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2018 FDA drug approvals

The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.

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The FDA’s Center for Drug Evaluation and Research (CDER) approved 59 novel drugs in 2018, breaking its record of 53 drugs in 1996 (Fig. 1; Table 1). This bumper approval crop follows on the heels of a few fruitful years for drug developers. The FDA’s 5-year annual average is now 43 drugs per year, nearly twice its nadir in 2009.

Fig. 1 | Novel FDA approvals since 1993. Annual numbers of new molecular entities (NMEs) and biologics license applications (BLAs) approved by the Center for Drug Evaluation and Research (CDER). See Table 1 for new approvals in 2018. Approvals of products such as vaccines by the Center for Biologics Evaluation and Research (CBER) are not included in this drug count (see Table 2). Source: Drugs@FDA.

Table 1 | CDER approvals in 2018

Drug (brand name)

Sponsor

Properties

Indication

Review type

Lutetium Lu 177 dotatate (Lutathera)

Advanced Accelerator Applications/Novartis

Somatostatin receptor-targeted radiopharmaceutical

GEP-NETs

P, O

Bictegravir, emtricitabine and tenofovir alafenamide (Biktarvy)

Gilead Sciences

HIV-1 integrase inhibitor and HIV-1 nucleoside/nucleotide reverse transcriptase inhibitors

HIV

P

Tezacaftor and ivacaftor (Symdeko)

Vertex Pharmaceuticals

CFTR corrector and CFTR potentiator

Cystic fibrosis

P, O, B

Apalutamide (Erleada)

Johnson & Johnson

Androgen receptor inhibitor

Prostate cancer

P

Ibalizumab (Trogarzo)a

TaiMed Biologics/Theratechnologies

CD4 antibody

HIV

P, O, B

Tildrakizumab (Ilumya)a

Sun Pharma

IL-23 antibody

Plaque psoriasis

S

Fostamatinib (Tavalisse)

Rigel Pharmaceuticals

SYK inhibitor

Immune thrombocytopenic purpura

S, O

Burosumab (Crysvita)a

Ultragenyx Pharmaceutical/Kyowa Hakko Kirin

FGF23 antibody

X-linked hypophosphataemia

P, O, B

Palonosetron and fosnetupitant (Akynzeo IV)

Helsinn Group

5-HT3 receptor antagonist and NK1 receptor antagonist

Chemotherapy-induced emesis

S

Lofexidine (Lucemyra)

US WorldMeds

α2-adrenoceptor agonist

Opioid withdrawal

P

Erenumab (Aimovig)a

Amgen/Novartis

CGRP receptor antibody

Migraine

S

Sodium zirconium cyclosilicate (Lokelma)

AstraZeneca

Potassium binder

Hyperkalaemia

S

Avatrombopag (Doptelet)

Dova Pharmaceuticals

Thrombopoietin receptor agonist

Thrombocytopenia

P

Pegvaliase (Palynziq)a

BioMarin Pharmaceutical

PAL replacement therapy

Phenylketonuria

P, O

Baricitinib (Olumiant)

Incyte/Eli Lilly

JAK inhibitor

Rheumatoid arthritis

S

Moxidectin (NA)

Medicines Development for Global Health

Antihelmintic GABA receptor and glutamate channel modulator

River blindness

P, O

Cannabidiol (Epidiolex)

GW Pharmaceuticals

Cannabinoid

Dravet syndrome and Lennox–Gastaut syndrome

P, O

Plazomicin (Zemdri)

Achaogen

Aminoglycoside antibacterial

Urinary tract infections

P

Binimetinib (Mektovi)

Array BioPharma

MEK inhibitor

BRAF-mutated melanoma

S, O

Encorafenib (Braftovi)

Array BioPharma

BRAF inhibitor

BRAF-mutated melanoma

S, O

Tecovirimat (TPOXX)

SIGA Technologies

Viral p37 protein inhibitor

Smallpox

P, O

Ivosidenib (Tibsovo)

Agios Pharmaceuticals

IDH1 inhibitor

IDH1-mutated AML

P, O

Tafenoquine (Krintafel)

