peptides and two oligonucleotides approved by the FDA in 2020 are shown Licensee MDPI, Basel, Switzerland. in Table1, together with the indication, target, and route of administration. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Pharmaceuticals 2021, 14, 145. https://doi.org/10.3390/ph14020145 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 145 2 of 14 Pharmaceuticals 2021, 14, 145 2 of 14

Figure 1. A total of 228 new drugs were approved by the Food and Drug Administration (FDA) from 2016 to 2020 [2]. Figure 1. A total of 228 new drugs were approved by the Food and Drug Administration (FDA) from 2016 to 2020 [2]. mAbs, monoclonal antibodies; ADCs, antibody drug conjugates; Oligos, oligonucleotides. mAbs, monoclonal antibodies; ADCs, antibody drug conjugates; Oligos, oligonucleotides. Although 2020 can be considered an excellent year from the perspective of both the Table 1. Summary of the 2020 FDA peptides and oligonucleotides (TIDES) harvest. total number of drugs approved and TIDES, it has been marked by the coronavirus Active Ingredientdisease 2019 (COVID‐19) pandemic. However, this unique situation has allowed # Type Indication Target Route (Trade Name) confirmation of the robustness of all pharmaceutical industry stakeholders. Indeed, in the Viltolarsen space ofAntisense approximately Duchenne’s10 months, muscular the disease was identified and the first vaccinations 1 DMD Exon 53 Intravenous (ViltepsoTM) were rolledoligonucleotide out. From the dystrophyperspective (DMD) of TIDES, it is important to highlight that the three Primary Hydroxyacid oxidase Lumasiran first vaccinesAntisense approved by the regulatory agencies could be considered first‐in‐class and 2 hyperoxaluria (glycolate oxidase) 1 Subcutaneous (OxlumoTM) oligonucleotide are based on either RNA or typeDNA. 1 (PH1) The explosion(HOA1) of oligonucleotides mRNA as drugs in recent Setmelanotide years and later as key componentsChronic weight of vaccines hasMelanocortin-4 been driven by intense research and 3 Peptide Subcutaneous (ImcivreeTM) investment in these intriguingmanagement molecules (obesity) by manyreceptor academic (MC4R) and industrial groups over 64Cu-DOTATATEmore than 30 years. 4 TM Peptide Scintigraphic imaging Somatostatin receptor Intravenous (Detectnet ) The four peptides and two oligonucleotides approved by the FDA in 2020 are shown Prostate-speciﬁc Diagnosis of recurrent 5 68Ga-PSMA-11 in Table 1,Peptide together with the indication, target, and routemembrane of administration.Intravenous prostate carcinoma antigen (PSMA) BelantamabTable 1. Summary of the 2020 FDA peptides and oligonucleotides (TIDES) harvest. ADC a with Relapsed or refractory B-cell maturation 6 mafodotin-blmf Intravenous Active IngredientTM peptide payload multiple myeloma antigen (BCMA) # (Blenrep ) Type Indication Target Route (Trade Name) a ADC, antibody drug conjugate. Antisense Duchenne’s muscular 1 Viltolarsen (ViltepsoTM) DMD Exon 53 Intravenous 2.oligonucleotide Oligonucleotides dystrophy (DMD) Hydroxyacid oxidase Lumasiran AntisenseOligonucleotides are becomingPrimary consolidated as therapeutic drugs after the success 2 (glycolate oxidase) 1 Subcutaneous (OxlumoTM) ofoligonucleotide this family in the treatmenthyperoxaluria of various type 1 (PH1) severe genetic disorders, mainly in the past few (HOA1) mRNA years. By the end of 2020, a dozen oligonucleotide drugs were on the market, nine of them Setmelanotide Chronic weight Melanocortin‐4 3 havingPeptide received approval since 2016. A summary of all authorized oligonucleotideSubcutaneous drugs (ImcivreeTM) management (obesity) receptor (MC4R) is shown in Table2. 64Cu‐DOTATATE 4 Peptide Scintigraphic imaging Somatostatin receptor Intravenous (DetectnetTM) 2.1. Viltolarsen (ViltepsoTM) Diagnosis of recurrent Prostate‐specific 5 68Ga‐PSMA‐11 ViltolarsenPeptide is an antisense oligonucleotide consisting of a 21 phosphorodiamidateIntravenous prostate carcinoma membrane antigen (PSMA) morpholino oligomer (PMO). In this kind of oligonucleotide analog, the natural sugar- Belantamab mafodotin‐ ADC a with peptide Relapsed or refractory B‐cell maturation 6 Intravenous blmf (BlenrepTM) payload multiple myeloma antigen (BCMA) a ADC, antibody drug conjugate.

Pharmaceuticals 2021, 14, 145 3 of 14

phosphate backbone has been replaced by phosphorodiamidate-morpholino units, leading to a neutral backbone. The sequence of the bases is shown in (Figure2)[4,5].

Table 2. FDA-approved oligonucleotides from 1998–2020.

Active # Ingredient Company Structure Indication Target FDA Approval (Trade Name) Ionis Pharma Fomivirsen (Carlsbad, CA, USA) Cytomegalovirus 1 Antisense PS-ON a CMV UL123 August 1998 (VitraveneTM) Novartis retinitis (Basel, Switzerland) NeXstar Pharma Neovascular Pegaptanib (Boulder, CO, USA) Polynucleotide age-related 2 VEGF-165 December 2004 (MacugenTM) Eyetech Pharma aptamer macular (Knolls, NJ, USA) degeneration Ionis Pharma (Carlsbad, CA, USA) Genzyme Homozygous Mipomersen 3 (Cambridge, Antisense PS-ON a familial hyperc- APOB January 2013 (KynamroTM) MA, USA) holesterolaemia Kastle Tx (Housten, TX, USA) Hepatic Deﬁbrotide Jazz Pharma Mixed single 4 veno-occlusive NA b March 2016 (DeﬁtelioTM) (Dublin, Ireland) strands of DNA disease Duchenne Eteplirsen Sarepta Tx Antisense PS-ON 5 muscular DMD exon 51 September 2016 (Exondys 51TM) (De Berry, TX, USA) a/(PMO c) dystrophy Ionis Pharma (Carlsbad, CA, USA) Nusinersen Antisense PS-ON Spinal muscular 6 Biogen SMN2 exon 7 December 2016 (SpinrazaTM) a/(PMO c) atrophy (Cambridge, MA, USA) Hereditary Alnylam Pharma Patisiran transthyretin 7 (Cambridge, siRNA d TTR August 2018 (OnpattroTM) amyloidosis MA, USA) polyneuropathy Ionis Pharma Hereditary Inotersen (Carlsbad, CA, USA) transthyretin; 8 Antisense PS-ON a TTR October 2018 (TegsediTM) Akcea Pharma Amyloidosis (Boston, MA, USA) polyneuropathy Aminolevulinate Alnylam Pharma Givosiran Acute hepatic synthase 1 November 2019 9 (Cambridge, siRNA d (GivlaariTM) porphyria (ALAS1) (Enhanced) MA, USA) mRNA e Duchenne Golodirsen Sarepta Tx 10 Antisense PMO c muscular DMD exon 53 December 2019 (Vyondys 53TM) (De Berry, TX, USA) dystrophy Nippon Shinyaku (Kisshoin, Duchenne Viltolarsen 11 Minami-ku Kyoto) Antisense PMO c muscular DMD exon 53 August 2020 (ViltepsoTM) with (NCNP) f dystrophy (Kodaira, Tokyo) Alnylam Pharma Primary Lumasiran 12 (Cambridge, siRNA d hyperoxaluria HOA1 mRNA e November 2020 (OxlumoTM) MA, USA) type 1 (PH1) a PS-ON: phosphorothioate oligonucleotide; b NA: not applicable, the mechanism of action is not well understood [3]; c PMO: phosphorodiamidate morpholino oligonucleotide; d siRNA: small interfering RNA; e mRNA: messenger RNA; f National Center of Neurology and Psychiatry. Pharmaceuticals 2021, 14, 145 4 of 14 Pharmaceuticals 2021, 14, 145 4 of 14

