The Pharmaceutical Industry in 2018. an Analysis of FDA Drug Approvals from the Perspective of Molecules

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Review The Pharmaceutical Industry in 2018. An Analysis of FDA Drug Approvals from the Perspective of Molecules

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

1 KRISP, School of Laboratory of Medicine and Medical Science, 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.)

Academic Editor: Diego Muñoz-Torrero Received: 29 January 2019; Accepted: 21 February 2019; Published: 23 February 2019

Abstract: The Food and Drug Administration approved 59 new drugs (42 New Chemical Entities and 17 Biologics) during 2018. This number breaks the previous record of 53 approved by the same organization in 1996. The 17 new biologics approved in 2018 also represent an important milestone for this kind of drug and they clearly exceed the 12 approved in 2015 and 2017. Herein, the 59 new drugs of the class of 2018 are analyzed from a strictly chemical perspective. The classiﬁcation has been carried out on the basis of the chemical structure and includes the following: Biologics (antibodies and enzymes); TIDES (peptides and oligonucleotides) and natural products; drug combinations; and small molecules.

Keywords: antibodies; API; biologics; chemical entities; drug discovery; ﬂuorine based drugs; natural products; oligonucleotides; peptide; TIDES; small molecules

1. Analysis 2018 stands out as a year in which the number of new drugs approved by the Food and Drug Administration (FDA) broke a record. In this regard, 59 new drugs (42 New Chemical Entities (NCE) and 17 Biologics) were approved, exceeding the 53 authorized in 1996 (47 NCEs and 6 Biologics) [1]. The numbers in 2018 are a continuation of the previous year, which witnessed the approval of 46 new entities (34 + 12) [1–3] (Figure1). Will this increasing trend of both kinds of drug continue in coming years? Analysts are cautious in responding to this question since the approval of a new drug by the corresponding agencies involves many variables that are difficult to predict [4,5]. Even for this year (2019), the current shutdown of the United States government could have a negative impact on the final number of approved drugs if it lasts for an extended period of time. Taking biologics into account, the 17 approved in 2018 also represent a record, clearly surpassing the 12 approved in 2015 and 2017. These numbers are a confirmation of the increasing importance of these kinds of pharmaceutical drug, which in the last five years (2014–2018) account for more than 25% (59 of 213) of all drugs approved, and therefore the consolidation of these molecules. In contrast to the excellent performance of biologics, fewer new products were approved by the Center for Biologics Evaluation and Research (CBER) in 2018 than in 2017 (3 vs. 6) [4,6]. However, in this regard, it is important to highlight the approval of the first hexavalent vaccine.

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Figure 1. New chemical entities and biologics approved by the FDA in the last two decades [1,4,5]. Figure 1. New chemical entities and biologics approved by the FDA in the last two decades [1,4,5]. 2. Discussion 2. Discussion Table1 shows the 17 biologics approved in 2018, of which 12 are monoclonal antibodies (mAb), threeTable pegylated 1 shows enzymes, the 17 onebiologics protein, approved and one in fusion 2018, proteinof which (Table 12 are1). monoclonal antibodies (mAb), three pegylated enzymes, one protein, and one fusion protein (Table 1). Table 1. Biologics approved by the FDA in 2018 [1]. Table 1. Biologics approved by the FDA in 2018 [1]. Active Ingredient a Trade Name b Class Disease Trade Name ActiveBurosumab Ingredient a CrysvitaTM monolclonalClass antibody X-linked dominantDisease hypophosphatemic rickets b TM Calaspargase pegol Asparlas monolclonalpegylated enzyme Acute lymphoblastic leukemia Burosumab Crysvita™ X-linked dominant hypophosphatemic rickets Cemiplimab LibtayoTM antibodymonolclonal antibody Cutaneous squamous cell carcinoma ™ CalaspargaseCenegermin pegol AsparlasOxervateTM pegylated enzymeprotein Acute lymphoblastic Neurotrophic leukemia keratitis ™ monolclonal Cemiplimab Libtayo CutaneousAdenosine squamous deaminase cell severe carcinoma combined Elapegademase RevcoviTM antibodypegylated enzyme immunodeﬁciency Cenegermin Oxervate™ protein Neurotrophic keratitis TM ElapegademaseEmapalumab RevcoviGamifant™ pegylatedmonolclonal enzyme antibodyAdenosine deaminase Hemophagocytic severe combined lymphohistiocytosis immunodeficiency TM Erenumab Aimovig™ monolclonalmonolclonal antibody Migraine prevention Emapalumab Gamifant Hemophagocytic lymphohistiocytosis antibody Fremanezumab AjovyTM monolclonal antibody Migraine prevention ™ monolclonal Erenumab Aimovig TM Migraine prevention Galcanezumab Emgality antibodymonolclonal antibody Migraine prevention TM Ibalizumab Trogarzo™ monolclonalmonolclonal antibody Multidrug-resistant HIV-1 Fremanezumab Ajovy Migraine prevention antibody Lanadelumab TakhzyroTM monolclonal antibody Hereditary angioedema attacks ™ monolclonal Galcanezumab Emgality RelapsedMigraine or refractory prevention mycosis fungoides and Mogamulizumab PoteligeoTM antibodymonolclonal antibody Sézary disease monolclonal ™ MoxetumomabIbalizumab Trogarzo Multidrug-resistant HIV-1 LumoxitiTM antibodymonolclonal antibody Relapsed or refractory hairy cell leukemia pasudotox monolclonal Lanadelumab Takhzyro™ Hereditary angioedema attacks Pegvaliase PalynziqTM antibodypegylated enzyme Phenylketonuria monolclonal Relapsed or refractory mycosis fungoides and Sézary ™ Paroxysmal nocturnal hemoglobinuria and MogamulizumabRavulizumab PoteligeoUltomiris TM monolclonal antibody antibody atypical hemolyticdisease uremic syndrome Moxetumomab ™ monolclonal Tagraxofusp-erzs LumoxitiElzonrisTM fusion proteinRelapsed Blastic or plasmacytoid refractory hairy dendritic cell leukemia cell neoplasm pasudotox antibody ™TM TildrakizumabPegvaliase PalynziqIlumya pegylatedmonolclonal enzyme antibody Moderate-to-severePhenylketonuria plaque psoriasis a b ™ monolclonalby alphabetical order;ParoxysmalUSA. nocturnal hemoglobinuria and atypical Ravulizumab Ultomiris antibody hemolytic uremic syndrome Tagraxofusp-erzs Elzonris™ fusion protein Blastic plasmacytoid dendritic cell neoplasm monolclonal Tildrakizumab Ilumya™ Moderate-to-severe plaque psoriasis antibody a by alphabetical order; b USA.