Medicines for Malaria Venture/GlaxoSmithKline

8-Aminoquinoline antimalarial

Plasmodium vivax malaria

P, O, B

Elagolix sodium (Orilissa)

AbbVie

GnRH receptor antagonist

Pain associated with endometriosis

P

Fish oil triglycerides (Omegaven)

Fresenius

Mixture of fatty acids

Parenteral nutrition-associated cholestasis

P, O

Lusutrombopag (Mulpleta)

Shionogi

Thrombopoietin receptor agonist

Thrombocytopenia

P

Mogamulizumab (Poteligeo)a

Kyowa Hakko Kirin

CCR4 antibody

Mycosis fungoides and Sézary syndrome

P, O, B

Patisiran (Onpattro)

Alnylam Pharmaceuticals

TTR-directed small interfering RNA

Hereditary TTR-mediated amyloidosis

P, O, B

Segesterone acetate and ethinyl estradiol vaginal system (Annovera)

TherapeuticsMD

Progestin and estrogen combined hormonal contraceptive

Female contraception

S

Migalastat (Galafold)

Amicus Therapeutics

α-galactosidase regulator

Fabry disease

P, O, A

Stiripentol (Diacomit)

Biocodex

GABA reuptake inhibitor

Dravet syndrome

P, O

Cenegermin (Oxervate)a

Dompé

Recombinant NGF

Neurotrophic keratitis

P, O, B

Lanadelumab (Takhzyro)a

Dyax/Shire

Kallikrein antibody

Hereditary angioedema

P, O, B

Eravacycline (Xerava)

Tetraphase Pharmaceuticals

Tetracycline antibiotic

Complicated intra-abdominal infections

P

Doravirine (Pifeltro)

Merck & Co.

NNRTI

HIV

S

Moxetumomab pasudotox (Lumoxiti)a

AstraZeneca

CD22-directed antibody–drug conjugate

Hairy cell leukaemia

P, O

Fremanezumab (Ajovy)a

Teva

CGRP antibody

Migraine

P

Duvelisib (Copiktra)

Verastem

PI3K inhibitor

CLL, FL and SLL

P, O, A

Galcanezumab (Emgality)a

Eli Lilly

CGRP antibody

Migraine

S

Dacomitinib (Vizimpro)

Pfizer

EGFR inhibitor

EGFR-mutated NSCLC

P, O

Cemiplimab (Libtayo)a

Regeneron/Sanofi

PD1 antibody

CSCC

P, B

Sarecycline (Seysara)

Allergan

Tetracycline antibiotic

Severe acne vulgaris

S

Omadacycline (Nuzyra)

Paratek Pharmaceuticals

Tetracycline antibiotic

CABP and ABSSSI

P

Elapegademase (Revcovi)a

Leadiant Biosciences

Recombinant adenosine deaminase

ADA-SCID

P, O

Inotersen (Tegsedi)

Ionis Pharmaceuticals

TTR-directed antisense oligonucleotide

Hereditary TTR-mediated amyloidosis

P, O

Talazoparib (Talzenna)

Pfizer

PARP inhibitor

BRCA-mutated HER2-negative breast cancer

P

Baloxavir marboxil (Xofluza)

Shionogi/Roche

Polymerase acidic endonuclease inhibitor

Acute uncomplicated influenza

P

Lorlatinib (Lorbrena)

Pfizer

ALK and ROS1 inhibitor

ALK-positive NSCLC

P, O, B, A

Revefenacin (Yupelri)

Theravance Biopharma/Mylan

Long-acting muscarinic receptor antagonist

COPD

S

Rifamycin (Aemcolo)

Cosmo Technologies

Ansamycin antibacterial

Travellers’ diarrhoea

P

Emapalumab (Gamifant)a

Novimmune

Interferon-γ-blocking antibody

Primary haemophagocytic lymphohistiocytosis

P, O, B

Glasdegib (Daurismo)

Pfizer

Hedgehog pathway inhibitor

AML

P, O

Larotrectinib (Vitrakvi)

