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Review The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Beatriz G. de la Torre 1,* and Fernando Albericio 2,3,*

1 KRISP, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa 2 School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa 3 CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain * Correspondence: [email protected] (B.G.d.l.T.); [email protected] (F.A.); Tel.: +27-61400-9144 (F.A.)  Received: 27 January 2020; Accepted: 7 February 2020; Published: 9 February 2020 

Abstract: During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

Keywords: antibodies; antibody drug conjugate; API; biologics; chemical entities; drug discovery; fluorine-based drugs; natural products; oligonucleotides; peptides; pyrazoles; TIDES; small molecules

1. Analysis In terms of the number of drugs approved by the Food and Drug Administration (FDA), 2019 (also referred to as “this year” herein) saw with the approval of 48 new drugs, a figure that consolidates the trend initiated in 2017, when 46 drugs were approved, followed by a record-breaking 59 approvals in 2018 [1]. The 48 new drugs of 2019 are divided between 10 Biologics (12 and 17 in 2017 and 2018, respectively) and 38 New Chemical Entities (NCEs) (34 and 42 in 2017 and 2018, respectively) Figure1[ 1]. In this same forum [2] last year, and in response to the large number of drugs accepted in 2018, we asked the following question: will this increasing trend of both kinds of drug continue in the coming years? We and other analysts were cautious in this regard [2–4], since the approval of a new drug by the corresponding agencies involves many variables that are difficult to predict. After seeing the results of 2019, our analyses are guardedly optimistic in the expectation that this trend will be maintained in the near future [5,6]. In this respect, it is important to take into consideration that the pharmaceutical industry heads the world ranking in total Research and Development (R&D) investment and it is one of the few sectors still growing.

Molecules 2020, 25, 745; doi:10.3390/molecules25030745 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 13

While the number of NCEs approved in 2019 is in line with the expectations based on previous years, the number of Biologics could be considered somewhat disappointing after the figures registered in 2017 and 2018 [1]. However, the approval of three antibody drug conjugates (ADCs) could be considered a breakthrough and something awaited by analysts for several years [7–9]. The approvals of ADCs granted in 2019 account for almost 50% (3 vs. 7) of all ADCs approved by the FDA to date. Overall, Biologics are clearly consolidated in the drug arena, accounting for more than 25% (58 out of 220) of all drugs approved in the last five years (2015–2019). In parallel, in 2019, the Center for Biologics Evaluation and Research (CBER) has added 10 new approvals, including three vaccines and one gene therapy [10]. This number clearly exceeds those of the previous years (6 and 3 in 2017 and Molecules 2020, 25, 745 2 of 13 2018, respectively) and paves the way for their further application for these kinds of treatments [10].

59 60 55 48 50 45 41 45 39 40 36 34 42 35 29 29 30 38 27 27 30 24 24 25 33 33 31 22 22 25 20 21 30 27 18 20 24 24 25 21 21 22 15 18 18 19 17 16 17 10 15 15 12 12 11 10 5 25765242366662 7 0

2000 2001 2002 2003 2004 Chemical2005 2006 entities2007 2008 2009 2010 Biologics2011 2012 2013 Total2014 2015 2016 2017 2018 2019

Figure 1. NewNew chemical entities and biol biologicsogics approved by the FDA in the last two decades [[1,6].1,6]. While the number of NCEs approved in 2019 is in line with the expectations based on previous 2. Discussion years, the number of Biologics could be considered somewhat disappointing after the figures registered in 2017Ten and Biologics 2018 [ 1were]. However, approved the in approval 2019 as ofshown three in antibody Table 1, drug of which conjugates three (ADCs)were ADCs, could five be consideredmonoclonal aantibodies breakthrough (mAbs), and and something two proteins—one awaited by a analysts for several and yearsone a [neurotoxin7–9]. The approvals (Table 1). of ADCs granted in 2019 account for almost 50% (3 vs. 7) of all ADCs approved by the FDA to date. Overall, Biologics areTable clearly 1. consolidatedBiologics approved in the by drug the FDA arena, in accounting2019 [1,5,6]. for more than 25% (58 out of 220)Active of allIngredient drugs a approvedTrade inName the blast five yearsClass (2015–2019). In parallel, Indication in 2019, the Center for BiologicsBrolucizumab Evaluation and ResearchBeovuTM (CBER) hasMonoclonal added antibody 10 new approvals,Wet age-related including macular three degeneration vaccines and Thrombosis and thrombotic one geneCaplacizumab therapy[ 10]. ThisCablivi numberTM clearly exceeds those of the previous years (6 and 3 in 2017 and (Nanobody) thrombocytopenic purpura 2018, respectively) and paves the way for their further application for these kinds of treatments [10]. Prevention of vaso-occlusive crisis in Crizanlizumab AdakveoTM Monoclonal antibody patients with Sickle cell 2. Discussion Risankizumab SkyriziTM Monoclonal antibody Moderate to severe plaque psoriasis TenRomosozumab Biologics were approvedEvenityTM in 2019Monoclonal as shown antibody in Table 1,Osteoporosis of which in three postmenopausal were ADCs, women five -ejfv PadcevTM Antibody drug conjugate Cancers expressing Nectin-4 monoclonal antibodies (mAbs), and two proteins—one a fusion protein and one a neurotoxin (Table1). - PolivyTM Antibody drug conjugate Diffuse large B-cell Althoughpiiq mAbs continue to be an important class of Biologics and even of drugs, 2019 registered a slightFam- decrease in the number of mAbs approved by the FDA. TheUnresectable number ofor mAbmetastatic authorized HER2-positive by this EnhertuTM Antibody drug conjugate regulatoryderuxtecan-nxki agency has experienced annual increases (7, 9, and 11 for 2016, 2017,breast and cancer 2018, respectively); Anemia in β-thalassemia and however, the fiveapproved Reblozyl in 2019,TM which stillFusion account Protein for 10% of total drugs and the 50% of Biologics myelodysplastic syndromes TM authorized,Prabotulinumtoxin is the lowest number in recent years. Of note, one of these mAb, (Cablivi ), JeuveauTM Neurotoxin protein Temporary improvement of frown lines is a nanobody(botulinum thattoxin) contains a single-domain antibody fragment. This is the first nanobody to make it to the market. Importantly, the medicinal targets of mAb continue to be broad, as shown in 2019: eye and diseases, osteoporosis and psoriasis (Table1). Molecules 2020, 25, 745 3 of 13

Table 1. Biologics approved by the FDA in 2019 [1,5,6].