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Once again, mAb are the most important class of biologics and even of drugs. In 2018, 11 mAb were approved, which account for almost 20% of all drugs authorized by the FDA in 2018. This number exceeds those registered in 2016 and 2017 (7 and 9, respectively), thus leading to the approval of 27 antibody-based drugs out of a total of 127 new drugs over these three years. Interestingly, three drugs Erenumab, Fremanezumab, and Galcanezumab are indicated for the migraine prevention. It is important to draw attention to the approval of three pegylated enzymes in 2018. After the approval of the highly pegylated peptide peginesatide (OmontysTM) by the FDA in 2012 and its later withdrawal from the market a few months later, it appeared that the pharmaceutical sector was somewhat reluctant to introduce polyethylenglycol (PEG) moieties into their drug discovery programs. The acceptance of three pegylated drugs in the same year is expected to once again strengthen the development of PEG-containing drugs. After the approval of trastuzumab emtansine (KadcylaTM) in 2013 and inotuzumab ozogamicin (BesponsaTM) in 2017—both antibody drug conjugates (ADCs), 2018 witnessed the approval of two drugs based on the same idea but with a different chemical construction to that of the ADCs. Thus, moxetumomab pasudotox (LumoxitiTM) is a recombinant immunotoxin formed by an antibody covalently bound to a fragment of Pseudomonas exotoxin-A. On the other hand, tagraxofusp-erzs (ElzonrisTM) is an interleukin 3-based fusion protein containing the diphtheria toxin. Analysts forecast that more ADCs or fusion proteins containing toxins will be approved by the FDA in the coming years, as reflected by the large clinical pipeline of this kind of compounds [7]. TIDES (oligonucleo- and pep-TIDES), which are prepared chemically, stand among biologics and the so-called small molecules, which are characterized by their tendency to follow the Lipinski rules. In this regard, 2018 showed a similar trend to 2016, in which three oligonucleotides and one peptide were approved [8,9]. The approval of patisiran (OnpattroTM) for the treatment of hereditary transthyretin-mediated amyloidosis in adults could probably be considered the most impressive breakthrough of recent years in the drug discovery arena. Patisiran, which is a double-stranded short interfering RNA (siRNA) encapsulated in a lipid nanoparticle, has met expectations after the discovery of the RNAi pathway in 1998 (Figure2). On this occasion, a reasonable period of 20 years has elapsed between the publication of the first seminal paper and the first siRNA drug to reach the market. Other RNAi therapeutics are in clinical phases and will presumably be approved in the coming years, thus extending the medical applications of this technology. For the treatment of the same disorder, inotersen (TegsediTM) (Figure2), which is a single-stranded phosphorothioate oligonucleotide that acts through an antisense mechanism, was also approved in 2018. The five oligonucleotide-based drugs approved in 2016 and 2018 are starting to give returns on the large investments made by the pharmaceutical industry in this field since the earlier 1990s and consolidate these chemical species as an important class of drugs. With regard to peptides, 2018 has witnessed the approval of Lutetium Lu 177 DOTA-TATE (LutatheraTM), which is used for PET imaging and peptide receptor radionuclide therapy. Lu 177 DOTA-TATE is composed by the cyclic octapeptide (Tyr3-octeotride) terminated at the N-terminal with a DOTA chelator, to which Lu-177 is bound (Figure3). Lu 177 DOTA-TATE is used for the diagnosis and treatment of neuroendocrine tumors, which overexpress somatostatin receptors and therefore show a high affinity for Tyr3-octeotride. Similar theranostics are expected to be accepted by the agencies in the coming years. Molecules 2019, 24, x 4 of 5

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Figure 2. Structure of oligonucleotide based drugs, patisiran and inotersen.

With regard to peptides, 2018 has witnessed the approval of Lutetium Lu 177 DOTA-TATE (Lutathera™), which is used for PET imaging and peptide receptor radionuclide therapy. Lu 177 DOTA-TATE is composed by the cyclic octapeptide (Tyr3-octeotride) terminated at the N-terminal with a DOTA chelator, to which Lu-177 is bound (Figure 3). Lu 177 DOTA-TATE is used for the diagnosis and treatment of neuroendocrine tumors, which overexpress somatostatin receptors and therefore show a high affinity for Tyr3-octeotride. Similar theranostics are expected to be accepted by Figure 2. Structure of oligonucleotide based drugs, patisiran and inotersen. the agencies in theFigure coming 2. Structure years. of oligonucleotide based drugs, patisiran and inotersen.

FigureFigure 3. 3.StructureStructure of of Lu Lu 177 177 DOTA-TATE. DOTA-TATE.

In the section of drugs inspired in natural products, 2018 has been a superb year, with 10 drugs approved, thus revalorizing once again the important role of natural products in drug discovery.

First of all, it is important to highlight three tetracycline antibiotics for several infectious disorders (Figure4). In this regard, eravacycline (Xerava TM), which is indicated for severe intra-abdominal infections, contains one atom of F (see above for comments about the large number of drugs approved containing F; F is indicated in green in all structures). Omadacycline (NuzyraTM) was approved Figure 3. Structure of Lu 177 DOTA-TATE.