Loxo Oncology/Bayer

TRKA, TRKB and TRKC inhibitor

NTRK-positive solid cancers

P, O, B, A

Gilteritinib (Xospata)

Astellas

FLT3 inhibitor

FLT3-positive AML

P, O, B

Amifampridine (Firdapse)

Catalyst Pharmaceuticals

Potassium channel blocker

Lambert–Eaton myasthenic syndrome

P, O

Prucalopride (Motegrity)

Shire/Takeda

5-HT4 receptor agonist

Chronic idiopathic constipation

S

Calaspargase pegol (Asparlas)a

Servier

Asparagine specific enzyme

ALL

S, O

Ravulizumab (Ultomiris)a

Alexion

Complement inhibitor

Paroxysmal nocturnal haemoglobinuria

S, O

Tagraxofusp (Elzonris)a

Stemline Therapeutics

IL-3 and diphtheria toxin fusion protein

Blastic plasmacytoid dendritic cell neoplasm

P, O, B

As in previous years, US regulators approved a high proportion of orphan drugs and cancer drugs (Fig. 2). The 34 orphan drugs approved in 2018 accounted for 58% of the total — higher than the 5-year average of 45%. Cancer drugs make up 27% of the total, in keeping with a 5-year average of 25%. 13 of the 16 cancer drugs were for orphan indications, representing 38% of the orphan cohort.

Fig. 2 | CDER approval trends. Source: Nature Reviews Drug Discovery, FDA.

Other therapeutic areas with high approval counts included infectious diseases and neurology (Fig. 3). Both of these therapeutic areas also scored multiple approvals in 2017 and 2016.

Fig. 3 | CDER approvals by therapeutic area in 2018. Source: Nature Reviews Drug Discovery.

The agency approved 14 drugs with breakthrough therapy designation, 24% of the cohort. This is down from the 5-year running average of 29%. Breakthrough designation is intended for drugs that promise substantial improvements over existing therapies in serious or life-threatening diseases.

However, the commercial potential of the class of 2018 is lacklustre. Only two of the newly approved products are expected to achieve annual sales of US$2 billion or more by 2024 or sooner, suggest consensus sales forecasts collected by Clarivate Analytics’s Cortellis platform. Another 11 products should reach peak sales of more than $1 billion (Fig. 4). In 2017, by contrast, 7 of the newly approved products were on track for multibillion-dollar annual sales and another 9 had billion-dollar sales potential.

Fig. 4 | 2018’s potential blockbuster approvals. Sales forecasts are average, annual, global consensus estimates for candidates that are expected to reach blockbuster status by 2024, as reported in Clarivate Analytics’ Cortellis database on January 8. *Drugs with breakthrough therapy designation.

The combined and average projected peak sales of the newly approved drugs is also on the decline, shows an annual analysis by Boston Consulting Group. These analysts forecast combined peak sales of $45 billion for this year’s newly approved drugs, corresponding to average peak sales of only $720 million per drug. This is down from a high point of $84 billion in 2014, when average peak sales potential was $1.6 billion per drug. The low point was 2008, with cumulative sales of $13 billion and average peak sales of $500 million.

Sales forecasts are notoriously unreliable, however, and can miss actual revenue numbers by more than 40%.

The agency’s Center for Biologics Evaluation and Research (CBER) approved only a few notable new products in 2018 (Table 2). FDA rejections were also down last year (Table 3).

Table 2 | Selected CBER approvals in 2018

Biologic name

Sponsor

Properties

Indication

Coagulation factor Xa (Andexxa)

Portola

Recombinant modified human factor Xa protein

Reversal of anticoagulation in rivaroxaban and apixaban-treated patients

Anti-haemophilic factor (JIVI)

Bayer

Recombinant DNA-derived factor VIII concentrate

Haemophilia A

Paediatric hexavalent combination vaccine (Vaxelis)

Merck & Co./Sanofi

Diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus, Haemophilus b conjugate and hepatitis B vaccine