Active Ingredient a Trade Name b Class Indication Brolucizumab BeovuTM Monoclonal antibody Wet age-related Monoclonal antibody Thrombosis and thrombotic Caplacizumab CabliviTM (Nanobody) thrombocytopenic purpura Prevention of vaso-occlusive crisis in Crizanlizumab AdakveoTM Monoclonal antibody patients with Sickle cell anemia Risankizumab SkyriziTM Monoclonal antibody Moderate to severe plaque psoriasis Osteoporosis in postmenopausal EvenityTM Monoclonal antibody women MoleculesEnfortumab 2020, 25, x 3 of 13 PadcevTM Antibody drug conjugate Cancers expressing Nectin-4 vedotin-ejfv Polatuzumab a By alphabetical order, bUSA. PolivyTM Antibody drug conjugate Diffuse large B-cell lymphoma vedotin- piiq Although mAbs continue to be an important class of Biologics and even of drugs, 2019 registered Fam-trastuzumab Unresectable or metastatic EnhertuTM Antibody drug conjugate a slightderuxtecan-nxki decrease in the number of mAbs approved by the FDA. The numberHER2-positive of mAb breast authorized cancer by this regulatory agency has experienced annual increases (7, 9, andAnemia 11 for in 2016,β-thalassemia 2017, and and 2018, Luspatercept ReblozylTM Fusion Protein respectively); however, the five approved in 2019, which still accountmyelodysplastic for 10% of total syndromes drugs and the Prabotulinumtoxin Temporary improvement of frown 50% of Biologics authorized,Jeuveau is TMthe lowestNeurotoxin number proteinin recent years. Of note, one of these mAb, (botulinum toxin) lines Caplacizumab (CabliviTM), is a nanobody that contains a single-domain antibody fragment. This is a By alphabetical order, b USA. the first nanobody to make it to the market. Importantly, the medicinal targets of mAb continue to be broad, as shown in 2019: eye and blood diseases, osteoporosis and psoriasis (Table 1). In this same report in 2018 [2], we drew attention to a forecast made by analysts, namely that that In this same report in 2018 [2], we drew attention to a forecast made by analysts, namely that more ADCs would be approved by the FDA in the coming years. In 2019, this prediction became that more ADCs would be approved by the FDA in the coming years. In 2019, this prediction became a reality, with the FDA approval three ADCs. With these ADCs approved this year, the FDA has a reality, with the FDA approval three ADCs. With these ADCs approved this year, the FDA has authorized seven ADCs to date, all of which are indicated for the treatment of cancer. authorized seven ADCs to date, all of which are indicated for the treatment of cancer. Two of this year’s ADCs, namely enfortumab vedotin-ejfv (PadcevTM) and polatuzumab Two of this year’s ADCs, namely enfortumab vedotin-ejfv (PadcevTM) and polatuzumab vedotin- vedotin-piiq (PolivyTM), share the same structure, differing only in the mAb (Figure2). The payload piiq (PolivyTM), share the same structure, differing only in the mAb (Figure 2). The payload drug of bothdrug agents of both is agents monomethyl is monomethyl auristatin auristatin E (MMAE), E (MMAE), which is whicha peptide is a derived peptide from derived the frommarine the mollusc marine dolastatinmollusc dolastatin that is too that toxic is to too be toxic administered to be administered as a drug itself. as a drugMMAE itself. is also MMAE the drug is also contained the drug in contained in (AdcetrisTM), which was approved by the FDA in 2011. In the brentuximab vedotin (AdcetrisTM), which was approved by the FDA in 2011. In the three ADCs, the cleavablethree ADCs, linker the is cleavable the dipeptide linker Val-Cit, is the dipeptide which contains Val-Cit, the which auto-inmolative contains the auto-inmolativemoiety p-aminobenzyl moiety alcoholp-aminobenzyl carbamate alcohol (PABC) carbamate at the C-terminal. (PABC) at Val-Cit the C-terminal. is cleavable Val-Cit by the protease is cleavable cathepsin, by the releasing protease thecathepsin, PABC bound releasing to the MMAE. PABC bound In turn, to thethe MMAE.PABC moiety In turn, spontaneou the PABCsly moiety releases spontaneously the MMAE. releases At the N-terminalthe MMAE. of At Val-Cit, the N-terminal the mAb of is Val-Cit, bound the through mAb is the bound thiol through of a Cys the via thiol a Michael of a Cys addition via a Michael to 6- maleimidohexanoyladdition to 6-maleimidohexanoyl linked to the linkedN-amino to theof the N-amino Val (Figure of the 2). Val Enfortumab (Figure2). Enfortumabvedotin-ejfv vedotin-ejfv is indicated foris indicated cancers expressing for cancers Nectin-4, expressing such Nectin-4, urothelial such cancers. urothelial cancers.

Figure 2. StructureStructure of of enfortumab vedotin and polatuzumab vedotin.

TM The thirdthird ADC ADC of 2019,of 2019, Fam-trastuzumab Fam--nxki deruxtecan (Enhertu-nxki (Enhertu) is theTM) same is the mAb same contained mAb TM containedin another in ADC, another trastuzumab ADC, emtansine (Kadcyla (Kadcyla), whichTM), was which approved was approved in 2013. in This 2013. mAb This is TM TM mAbalso commercialized is also commerciali alonezed as Herceptin alone as Herceptin. The payloadTM. The drug payload on Enhertu drug ison the Enhertu topoisomeraseTM is the I topoisomeraseinhibitor deruxtecan, I inhibitor which deruxtecan, is a derivative which of exatecan.is a derivative As in of the exatecan. two other As ADCs in the of two this other year, ADCs the mAb of this year, the mAb is linked to the payload, deruxtecan, through Cys residues incorporated into a 6- maleimidohexanoyl moiety (Figure 3). Deruxtecan also contains the tetrapeptide Gly–Gly–Phe–Gly (GGFG), which is a protease cleavable linker releasing an analogue of exatecan. Fam-trastuzumab deruxtecan-nxki is indicated for metastatic breast cancer.

Molecules 2020, 25, x 3 of 13

a By alphabetical order, bUSA. Although mAbs continue to be an important class of Biologics and even of drugs, 2019 registered a slight decrease in the number of mAbs approved by the FDA. The number of mAb authorized by this regulatory agency has experienced annual increases (7, 9, and 11 for 2016, 2017, and 2018, respectively); however, the five approved in 2019, which still account for 10% of total drugs and the 50% of Biologics authorized, is the lowest number in recent years. Of note, one of these mAb, Caplacizumab (CabliviTM), is a nanobody that contains a single-domain antibody fragment. This is the first nanobody to make it to the market. Importantly, the medicinal targets of mAb continue to be broad, as shown in 2019: eye and blood diseases, osteoporosis and psoriasis (Table 1). In this same report in 2018 [2], we drew attention to a forecast made by analysts, namely that that more ADCs would be approved by the FDA in the coming years. In 2019, this prediction became a reality, with the FDA approval three ADCs. With these ADCs approved this year, the FDA has authorized seven ADCs to date, all of which are indicated for the treatment of cancer. Two of this year’s ADCs, namely enfortumab vedotin-ejfv (PadcevTM) and polatuzumab vedotin- piiq (PolivyTM), share the same structure, differing only in the mAb (Figure 2). The payload drug of both agents is monomethyl auristatin E (MMAE), which is a peptide derived from the marine mollusc dolastatin that is too toxic to be administered as a drug itself. MMAE is also the drug contained in brentuximab vedotin (AdcetrisTM), which was approved by the FDA in 2011. In the three ADCs, the cleavable linker is the dipeptide Val-Cit, which contains the auto-inmolative moiety p-aminobenzyl alcohol carbamate (PABC) at the C-terminal. Val-Cit is cleavable by the protease cathepsin, releasing the PABC bound to the MMAE. In turn, the PABC moiety spontaneously releases the MMAE. At the N-terminal of Val-Cit, the mAb is bound through the thiol of a Cys via a Michael addition to 6- maleimidohexanoyl linked to the N-amino of the Val (Figure 2). Enfortumab vedotin-ejfv is indicated for cancers expressing Nectin-4, such urothelial cancers.

Figure 2. Structure of enfortumab vedotin and polatuzumab vedotin.

The third ADC of 2019, Fam-trastuzumab deruxtecan-nxki (EnhertuTM) is the same mAb contained in another ADC, trastuzumab emtansine (KadcylaTM), which was approved in 2013. This Molecules 2020, 25, 745 4 of 13 mAb is also commercialized alone as HerceptinTM. The payload drug on EnhertuTM is the topoisomerase I inhibitor deruxtecan, which is a derivative of exatecan. As in the two other ADCs of thisis linked year, tothe the mAb payload, is linked deruxtecan, to the payload, through deruxt Cys residuesecan, through incorporated Cys residues into a incorporated 6-maleimidohexanoyl into a 6- maleimidohexanoylmoiety (Figure3). Deruxtecan moiety (Figure also contains3). Deruxtecan the tetrapeptide also contains Gly–Gly–Phe–Gly the tetrapeptide (GGFG), Gly–Gly–Phe–Gly which is a (GGFG),protease which cleavable is a linkerprotease releasing cleavable an analoguelinker releasing of exatecan. an analogue Fam-trastuzumab of exatecan. deruxtecan-nxkiFam-trastuzumab is deruxtecanindicated for-nxki metastatic is indicated breast for cancer. metastatic breast cancer.

Figure 3. Structure of Fam-trastuzumab deruxtecan.