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In the section of drugs inspired in natural products, 2018 has been a superb year, with 10 drugs approved, thus revalorizing once again the important role of natural products in drug discovery. First of all, it is important to highlight three tetracycline antibiotics for several infectious Molecules 2019, 24, 809 ™ 5 of 12 disorders (Figure 4). In this regard, eravacycline (Xerava™), which is indicated for severe intra- abdominal infections, contains one atom of F (see above for comments about the large number of ™ for thedrugs treatment approved of containing community-acquired F; F is indicated bacterial in green pneumonia in all structures). (CABP) Omadacycline and acute bacterial(Nuzyra ) skin was and skinapproved structure for infections the treatment (ABSSSI). of community-acquired Finally, sarecycline bacterial (Seysara pneumoniaTM), which (CABP) is the and simplest acute bacterial of the three skin and skin structure infections (ABSSSI). Finally, sarecycline (Seysara™), which is the simplest of tetracyclines,skin and skin is recommended structure infections for the (ABSSSI). treatment Finally, of moderate-severe sarecycline (Seysara acne), vulgaris. which is the simplest of the three tetracyclines, is recommended for the treatment of moderate-severe acne vulgaris.

Figure 4. Structures of tetracycline drugs. In red the variable part. Figure 4. Structures of tetracycline drugs. In red the variable part. Two carbohydrate-inspired drugs were also approved—migalastat (GalafoldTM) and plazomicin Two carbohydrate-inspired drugs were also approved—migalastat (Galafold™) and plazomicin (ZemdriTMTwo) (Figure carbohydrate-inspired5). The former isdrugs an iminosugar were also approved—migalastat with a stereochemistry (Galafold similar) toand the plazomicin D-galactose (Zemdri™) (Figure 5). The former is an iminosugar with a stereochemistry similar to the D-galactose derived(Zemdri from) (Figure the natural 5). The product former is njirimycin, an iminosugar while with the a stereochemistry latter is an aminoglycoside similar to the D-galactose derived from derived from the natural product njirimycin, while the latter is an aminoglycoside derived from sisomicin, which is turn is derived from gentamicin. Migalstat is used to treat Fabry disease and sisomicin, which is turn is derived from gentamicin. Migalstat is used to treat Fabry disease and plazomicin to treat infections of the urinary tract. plazomicin to treat infections of the urinary tract. HO O H N H2N O OH OH HN HO HO NH O O NH HO HN NH2 HO OH HO O OH Migalastat

H2N 2 Plazomicin Figure 5. Structure of carbohydrate derived drugs. Figure 5. Structure of carbohydrate derived drugs. Two macrocycles, moxidectin (MoxidectinTM) and rifamycin SV (AemcoloTM) were approved Two macrocycles, moxidectin (Moxidectin™) and rifamycin SV (Aemcolo™) were approved in in 2018 (FigureTwo macrocycles,6). The former moxidectin is derived (Moxidectin from nemadectin) and rifamycin and wasSV (Aemcolo ﬁrst used) as were an antiparasiticapproved in in 2018 (Figure 6). The former is derived from nemadectin and was first used as an antiparasitic in veterinary medicine. It was approved by the FDA for the treatment of onchocerciasis (river blindness). veterinary medicine. It was approved by the FDA for the treatment of onchocerciasis (river Rifamycin SV belongs to a group of antibiotics that are effective against mycobacteria, but that has blindness). Rifamycin SV belongs to a group of antibiotics that are effective against mycobacteria, but beenMoleculesthat approved has 2019 been, 24 for approved, x the treatment for the tr ofeatment travelers’ of travelers’ diarrhea. diarrhea. 6 of 5

O N HO O AcO OH O O OH OH MeO NH O O HO O O OH O O H OH Rifamycin SV Moxidectin FigureFigure 6. 6.Structure Structure ofof drugs containing containing a amacrocycle. macrocycle.

With regard to the steroid family, this year has seen the approval of Annovera™ (Figure 7), which is a combination of two steroids, namely the estrogen ethinylestradiol and the progestin segesterone acetate. This drug is indicated as a contraceptive vaginal ring

Figure 7. Structure of Annovera™, a combined steroid derived drug.

2018 also witnessed the approval of the first marijuana-derived drug by the FDA (Figure 8). Cannabidiol (Epidiolex™) is indicated for the treatment of the syndromes of Dravet and Lennox– Gastaut, which are two severe forms of epilepsy in infancy.

Figure 8. Structure of cannabidiol.

Finally, Omegaven™, which is a fatty acid emulsion derived from fish oil and very rich in omega- 3, was approved for parenteral nutrition associated with cholestasis, which describes a condition in which bile cannot flow from the liver to the duodenum. In addition to Annovera™, three other drug combinations were approved in 2018, thereby confirming the tendency in recent years for these drugs to contain more than one API. Biktarvy™ is a combination of bictegravir, emtricitabinem and tenofovir alafenamide in a single tablet for the treatment of HIV-1 infection (Figure 9).

MoleculesMolecules 2019 2019, ,24 24, ,x x 66 of of 5 5

OO NN HOHO OO AcOAcO OH O OH OO O OHOH OHOH MeOMeO NHNH OO OO HOHO OO OO OHOH OO OO HH OHOH Molecules 2019, 24, 809 Moxidectin RifamycinRifamycin SV SV 6 of 12 Moxidectin FigureFigure 6. 6. Structure Structure of of drugs drugs containing containing a a macrocycle. macrocycle. With regard to the steroid family, this year has seen the approval of AnnoveraTM (Figure7), which ™ is a combinationWithWith regard regard to ofto the twothe steroid steroid steroids, family, family, namely this this the year year estrogen has has seen seen ethinylestradiol the the approval approval of of and Annovera Annovera the progestin™ (Figure (Figure segesterone 7), 7), which which isacetate.is a a combinationcombination This drug ofof is twotwo indicated steroids, steroids, as namelynamely a contraceptive the the estrogestrog vaginalenen ethinylestradiol ethinylestradiol ring. and and thethe progestinprogestin segesterone segesterone acetate.acetate. ThisThis drug drug isis indicatedindicated asas aa contraceptivecontraceptive vaginalvaginal ringring