This drug is prescribed to treat Duchenne’s muscular dystrophy (DMD) amenable to exon 53 skipping [5]. DMD is an X chromosome-linked genetic disorder in which young patients suffer progressive deterioration of body muscles that ends with death in the2.1. second Viltolarsen or third decade (Viltepso of life [TM4].) The dystrophin gene consists of 79 exons that encode for the 427-kDa cytoskeletal protein dystrophin. The protein protects and stabilizes the plasmaViltolarsen membrane of muscle is an cells antisense from the mechanical oligonucleotide stress placed on muscle consisting ﬁbers upon of a 21 phosphorodiamidate contractionmorpholino [4,6]. Theoligomer absence of (PMO). dystrophin In damages this kind muscle of cell oligonucleotide membranes, thereby analog, the natural sugar‐ leading to muscle degeneration and wasting [7]. Various genetic mutations in one or more ofphosphate the exons mainly backbone cause out-of-frame has translationalbeen replaced reading, which by prevents phosphorodiamidate transcription ‐morpholino units, andleading consequently to a neutral causes complete backbone. loss of the The protein sequence [4,5]. of the bases is shown in (Figure 2) [4,5].

. Figure 2. Structure of viltolarsen (ViltepsoTM). Figure 2. Structure of viltolarsen (ViltepsoTM). ViltepsoTM binds to exon 53 of the dystrophin mRNA precursor, thereby masking the exon. It then allows restoration of the reading frame. The reading process proceeds, but skippingThis exon drug 53 and is consequently prescribed producing to treat a shorter, Duchenne’s but still functional, muscular dystrophin dystrophy (DMD) amenable to protein [4,5]. This outcome delays muscle deterioration and turns the overall condition intoexon a Becker 53 skipping muscular dystrophy [5]. DMD (BMD)-like is an condition, X chromosome thus increasing‐ thelinked life expectancy genetic disorder in which young ofpatients DMD patients. suffer [4]. progressive deterioration of body muscles that ends with death in the ViltepsoTM is the third PMO antisense oligonucleotide used to treat DMD by exon skipping.second The or first third two weredecade eteplirsin of life and golodirsin [4]. The for dystrophin exons 51 and 53, gene respectively consists [6,8]. of 79 exons that encode for Sharingthe 427 the‐kDa same structurecytoskeletal as viltolarsen protein but with dystrophin. an additional four The subunits protein and a protects and stabilizes the triethylene glycol moiety at its 50 end, golodirsin reached the market in 2019. Exon 51 skippingplasma therapy membrane is applicable of to 14%muscle of DMD cells patients, from while exonthe 53 mechanical skipping is applicable stress placed on muscle fibers toupon 10%. Acontraction multi-exon skipping [4,6]. approach The is nowabsence under investigation of dystrophin and is expected damages to be muscle cell membranes, beneficial for 45% of DMD patients [4]. therebyViltepso leadingTM is administered to muscle intravenously degeneration and has shown and some wasting adverse effects, [7]. Various includ- genetic mutations in one ingor cough,more nasopharyngitis, of the exons upper mainly respiratory cause tract infection, out‐of vomiting,‐frame and translational diarrhea [5,9]. reading, which prevents Developed in Japan by Nippon Shinyaku and in collaboration with the National Center of Neurologytranscription and Psychiatry and consequently (NCNP), it was first causes approved complete in Japan in March loss 2020of the [5] and protein [4,5]. receivedViltepso authorizationTM binds from the to FDA exon on 12 53 August of the of the dystrophin same year [10]. mRNA precursor, thereby masking the

2.2.exon. Lumasiran It then (Oxlumo allowsTM) restoration of the reading frame. The reading process proceeds, but skippingLumasiran exon is a double-stranded 53 and consequently small interference producing RNA (siRNA). a Itshorter, consists of but the still functional, dystrophin sodiumprotein salt [4,5]. of a sense This and an outcome antisense strands delays containing muscle some chemicallydeterioration modiﬁed and units. turns the overall condition Moreover, an N-acetyl galactosamine-bearing dendrimer is covalently attached to the 30 terminusinto a of theBecker sense strand muscular (Figure3)[ 11dystrophy]. After givosiran, (BMD) which is‐ usedlike for condition, the treatment thus increasing the life ofexpectancy acute hepatic porphyriaof DMD (AHP) patients. and was [4]. approved in November 2019 [12], lumasiran ViltepsoTM is the third PMO antisense oligonucleotide used to treat DMD by exon skipping. The first two were eteplirsin and golodirsin for exons 51 and 53, respectively [6,8]. Sharing the same structure as viltolarsen but with an additional four subunits and a triethylene glycol moiety at its 5′ end, golodirsin reached the market in 2019. Exon 51 skipping therapy is applicable to 14% of DMD patients, while exon 53 skipping is applicable to 10%. A multi‐exon skipping approach is now under investigation and is expected to be beneficial for 45% of DMD patients [4]. ViltepsoTM is administered intravenously and has shown some adverse effects, including cough, nasopharyngitis, upper respiratory tract infection, vomiting, and diarrhea [5,9]. Developed in Japan by Nippon Shinyaku and in collaboration with the National Center of Neurology and Psychiatry (NCNP), it was first approved in Japan in March 2020 [5] and received authorization from the FDA on 12 August of the same year [10].

2.2. Lumasiran (OxlumoTM) Lumasiran is a double‐stranded small interference RNA (siRNA). It consists of the sodium salt of a sense and an antisense strands containing some chemically modified units. Moreover, an N‐acetyl galactosamine‐bearing dendrimer is covalently attached to the 3′ terminus of the sense strand (Figure 3) [11]. After givosiran, which is used for the

Pharmaceuticals 2021, 14, 145 5 of 14

treatment of acute hepatic porphyria (AHP) and was approved in November 2019 [12], lumasiranis the second is the drug second to exploit drug enhancedto exploit stabilization enhanced stabilization chemistry (ECT)-GalNAc chemistry (ECT) conjugate‐GalNAc conjugatetechnology technology [12,13]. [12,13].

FigureFigure 3. 3. ChemicalChemical structure ofof lumasiranlumasiran (Oxlumo (OxlumoTMTM).).