In addition to the five ADCs mentioned above, the FDA also approved cemtuzumab ozogamicin (MylotargTM) in 2001. However, authorization was withdrawn in 2010; the drug was later re-introduced in 2017. (BesponsaTM) was also approved in 2017. Furthermore, it is important to highlight that in 2018, two drugs based on the same idea but with a different chemical construction to that of the ADCs were approved. (LumoxitiTM) is a recombinant immunotoxin formed by an antibody covalently bound to a fragment of Pseudomonas exotoxin-A, and tagraxofusp-erzs (ElzonrisTM) is an 3-based fusion protein containing the diphtheria toxin. All these approvals reinforce the notion of the benefits of constructing chimeras of mAb/protein and toxic moieties. Prabotulinumtoxin (botulinum toxin, JeuveauTM) deserves comment. This toxin, which is probably the most lethal toxin known, had already been used extensively in cosmetics to reduce facial wrinkles and it had several pros and cons. One advantage was evident cosmetic effects; however, inappropriate administration can lead to the paralysis of unintended muscles. Prabotulinumtoxin shows an improved purity that contributed to its improved safety profile, therefore its approval by the FDA is expected to increase the safety of its use as a cosmetic. Although TIDES (oligonucleo- and pep-TIDES) are synthesized chemically, they fall among Biologics and the so-called small molecules. For TIDES, 2019 was another excellent year. In this regard, in addition to the two ADCs based on MMAE, a peptide of marine origin, three more peptides and two oligonucleotides were received the green from the FDA. This number indicates that more than 10% of the total drugs approved by this agency in 2019 were TIDES. Gallium Ga 68 DOTA-TOC, composed by the cyclic octapeptide (Tyr3-octeotride, TOC) terminated at the C-terminal with threoninol and at the N-terminal with a dodecanetetraacetic acid (DOTA) chelator, to which Ga-68 is bound, received approval in 2019 (Figure4). Ga 68 DOTA-TATE is used in diagnostics to measure the density and whole-body biodistribution of tumor somatostatin receptors (SSRs) via positron emission tomography (PET) imaging. In 2018, Lutetium Lu 177 DOTA-TATE (LutatheraTM), which is build up in turn to octeotrate or octreotide acid (Thr as C-terminal) was approved for peptide receptor radionuclide therapy and PET imaging. Lu 177 DOTA-TATE is considered a theragnostic drug, therapy, and diagnosis, for neuroendocrine tumors. Molecules 2020, 25, x 4 of 13

Figure 3. Structure of Fam-trastuzumab deruxtecan.

In addition to the five ADCs mentioned above, the FDA also approved cemtuzumab ozogamicin (MylotargTM) in 2001. However, authorization was withdrawn in 2010; the drug was later re- introduced in 2017. Inotuzumab ozogamicin (BesponsaTM) was also approved in 2017. Furthermore, it is important to highlight that in 2018, two drugs based on the same idea but with a different chemical construction to that of the ADCs were approved. Moxetumomab pasudotox (LumoxitiTM) is a recombinant immunotoxin formed by an antibody covalently bound to a fragment of Pseudomonas exotoxin-A, and tagraxofusp-erzs (ElzonrisTM) is an interleukin 3-based fusion protein containing the diphtheria toxin. All these approvals reinforce the notion of the benefits of constructing chimeras of mAb/protein and toxic moieties. Prabotulinumtoxin (botulinum toxin, JeuveauTM) deserves comment. This toxin, which is probably the most lethal toxin known, had already been used extensively in cosmetics to reduce facial wrinkles and it had several pros and cons. One advantage was evident cosmetic effects; however, inappropriate administration can lead to the paralysis of unintended muscles. Prabotulinumtoxin shows an improved purity that contributed to its improved safety profile, therefore its approval by the FDA is expected to increase the safety of its use as a cosmetic. Although TIDES (oligonucleo- and pep-TIDES) are synthesized chemically, they fall among Biologics and the so-called small molecules. For TIDES, 2019 was another excellent year. In this regard, in addition to the two ADCs based on MMAE, a peptide of marine origin, three more peptides and two oligonucleotides were received the green light from the FDA. This number indicates that more than 10% of the total drugs approved by this agency in 2019 were TIDES. Gallium Ga 68 DOTA-TOC, composed by the cyclic octapeptide (Tyr3-octeotride, TOC) terminated at the C-terminal with threoninol and at the N-terminal with a dodecanetetraacetic acid (DOTA) chelator, to which Ga-68 is bound, received approval in 2019 (Figure 4). Ga 68 DOTA-TATE is used in diagnostics to measure the density and whole-body biodistribution of tumor somatostatin receptors (SSRs) via positron emission tomography (PET) imaging. In 2018, Lutetium Lu 177 DOTA- TATE (LutatheraTM), which is build up in turn to octeotrate or octreotide acid (Thr as C-terminal) was approved for peptide receptor radionuclide therapy and PET imaging. Lu 177 DOTA-TATE is Moleculesconsidered2020 ,a25 theragnostic, 745 drug, therapy, and diagnosis, for neuroendocrine tumors. 5 of 13

HO

HO HO NH H O N O NH HO N 2 O H S HN O O NH S O O N H H HN N N N 68Ga N N H O HO O O N

O OH OH

Chelator + radionuclide Somatostatine receptor antagonist peptide (octreotide) Figure 4. Structure of Ga 68 dodecanetetraacetic acid-Tyr3-octeotride (DOTA-TOC). Figure 4. Structure of Ga 68 dodecanetetraacetic acid-Tyr3-octeotride (DOTA-TOC). Afamelanotide (ScenesseTM), first known as melanotan I, is a 13mer lineal peptide with a C-terminal amideAfamelanotide and acetylated (Scenesse N-terminalTM), (Figurefirst known5). It isas formed melanotan by proteinogenic I, is a 13mer aminolineal acids,peptide except with two,a C- aterminal norleucine amide (Nle) and and acetylated a D-phenylalanine. N-terminal It (Figure is a potent 5). αIt-melanocyte-stimulating is formed by proteinogenic hormone amino (α MSH)acids, analogueexcept two, (Figure a norleucine5). It promotes (Nle) theand production a D-phenylalanine. of eumelanin It inis thea potent skin and α-melanocyte- is used to preventstimulating skin Molecules 2020, 25, x 5 of 13 damagehormone and (αMSH) the concomitant analogue (Figure pain experienced 5). It promotes by people the production with erythropoietic of eumelanin protoporphyria in the skin and when is used to prevent skin damage and the concomitant pain experienced by people with erythropoietic protoporphyriaexposed to the sun. when Due exposed to its short to the half-life sun. ofDue 30 min,to its afamelanotide short half-life is administeredof 30 min, afamelanotide in subcutaneous is administeredimplant form in and subcutaneous it lasts for two implant months. form and it lasts for two months.

FigureFigure 5. 5. StructureStructure of of αα-melanocyte-stimulating-melanocyte-stimulating hormone hormone ( (ααMSH)MSH) vs. vs. afamelanotide. afamelanotide.

BremelanotideBremelanotide (Vyleesi TM)) is is a a hepta hepta side-chain side-chain to to side-chain side-chain homodetic homodetic cyclic cyclic peptide peptide (formed (formed onlyonly by amide bonds),bonds), wherewhere the the bridge bridge is is between between the the side-chain side-chain of theof the Lys Lys at the at the C-terminal C-terminal and and that thatof the of Asp the atAsp position at position 2. While 2. Wh theile Lys the residue Lys residue is in the is form in the of anform acid, of thean exocyclicacid, the partexocyclic is formed part byis formed by an acetylated Nle (Figure 6). Bremelanotide is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women with no further problems (psychiatric and/or of the relationship).

Figure 6. Structure of bremelanotide.

Like the previous peptide, bremelanotide is also an analogue of α-MSH. Comparison of the sequences of bremelanotide and afamelanotide reveals that the former has a shorter sequence and lacks the following parts: The tripetide Ser–Tyr–Ser at the N-terminal, the dipeptide Pro-Val at the C-

Molecules 2020, 25, x 5 of 13 protoporphyria when exposed to the sun. Due to its short half-life of 30 min, afamelanotide is administered in subcutaneous implant form and it lasts for two months.

Figure 5. Structure of α-melanocyte-stimulating hormone (αMSH) vs. afamelanotide.

Bremelanotide (VyleesiTM) is a hepta side-chain to side-chain homodetic cyclic peptide (formed only by amide bonds), where the bridge is between the side-chain of the Lys at the C-terminal and Molecules 2020, 25, 745 6 of 13 that of the Asp at position 2. While the Lys residue is in the form of an acid, the exocyclic part is formed by an acetylated Nle (Figure 6). Bremelanotide is indicated for the treatment of hypoactive sexualan acetylated desire disorder Nle (Figure in premenopausal6). Bremelanotide women is indicated with no for further the treatment problems of (psychiatric hypoactive sexualand/or desireof the relationship).disorder in premenopausal women with no further problems (psychiatric and/or of the relationship).

FigureFigure 6. 6. StructureStructure of of bremelanotide. bremelanotide.

Molecules 2020, 25, x 6 of 13 LikeLike the the previous peptide, bremelanotide bremelanotide is is also also an an analogue of of α-MSH.-MSH. Comparison Comparison of of the the Moleculessequences 2020 of, 25 bremelanotide, x and afamelanotide reveals that the former has a shorter sequence6 andof 13 sequencesterminal, and of bremelanotide the Gly (Figure and 7). Furthermore,afamelanotide the reve Glalsu of that bremelanotide the former ishas su abstituted shorter bysequence Asp, which and lacks the following parts: The tripetide Ser–Tyr–Ser at the N-terminal, the dipeptide Pro-Val at the lacksforms the the following bridge with parts: the The ε-amino tripetide of the Ser–Tyr–Ser Lys. at the N-terminal, the dipeptide Pro-Val at the C- terminal,C-terminal, and and the the Gly Gly (Figure (Figure 7).7). Furthermore, Furthermore, the the Gl Gluu of of bremelanotide bremelanotide is su substitutedbstituted by Asp, whichwhich forms the bridge with the ε-amino of the Lys. forms the bridge with the -amino of the Lys.