.. TM Figure 7. Structure of Annovera™ , a combined steroid derived drug. FigureFigure 7. 7. Structure Structure of of Annovera Annovera™, ,a a combined combined steroid steroid derived derived drug. drug. 2018 also witnessed the approval of the ﬁrst marijuana-derived drug by the FDA (Figure8). 2018 also witnessed the approval of the first marijuana-derived drug by the FDA (Figure 8). Cannabidiol2018 also (Epidiolex witnessedTM the) isapproval indicated of the for first the marijuana-derived treatment of the drug syndromes by the FDA of Dravet (Figure and 8). Cannabidiol (Epidiolex™™) is indicated for the treatment of the syndromes of Dravet and Lennox– Lennox–Gastaut,Cannabidiol (Epidiolex which are) is two indicated severe formsfor the of treatment epilepsy inof infancy.the syndromes of Dravet and Lennox– Gastaut,Gastaut, whichwhich areare twotwo severesevere formsforms ofof epilepsyepilepsy inin infancy.infancy.

Figure 8. Structure of cannabidiol. FigureFigure 8. 8. Structure Structure of of cannabidiol. cannabidiol. TM Finally, Omegaven™ , which is a fatty acid emulsion derived from fish oil and very rich in omega-3, Finally,Finally, Omegaven Omegaven™,, which which is is a a fatty fatty acid acid emulsion emulsion derived derived from from fish fish oil oil and and very very rich rich in in omega- omega- was approved for parenteral nutrition associated with cholestasis, which describes a condition in 3,3, waswas approvedapproved forfor parenteralparenteral nutritionnutrition associatedassociated withwith cholestasis,cholestasis, whichwhich describesdescribes aa conditioncondition inin which bile cannot flow from the liver to the duodenum. whichwhich bilebile cannotcannot flowflow from from thetheTM liverliver toto thethe duodenum.duodenum. In addition to Annovera™ , three other drug combinations were approved in 2018, thereby InIn additionaddition toto AnnoveraAnnovera™,, threethree otherother drugdrug combinationscombinations werewere approvedapproved inin 2018,2018, therebythereby confirming the tendency in recent years for these drugs to contain more than one API. confirmingconfirming thetheTM tendencytendency in in recentrecent yearsyears for for these these drugsdrugs toto containcontain more more thanthan oneone API.API. Biktarvy™ is a combination of bictegravir, emtricitabinem and tenofovir alafenamide in a single BiktarvyBiktarvy™ isis aa combinationcombination ofof bictegravir,bictegravir, emtricitabemtricitabineminem andand tenofovirtenofovir alafenamidealafenamide inin aa singlesingle tabletMolecules for 2019 the, 24 treatment, x of HIV-1 infection (Figure9). 7 of 5 tablettablet forfor thethe treatment treatment ofof HIV-1 HIV-1 infection infection (Figure(Figure 9). 9).

TM FigureFigure 9. 9.Structure Structure of of Biktarvy Biktarvy™,, aa drugdrug combination.combination.

TM AkynzeoAkynzeo™ isis a a fixed ﬁxed dose dose combination combination of of palonosetron palonosetron and and fosnetupitant fosnetupitant for for the the treatment treatment of ofacute acute nausea nausea and and vomiting vomiting produced produced by by chemothera chemotherapy.py. Again, Again, it is interestinginteresting toto highlighthighlight thatthat fosnetupitantfosnetupitant has has two two triﬂuoromethyl trifluoromethyl groups groups in in its its structure structure (Figure (Figure 10 10).).

Figure 10. Structure of Akynzeo™, a drug combination.

Symdeko™, which has been approved for the treatment of cystic fibrosis, is a combination of tezacaftor and ivacaftor (Figure 11). The structure of the former also contains several F.

Figure 11. Structure of Symdeko™, a drug combination.

In addition to eravacycline, bictegravir and emtricitabine –part of Biktarvy™–, fosnetupitant – part of Akynzeo™–, and tezacaftor–part of Symdeko™–, another 14 drugs contain F. This implies that almost one third (18 over 59) of all drugs approved by the FDA during 2018 contain F. Taking into account the NCE alone, this proportion increases to slightly more than 40% (18 vs. 42). In addition to fosnetupitant, five more drugs with trifluoromethyl groups were approved in 2018. Apalutamide (Erleada™), which contains a trifluoromethyl pyridine and an additional fluorophenyl moiety, is indicated for the treatment of non-metastatic castration-resistant prostate cancer. Apalutamide could be considered the “n” generation of flutamide (Eulexin™), which also contains the trifluoromethyl group and is indicated for the treatment of prostate cancer (Figure 12).

Molecules 2019, 24, x 7 of 5

™ Figure 9. Structure of Biktarvy™, a drug combination.

™ Akynzeo™ is a fixed dose combination of palonosetron and fosnetupitant for the treatment of Molecules 2019 24 acute nausea, ,and 809 vomiting produced by chemotherapy. Again, it is interesting to highlight7 that of 12 fosnetupitant has two trifluoromethyl groups in its structure (Figure 10).

Figure 10. Structure of AkynzeoTM™ , a drug combination. Figure 10. Structure of Akynzeo™, a drug combination. TM Symdeko™ , which has been approved for the treatment of cystic ﬁbrosis, is a combination of Symdeko™, which has been approved for the treatment of cystic fibrosis, is a combination of tezacaftor and ivacaftor (Figure 11). The structure of the former also contains several F. tezacaftor and ivacaftor (Figure 11). The structure of the former also contains several F.