LumasiranLumasiran is thethe first first siRNA siRNA drug drug to be to used be forused the treatmentfor the treatment of primary of hyperox- primary hyperoxaluriaaluria type 1 (PH1), type 1 a (PH1), hereditary a hereditary disorder thatdisorder results that in theresults recurrent in the formation recurrent of formation kidney ofand kidney bladder and stones bladder as a stones result of as the a result deposition of the of deposition endogenous of oxalate endogenous as the poorly oxalate soluble as the poorlycalcium soluble oxalate calcium salt (CaOx) oxalate [14 salt]. All (CaOx) previous [14] treatments. All previous addressed treatments mainly addressed the symptoms mainly therather symptoms than the rather primary than cause the [15 primary]. The metabolism cause [15] of. hydroxyprolineThe metabolism amino of hydroxyproline acid produces glyoxylate, which is further metabolized by certain hepatic enzymes to produce oxalate as amino acid produces glyoxylate, which is further metabolized by certain hepatic enzymes final metabolite [16]. Oxalate is normally excreted in urine through the kidneys. Some ge- to produce oxalate as final metabolite [16]. Oxalate is normally excreted in urine through netic mutations cause a decrease in the production or activity of alanine-glyoxylate amino the kidneys. Some genetic mutations cause a decrease in the production or activity of transferase (AGT), the enzyme responsible for breaking down glyoxylate. As a result, alanineglyoxylate,‐glyoxylate and consequently amino transferase the oxalate, (AGT), accumulates the enzyme [15– responsible17]. Lumasiran for (drivenbreaking by down the glyoxylate.galactosamine As a moieties) result, glyoxylate, targets hepatic and cells consequently and silences the the oxalate, gene encoding accumulates for glycolate [15–17]. Lumasiranoxidase (GO) (driven enzyme, by therebythe galactosamine halting its production. moieties) Thetargets depletion hepatic of cells this enzyme and silences reduces the genethe amountsencoding of for glyoxylate glycolate present oxidase and (GO) therefore enzyme, the production thereby halting of the oxalateits production. [17]. The depletionThe drugof this is administeredenzyme reduces subcutaneously the amounts and of its glyoxylate main adverse present effect and is injection therefore site the productionreactions [ 11of]. the It wasoxalate developed [17]. by Alnylam pharma and was approved by the FDA on 23 NovemberThe drug is 2020 administered [18]. subcutaneously and its main adverse effect is injection site reactions [11]. It was developed by Alnylam pharma and was approved by the FDA on 23 November3. Peptides 2020 [18]. The last five years (2016–2020) have witnessed the authorization of 14 peptides, four 3.being Peptides approved this year. These numbers reinforce the importance of peptides in the 64 overallThe pharmaceutical last five years (2016–2020) market. Two have of the witnessed class of 2020 the authorization are radiopharmaceuticals of 14 peptides, ( Cu four and 68Ga), one a disulfide-containing peptide, and the last one the payload of an antibody being approved this year. These numbers reinforce the importance of peptides in the drug conjugate (ADC). Table3 shows the peptides approved by the FDA in the period overall pharmaceutical market. Two of the class of 2020 are radiopharmaceuticals (64Cu 2016–2020. and 68Ga), one a disulfide‐containing peptide, and the last one the payload of an antibody drug3.1. Setmelanotideconjugate (ADC). (Imcivree TableTM) 3 shows the peptides approved by the FDA in the period 2016–2020.Setmelanotide (formerly known as RM-493 or BIM-22493) is an eight-amino acid peptide that forms a cycle through a disulfide bridge between two Cys residues (Figure4) [19].

TheTable two 3. D-amino FDA‐approved acids (red) peptides present between in the 2016 sequence and 2020. and its cyclic structure enhance Active resistance to proteolytic degradation, thereby increasing the half-life of the drug [20,21]. FDA # Ingredient CompanyFurthermore, the positivelyStructure charged aminoIndication acids (blue) are consideredTarget essential for ligand- Approval (Trade Name) receptor recognition and for activity [22]. Setmelanotide is prescribedFree Peptides for the treatment of rare genetic diseases of obesity caused Lixisenatide Sanofiby‐Aventis certain variants of the genes encoding for pro-opiomelanocortinGlucagon (POMC),‐like proprotein 1 44 AAs Diabetes type (II) July 2016 (AdlyxinTM) (Paris,convertase France) subtilisin/kexin type 1 (PCSK1), or leptin receptorpeptide (LEPR) 1 receptor all of which cause

Pharmaceuticals 2021, 14, 145 6 of 14

a deﬁciency of these molecules [23]. Patients with such genetic alterations suffer from excessive or extreme hunger, severe early-onset obesity, and endocrine disorders [24,25].

Table 3. FDA-approved peptides between 2016 and 2020.

Active Ingredient FDA # Company Structure Indication Target (Trade Name) Approval Free Peptides Lixisenatide Sanofi-Aventis Glucagon-like 1 44 AAs Diabetes type (II) July 2016 (AdlyxinTM) (Paris, France) peptide 1 receptor Synergy Plecanatide 16 AAs 2 Chronic idiopathic Guanylate 2 Pharmaceuticals January 2017 (TrulanceTM) disulfides constipation cyclase-C (New York, NY, USA) KAI Pharmaceuticals (South of San Francisco, 7 AAs (all D) 1 Secondary Etelcalcetide CA, USA) disulfide hyperparathyroidism Calcium-sensing 3 February 2017 (ParsabivTM) Amgen intermolecular in adult chronic receptor (Thousand Oaks, L-Cys kidney disease CA, USA) Parathyroid Abaloparatide Radius Health 4 34 AAs Anabolic agent hormone 1 April 2017 (TymloTM) (Boston, MA, USA) receptor Semaglutide Novo Nordisk 31 AAs branched Glucagon-like 5 Diabetes type (II) December 2017 (OzempicTM) (Måløv, Denmark) PEG-fatty acid peptide 1 receptor Diagnosis of adult Growth hormone Macimorelin Aeterna Zentaris 3 residues 6 growth hormone secretagogue December 2017 (MacrilenTM) (Frankfurt, Germany) pseudopeptide deficiency receptor type 1 Septic shock, diabetes Type-1 Angiotensin II La Jolla Pharmaceutical 7 8 AAs mellitus, and acute angiotensin II December 2017 (GiaprezaTM) (San Diego, CA, USA) renal failure receptor University of Arizona Afamelanotide (Tucson, Arizona, USA) Erythropoietic Melanocortin 1 8 13 AAs October 2019 (ScenesseTM) Clinuvel Inc. protoporphyria receptor (Menlo Park, CA, USA) Palatin Technology Bremelanotide (East Windsor, NJ, USA) 7AAs cyclic Hypoactive sexual Melanocortin 9 June 2019 (VyleesiTM) AMAG Pharmaceuticals sidechain to tail desire disorder receptors (Waltham, MA, USA) Rhythm Setmelanotide 8AAs Cyclic Melanocortin-4 10 Pharmaceuticals Obesity November 2020 (ImcivreeTM) disulfide receptor (Boston, MA, USA) Peptide-Chelator-radionuclide conjugates [177Lu]-DOTA- Advanced Accelerator Gastroenteropancreatic 7AAs Cyclic Somatostatin 11 TATE Applications neuroendocrine January 2018 disulfide receptor (LutatheraTM) (Millburn, NJ, USA) tumors University of Iowa A 7AAs Cyclic Somatostatin 12 [68Ga]-DOTATOC Health Care PET imaging August 2019 disulfide receptor (Iowa City, IA, USA) [64Cu]-DOTATATE Radiomedix Inc. A 7AAs Cyclic Somatostatin 13 PET imaging September 2020 (DetectnetTM) (Housten, TX, USA) disulfide receptor Diagnosis of recurrent Prostate-specific University of California Peptidomemitic 14 [68Ga]-PSMA-11 prostate carcinoma by membrane December 2020 (Oakland, CA, USA) 2AAs urea linked PET antigen Peptides in ADC’s Enfortumab Astellas Pharma 5 residues with 15 vedotin-ejfv Urothelial cancers Nectin-4 receptor December 2019 (Northbrook, IL, USA) γ-AA (PadcevTM) Polatuzumab Roche Refractory diffuse CD79b receptor 5 residues with 16 vedotin-piiq (South of San Francisco, large B-cell expressed in June 2019 γ-AA (PolivyTM) CA, USA) lymphoma mature Bcells Belantamab GlaxoSmithKline 5 residues with Relapsed or refractory B-cell maturation 17 mafodotin-blmf August 2020 (Brentford, UK) γ-AA multiple myeloma antigen (BlenrepTM) Pharmaceuticals 2021, 14, 145 7 of 14

Pharmaceuticals 2021, 14, 145 7 of 14 [20,21]. Furthermore, the positively charged amino acids (blue) are considered essential for ligand‐receptor recognition and for activity [22].