Figure 7. Comparison of the sequences of afamelanotide and bremelanotide (in pink, the common part). Figure 7. Comparison of the sequences of afamelanotideafamelanotide and bremelanotide (in pink, the common part). With regards to the oligonucleotide class, following the trends of 2016 and 2018, when three and two Witholigos regards were approved to the oligonucleotide by the FDA, class, respec followingtively, in the 2019 trends two of oligos 2016 andwere 2018, approved—one when three With regards to the oligonucleotide class, following the trends of 2016 and 2018, when three and andphosphorodiamidate two oligos were morpholino approved by ol theigomer FDA, (PMO) respectively, and one ina double-stranded 2019 two oligos short were interfering approved—one RNA two oligos were approved by the FDA, respectively, in 2019 two oligos were approved—one phosphorodiamidate(siRNA). Golodirsen morpholino(Vyondys 53 oligomerTM) is used (PMO) for andthe treatment one a double-stranded of Duchenne short muscular interfering dystrophy RNA phosphorodiamidate morpholino oligomer (PMO) and one a double-stranded short interfering RNA (siRNA).(DMD) with Golodirsen genetic (Vyondysmutations 53 subjectTM) is used to skipping for the treatment exon 53 of of the Duchenne dystrophin muscular gene. dystrophy It is an antisense (DMD) (siRNA). Golodirsen (Vyondys 53TM) is used for the treatment of Duchenne muscular dystrophy with25 mer genetic PMO mutations ending at subject 5’ with to a skipping short polyethyleneglycol exon 53 of the dystrophin chain (Figure gene. 8). It is Golodirsen an antisense was 25 merfirst (DMD) with genetic mutations subject to skipping exon 53 of the dystrophin gene. It is an antisense PMOrefused ending by FDA at 5’ (August with a short2019), polyethyleneglycol and after the appeal chain by Sarepta (Figure8 Therapeutics,). Golodirsen wasit was first authorized refused by in 25 mer PMO ending at 5’ with a short polyethyleneglycol chain (Figure 8). Golodirsen was first FDADecember (August 2019. 2019), Another and after PMO, the eterlipsen appeal by (Exondys Sarepta Therapeutics, 51TM), from the it wassame authorized company, in was December approved 2019. in refused by FDA (August 2019), and after the appeal by Sarepta Therapeutics, it was authorized in Another2016. PMO, eterlipsen (Exondys 51TM), from the same company, was approved in 2016. December 2019. Another PMO, eterlipsen (Exondys 51TM), from the same company, was approved in 2016.

Figure 8.8. Structure of Golodirseen.

TM Figure 8. Structure of Golodirseen. Givosiran (Givlaari(GivlaariTM)) is is used used for for the the treatment treatment of of adults adults with acute hepatic porphyria, a genetic disorder thatthat causes causes the the buildup buildup of toxic of porphyrintoxic porp molecules,hyrin molecules, which are which formed are during formed the during production the Givosiran (GivlaariTM) is used for the treatment of adults with acute hepatic porphyria, a genetic production of heme, a compound that is essential for blood-oxygen binding. Givosiran is a double- disorder that causes the buildup of toxic porphyrin molecules, which are formed during the stranded siRNA. Both strands contain in total 16 2’-F-ribonucleosides units and six thiphosphate production of heme, a compound that is essential for blood-oxygen binding. Givosiran is a double- linkages. The F improved the stability of the double-strand. Givosiran was developed by Alnylam, stranded siRNA. Both strands contain in total 16 2’-F-ribonucleosides units and six thiphosphate the same company that last year saw the approval of patisiran (OnpattroTM). While patisiran is linkages. The F improved the stability of the double-strand. Givosiran was developed by Alnylam, encapsulated in a lipid nanoparticle, givosiran is built through a proprietary Enhanced Stabilization the same company that last year saw the approval of patisiran (OnpattroTM). While patisiran is Chemistry (ESC), where in addition of F- and methoxy-ribonucleosides, the short dendrimer bearing encapsulated in a lipid nanoparticle, givosiran is built through a proprietary Enhanced Stabilization N-acetylgalactosamine (GalNAc) conjugated to the sense strand, there are six thiophosphate linkages Chemistry (ESC), where in addition of F- and methoxy-ribonucleosides, the short dendrimer bearing at the other ends (Figure 9). Furthermore, the presence of GalNAc mediates its binding and N-acetylgalactosamine (GalNAc) conjugated to the sense strand, there are six thiophosphate linkages internalization by hepatocytes. at the other ends (Figure 9). Furthermore, the presence of GalNAc mediates its binding and internalization by hepatocytes.

Molecules 2020, 25, 745 7 of 13 of heme, a compound that is essential for blood-oxygen binding. Givosiran is a double-stranded siRNA. Both strands contain in total 16 2’-F-ribonucleosides units and six thiphosphate linkages. The F improved the stability of the double-strand. Givosiran was developed by Alnylam, the same company that last year saw the approval of patisiran (OnpattroTM). While patisiran is encapsulated in a lipid nanoparticle, givosiran is built through a proprietary Enhanced Stabilization Chemistry (ESC), where in addition of F- and methoxy-ribonucleosides, the short dendrimer bearing N-acetylgalactosamine (GalNAc) conjugated to the sense strand, there are six thiophosphate linkages at the other ends (Figure9). MoleculesFurthermore,Molecules 20202020,, 2525 the,, xx presence of GalNAc mediates its binding and internalization by hepatocytes. 77 ofof 1313

FigureFigure 9. 9. StructureStructure of of givosiran. givosiran.

TheseThese seven seven oligonucleotide-based oligonucleotide-based drugsdrugs approvedapproved betweenbetween 20162016 andand 20192019 are are a a clear clear indication indication ofof thethe potentialpotentialpotential of ofof this thisthis class classclass of ofof compounds compoundscompounds and andand they thth areeyey are expectedare expectedexpected to fuel toto thefuelfuel development thethe developmentdevelopment of more ofof drugsmoremore drugsbelongingdrugs belongingbelonging to this class.toto thisthis Furthermore, class.class. Furthermore,Furthermore, these drugs thesthes shouldee drugsdrugs now shouldshould bring nownow about bringbring a return aboutabout on aa the returnreturn investment onon thethe investmentmadeinvestment by several mademade pharmaceutical byby severalseveral pharmaceuticalpharmaceutical industries over industriesindustries the last overover thirty thethe years. lastlast thirtythirty years.years. AsAs ininin recent recentrecent years, years,years, where wherewhere drugs drugsdrugs containing containingcontaining more moremore than one thanthan API oneone were APIAPI approved, werewere approved,approved, 2019 has witnessed20192019 hashas TM TM witnessedthewitnessed authorization thethe authorizationauthorization of two combination ofof twotwo combinationcombination drugs: Trikafta drugs:drugs:to Trikafta treatTrikafta cysticTMTM toto fibrosis treattreat (CF)cysticcystic and fibrosisfibrosis Recarbrio (CF)(CF) andandas RecarbrioanRecarbrio antibiotic.TMTM asas Both anan antibiotic.antibiotic. are triple Both combinationBoth areare tripletriple drugs. combinationcombination drugs.drugs. TM TM TrikaftaTrikaftaTMTM isisis formedformed formed byby elexacaftor, elexacaftor, ivacaftorivacaftor (Kalydeco(Kalydeco(KalydecoTMTM),), andand tezacaftortezacaftor (Figure (Figure 10).1010).). Ivacaftor Ivacaftor TM waswas approvedapproved alonealone inin 2012,2012, ininin combinationcombinationcombination with withwith lumacaftor lumacaftorlumacaftor under underunder the thethe trade tradetrade name namename of ofof Orkambi OrkambiOrkambiTMTM ininin TM TM 2015,2015, and and withwith tezacaftortezacaftor —also—also—also presentpresentpresent ininin Trikafta TrikaftaTrikaftaTMTM—under—under thethe namenamename ofofof SymdekoSymdekoSymdekoTMTM inin 2018 2018 for for severalseveral variationsvariations ofofof CF. CF.CF. In InIn this thisthis regard, regard,regard, ivacaftor ivacaftorivacaftor is isis present presentpresent in inin four fourfour APIs. APIs.APIs. A A commonA commoncommon characteristic characteristiccharacteristic of allofof alltheseall thesethese drugs drugsdrugs is the isis thethe yearly yearlyyearly cost costcost of the ofof thethe treatment, treatment,treatment, which whichwhich reaches reachesreaches a 6-digit aa 6-digit6-digit figure. figure.figure.