Figure 11. Structure of SymdekoTM, a drug combination. ™ Figure 11. Structure of Symdeko™, a drug combination. In addition to eravacycline, bictegravir and emtricitabine –part of BiktarvyTM–, fosnetupitant ™ –partIn of addition Akynzeo toTM eravacycline,–, and tezacaftor–part bictegravir of Symdekoand emtricitabineTM–, another –part 14 of drugs Biktarvy contain–, fosnetupitant F. This implies – ™ ™ thatpart almostof Akynzeo one third–, and (18 tezacaftor–part over 59) of all drugs of Symdeko approved–, byanother the FDA 14 drugs during contain 2018 contain F. This F. implies Taking intothat accountalmost one the third NCE (18 alone, over this 59) proportion of all drugs increases approved to slightly by the FDA more during than 40% 2018 (18 contain vs. 42). F. Taking into accountIn additionthe NCE toalone, fosnetupitant, this proportion five in morecreases drugs to slightly with trifluoromethylmore than 40% (18 groups vs. 42). were approved in 2018.In addition Apalutamide to fosnetupitant, (ErleadaTM five), which more contains drugs with a trifluoromethyl trifluoromethyl pyridine groups andwere an approved additional in ™ fluorophenyl2018. Apalutamide moiety, (Erleada is indicated), which for the contains treatment a oftrifluoromethyl non-metastatic pyridine castration-resistant and an additional prostate cancer.fluorophenyl Apalutamide moiety, couldis indicated be considered for the treatment the “n” generation of non-metastatic of flutamide castration-resistant (EulexinTM), which prostate also ™ Moleculescontainscancer. 2019Apalutamide the, 24 trifluoromethyl, x could be group considered and is indicated the “n” forgeneration the treatment of flutamide of prostate (Eulexin cancer™ (Figure), which 12 8also of). 5 contains the trifluoromethyl group and is indicated for the treatment of prostate cancer (Figure 12).

Figure 12. Structure of apalutamide. Figure 12. Structure of apalutamide. TM Elagolix sodium (Orilissa™ ), which contains one triﬂuoromethyl group and two additional Elagolix sodium (Orilissa ), which contains one trifluoromethyl group and two additional ﬂuoroaryl moieties, was approved for the treatment of pain associated with endometriosis (Figure 13). fluoroaryl moieties, was approved for the treatment of pain associated with endometriosis (Figure 13). O

F F O F F O Na N O N HN F O

Elagolix sodium

Figure 13. Structure of elagolix sodium.

Finally, doravirine (Pifeltro™), tafenoquine (Krintafel™), and tecovirimat (TPOXX™) contain just a single trifluoromethyl group and are indicated for the treatment of HIV/AIDS, Plasmodium vivax malaria, and smallpox, respectively (Figure 14). Tafenoquine is a mixture of two enantiomers.

Figure 14. Structure of doravirine, tafenoquine, and tecovirimat (* denotes a chiral center).

Nine more drugs approved in 2018 contain fluoroaryl moieties and in all cases nitrogen-based heterocycles. The presence of these drugs is also a highlight of the year. This is probably due to the large number of so-called small molecules that gained approval. In spite of having an unrelated chemical structure, binimetinib (Mektovi™) and encorafenib (Braftovi™) were approved for the treatment of BRAF-mutated melanoma (Figure 15).

Molecules 2019, 24, x 8 of 5 Molecules 2019, 24, x 8 of 5

Figure 12. Structure of apalutamide. Figure 12. Structure of apalutamide. Elagolix sodium (Orilissa™), which contains one trifluoromethyl group and two additional Elagolix sodium (Orilissa™), which contains one trifluoromethyl group and two additional fluoroaryl moieties, was approved for the treatment of pain associated with endometriosis (Figure fluoroarylMolecules 2019 moieties,, 24, 809 was approved for the treatment of pain associated with endometriosis (Figure8 of 12 13). 13). O O F F F O F F F O F F O Na N O O Na N N OHN N HN F O F O

Elagolix sodium Elagolix sodium Figure 13. Structure of elagolix sodium. Figure 13. Structure of elagolix sodium. TM TM TM Finally, doravirinedoravirine (Pifeltro(Pifeltro™),), tafenoquine tafenoquine (Krintafel (Krintafel™), and), and tecovirimat tecovirimat (TPOXX (TPOXX™) contain) contain just Finally, doravirine (Pifeltro™), tafenoquine (Krintafel™), and tecovirimat (TPOXX™) contain just justa single a single trifluoromethyl triﬂuoromethyl group group and are and indicated are indicated for the for treatment the treatment of HIV/AIDS, of HIV/AIDS, Plasmodium Plasmodium vivax a single trifluoromethyl group and are indicated for the treatment of HIV/AIDS, Plasmodium vivax vivaxmalaria, malaria, and smallpox, and smallpox, respectively respectively (Figure (Figure 14). Tafenoquine 14). Tafenoquine is a mixtur is a mixturee of two of enantiomers. two enantiomers. malaria, and smallpox, respectively (Figure 14). Tafenoquine is a mixture of two enantiomers.

Figure 14. Structure of doravirine, tafenoquine, and tecovirimat (* denotes a chiral center). Figure 14. Structure of doravirine, tafenoquine, and tecovirimat (* denotes a chiral center). Nine more drugs approved in 2018 contain ﬂuoroarylfluoroaryl moieties and in all cases nitrogen-based Nine more drugs approved in 2018 contain fluoroaryl moieties and in all cases nitrogen-based heterocycles. The presence of these drugs is also a highlight of the year. This is probably due to the heterocycles. The presence of these drugs is also a highlight of the year. This is probably due to the large number of so-called smallsmall moleculesmolecules thatthat gainedgained approval.approval. largeIn number spite of of havingso-called an small unrelated molecules chemical that structure,gained approval. binimetinib (MektoviTM™ ) and encorafenib In spite of having an unrelated chemical structure, binimetinib (Mektovi™) and encorafenib In spiteTM™ of having an unrelated chemical structure, binimetinib (Mektovi ) and encorafenib Molecules(Braftovi 2019, 24) were), x were approved approved for for the the treatment treatment of of BRAF-mutated BRAF-mutated melanoma melanoma (Figure (Figure 15). 15). 9 of 5 (Braftovi™) were approved for the treatment of BRAF-mutated melanoma (Figure 15).