Children from 6 weeks through 4 years of age

Table 3 | Selected Complete Response Letters and Refuse to File letters in 2018

Drug name

Sponsor

Properties

Indication

Status

Ozanimod

Celgene

S1P1 and S1P5 receptor modulator

Multiple sclerosis

Resubmission expected

Volanesorsen

Akcea Therapeutics/Ionis Pharmaceuticals

Apolipoprotein CIII antisense

Dyslipidaemia and hypercholesterolaemia

Resubmission expected

Oliceridine

Trevena

Biased opioid agonist

Acute pain

Undisclosed

Stannsoporfin

Mallinckrodt

Haem oxygenase inhibitor

Hyperbilirubinaemia

Undisclosed

Notable approvals

The new approval with the greatest commercial potential is Gilead Sciences’ combination product Biktarvy, for the treatment of HIV.

This once-daily drug combines the newly approved integrase inhibitor bictegravir with the nucleoside/nucleotide reverse transcriptase inhibitors emtricitabine and tenofovir. Gilead says it is the smallest three-drug integrase-inhibitor-containing tablet on the market. It is approved for adults who are new to antiretroviral treatment and for those who want to replace their current antiretroviral regimen with a more convenient option. Analysts expect the drug to achieve annual sales of $6.7 billion by 2024.

Vertex’s cystic fibrosis combination therapy Symdeko is also set to achieve multibillion-dollar peak sales. The product is for patients who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or who have at least one mutation that is responsive to the therapy. It combines the novel CFTR corrector tezacaftor with the established CFTR potentiator ivacaftor. Symdeko’s improved efficacy and tolerability over Vertex’s Orkambi — which combines the CFTR corrector lumacaftor and ivacaftor — are expected to drive uptake of the new combination, and analysts forecast annual sales of $2 billion by 2024. Vertex is also working on triple-agent combinations that could further expand the treatable patient population and the expected commercial potential.

From a scientific novelty perspective, 2018 saw the landmark approval of Alnylam’s patisiran as the first small interfering RNA (siRNA) drug, which uses RNA interference (RNAi) to downregulate protein expression.

Researchers first discovered the RNAi pathway in 1998, and a Nobel prize was awarded for this work in 2006. RNAi-based drugs harness the RNA-induced silencing complex to neutralize the expression of mRNA transcripts. Alnylam’s patisiran is a double-stranded siRNA oligonucleotide that downregulates the expression of transthyretin (TTR), a transport protein that can misfold and aggregate to cause hereditary TTR-mediated amyloidosis.

At least six other RNAi therapeutics are in phase III trials for other indications. Next-generation delivery approaches stand to offer improved therapeutic indices and opportunities beyond liver diseases.

The agency also approved Ionis Pharmaceuticals’ inotersen for the treatment of hereditary TTR-mediated amyloidosis in 2018. Inotersen is a single-stranded oligonucleotide that uses an antisense mechanism to lower TTR expression. It is the fifth antisense drug to gain approval.

In a closely watched race, the agency approved three calcitonin gene-related peptide (CGRP) antagonists for the preventive treatment of migraines. First across the finish line was Amgen and Novartis’s erenumab, which binds to the CGRP receptor. Months later, Teva secured approval for fremanezumab and Eli Lilly got the green light for galcanezumab. Both of these antibodies target the CGRP ligand itself. Analysts expect that erenumab and galcanezumab will both reach blockbuster status, with respective sales of $1.6 billion and $1 billion by 2024.

Drug developers were working on small molecules against the CGRP target for decades, before achieving success with their antibody-based approaches.

Erenumab is also the first G protein-coupled receptor (GPCR)-targeted antibody to secure an FDA approval, just beating Kyowa Hakko Kirin’s CCR4-targeted lymphoma therapy mogamulizumab to this title. GPCRs are the most commonly exploited therapeutic targets for small-molecule drugs, but they have proved challenging for antibody developers. Scientific and technological advances are opening up these targets to antibody interventions, and around 10 antibodies against other GPCR targets are now in the clinic.