FigureFigure 4. Chemical structure of setmelanotide (Imcivree TMTM).).

Setmelanotide actsis prescribed as a selective for melanocortin-4the treatment (MC4)of rare receptor genetic agonistdiseases and of presentsobesity acaused 20-fold by higher certain potency variants than of the the endogenous genes encoding agonist forα pro-MSH‐opiomelanocortin [19,26]. In the brain, (POMC), MC4 receptorsproprotein are convertase involved subtilisin/kexin in regulating hunger type 1 and (PCSK1), satiety, or in leptin addition receptor to energy (LEPR) expendi- all of turewhich [27 cause]. Deficiency a deficiency of POMC, of these PCSK1, molecules and [23]. LEPR Patients cause thewith MC4 such receptor genetic pathwayalterations to besuffer insufficiently from excessive activated. or extreme Therefore, hunger, the binding severe of early setmelanotide‐onset obesity, to the and MC4 endocrine receptor reactivatesdisorders [24,25]. the pathway, inducing a reduction of hunger that promotes weight loss due to decreasedSetmelanotide caloric intake acts as and a selective increased melanocortin energy expenditure.‐4 (MC4) Afterreceptor receiving agonist setmelanotide, and presents aa noticeable20‐fold higher reduction potency in body than weight,the endogenous as well as agonist reversing α‐MSH hyperphagia, [19,26]. In is observedthe brain, within MC4 45receptors to 61 weeks are involved [22,28]. in regulating hunger and satiety, in addition to energy expenditure [27]. SetmelanotideDeficiency of POMC, shows high PCSK1, efficacy and withLEPR fewer cause side the effects, MC4 receptor especially pathway those related to be toinsufficiently hypertension activated. and adverse Therefore, cardiovascular the binding effects, of setmelanotide which were to observed the MC4 in receptor the first generationreactivates MC4Rthe pathway, agonists, inducing such as a LY2112688reduction of [22 hunger,27,29]. that promotes weight loss due to decreasedIt is administered caloric intake subcutaneously and increased energy and common expenditure. adverse After effects receiving include setmelanotide, skin hyperpigmentation,a noticeable reduction nausea, headache,in body weight, diarrhea, as abdominalwell as reversing pain, back hyperphagia, pain, fatigue, is observed vomiting, depression,within 45 to upper 61 weeks respiratory [22,28]. tract infection, and spontaneous penile erection [23]. It also has severalSetmelanotide warnings shows and precautions,high efficacy suchwith asfewer disturbance side effects, of sexualespecially arousal, those depression related to andhypertension suicidal ideation, and adverse skin pigmentation cardiovascular and darkeningeffects, which of pre-existing were observed nevi, risk in ofthe serious first adversegeneration reactions MC4R in agonists, neonates, such and as low LY2112688 birth weight [22,27,29]. infants due to benzyl alcohol preservative [It23 ].is It administered was developed subcutaneously by Rhythm Pharmaceuticals and common and adverse was approved effects byinclude the FDA skin on 25hyperpigmentation, November 2020 [30 nausea,]. headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection 64 TM 3.2.[23]. ItCu also -DOTATATE has several (Detectnet warnings and) precautions, such as disturbance of sexual arousal, depression64Cu -DOTATATE and suicidal is ideation, composed skin of pigmentation the radionuclide and64 darkeningCu (purple) of chelatedpre‐existing by DOTA nevi, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticrisk of serious adverse reactions in neonates, and low acid) birth (blue), weight which infants is due linked to benzyl to the somatostatinalcohol preservative analog octreotate[23]. It was peptide developed (black) (Figureby Rhythm5). It isPharmaceuticals a radioactive diagnostic and was agentapproved to be by used the withFDA positronon 25 November emission 2020 tomography [30]. (PET) for the localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adults [31]. Although 64Cu was previously3.2. 64Cu ‐DOTATATE used in nuclear (Detectnet medicineTM) as 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM)64Cu ‐DOTATATE for PET imaging is composed in head of and the neckradionuclide cancer [32 64],Cu and (purple) hypoxic chelated myocardium by DOTA [33], 64 64 and(1,4,7,10 in ‐Cu-labeledtetraazacyclododecane anti-colorectal‐1,4,7,10 carcinoma‐tetraacetic mAbs acid) (MAb (blue), 1A3) [which34], Cu-DOTATATEis linked to the is 64 consideredsomatostatin the analog first FDA-approved octreotate peptideCu-labeled (black) radiopharmaceutical(Figure 5). It is a radioactive for Positron diagnostic emission tomography–computed tomography (PET/CT) imaging.

Pharmaceuticals 2021, 14, 145 8 of 14

agent to be used with positron emission tomography (PET) for the localization of somatostatin receptor‐positive neuroendocrine tumors (NETs) in adults [31]. Although 64Cu was previously used in nuclear medicine as 64Cu‐diacetyl‐bis(N4‐ methylthiosemicarbazone) (64Cu‐ATSM) for PET imaging in head and neck cancer [32], and hypoxic myocardium [33], and in 64Cu‐labeled anti‐colorectal carcinoma mAbs (MAb 1A3) [34], 64Cu‐DOTATATE is considered the first FDA‐approved 64Cu‐labeled Pharmaceuticals 2021, 14, 145 8 of 14 radiopharmaceutical for Positron emission tomography–computed tomography (PET/CT) imaging.