FigureFigure 15. 15.StructureStructure of drugs of drugs for forBRAF-mutated BRAF-mutated melanoma. melanoma.

TwoTwo drugs drugs for for non-small-cell non-small-cell lung lung carcinoma carcinoma (NSCLC) (NSCLC) were were approved, approved, namely namely dacomitinib dacomitinib TM TM (Vizimpro(Vizimpro™) for) forEGRF-mutated EGRF-mutated NSCLC NSCLC and and lorlatinib lorlatinib (Lorbrena (Lorbrena™) for) forALK-positive ALK-positive metastatic metastatic NSCLCNSCLC (Figure (Figure 16). 16 The). The latter latter is 12-member is 12-member medi mediumum macrocycle macrocycle with with three three aryl aryl moieties. moieties.

Figure 16. Structure of drugs for NSCLC.

The rest of molecules approved in 2018 having F were baloxavir marboxil (Xofluza™) for the treatment of influenza A and B; fostamatinib (Tavalisse™), which contains a phosphate, for chronic immune thrombocytopenia (ITP); ivosidenib (Tibsovo™), which also contains a difluorociclobutyl, for acute myeloid leukemia and cholangiocarcinoma; larotrectinib (Vitrakvi™) for NTRK gene fusion– positive solid tumors; and talazoparib (Talzenna™) for BRCA-mutated HER2-negative breast cancer (Figure 17).

Figure 17. Structure of drugs containing fluoroaryl moieties.

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Figure 15. Structure of drugs for BRAF-mutated melanoma.

Two drugs for non-small-cell lung carcinoma (NSCLC) were approved, namely dacomitinib Molecules 2019™, 24, 809 ™ 9 of 12 (Vizimpro™) for EGRF-mutated NSCLC and lorlatinib (Lorbrena™) for ALK-positive metastatic NSCLC (Figure 16). The latter is 12-member medium macrocycle with three aryl moieties.

Figure 16. Structure of drugs for NSCLC. Figure 16. Structure of drugs for NSCLC. The rest of molecules approved in 2018 having F were baloxavir marboxil (XofluzaTM) for the The rest of molecules approved in 2018 having F were baloxavir marboxil (Xofluza™) for the treatmentThe rest of influenza of molecules A and approved B; fostamatinib in 2018 (Tavalissehaving FTM were), which baloxavir contains marboxil a phosphate, (Xofluza for) chronicfor the treatment of influenza A and B; fostamatinib (Tavalisse™), which contains a phosphate, for chronic immunetreatment thrombocytopenia of influenza A and (ITP); B; fostamatinib ivosidenib (Tibsovo(TavalisseTM),), whichwhich alsocontains contains a phosphate, a difluorociclobutyl, for chronic immune thrombocytopenia (ITP); ivosidenib (Tibsovo™), which also contains a difluorociclobutyl, for forimmune acute thrombocytopenia myeloid leukemia (ITP); and ivosidenib cholangiocarcinoma; (Tibsovo ), which larotrectinib also contains (Vitrakvi a difluorociclobutyl,TM) for NTRK gene for acute myeloid leukemia and cholangiocarcinoma; larotrectinib (Vitrakvi™) for NTRK gene fusion– fusion–positiveacute myeloid leukemia solid tumors; and andcholangi talazoparibocarcinoma; (Talzenna larotrectinibTM) for BRCA-mutated (Vitrakvi ) for HER2-negative NTRK gene fusion– breast positive solid tumors; and talazoparib (Talzenna™) for BRCA-mutated HER2-negative breast cancer cancerpositive (Figure solid tumors;17). and talazoparib (Talzenna ) for BRCA-mutated HER2-negative breast cancer (Figure 17).

Figure 17. Structure of drugs containing ﬂuoroaryl moieties. Molecules 2019, 24, x 10 of 5 Figure 17. Structure of drugs containing fluoroaryl moieties. TM Two thiazol-2-amide containing molecules, namely avatrombopag (Doptelet ™ ) and Two thiazol-2-amideTM containing molecules, namely avatrombopag (Doptelet ) and lusutrombopag (Mulpleta™ ) (Figure 18), were approved for the treatment of thrombocytopenia, whichlusutrombopag is characterized (Mulpleta by abnormally) (Figure 18), low were platelet approved counts andfor associatedthe treatment with of chronic thrombocytopenia, liver disease.

Bothwhich show is characterized related chemical by abnormally structures. low platelet counts and associated with chronic liver disease. Both show related chemical structures.

Figure 18. Structure of thiazol-2-amide (in red) containing molecules.

Two drugs with unrelated chemical structures, glasdegib (Daurismo™) and gilteritinib (Xospata™) (Figure 19), received approval for the treatment also of acute myeloid leukemia. Including ivosidenib (see above), three drugs were approved for this indication in 2018.

Figure 19. Structure of drugs for the treatment of acute myeloid leukemia.

The following drugs with nitrogen-based aromatic heterocycles were also approved last year: baricitinib (Olumiant™) for rheumatoid arthritis; duvelisib (Copiktra™) for various hematologic malignancies such as chronic lymphocytic, small lymphocytic, and follicular lymphomas; and amifampridine (Firdapse™), which just is 3,4-diaminopyridine, for Lambert–Eaton myasthenic syndrome, which is a muscle disease (Figure 20). In 2010, the FDA also approved 4-diaminopyridine Ampyra™ to improve walking in adults with multiple sclerosis.

Figure 20. Structure of baricitinib, duvelisib, and amifampridine.

Four more small-molecule drugs were approved in 2018, namely stiripentol (Diacomit™) for Dravet syndrome, which is an intractable infancy epilepsy, lofexidine (Lucemyra™) for the management of the physical symptoms of opioid withdrawal, prucalopride (Motegrity™) for chronic idiopathic constipation, and revefenacin (Yupelri™) for chronic obstructive pulmonary disease (COPD). Lofexidine is a racemic mixture (Figure 21).