TM FigureFigure 10. 10. StructureStructure of of Trikafta TrikaftaTMTM,, , aa a drugdrug drug combinationcombination combination (in(in (in greengreen green thethe structurestructure of of pyrazole, pyrazole, in inin blue blueblue the thethe fluorine).fluorine).fluorine).

TM TM RecarbrioRecarbrioTMTM isisis formed formedformed by imipenem,byby imipenem,imipenem, cilastatin, cilastatin,cilastatin, and relebactam anandd relebactamrelebactam (Figure 11 ).(Figure(Figure Imipenem 11).11). (Primaxin ImipenemImipenem β (Primaxinamong(Primaxin others)TMTM amongamong is a others)others)-lactam isis antibiotic aa ββ-lactam-lactam that antibioticantibiotic was approved thatthat waswas in approved 1985.approved It belongs inin 1985.1985. to ItIt the belongsbelongs carbapenem toto thethe carbapenemfamilycarbapenem and is familyfamily derived andand from isis derivedderived the natural fromfrom thethe product naturalnatural thienamycin. productproduct thienamycin.thienamycin. It has a broad ItIt hashas spectrumaa broadbroad spectrumspectrum of activity ofof activityactivity againstagainst Gram-positiveGram-positive andand Gram-negativeGram-negative bacteria.bacteria. CilastatinCilastatin isis aa derivativederivative ofof thethe aminoamino acidacid cysteinecysteine andand itit inhibitsinhibits thethe humanhuman enzymeenzyme dehydropeptidehydropeptidase,dase, whichwhich isis responsibleresponsible forfor degradingdegrading thethe imipenem.imipenem. Finally,Finally, relebactamrelebactam isis aa beta-lactamasebeta-lactamase inhibitor.inhibitor. RecarbrioRecarbrioTMTM isis specificallyspecifically recommendedrecommended forfor complicatedcomplicated urinaryurinary tracttract andand intra-abdominalintra-abdominal infections.infections.

Molecules 2020, 25, 745 8 of 13 against Gram-positive and Gram-negative bacteria. Cilastatin is a derivative of the amino acid cysteine and it inhibits the human enzyme dehydropeptidase, which is responsible for degrading the TM Moleculesimipenem. 2020, Finally, 25, x relebactam is a beta-lactamase inhibitor. Recarbrio is specifically recommended8 of 13 forMolecules complicated 2020, 25, x urinary tract and intra-abdominal infections. 8 of 13

TM Figure 11. Structure of RecarbrioTM, a combination drug. FigureFigure 11.11. Structure ofof RecarbrioRecarbrioTM,, a a combination combination drug. drug. 2019 has once again been a good year for drugsdrugs inspiredinspired onon naturalnatural products.products. In addition to 2019 has once again been a good year for drugs inspired on natural products. In addition to imipenem and cilastatin, cilastatin, seven seven more more drugs drugs from from this this source source were were approved, approved, thereby thereby highlighting highlighting the the imipenem and cilastatin, seven more drugs from this source were approved, thereby highlighting the importance of natural products in the drug discovery processprocess (Figure(Figure 1212).). importance of natural products in the drug discovery process (Figure 12).

FigureFigure 12. StructureStructure of of the the natural natural product-based product-based drugs (in blue the fluorine). fluorine). Figure 12. Structure of the natural product-based drugs (in blue the fluorine). Cefiderocol (FetrojaTM) is from the cephalosporin family and is indicated for the treatment of Cefiderocol (FetrojaTM) is from the cephalosporin family and is indicated for the treatment of urinary tract infection causedTM mainly by multidrug-resistant Gram-negative bacteria. urinaryCefiderocol tract infection (Fetroja caused) is mainly from the by multidrug-resistantcephalosporin family Gram-negative and is indicated bacteria. for the treatment of Two drugs belong to the family of the bases found in nucleic acids. Istradefylline (NourianzTM) urinaryTwo tract drugs infection belong caused to the mainlyfamily ofby the multidrug-resistant bases found in nucleic Gram-negative acids. Istradefylline bacteria. (NourianzTM) belongs to the purines and it is administered as an add-on to levodopa/carbidopa patients withTM belongsTwo to drugs the purines belong toand the it family is administered of the bases as fo anund add-on in nucleic to levodopa/carbidopa acids. Istradefylline patients(Nourianz with) Parkinson’s disease experiencing “off” episodes. (InrebicTM) is a pyrimidine and a Parkinson'sbelongs to thedisease purines experiencing and it is “oadministeredff” episodes. as Fedratinib an add-on (Inrebic to levodopa/carbidopaTM) is a pyrimidine patients and a semi- with semi-selective inhibitor of 2 (JAK-2). It is indicated for theTM treatment of myeloproliferative selectiveParkinson's inhibitor disease of experiencing Janus kinase “o 2 ff”(JAK-2). episodes. It is Fedratinibindicated for(Inrebic the treatment) is a pyrimidine of myeloproliferative and a semi- diseases. diseases.selective inhibitor of (JAK-2). It is indicated for the treatment of myeloproliferative In the steroid family, allopregnanolone or brexanolone (ZulressoTM) was approved this year for diseases.In the steroid family, allopregnanolone or brexanolone (ZulressoTM) was approved this year for the treatment of postpartum depression. TM the treatmentIn the steroid of postpartum family, allopregnanolone depression. or brexanolone (Zulresso ) was approved this year for The fluorine-18 isotopologue of L-DOPA, fluorodopa (FDOPATM), was approved as a radiotracer in the treatmentThe fluorine-18 of postpartum isotopologue depression. of L-DOPA, fluorodopa (FDOPATM), was approved as a radiotracer PET for the visualization of nerve cells in patients with symptoms ofTM Parkinson’s disease. Also derived in PETThe for fluorine-18 the visualization isotopologue of nerve of L-DOPA, cells in patientsfluorodopa with (FDOPA symptoms), was of Parkinson’s approved as disease. a radiotracer Also from the amino acid phenylalanine, Solriamfetol (SunosiTM) is indicated for symptoms associated with derivedin PET forfrom the thevisualization amino acid of phenylalanine,nerve cells in patients Solriamfetol with symptoms(SunosiTM) ofis Parkinson’sindicated for disease. symptoms Also sleepiness such as narcolepsy and sleep apnea. TM associatedderived from with the sleepiness amino acidsuch phenylalanine,as narcolepsy and Solriamfetol sleep apnea. (Sunosi ) is indicated for symptoms Finally, in this natural product chapter, lefamulin (XenletaTM) is an antibiotic to treat community- associatedFinally, with in this sleepiness natural suchproduct as narcolepsy chapter, lefamulin and sleep (Xenleta apnea.TM ) is an antibiotic to treat community- acquired bacterial . Lefamulin belongs to the familyTM of pleuromutilin, which is derived acquiredFinally, bacterial in this pneumonia. natural product Lefamulin chapter, belongs lefamulin to the(Xenleta family )of is pleuromutilin,an antibiotic to treatwhich community- is derived from the fungus Clitopilus passeckerianus. Although pleuromutilin antibiotics have been widely used fromacquired the fungusbacterial Clitopilus pneumonia. passeckerianus. Lefamulin Although belongs topleuromutilin the family of antibiotics pleuromutilin, have been which widely is derived used in veterinary medicine, lefamulin is the first to be used for systemic treatment of bacterial infections infrom veterinary the fungus medicine, Clitopilus lefamulin passeckerianus. is the first Although to be used pleuromutilin for systemic antibiotics treatment have of bacterial been widely infections used in humans. inin humans.veterinary medicine, lefamulin is the first to be used for systemic treatment of bacterial infections in humans.In addition to givosiran, elexacaftor, and tezacaftor (both part of TrikaftaTM), fluorodopa, and TM entrectinibIn addition (see belowto givosiran, in the pyrazoleelexacaftor, section), and tezacaftor another 10(both drugs part contain of Trikafta fluorine), fluorodopa, (in blue in andthe figures). This (see implies below that in morethe pyrazole than a quarter section), (14 anoutother of 48) 10 of drugs all drugs contain approved fluorine by the (in FDA blue during in the 2019figures). contain This this implies atom. that Considering more than onlya quarter the NCEs, (14 out th ofis 48)proportion of all drugs increases approved to slightly by the moreFDA duringthan a 2019 contain this atom. Considering only the NCEs, this proportion increases to slightly more than a