Figure 5. ChemicalFigure structure 5. Chemical of 64Cu structure ‐DOTATATE of 64Cu -DOTATATE (Detectnet (DetectnetTM). TM). Among the most important Cu radioisotopes, 64Cu is considered the most convenient 64 Among thefor most clinical important applications Cu radioisotopes, since it has an intermediateCu is considered half-life the of most 12.7 hconvenient and can decay for clinical applicationsvia various since routes, it includinghas an intermediate electron capture, half beta‐life emission, of 12.7 h and and positron can decay emission. via Its various routes,low including positron electron energy allows capture, high beta quality emission, and high-resolution and positron images, emission. plus the Its absence low of positron energyabundant allows gamma high emissionquality and (in contrast high‐resolution to other positron images, emitters), plus athe type absence of emission of that abundant gammamay emission also impair (in the contrast imaging to process other [positron34]]. emitters), a type of emission that 64 68 may also impair the Cu-DOTATATEimaging process outperforms [34]]. Ga-DOTATOC, which was approved in 2019 [8]. This is explained by the fact that the radionuclide of 68Ga-DOTATOC has a shorter half-life 64Cu‐DOTATATE outperforms 68Ga‐DOTATOC, which was approved in 2019 [8]. (68 min), and its images are of lower resolution as a result of its higher positron energy [8]. 68 This is explainedA study by the by fact Johnbeck that the et al. radionuclide showed that of64Cu-DOTATATEGa‐DOTATOC gave has improved a shorter and half greater‐ life (68 min), anddetection its images of lesions are of than lower68Ga-DOTATOC resolution as [35 a]. result Furthermore, of its higher another positron study carried energy out by [8]. A study byPfeifer Johnbeck et al. et also al. demonstratedshowed that a64 higherCu‐DOTATATE spatial resolution gave improved of the images and taken greater by 64 Cu- detection of lesionsDOTATATE than 68 versusGa‐DOTATOC those by 111 [35].In-DTPA-octreotide Furthermore, and another also reported study carried greater detectionout by of 64 Pfeifer et al. alsolesions demonstrated by Cu-DOTATATE a higher [36 spatial]. resolution of the images taken by 64Cu‐ 64Cu-DOTATATE is administered intravenously and has some adverse effects, includ- DOTATATE versus those by 111In‐DTPA‐octreotide and also reported greater detection of ing nausea, vomiting, and flushing [37]. It was developed by Radiomedix inc. and was 64 lesions by Cuapproved‐DOTATATE by the [36]. FDA on 3 September 2020 [38]. 64Cu‐DOTATATE is administered intravenously and has some adverse effects, including nausea,3.3. 68vomiting,Ga-PSMA-11 and flushing [37]. It was developed by Radiomedix inc. and was approved by the68Ga-PSMA-11 FDA on 3 September or (68Ga gozetotide) 2020 [38]. consists of the lipophilic acyclic chelator HBED-CC (N,N0-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamineN,N0- diacetic acid) (blue), 3.3. 68Ga‐PSMAwhich‐11 is coordinated to the radionuclide 68Ga (purple) and a urea-based peptidomimetic HO-Glu-NH-CO-NH-Lys-OH (black). Both moieties are linked by a 6-aminohexanoic acid 68Ga‐PSMA‐11 or (68Ga gozetotide) consists of the lipophilic acyclic chelator HBED‐ (green) through the side chain (ε-NH2) of the Lys residue (Figure6)[39,40]. CC (N,N′‐bis [2‐hydroxy68Ga-PSMA-11‐5‐(carboxyethyl)benzyl] is indicated for PET imagingethylenediamineN,N of prostate-specific′‐ diacetic membrane acid) antigen (blue), which (PSMA)-positiveis coordinated lesions to the in men radionuclide with prostate 68 cancerGa (purple) [41]. It is theand first a PETurea drug‐based to trace peptidomimeticand HO detect‐Glu prostate‐NH‐CO carcinoma‐NH‐Lys relapses‐OH (black). and metastases Both moieties with high are contrastlinked by targetinga 6‐ aminohexanoicthe acid extracellular (green) through domain ofthe the side PSMA. chain It is(ε‐ aNH transmembrane2) of the Lys glycoprotein residue (Figure expressed 6) in [39,40]. the prostate, kidneys, small intestines, salivary glands, and brain [39,40]. However, it is overexpressed 100- to 1000-fold in prostate tumors compared to other tissues [40,42], thereby offering a specific target for diagnostic and therapeutic purposes.

Pharmaceuticals 2021, 14, 145 9 of 14

The active binding site of PSMA combines a hydrophilic motif that interacts with the urea-based inhibitor Glu-NH-CO-NH-Lys- (its role being to drive the radionuclide to the cancer cells with high specificity), and a lipophilic pocket. Thus, the lipophilic nature of the HBED-CC chelator has a positive impact on the binding properties. Moreover, the chelator has shown high efficiency to complex with Ga(III) [40]. Compared to the corresponding DOTA-conjugate of the same pharmacophore, the HBED-CC chelator-conjugate demon- Pharmaceuticals 2021, 14, 145 strated improved PET imaging performance as it showed reduced unspecific binding and 9 of 14 considerably higher specificity, fast blood, and organ clearances, and low accumulation in liver [40].

68 FigureFigure 6. 6.Chemical Chemical structure structure of Ga-PMSA-11. of 68Ga‐PMSA‐11. Other conjugates, i.e., labeled antibodies, can also be used for targeting the cytoplasmic PMSA,68Ga such‐PSMA as 111In-capromab‐11 is indicated pendetide for (ProstaScint PET imaging®), which of is prostate used for scintigraphy.‐specific membrane antigen (PSMA)However,‐ accessibilitypositive lesions to the cytoplasmic in men with PMSA prostate compared cancer to the [41]. extracellular It is the protein first PET drug to trace is lower, especially for large molecules. Furthermore, the long half-life of 111In and, con- andsequently, detect the prostate long length carcinoma of exposure relapses to radiation and and metastases the prolonged with circulation high contrast of the by targeting the extracellularantibody in the body,domain which of causes the highPSMA. background It is a noise,transmembrane make PET imaging glycoprotein with 68Ga expressed in the prostate,more favorable kidneys, than the small scintigraphic intestines, method [salivary42]. glands, and brain [39,40]. However, it is 68Ga-PSMA-11 is administered intravenously and has some adverse effects, including overexpressednausea, diarrhea, and100 dizziness‐ to 1000 [41‐fold]. It was in developedprostate bytumors the University compared of California to other tissues [40,42], thereby(Los Angeles) offering and was a specific approved target by the FDA for ondiagnostic 1 December and 2020 therapeutic [43]. purposes. The active binding site of PSMA combines a hydrophilic motif that interacts with the 3.4. Belantamab Mafodotin-Blmf (BlenrepTM) urea‐based inhibitor Glu‐NH‐CO‐NH‐Lys‐ (its role being to drive the radionuclide to the Belantamab mafodotin-blmf is the ninth ADC approved by the FDA. It is composed cancerby afucosylated cells with humanized high immunoglobulinspecificity), and G1 monoclonala lipophilic antibody pocket. (IgG1) Thus, (blue) the and lipophilic nature of thea peptide HBED payload‐CC calledchelator monomethyl has a positive auristatin Fimpact (MMAF) on (red) the [44 binding]. The two properties. units are Moreover, the chelatorlinked by thehas protease-resistant shown high maleimidohexanoic efficiency to linkercomplex (green) with (Figure Ga(III)7). [40]. Compared to the The afucosylated IgG1 antibody, which targets B-cell maturation antigen (BCMA) [45], correspondingis produced by recombinant DOTA‐ DNAconjugate technology of inthe a mammalian same pharmacophore, cell line (Chinese Hamster the HBED‐CC chelator‐ conjugateOvary), whereas demonstrated the payload-linker improved is prepared PET synthetically. imaging performance Final attachment as is byit showed reduced unspecificconjugation of binding the maleimide and toconsiderably the Cys residues higher on the antibody. specificity, To this fast end, blood, a controlled and organ clearances, andreduction low of accumulation various interchain in disulﬁde liver [40]. bonds on the antibody must be achieved to prevent its denaturation. Usually, this step is done using the reducing agent tris-(2-carboxyethyl)- phosphineOther (TCEP), conjugates, then the free i.e., thiol labeled of such Cys antibodies, residues react can with also maleimides be used under for targeting the cytoplasmic PMSA, such as 111In‐capromab pendetide (ProstaScint®), which is used for scintigraphy. However, accessibility to the cytoplasmic PMSA compared to the extracellular protein is lower, especially for large molecules. Furthermore, the long half‐ life of 111In and, consequently, the long length of exposure to radiation and the prolonged circulation of the antibody in the body, which causes high background noise, make PET imaging with 68Ga more favorable than the scintigraphic method [42]. 68Ga‐PSMA‐11 is administered intravenously and has some adverse effects, including nausea, diarrhea, and dizziness [41]. It was developed by the University of California (Los Angeles) and was approved by the FDA on 1 December 2020 [43].