Molecules 2019, 24, x 10 of 5 Molecules 2019, 24, x 10 of 5

™ Two thiazol-2-amide containing molecules, namely avatrombopag (Doptelet™ ) and Two thiazol-2-amide™ containing molecules, namely avatrombopag (Doptelet ) and lusutrombopag (Mulpleta™ ) (Figure 18), were approved for the treatment of thrombocytopenia, lusutrombopag (Mulpleta ) (Figure 18), were approved for the treatment of thrombocytopenia, which is characterized by abnormally low platelet counts and associated with chronic liver disease. which is characterized by abnormally low platelet counts and associated with chronic liver disease. Both show related chemical structures. Both show related chemical structures.

Molecules 2019, 24, 809 10 of 12 Figure 18. Structure of thiazol-2-amide (in red) containing molecules. Figure 18. Structure of thiazol-2-amide (in red) containing molecules. TM™ TwoTwo drugsdrugs withwith unrelatedunrelated chemicalchemical structures,structures, glasdegibglasdegib (Daurismo(Daurismo™ ) andand gilteritinibgilteritinib TwoTM ™ drugs with unrelated chemical structures, glasdegib (Daurismo ) and gilteritinib (Xospata(Xospata™ ) )(Figure (Figure 19), 19), received received approval approval for for the the treatm treatmentent also also of acute acute myeloid leukemia. Including (Xospata ) (Figure 19), received approval for the treatment also of acute myeloid leukemia. Including ivosidenibivosidenib (see(see above),above), threethree drugsdrugs werewere approvedapproved forfor thisthis indicationindication inin 2018.2018. ivosidenib (see above), three drugs were approved for this indication in 2018.

Figure 19. Structure of drugs for the treatmenttreatment ofof acuteacute myeloidmyeloid leukemia.leukemia. Figure 19. Structure of drugs for the treatment of acute myeloid leukemia. The following drugs with nitrogen-based aromatic heterocycles were also approved last year: The following drugsTM with nitrogen-based aromatic heterocycles wereTM also approved last year: baricitinibThe following (Olumiant drugs™ ) forwith rheumatoid nitrogen-based arthritis; aromatic duvelisib heterocycles (Copiktra were™ ) also for variousapproved hematologic last year: baricitinib (Olumiant™ ) for rheumatoid arthritis; duvelisib (Copiktra™ ) for various hematologic baricitinibmalignancies (Olumiant such as) chronic for rheumatoid lymphocytic, arthritis; small duvelisib lymphocytic, (Copiktra and follicular) for various lymphomas; hematologic and malignancies such as chronicTM lymphocytic, small lymphocytic, and follicular lymphomas; and malignanciesamifampridine such (Firdapse as chronic™ ), whichlymphocytic, just is 3,4-diaminopyridine,small lymphocytic, and for Lambert–Eatonfollicular lymphomas; myasthenic and amifampridine (Firdapse™ ), which just is 3,4-diaminopyridine, for Lambert–Eaton myasthenic amifampridinesyndrome, which (Firdapse is a muscle), diseasewhich just (Figure is 3,4-diaminopyridine,20). In 2010, the FDA alsofor approvedLambert–Eaton 4-diaminopyridine myasthenic syndrome,TM which is a muscle disease (Figure 20). In 2010, the FDA also approved 4-diaminopyridine syndrome,Ampyra ™ whichto improve is a muscle walking disease in adults (Figure with 20). multiple In 2010, sclerosis. the FDA also approved 4-diaminopyridine Ampyra™ to improve walking in adults with multiple sclerosis. Ampyra to improve walking in adults with multiple sclerosis.

Figure 20. Structure of baricitinib, duvelisib, and amifampridine. Figure 20. Structure of baricitinib, duvelisib, and amifampridine. Figure 20. Structure of baricitinib, duvelisib, and amifampridine. Four more small-molecule drugs were approved in 2018, namely stiripentol (DiacomitTM) ™ for DravetFour more syndrome, small-molecule which is drugs an intractable were approved infancy in epilepsy, 2018, namely lofexidine stiripentol (Lucemyra (DiacomitTM) for™ ) thefor Four more small-molecule drugs were approved in 2018, namely stiripentol (Diacomit™ ) for managementDravet syndrome, of the physicalwhich symptomsis an intractabl of opioide infancy withdrawal, epilepsy, prucalopride lofexidine (Motegrity (LucemyraTM)™ for) chronicfor the Dravet syndrome, which is an intractable infancy epilepsy, lofexidine (Lucemyra™ ) for the idiopathicmanagement constipation, of the physical and symptoms revefenacin of opioid (Yupelri withdrawal,TM) for chronic prucalopride obstructive (Motegrity pulmonary™ ) for diseasechronic managementMolecules 2019, 24 of, x the physical symptoms of opioid withdrawal,™ prucalopride (Motegrity ) for chronic11 of 5 idiopathic constipation, and revefenacin (Yupelri™ ) for chronic obstructive pulmonary disease idiopathic(COPD). Lofexidine constipation, is a racemicand revefenacin mixture (Figure (Yupelri 21). ) for chronic obstructive pulmonary disease (COPD). Lofexidine is a racemic mixture (Figure 21). (COPD). Lofexidine is a racemic mixture (Figure 21).

Figure 21. Structure of stiripentol, lofexidine, prucalopride, and revefenacin. (* denotes a chiral center). Figure 21. Structure of stiripentol, lofexidine, prucalopride, and revefenacin. (* denotes a chiral Finally,center). the FDA approved an inorganic compound, sodium zirconium cyclosilicate (LokelmaTM) [(2Na·H2O·3H4SiO4·H4ZrO6)n], an oral sorbent for potassium ions throughout the gastrointestinal Finally, the FDA approved an inorganic compound, sodium zirconium cyclosilicate (Lokelma™) [(2Na·H2O·3H4SiO4·H4ZrO6)n], an oral sorbent for potassium ions throughout the gastrointestinal tract used for the treatment of hyperkalemia, which is characterized by elevated levels of serum potassium.