Molecules 2020, 25, 745 9 of 13

In addition to givosiran, elexacaftor, and tezacaftor (both part of TrikaftaTM), fluorodopa, and Molecules 2020, 25, x 9 of 13 Moleculesentrectinib 2020 (see, 25, x below in the pyrazole section), another 10 drugs contain fluorine (in blue in the figures).9 of 13 This implies that more than a quarter (14 out of 48) of all drugs approved by the FDA during 2019 third (13 vs. 38). This observation clearly emphasizes the significant impact of fluorine in the drug thirdcontain (13 this vs. atom.38). This Considering observation only clearly the NCEs, emphasizes this proportion the significant increases impact to slightly of fluorine more thanin the a thirddrug arena. (13arena. vs. 38). This observation clearly emphasizes the significant impact of fluorine in the drug arena. Lumateperone tosylate (CaplytaTM), which contains a fluorophenyl moiety, belongs to the Lumateperone tosylate (CaplytaTM),), which which contains contains a a fluoroph fluorophenylenyl moiety, moiety, belongs to the butyrophenone family and is indicated for the treatment of schizophrenia and is currently in butyrophenone family and is indicated for the treatmenttreatment of schizophrenia and is currently in development for bipolar depression and other neurological indications. Lemborexant (DayvigoTM) development for bipolar depressiondepression andand otherother neurologicalneurological indications.indications. LemborexantLemborexant (Dayvigo(DayvigoTMTM)) contains a fluorophenyl and a fluoropyridinyl moiety and is indicated for the treatment of insomnia. contains a fluorophenyl fluorophenyl and a fluoropyridinyl fluoropyridinyl moiety and is indicated indicated for for the the treatment treatment of of insomnia. insomnia. Lasmiditan (ReyvowTM) contains a trifluorobenzoyl moiety and is recommended for the acute Lasmiditan (Reyvow(ReyvowTMTM)) contains contains a trifluorobenzoyla trifluorobenzoyl moiety moiety and isand recommended is recommended for the acute for the treatment acute treatment of migraine (Figure 13). treatmentof migraine of(Figure migraine 13 ).(Figure 13).

Figure 13. Structure of drugs containing fluoroaryl moieties. Figure 13. StructureStructure of drugs containing fluoroaryl fluoroaryl moieties.

SelinexorSelinexor (Xpovio(XpovioTMTM),), which which contains contains two trifluoromethyltrifluoromethyl groups, is anan anti-anticanceranti-anticancer drugdrug Selinexor (XpovioTM), which contains two trifluoromethyl groups, is an anti-anticancer drug (multiple(multiple myeloma).myeloma). It is the firstfirst inin classclass withwith aa novelnovel mechanismmechanism ofof actionaction basedbased onon blockingblocking thethe (multiple myeloma). It is the first in class with a novel mechanism of action based on blocking the transporttransport ofof severalseveral proteinsproteins involvedinvolved inin cancercancer cellcell growthgrowth fromfrom thethe cellcell nucleusnucleus to thethe cytoplasm,cytoplasm, transport of several proteins involved in cancer cell growth from the cell nucleus to the cytoplasm, therebythereby ultimatelyultimately arrestingarresting thethe cellcell cyclecycle andand leadingleading toto .apoptosis. ThereThere areare sixsix drugsdrugs withwith justjust oneone thereby ultimately arresting the cell cycle and leading to apoptosis. There are six drugs with just one trifluoromethyltrifluoromethyl group.group. UbrogepantUbrogepant (Ubrelvy(UbrelvyTMTM) is also indicated for the acute treatment of migraine; trifluoromethyl group. Ubrogepant (UbrelvyTM) is also indicated for the acute treatment of migraine; however, it has a different mechanism of action to lasmiditan. Ubrogepant is the first drug in class of however, it has a didifferentfferent mechanismmechanism ofof actionaction toto lasmiditan.lasmiditan. Ubrogepant is the firstfirst drug in class of oraloral calcitonincalcitonin gene-related gene-related peptide peptide receptor receptor antagonists. antagonists. Upadacitinib (Rinvoq (RinvoqTM)TM is) approved is approved for thefor oral calcitonin gene-related peptide receptor antagonists. Upadacitinib (RinvoqTM) is approved for treatmentthe treatment of rheumatoid of . arthritis. Pexidartinib (Turalio (TuralioTM) isTM indicated) is indicated for thefor the treatment treatment of giant-cell of giant- the treatment of rheumatoid arthritis. Pexidartinib (TuralioTM) is indicated for the treatment of giant- tumorcell tumor of the of tendonthe tendon sheath sheath (GC-TS). (GC-TS). Alpelisib Alpelisib (Piqray (PiqrayTM)TM is) recommended is recommended to treatto treat certain certain types types of cell tumor of the tendon sheath (GC-TS). Alpelisib (PiqrayTM) is recommended to treat certain types breastof breast cancer. cancer. Siponimod Siponimod (Mayzent (MayzentTM) isTM used) is used for relapsing for relapsing multiple multiple sclerosis sclerosis (MS) and (MS) is a selectiveand is a of breast cancer. Siponimod (MayzentTM) is used for relapsing multiple sclerosis (MS) and is a selective sphingosine-1-phosphate receptor modulator (Figure 14). selectivesphingosine-1-phosphate sphingosine-1-phosphate receptor modulatorreceptor modulator (Figure 14 (Figure). 14).

FigureFigure 14.14. Structures of drugs containingcontaining trifluoromethyltrifluoromethyl groups.groups. Figure 14. Structures of drugs containing trifluoromethyl groups. These six drugs contain either trifluoromethyl aryl or alkyl moieties. The last one, pretomanid, These six drugs contain either trifluoromethyl aryl or alkyl moieties. The last one, pretomanid, contains a trifluoromethoxy moiety and is used for the treatment of multi-drug-resistant contains a trifluoromethoxy moiety and is used for the treatment of multi-drug-resistant tuberculosis (Figure 15). It is administered in a combination regimen with bedaquiline and linezolid. Furthermore, (Figure 15). It is administered in a combination regimen with bedaquiline and linezolid. Furthermore,

Molecules 2020, 25, 745 10 of 13

These six drugs contain either trifluoromethyl aryl or alkyl moieties. The last one, pretomanid, Molecules 2020, 25, x 10 of 13 Moleculescontains 2020 a trifluoromethoxy, 25, x moiety and is used for the treatment of multi-drug-resistant tuberculosis10 of 13 (Figurepretomanid 15). Ithas is administeredan interesting in history. a combination The “preto” regimen prefix with honors bedaquiline the administrative and linezolid. capital Furthermore, of South pretomanid has an interesting history. The “preto” prefix honors the administrative capital of South pretomanidAfrica, Pretoria, has anwhich interesting is the home history. of the The non-profit “preto” prefix TB Alliance. honors thePretomanid administrative is the capitalfirst drug of Southto be Africa, Pretoria, which is the home of the non-profit TB Alliance. Pretomanid is the first drug to be Africa,developed Pretoria, and registered which is theby a home not-for-profit of the non-profit organization TB Alliance. and the third Pretomanid new anti-TB is the drug first drugapproved to be developed and registered by a not-for-profit organization and the third new anti-TB drug approved fordeveloped use by the and FDA registered in more by than a not-for-profit 40 years. It organization is a member andof the the family thirdnew of the anti-TB nitroimidazooxazines. drug approved for foruse use by theby the FDA FDA in more in more than than 40years. 40 years. It is It a is member a member of the of the family family of the of the nitroimidazooxazines. nitroimidazooxazines.