3.4. Belantamab Mafodotin‐Blmf (BlenrepTM) Belantamab mafodotin‐blmf is the ninth ADC approved by the FDA. It is composed by afucosylated humanized immunoglobulin G1 monoclonal antibody (IgG1) (blue) and a peptide payload called monomethyl auristatin F (MMAF) (red) [44]. The two units are linked by the protease‐resistant maleimidohexanoic linker (green) (Figure 7).

Pharmaceuticals 2021, 14, 145 10 of 14

Pharmaceuticals 2021, 14, 145 10 of 14 very mild conditions [46]. The conjugate obtained carries approximately four molecules of MMAF per antibody molecule.

Figure 7. Chemical structure of belantamab mafodotin‐blmf (BlenrepTM).

The afucosylated IgG1 antibody, which targets B‐cell maturation antigen (BCMA) [45], is produced by recombinant DNA technology in a mammalian cell line (Chinese Hamster Ovary), whereas the payload‐linker is prepared synthetically. Final attachment is by conjugation of the maleimide to the Cys residues on the antibody. To this end, a controlled reduction of various interchain disulfide bonds on the antibody must be achieved to prevent its denaturation. Usually, this step is done using the reducing agent tris‐(2‐carboxyethyl)‐phosphine (TCEP), then the free thiol of such Cys residues react with

maleimides under very mild conditions [46]. The conjugate obtained carries TM FigureFigureapproximately 7. 7. ChemicalChemical structure structure four molecules of belantamabbelantamab of MMAF mafodotin-blmf mafodotin per antibody‐blmf (Blenrep (Blenrep molecule.).TM). MMAF is a synthetically modified analog of natural dolastatin 10 (Figure 8), which TheMMAF afucosylated is a synthetically IgG1 antibody, modiﬁed which analog oftargets natural B‐ dolastatincell maturation 10 (Figure antigen8), which (BCMA) acts asas anan antimitoticantimitotic agent, agent, inhibiting inhibiting cell cell division division by by blocking blocking the the polymerization polymerization of of [45], is produced by recombinant DNA technology in a mammalian cell line (Chinese tubulin [[45].45]. DueDue toto the the high high cytotoxicity cytotoxicity of of both both dolastatin dolastatin 10 10 and and its its synthetic synthetic analogs, analogs, Hamsterthey cannot Ovary), bebe administeredadministered whereas the directly directlypayload but but‐linker have have to is to be prepared be delivered delivered synthetically. and and deposited deposited Final at theat attachmentthe tumor tumor is site.by conjugation The maleimidohexanoyl of the maleimide linkerlinker to is is considered theconsidered Cys residues non-cleavable non‐cleavable on the becauseantibody. because it isit To protease-is thisprotease end,‐ a controlledresistant. Thus,reductionThus, catabolismcatabolism of various of of the the mAbinterchain mAb backbones backbones disulfide is is required required bonds to to releaseon release the the antibody the drug drug [47 must],[47], in in be achievedwhich aa to cysteine-adductcysteine prevent‐adduct its denaturation. of of the the linker-MMAF linker ‐Usually,MMAF derivative derivative this step is is releasedis donereleased using [44 [44].]. the reducing agent tris‐(2‐carboxyethyl)‐phosphine (TCEP), then the free thiol of such Cys residues react with maleimides under very mild conditions [46]. The conjugate obtained carries approximately four molecules of MMAF per antibody molecule. MMAF is a synthetically modified analog of natural dolastatin 10 (Figure 8), which acts as an antimitotic agent, inhibiting cell division by blocking the polymerization of tubulin [45]. Due to the high cytotoxicity of both dolastatin 10 and its synthetic analogs, they cannot be administered directly but have to be delivered and deposited at the tumor site. The maleimidohexanoyl linker is considered non‐cleavable because it is protease‐ resistant. Thus, catabolism of the mAb backbones is required to release the drug [47], in which a cysteine‐adduct of the linker‐MMAF derivative is released [44].

Figure 8.8. ChemicalChemical structure structure of: of: (A (A) natural) natural dolastatin dolastatin 10; 10; (B) ( monomethylB) monomethyl auristatin auristatin F (MMAF); F (MMAF); and (andC) monomethyl (C) monomethyl auristatin auristatin E (MMAE). E (MMAE). Differences Differences from the from natural the natural molecule molecule are shown are in shown red [44 in]. red [44]. The ADCs approved in 2019 (Padcev and Polivy) used a monomethyl auristatin E (MMAE) analog as payload [8], which is more membrane-permeable than MMAF [48]. On the other hand, MMAF is more hydrophilic and this property decreases aggregation tendencies [48]. Most importantly, MMAF has lower bystander activities (drug release to neighboring antigen-negative cells or tissues) than MMAE [49]. Finally, MMAF shows im-

Figure 8. Chemical structure of: (A) natural dolastatin 10; (B) monomethyl auristatin F (MMAF); and (C) monomethyl auristatin E (MMAE). Differences from the natural molecule are shown in red [44].

Pharmaceuticals 2021, 14, 145 11 of 14

proved pharmacokinetics and also a better therapeutic index [50] (Figure8). Furthermore, the (Padcev and Polivy) were built using a cleavable linker. Of note, in contrast to ADCs with cleavable linkers, those with non-cleavable linkers have an extended plasma half-life as their bonds are not susceptible to lysosomal processes [51]. Belantamab mafodotin-blmf is prescribed for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomod- ulatory agent [45]. Upon the binding of the mAb to the surface of the BCMA cell, belantamab mafodotin-blmf is internalized and MMAF is released via the proteolysis of the mAb component (as the linker is non-cleavable), ending with apoptosis [52]. Belantamab mafodotin-blmf is administered intravenously every three weeks [45,52]. It has various adverse effects: ≥20% are keratopathy (corneal epithelium change on eye exam), decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue; and ≥5% are decreased platelets, decreased lymphocytes, decreased hemoglobin, decreased neutrophils, increased creatinine, and increased gamma-glutamyl transferase. Belantamab mafodotin-blmf was developed by GlaxoSmithKline and approved by the FDA on 5 August 2020 [53] and by the European Medicines Agency (EMA) on 25 August 2020 [52].

4. Conclusions A total of 6 out of the 53 drugs approved by the FDA in 2020 belong to the TIDES category. The continued authorization of these chemical entities highlights their efficacy and safety profiles, and therefore the growing relevance of this family of drugs. The peptide market has been strengthened over many years and this trend is expected to continue. During the preparation of this manuscript, it was disclosed that PlitidepsinTM (aplidin), a peptide of marine origin approved a few years ago in Australia for multiple myeloma [54], shows potent preclinical efficacy against SARS-CoV-2 [55] and is expected to enter clinical phase III very shortly. Futhermore, on 22 January 2021, voclosporin (LupkynisTM) was approved for the treatment of treat lupus nephritis [56]. Voclosporin is cyclosporine analogue. Several newcomers to the oligonucleotide family, namely siRNAs and antisense oligonucleotides, are expected to join the pharmaceutical market arena shortly. Inclisiran, a siRNA for the treatment of hypercholesterolemia, was developed by Novartis under a license in collaboration with Alnylam Pharmaceuticals. It has been approved in Europe and is expected to receive authorization from the FDA soon [13,57,58]. Early members of the oligonucleotide drugs family demonstrated their efficacy in the treatment of some rare hereditary disorders. However, new promising candidates are now widening the applicability of this family for the treatment of more common diseases. The applications of TIDES as drugs will undoubtedly continue to play an important role as drugs, as they are fuelled by the continuous research undertaken in both the academic and industrial setting.