3. Conclusions Figure 22 shows the drugs approved by the FDA in 2018 and classified on the basis of their chemical structure.

Figure 22. Drugs approved by the FDA in 2018 and classified on the basis of their chemical structure.

Although it is widely recognized that trends and tendencies in “Drugs to the Market” are difficult to analyze and even more difficult to forecast for the coming years, it is clear that 2018, together with previous years, indicate the dominance of antibodies as the “Drugs of the Future”. In this regard, 11 mAb and an additional one covalently bound to a fragment of an exotoxin were approved in 2018. Furthermore, and although no ADC has been approved to date, two macromolecules bound to toxin fragments were approved, thus reaffirming the concept of ADCs [8]. Another highlight regarding biologics has been the reinstatement of pegylation as a tool in drug discovery. From a strictly chemical point of view, the “Molecule of the Year” was probably patisiran (Onpattro™). This drug marks the approval of the first double-stranded siRNA and therefore opens the door for the authorization of others. A second oligonucleotide also entered the market in this reporting year, which may indicate the consolidation of these kinds of molecules as drugs. From a quantitative perspective, it is important to highlight the 10 drugs inspired in natural products. Although such compounds always have critics, their relevance for the discovery of new

Molecules 2019, 24, x 11 of 5

Figure 21. Structure of stiripentol, lofexidine, prucalopride, and revefenacin. (* denotes a chiral center).

Finally, the FDA approved an inorganic compound, sodium zirconium cyclosilicate (Lokelma™) Molecules 2019, 24, 809 11 of 12 [(2Na·H2O·3H4SiO4·H4ZrO6)n], an oral sorbent for potassium ions throughout the gastrointestinal tract used for the treatment of hyperkalemia, which is characterized by elevated levels of serum potassium.tract used for the treatment of hyperkalemia, which is characterized by elevated levels of serum potassium. 3. Conclusions 3. Conclusions Figure 22 shows the drugs approved by the FDA in 2018 and classified on the basis of their chemicalFigure structure. 22 shows the drugs approved by the FDA in 2018 and classiﬁed on the basis of their chemical structure.

FigureFigure 22. 22.DrugsDrugs approved approved by bythe the FDA FDA in 2018 in 2018 and and classified classiﬁed on onthe the basis basis of their of their chemical chemical structure. structure.

AlthoughAlthough it itis is widely widely recognized recognized thatthat trendstrends and and tendencies tendencies in “Drugsin “Drugs to the to Market”the Market” are difficult are difficultto analyze to analyze and even and more even difficult more difficult to forecast to forforecast the coming for the years, coming it is years, clear thatit is 2018, clear together that 2018, with togetherprevious with years, previous indicate years, the indicate dominance the dominanc of antibodiese of antibodies as the “Drugs as the of “Drugs the Future”. of the InFuture”. this regard, In this11 regard, mAb and 11 anmAb additional and an oneadditional covalently one bound covalently to a fragment bound to of a an fragment exotoxin of were an approvedexotoxin were in 2018. approvedFurthermore, in 2018. and althoughFurthermore, no ADC and has although been approved no ADC to date, has two been macromolecules approved to bound date, totwo toxin macromoleculesfragments were bound approved, to toxin thus frag reaffirmingments were the approved, concept thus of ADCs reaffirming [8]. Another the concept highlight of ADCs regarding [8]. Anotherbiologics highlight has been regarding the reinstatement biologics ofhas pegylation been the asreinstatement a tool in drug of discovery. pegylation as a tool in drug discovery.From a strictly chemical point of view, the “Molecule of the Year” was probably patisiran TM (OnpattroFrom a strictly). This chemical drug marks point the of approval view, the of the“Molecule first double-stranded of the Year” siRNAwas probably and therefore patisiran opens (Onpattrothe door™). for This the drug authorization marks the ofapproval others. of A the second first oligonucleotidedouble-stranded also siRNA entered and thetherefore market opens in this thereporting door for year,the authorization which may indicate of others. the consolidationA second oligonucleotide of these kinds also of moleculesentered the as market drugs. in this reportingFrom year, a quantitativewhich may indicate perspective, the consolidation it is important of these to highlight kinds of the molecules 10 drugs as inspireddrugs. in natural products.From a Althoughquantitative such perspective, compounds it always is importan have critics,t to highlight their relevance the 10 for drugs thediscovery inspired ofin newnatural drugs TM products.is unquestionable. Although such Cannabidiol compounds (Epidiolex always have) has cr beenitics, the their first relevance marijuana-derived for the discovery drug approved of new by the FDA. Fluorine deserves nomination as the “Atom of the Year”, not only because three out of ten drugs of the 2018 class contain this atom, but because a total of 49 F are present in the 18 fluorine-containing drugs. Most small molecule-based drugs contain nitrogen-based aromatic heterocycles such as pyrazoles, imidazoles, benzoimidazoles, triazoles, and 2-amine-pyrimidine moieties. As in 2017 [9,10], oncology drugs received the most approvals in 2018, but were followed very closely by drugs indicated for the treatment of infectious diseases. The efforts of the pharmaceutical industry to tackle these diseases are paying off, as reflected by the large number of drugs (14) accepted this year. Although 2018 was overall a terrific year in terms of the number of drugs accepted by the FDA, it is important to highlight the increase in the cost of treatments. For many of these new drugs, the yearly cost is estimated to reach a six-digit figure. Consequently, these drugs will be unaffordable for Molecules 2019, 24, 809 12 of 12 most of the population, even in developed countries with excellent medical care programs. This is a message to take home.

Funding: The work was funded in part by the following: the National Research Foundation (NRF) (# 105892 and Blue Sky’s Research Programme # 110960) and the University of KwaZulu-Natal (South Africa); and the Spanish Ministry of Science, Innovation, and Universities (CTQ2015-67870-P) and the Generalitat de Catalunya (2017 SGR 1439) (Spain). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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