Figure 15. Structure of pretomanid. Figure 15. StructureStructure of pretomanid. All the small small molecules molecules in in 2019, 2019, except except five, five, cont containain nitrogen nitrogen heterocycles, heterocycles, thereby thereby indicating indicating a All the small molecules in 2019, except five, contain nitrogen heterocycles, thereby indicating a certaina certain supremacy supremacy of this of this kind kind of chemistry of chemistry and andaccounting accounting for almost for almost 85% (27 85% vs. (27 32) vs.of this 32) class of this of certain supremacy of this kind of chemistry and accounting for almost 85% (27 vs. 32) of this class of drugs.class of Of drugs. all these Of allAPIs these approved APIs approved this year, thissix year,contain six pyrazole, contain pyrazole,or its related or its indazole, related indazole,moieties drugs. Of all these APIs approved this year, six contain pyrazole, or its related indazole, moieties (bothmoieties are (both indicated are indicated in green in greenin the in figures) the figures) (Figure (Figure 16). 16 Elexacaftor,). Elexacaftor, which which is ispart part of of Trikafta TMTM,, (both are indicated in green in the figures) (Figure 16). Elexacaftor, which is part of TrikaftaTM, contains twotwo pyrazole pyrazole rings. ring Darolutamides. Darolutamide (Nubeqa (NubeqaTM), whichTM), alsowhich contains also twocontains of these two heterocycles, of these contains two pyrazole rings. Darolutamide (NubeqaTM), which also contains two of these washeterocycles, approved was for approved the treatment for the of treatment non-metastatic of non- castration-resistantmetastatic castration-resistant prostate cancer prostate (nmCRPC). cancer heterocycles, was approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Zanubrutinib (BrukinsaTM (Brukinsa) is a Bruton’sTM) is tyrosine a Bruton's kinase tyrosine (BTK) kinase inhibitor (BTK) indicated inhibitor for indicated the treatment for the of (nmCRPC). Zanubrutinib (BrukinsaTM) is a Bruton's (BTK) inhibitor indicated for the treatmentmantle cell of lymphoma mantle cell (MCL). lymphoma Erdafitinib (MCL). (Balversa ErdafitinibTM) also (Balversa belongsTM to) also the familybelongs of to tyrosine the family kinases of treatment of mantle cell lymphoma (MCL). (BalversaTM) also belongs to the family of tyrosineand has beenkinases authorized and has forbeen the authorized treatment offor bladder the treatment cancer. of Voxelotor bladder (Oxbrytacancer. VoxelotorTM), which (Oxbryta containsTM an), tyrosine kinases and has been authorized for the treatment of . Voxelotor (OxbrytaTM), whichaldehyde contains function, an aldehyde is indicated function, for the is treatment indicated of fo sickler the celltreatment disease, of which sickle iscell a hemoglobin-related disease, which is a which contains an aldehyde function, is indicated for the treatment of sickle cell disease, which is a hemoglobin-relateddisorder. Voxelotor disorder. acts as a hemoglobinVoxelotor acts oxygen-a as a hemoglobinffinity modulator, oxygen-affinity increasing modulator, hemoglobin increasing levels hemoglobin-related disorder. Voxelotor acts as a hemoglobin oxygen-affinity modulator, increasing hemoglobinand decreasing levels hemolysis and decreasing indicators hemolysis in patients indicators with this condition.in patients Entrectinibwith this condition. (Rozlytrek EntrectinibTM), which hemoglobin levels and decreasing hemolysis indicators in patients with this condition. Entrectinib (Rozlytrekcontains theTM), indazole which contains moiety, the isalso indazole a tyrosine moiety, kinase is also inhibitor a tyrosine for kinase the treatment inhibitor offor ROS1-positive the treatment (RozlytrekTM), which contains the indazole moiety, is also a tyrosine kinase inhibitor for the treatment ofnon-small ROS1-positive cell lung non-small cancer and cell NTRK lung canc fusion-positiveer and NTRK solid fusion-positive tumors. solid tumors. of ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors.

Figure 16. StructureStructure of of drugs, drugs, containing containing pyrazole/indazole pyrazole/indazole moieties (* denotes a chiral center). Figure 16. Structure of drugs, containing pyrazole/indazole moieties (* denotes a chiral center). Three other nitrogen-containing aromatic compounds were approved in 2019. Cenobamate Three other nitrogen-containing aromatic compounds were approved in 2019. Cenobamate (XcopriThreeTM) other contains nitrogen-containing a tetrazole moiety aromatic and is compounds used for the were treatment approved of partial-onsetin 2019. Cenobamate seizures. (XcopriTM) contains a tetrazole moiety and is used for the treatment of partial-onset seizures. Triclabendazole(XcopriTM) contains (Egaten a tetrazoleTM) is a moiety benzoimidazole and is used and for is indicated the treatment for the of treatment partial-onset of fascioliasis seizures. Triclabendazole (EgatenTM) is a benzoimidazole and is indicated for the treatment of fascioliasis and Triclabendazoleand paragonimiasis, (Egaten whichTM) is are a benzoimidazole flukes. It is and also is being indicated used for in veterinarythe treatment medicine. of fascioliasis Tafamidis and paragonimiasis, which are liver flukes. It is also being used in veterinary medicine. Tafamidis (Vyndaqelparagonimiasis,TM) is awhich benzoxazole are liver administered flukes. It tois patientsalso being with used familial in amyloidveterinary polyneuropathy medicine. Tafamidis to delay (VyndaqelTM) is a benzoxazole administered to patients with familial amyloid polyneuropathy to (Vyndaqelthe loss ofTM peripheral) is a benzoxazole nerve function administered (Figure 17 to). patients with familial amyloid polyneuropathy to delay the loss of peripheral nerve function (Figure 17). delay the loss of peripheral nerve function (Figure 17).

Molecules 2020, 25, 745 11 of 13 Molecules 2020, 25, x 11 of 13 Molecules 2020,, 25,, xx 11 of 13

Figure 17. Structure of cenobamate, triclabendazole, and tafamidis. Figure 17. StructureStructure of cenobamate, triclabendazole, and tafamidis.

In this year, three moremore drugsdrugs containcontain nitrogennitrogen non-aromaticnon-aromatic heterocycles were approved InIn thisthis year,year, threethree moremore drugsdrugs containcontain nitrognitrogen non-aromatic heterocycles were approved (Figure 1818).). Tenapanor (Ibsrela(IbsrelaTM)) inhibits inhibits the the sodium-proton sodium-proton exchange exchange and and is is used used to to treat irritable (Figure(Figure 18).18). TenapanorTenapanor (Ibsrela(IbsrelaTMTM)) inhibitsinhibits thethe sodium-protonsodium-proton exchangeexchange andand isis usedused toto treattreat irritableirritable bowel syndrome with constipation. From From a a chemical chemical structural structural point point view, view, this is an interesting bowel syndrome with constipation. From a chemical structural point view, this is an interesting molecule because it is dimericdimeric andand containscontains dichloro-tetrahydroisoquinoline,dichloro-tetrahydroisoquinoline, benzenesulfonamide, molecule because it is dimeric and contains dichloro-tetrahydroisoquinoline, benzenesulfonamide, and single polyethylene glycol moieties. Trifarotene (Aklief(AkliefTMTM),), which which contains contains a a pyrrolidine, is used and single polyethylene glycol moieties. Trifarotene (AkliefTMTM),), whichwhich containscontains aa pyrrolidine, is used for thethe topical topical treatment treatment of acneof acne vulgaris. vulgaris. Pitolisant Pitolisant (Wakix (WakixTM) is aTM potent) is a andpotent highly and selective highly histamineselective forfor thethe topicaltopical treatmenttreatment ofof acneacne vulgaris.vulgaris. PitolisantPitolisant (Wakix(WakixTMTM)) isis aa potentpotent andand highlyhighly selectiveselective histamine3 (H ) receptor 3 (H₃ antagonist.) receptor antagonist. It contains aIt piperidinecontains a andpiperidine is the first and in is its the class. first Pitolisant in its class. enhances Pitolisant the histamine3 3 (H₃₃)) receptorreceptor antagonist.antagonist. ItIt containscontains aa piperidinepiperidine andand isis thethe firstfirst inin itsits class.class. PitolisantPitolisant enhancesactivity of the histaminergic activity of neurons histaminergic in the brain, neurons thereby in the improving brain, thereby wakefulness improving and decreasing wakefulness episodes and enhances the activity of histaminergic neurons in the brain, thereby improving wakefulness and decreasing episodes of cataplexy in those suffering from narcolepsy. decreasingof cataplexy episodes in those of su cataplexyffering from in those narcolepsy.those sufferingsuffering fromfrom narcolepsy.narcolepsy.