Author Contributions: All authors participated in the search for information and in writing the manuscript, and approved the final version. All authors have read and agreed to the published version of the manuscript. Funding: This work was funded in part by the following: the National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); MINECO, (RTI2018-093831-B-100), and the Generalitat de Catalunya (2017 SGR 1439) (Spain). Conflicts of Interest: The authors declare no conflict of interest. Pharmaceuticals 2021, 14, 145 12 of 14

References 1. Mullard, A. 2020 FDA drug approvals. Nat. Rev. Drug Discov. 2021.[CrossRef] 2. De la Torre, B.G.; Albericio, F. The pharmaceutical industry in 2020. An analysis of FDA drug approvals from the perspective of molecules. Molecules 2021, 26, 627. [CrossRef] 3. Defitelio Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf (accessed on 28 January 2021). 4. Dzierlega, K.; Yokota, T. Optimization of antisense-mediated exon skipping for duchenne muscular dystrophy. Gene Ther. 2020, 27, 407–416. [CrossRef][PubMed] 5. Dhillon, S. Viltolarsen: First approval. Drugs 2020, 80, 1027–1031. [CrossRef] 6. Iftikhar, M.; Frey, J.; Shohan, M.J.; Malek, S.; Mousa, S.A. Current and emerging therapies for duchenne muscular dystrophy and spinal muscular atrophy. Pharmacol. Ther. 2020, 107719. [CrossRef] 7. Komaki, H.; Takeshima, Y.; Matsumura, T.; Ozasa, S.; Funato, M.; Takeshita, E.; Iwata, Y.; Yajima, H.; Egawa, Y.; Toramoto, T.; et al. Viltolarsen in japanese duchenne muscular dystrophy patients: A phase 1/2 study. Ann. Clin. Transl. Neurol. 2020.[CrossRef] 8. Al Shaer, D.; Al Musaimi, O.; Albericio, F.; de la Torre, B.G. 2019 FDA tides (peptides and oligonucleotides) harvest. Pharmaceuticals 2020, 13, 40. [CrossRef][PubMed] 9. Viltepso Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212154Orig1s000lbl.pdf (accessed on 16 January 2021). 10. Viltepso Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/212154Orig1s000 ltr.pdf (accessed on 16 January 2021). 11. Oxlumo Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214103lbl.pdf (accessed on 16 January 2021). 12. Scott, L.J. Givosiran: First approval. Drugs 2020, 80, 335–339. [CrossRef] 13. Debacker, A.J.; Voutila, J.; Catley, M.; Blakey, D.; Habib, N. Delivery of oligonucleotides to the liver with galnac: From research to registered therapeutic drug. Mol. Ther. 2020, 28, 1759–1771. [CrossRef] 14. Cochat, P.; Rumsby, G. Primary hyperoxaluria. N. Engl. J. Med. 2013, 369, 649–658. [CrossRef][PubMed] 15. Dindo, M.; Conter, C.; Oppici, E.; Ceccarelli, V.; Marinucci, L.; Cellini, B. Molecular basis of primary hyperoxaluria: Clues to innovative treatments. Urolithiasis 2019, 47, 67–78. [CrossRef] 16. Liebow, A.; Li, X.; Racie, T.; Hettinger, J.; Bettencourt, B.R.; Najafian, N.; Haslett, P.; Fitzgerald, K.; Holmes, R.P.; Erbe, D.; et al. An investigational rnai therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. J. Am. Soc. Nephrol. 2017, 28, 494–503. [CrossRef] 17. Scott, L.J.; Keam, S.J. Lumasiran: First approval. Drugs 2021.[CrossRef][PubMed] 18. Oxlumo Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/214103Orig1s000 ltr.pdf (accessed on 16 January 2021). 19. Falls, B.A.; Zhang, Y. Insights into the allosteric mechanism of setmelanotide (rm-493) as a potent and first-in-class melanocortin-4 receptor (mc4r) agonist to treat rare genetic disorders of obesity through an in silico approach. ACS Chem. Neurosci. 2019, 10, 1055–1065. [CrossRef] 20. Al Musaimi, O.; Al Shaer, D.; de la Torre, B.G.; Albericio, F. 2017 FDA peptide harvest. Pharmaceuticals 2018, 11, 42. [CrossRef] [PubMed] 21. Brayden, D.J.; Hill, T.A.; Fairlie, D.P.; Maher, S.; Mrsny, R.J. Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches. Adv. Drug. Deliv. Rev. 2020, 157, 2–36. [CrossRef][PubMed] 22. Clément, K.; Biebermann, H.; Farooqi, I.S.; Van der Ploeg, L.; Wolters, B.; Poitou, C.; Puder, L.; Fiedorek, F.; Gottesdiener, K.; Kleinau, G.; et al. Mc4r agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat. Med. 2018, 24, 551–555. [CrossRef][PubMed] 23. Imcivree Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213793s000lbl.pdf (accessed on 16 January 2021). 24. Ayers, K.L.; Glicksberg, B.S.; Garfield, A.S.; Longerich, S.; White, J.A.; Yang, P.; Du, L.; Chittenden, T.W.; Gulcher, J.R.; Roy, S.; et al. Melanocortin 4 receptor pathway dysfunction in obesity: Patient stratification aimed at mc4r agonist treatment. J. Clin. Endocrinol. Metab. 2018, 103, 2601–2612. [CrossRef] 25. Clément, K.; Vaisse, C.; Lahlou, N.; Cabrol, S.; Pelloux, V.; Cassuto, D.; Gourmelen, M.; Dina, C.; Chambaz, J.; Lacorte, J.M.; et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998, 392, 398–401. [CrossRef] 26. Collet, T.H.; Dubern, B.; Mokrosinski, J.; Connors, H.; Keogh, J.M.; Mendes de Oliveira, E.; Henning, E.; Poitou-Bernert, C.; Oppert, J.M.; Tounian, P.; et al. Evaluation of a melanocortin-4 receptor (mc4r) agonist (setmelanotide) in mc4r deficiency. Mol. Metab. 2017, 6, 1321–1329. [CrossRef] 27. Haws, R.; Brady, S.; Davis, E.; Fletty, K.; Yuan, G.; Gordon, G.; Stewart, M.; Yanovski, J. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in bardet-biedl syndrome. Diabetes Obes. Metab. 2020, 22, 2133–2140. [CrossRef] 28. Kühnen, P.; Clément, K.; Wiegand, S.; Blankenstein, O.; Gottesdiener, K.; Martini, L.L.; Mai, K.; Blume-Peytavi, U.; Grüters, A.; Krude, H. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N. Eng. J. Med. 2016, 375, 240–246. [CrossRef][PubMed] Pharmaceuticals 2021, 14, 145 13 of 14