Figure 18. Structure of tenapanor, trifarotene, and pitolisant. Figure 18. StructureStructure of of tenapanor, tenapanor, trifarotene, and pitolisant. Ferric maltol (AccruferTM) is an -chelating compound used for the treatment of patients with Ferric maltol (Accrufer TMTM))) isis is anan an iron-chelatingiron-chelating iron-chelating compoundcompound compound usedused forfor thethe treatmenttreatment ofof patientspatients with with low iron stores ( anemia). Also related to Fe, Tissue Blue (brilliant blue G, methylene lowlow iron iron storesstores (iron(iron deficiencydeficiencydeficiency anemia).anemia). AlsoAlso relate relatedrelated to Fe, Tissue Blue (brilliant blue G, methylenemethylene blue, methylthioninium chloride) is a dye approved by the FDA for treating methemoglobinemia. It blue, methylthioninium methylthioninium chloride) chloride) is is a a dye dye approved approved byby by thethe the FDAFDA FDA forfor for treatingtreating treating methemoglobinemia.methemoglobinemia. methemoglobinemia. ItIt acts by converting the ferric iron in hemoglobin to ferrous iron (Figure 19). actsIt acts by by converting converting the the ferric ferric iron iron in inhemoglobin hemoglobin to to ferrous ferrous iron iron (Figure (Figure 19). 19 ).

Figure 19. Structure of ferric maltol and Tissue Blue. Figure 19. Structure of ferric maltol and Tissue Blue. Figure 19. Structure of ferric maltol and Tissue Blue. Finally, this year, the FDA approved a polymer, ExEmTM, which is indicated as a contrast agent for Finally, this year, the FDA approved a polymer, ExEmTM, which is indicated as a contrast agent imagingFinally, studies this of year, the uterusthe FDA (sonohysterosalpingography) approved a polymer, ExEm toTMTM assess,, whichwhich fallopian isis indicatedindicated tube asas patency aa contrastcontrast in women agentagent for imaging studies of the uterus (sonohysterosalpingography) to assess fallopian tube patency in withforfor imagingimaging known orstudiesstudies suspected ofof thethe infertility. uterusuterus (sonohysterosalp(sonohysterosalp ExEmTM is formedingography)ingography) from hydroxyethyl toto assessassess fallopianfallopian cellulose tube andtube glycerol. patencypatency inin women with known or suspected infertility. ExEmTM is formed from hydroxyethyl cellulose and women with known or suspected infertility. ExEmTMTM isis formedformed fromfrom hydroxyethylhydroxyethyl cellulosecellulose andand glycerol. glycerol.

3. Conclusions 3. Conclusions

Molecules 2020, 25, 745 12 of 13

Molecules3. Conclusions 2020, 25, x 12 of 13

FigureFigure 20 20 shows shows the the drugs drugs approved approved by by the the FDA FDA in in2019 2019 and and classified classified on on the the basis basis of oftheir their chemicalchemical structure. structure.

Figure 20. Drugs approved by the FDA in 2019 and classified on the basis of their chemical structure (drugs could belong to two different classes).

FigureAlthough 20. Drugs analysts approved are very by the cautious FDA in when2019 and addressing classified the on pharmaceuticalthe basis of their chemical industry structure in general, and particularly(drugs could regarding belong to “Drugs two different to the classes). Market”, we think that 2019 could be considered an exemplary year. It is clear that the number of the drugs accepted by the FDA this year was slightly inferior to Although analysts are very cautious when addressing the pharmaceutical industry in general, those of 2018, which marked a record, and that there were fewer approvals of Biologics than expected. and particularly regarding “Drugs to the Market”, we think that 2019 could be considered an However, 2019 was marked by several milestones, thus supporting the optimistic overview of the year. exemplary year. It is clear that the number of the drugs accepted by the FDA this year was slightly Thus, the last five years (2015–2019), including the poor 2016 (with respect to the number of drugs inferior to those of 2018, which marked a record, and that there were fewer approvals of Biologics approved), stand out as the best period in terms of FDA authorization of drugs. than expected. However, 2019 was marked by several milestones, thus supporting the optimistic We nominated patisiran (OnpattroTM) as the “Molecule of the Year” in 2018. This nomination was overview of the year. Thus, the last five years (2015–2019), including the poor 2016 (with respect to made based on the fact that patisiran was the first double-stranded siRNA drug approved, and we the number of drugs approved), stand out as the best period in terms of FDA authorization of drugs. highlighted that it “opens the door for the authorization of others”. This has been confirmed this year with We nominated patisiran (OnpattroTM) as the “Molecule of the Year” in 2018. This nomination the approval of givosiran (GivlaariTM) for a different medical target. Of note, givosiran is delivered was made based on the fact that patisiran was the first double-stranded siRNA drug approved, and through a novel chemical-based mechanism, the so-called “enhanced stabilization chemistry (ESC)”, we highlighted that it “opens the door for the authorization of others”. This has been confirmed this year which again will open up new avenues for the oligonucleotide drug field. A second oligonucleotide was with the approval of givosiran (GivlaariTM) for a different medical target. Of note, givosiran is approved in 2019, the antisense PMO golodirsen (Vyondys 53TM), which follows eterlipsen (Exondys delivered through a novel chemical-based mechanism, the so-called “enhanced stabilization 51TM), another PMO authorized in 2016, thereby validating PMOs as drugs. chemistry (ESC)”, which again will open up new avenues for the oligonucleotide drug field. A second As discussed in the introduction, three ADCs were approved in 2019, an accomplishment oligonucleotide was approved in 2019, the antisense PMO golodirsen (Vyondys 53TM), which follows considered one of the highlights of the year. Two of them, enfortumab vedotin (PadcevTM) and eterlipsen (Exondys 51TM), another PMO authorized in 2016, thereby validating PMOs as drugs. polatuzumab vedotin (PolivyTM) contain the peptide MMAE as payload drug, as well as a peptide As discussed in the introduction, three ADCs were approved in 2019, an accomplishment base linker. Taking all this into consideration, 2019 can be deemed an excellent year for peptides. considered one of the highlights of the year. Two of them, enfortumab vedotin (PadcevTM) and Of the five mAbs accepted, we would like to highlight caplacizumab (CabliviTM), which is polatuzumab vedotin (PolivyTM) contain the peptide MMAE as payload drug, as well as a peptide a nanobody. These chemical structures contain a single-domain antibody fragment, representing base linker. Taking all this into consideration, 2019 can be deemed an excellent year for peptides. 10%–20% of the full antibody. This is the first nanobody to receive approval from the FDA. Due to the Of the five mAbs accepted, we would like to highlight caplacizumab (CabliviTM), which is a novelty and the potential for future drugs with similar characteristics, we believe that caplacizumab nanobody. These chemical structures contain a single-domain antibody fragment, representing 10%– deserves to be nominated “Molecule of the Year 2019”. 20% of the full antibody. This is the first nanobody to receive approval from the FDA. Due to the Natural products continue to be the main inspiration for the development of new drugs. In the novelty and the potential for future drugs with similar characteristics, we believe that caplacizumab section of small molecules, nine APIs belong to this category. The presence of fluorine is a constant, deserves to be nominated “Molecule of the Year 2019”. with four of every ten small molecules containing at least one of these atoms. More important still is Natural products continue to be the main inspiration for the development of new drugs. In the the concurrence of nitrogen-based aromatic heterocycles, which are present in two out of three small section of small molecules, nine APIs belong to this category. The presence of fluorine is a constant, molecules approved this year (21 vs. 32). with four of every ten small molecules containing at least one of these atoms. More important still is It is hoped that the approval of pretomanid will bring about a new paradigm in the drug discovery the concurrence of nitrogen-based aromatic heterocycles, which are present in two out of three small process. Pretomanid was developed and registered by the TB Alliance, a non-profit organization. It took molecules approved this year (21 vs. 32). this organization 20 years to reach this point, but its achievement shows that there are alternatives to It is hoped that the approval of pretomanid will bring about a new paradigm in the drug discovery process. Pretomanid was developed and registered by the TB Alliance, a non-profit organization. It took this organization 20 years to reach this point, but its achievement shows that there are alternatives to the pharmaceutical industry with respect to the development of drugs that

Molecules 2020, 25, 745 13 of 13 the pharmaceutical industry with respect to the development of drugs that will enhance the lives of many people. We hope that new alliances involving civil society and the public and private sectors will be built to respond to the needs of sections of society that suffer from diseases that are not of interest to the pharmaceutical industry. As in recent years, oncology drugs received the most approvals in 2019. The novelty this year is that oncology drugs were followed by drugs indicated for neurology and hematology. Furthermore, the efforts of the pharmaceutical industry to tackle infectious diseases continues to pay off, as reflected by the drugs approved this year with these indications. Unfortunately, the final message of this report resembles that of last year and refers to the cost of the treatments [2], which stands several of these drugs in six-digit figures. Although there is no clear solution to this challenge, we consider it pertinent to highlight this issue in these annual reports.

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). Acknowledgments: Authors like to thank Othman AlMusaimi for fruitful discussions during the preparation of the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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