29. Kievit, P.; Halem, H.; Marks, D.L.; Dong, J.Z.; Glavas, M.M.; Sinnayah, P.; Pranger, L.; Cowley, M.A.; Grove, K.L.; Culler, M.D. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes 2013, 62, 490–497. [CrossRef] 30. Imcivree Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/213793Orig1s0 00ltr.pdf (accessed on 16 January 2021). 31. Gutfilen, B.; Souza, S.A.; Valentini, G. Copper-64: A real theranostic agent. Drug Des. Devel. Ther. 2018, 12, 3235–3245. [CrossRef] [PubMed] 32. Grassi, I.; Nanni, C.; Cicoria, G.; Blasi, C.; Bunkheila, F.; Lopci, E.; Colletti, P.M.; Rubello, D.; Fanti, S. Usefulness of 64cu-atsm in head and neck cancer: A preliminary prospective study. Clin. Nucl. Med. 2014, 39, e59–e63. [CrossRef] 33. Handley, M.G.; Medina, R.A.; Mariotti, E.; Kenny, G.D.; Shaw, K.P.; Yan, R.; Eykyn, T.R.; Blower, P.J.; Southworth, R. Cardiac hypoxia imaging: Second-generation analogues of 64cu-atsm. J. Nucl. Med. 2014, 55, 488–494. [CrossRef][PubMed] 34. Jalilian, A.R.; Osso, J., Jr. The current status and future of theranostic copper-64 radiopharmaceuticals. Iran. J. Nucl. Med. 2017, 25, 1–10. Available online: https://irjnm.tums.ac.ir/article_23081.html (accessed on 1 February 2021). 35. Johnbeck, C.B.; Knigge, U.; Loft, A.; Berthelsen, A.K.; Mortensen, J.; Oturai, P.; Langer, S.W.; Elema, D.R.; Kjaer, A. Head-to-head comparison of (64)cu-dotatate and (68)ga-dotatoc pet/ct: A prospective study of 59 patients with neuroendocrine tumors. J. Nucl. Med. 2017, 58, 451–457. [CrossRef] 36. Pfeifer, A.; Knigge, U.; Mortensen, J.; Oturai, P.; Berthelsen, A.K.; Loft, A.; Binderup, T.; Rasmussen, P.; Elema, D.; Klausen, T.L.; et al. Clinical pet of neuroendocrine tumors using 64cu-dotatate: First-in-humans study. J. Nucl. Med. 2012, 53, 1207–1215. [CrossRef] 37. Detectnet Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213227s000lbl.pdf (accessed on 16 January 2021). 38. Detectnet Aprroval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/213227Orig1s0 00ltr.pdf (accessed on 16 January 2021). 39. Minamimoto, R.; Hancock, S.; Schneider, B.; Chin, F.T.; Jamali, M.; Loening, A.; Vasanawala, S.; Gambhir, S.S.; Iagaru, A. Pilot comparison of (6)(8)ga-rm2 pet and (6)(8)ga-psma-11 pet in patients with biochemically recurrent prostate cancer. J. Nucl Med. 2016, 57, 557–562. [CrossRef] 40. Eder, M.; Schafer, M.; Bauder-Wust, U.; Hull, W.E.; Wangler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68ga-complex lipophilicity and the targeting property of a urea-based psma inhibitor for pet imaging. Bioconjug. Chem. 2012, 23, 688–697. [CrossRef] 41. Gallium 68 psma-11 Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212642s000lbl. pdf (accessed on 16 January 2021). 42. Afshar-Oromieh, A.; Malcher, A.; Eder, M.; Eisenhut, M.; Linhart, H.G.; Hadaschik, B.A.; Holland-Letz, T.; Giesel, F.L.; Kratochwil, C.; Haufe, S.; et al. Pet imaging with a [68ga]gallium-labelled psma ligand for the diagnosis of prostate cancer: Biodistribution in humans and first evaluation of tumour lesions. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 486–495. [CrossRef] 43. Gallium 68 psma-11 Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/212 642Orig1s000ltr.pdf (accessed on 16 January 2021). 44. Bouchard, H.; Viskov, C.; Garcia-Echeverria, C. Antibody-drug conjugates-a new wave of cancer drugs. Bioorg. Med. Chem. Lett. 2014, 24, 5357–5363. [CrossRef][PubMed] 45. Blenrep Drug Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761158s000lbl.pdf (accessed on 16 January 2021). 46. Matsuda, Y.; Mendelsohn, B.A. An overview of process development for antibody-drug conjugates produced by chemical conjugation technology. Expert. Opin. Biol. Ther. 2020.[CrossRef][PubMed] 47. Han, T.H.; Zhao, B. Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab. Dispos. 2014, 42, 1914–1920. [CrossRef] 48. Park, M.H.; Lee, B.I.; Byeon, J.J.; Shin, S.H.; Choi, J.; Park, Y.; Shin, Y.G. Pharmacokinetic and metabolism studies of monomethyl auristatin f via liquid chromatography-quadrupole-time-of-flight mass spectrometry. Molecules 2019, 24, 2754. [CrossRef] 49. Moquist, P.N.; Bovee, T.D.; Waight, A.B.; Mitchell, J.A.; Miyamoto, J.B.; Mason, M.L.; Emmerton, K.K.; Stevens, N.; Balasubrama- nian, C.; Simmons, J.K.; et al. Novel auristatins with high bystander and cytotoxic activities in drug-efflux positive tumor models. Mol. Cancer Ther. 2020.[CrossRef] 50. Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sabourin, C. Antibody-drug conjugates: The last decade. Pharmaceuticals 2020, 13, 245. [CrossRef][PubMed] 51. Jain, N.; Smith, S.W.; Ghone, S.; Tomczuk, B. Current adc linker chemistry. Pharm. Res. 2015, 32, 3526–3540. [CrossRef] 52. Tzogani, K.; Penttilä, K.; Lähteenvuo, J.; Lapveteläinen, T.; Lopez Anglada, L.; Prieto, C.; Garcia-Ochoa, B.; Enzmann, H.; Gisselbrecht, C.; Delgado, J.; et al. Ema review of belantamab mafodotin (blenrep) for the treatment of adult patients with relapsed/refractory multiple myeloma. Oncologist 2020.[CrossRef] 53. Blenrep Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/761158Orig1s000 ltr.pdf (accessed on 16 January 2021). 54. El Bairi, K.; Trapani, D.; Petrillo, A.; Le Page, C.; Zbakh, H.; Daniele, B.; Belbaraka, R.; Curigliano, G.; Afqir, S. Repurposing anticancer drugs for the management of covid-19. Eur. J. Cancer 2020, 141, 40–61. [CrossRef][PubMed] Pharmaceuticals 2021, 14, 145 14 of 14

55. White, K.M.; Rosales, R.; Yildiz, S.; Kehrer, T.; Miorin, L.; Moreno, E.; Jangra, S.; Uccellini, M.B.; Rathnasinghe, R.; Coughlan, L.; et al. Plitidepsin has potent preclinical efﬁcacy against sars-cov-2 by targeting the host protein eef1a. Science 2021.[CrossRef] 56. Lupkynis Approval Letter. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213716Orig1s0 00ltr.pdf (accessed on 1 February 2021). 57. Novartis Successfully Completes Acquisition of the Medicines Company, Adding a Potentially First-in-Class, Investigational Cholesterol-Lowering Therapy Inclisiran. Available online: https://www.novartis.com/news/media-releases/novartis- successfully-completes-acquisition-medicines-company-adding-potentially-ﬁrst-class-investigational-cholesterol-lowering- therapy-inclisiran (accessed on 16 January 2021). 58. New Novartis Data for Inclisiran Shows Effective and Sustained ldl-c Reduction at 17 Regardless of Age or Gender. Available online: https://www.dicardiology.com/content/new-novartis-data-inclisiran-shows-effective-and-sustained-ldl-c-reduction- 17-regardless-age (accessed on 16 January 2021).