Loxo Oncology and Bayer’s larotrectinib scored the first approval for a drug that was developed entirely for a tissue-agnostic cancer indication. Whereas cancer indications are typically defined by the tissue of origin of the cancer, larotrectinib is approved for use in all solid tumours that have neurotrophic receptor tyrosine kinase (NTRK) gene fusions.

The FDA granted a supplementary approval to Merck & Co.’s PD1 blocker pembrolizumab for all tumours with microsatellite instability-high (MSI-H) signatures in 2017, but this immunotherapy was already approved and used at the time on a tissue-dependent basis. Larotrectinib, by contrast, was developed specifically for a tissue-agnostic indication. In January 2019, Eli Lilly bought Loxo for $8 billion for rights to larotrectinib and the rest of the firm’s pipeline. Although some oncologists suspect that opportunities for tissue-agnostic drugs may be limited, a number of other tissue-agnostic candidates are in development by Loxo and others.

Other new oncology approvals are by contrast set to face more competition. Regeneron and Sanofi’s cemiplimab, approved for cutaneous squamous cell carcinoma, is the sixth PD1–PDL1 blocker to make it to market in the US. Analysts nevertheless still expect the immunotherapy to reach blockbuster status. Pfizer’s lorlatinib, for the treatment of ALK-positive non-small-cell lung cancer, is the fifth ALK inhibitor to market. And Pfizer’s glasdegib, for acute myeloid leukaemia, is the third hedgehog pathway inhibitor to market.

Notable global health, infectious disease approvals included GlaxoSmithKline’s tafenoquine, for the treatment of Plasmodium vivax malaria, and Medicines Development for Global Health’s moxidectin, for river blindness. Tafenoquine, first discovered 40 years ago, provides a key new tool to purge P. vivax from patients. Moxidectin is the first new drug for river blindness to gain approval in 20 years. Both approvals show how non-profits are using repurposing and re-prioritization strategies to advance drugs at low cost.

Other infectious disease standouts include Roche’s polymerase acidic endonuclease inhibitor baloxavir marboxil, the first novel flu drug to reach the market in 20 years, and TaiMed Biologics’ ibalizumab, the first monoclonal antibody to be approved for the treatment of HIV-1 infection.

GW Pharmaceuticals’ cannabidiol (CBD) is the first marijuana-derived drug to gain approval. CBD has activity that is distinct from the effects of tetrahydrocannabinol (THC), which causes the intoxication and euphoria associated with marijuana. CBD is approved for the treatment of two rare and severe forms of epilepsy, Lennox–Gastaut syndrome and Dravet syndrome. GW Pharmaceuticals and other firms are also developing CBD and THC for the treatment of other indications.

2019 is set to see another robust approval cohort, if not necessarily quite as large as 2018. As of the end of November 2018, sponsors had filed 43 applications for regulatory review. Drugs that are currently under review include Johnson & Johnson’s fast-acting antidepressant esketamine, Aimmune’s peanut-based peanut allergy treatment AR101, and Novartis’s gene therapy for spinal muscular atrophy, onasemnogene abeparvovec (Table 4). The FDA has cautioned, however, that a US government shutdown could cause regulatory timelines to slip. It also limits the agency’s ability to accept new drug applications.

Table 4 | Selected potential approvals for new drugs in 2019

Drug name

Sponsor

Properties

Indication

Expected PDUFA date

Sacituzumab govitecana

Immunomedics

Anti-TROP2 antibody–drug conjugate

Breast cancer

January

Cladribine

Merck KGaA

Purine nucleoside analogue

Multiple sclerosis

January (third review)

Caplacizumab

Sanofi

Anti-vWF nanobody

Thrombotic thrombocytopenic purpura

February

Esketaminea

Johnson & Johnson

Fast-acting antidepressant

Major depressive disorder

March

Brexanolonea

SAGE Therapeutics

GABAA receptor modulator

Postpartum depression

March

Siponimod

Novartis

S1P receptor modulator

Multiple sclerosis

March

Risankizumabb

AbbVie

IL-23 antibody

Psoriasis

April

Quizartiniba

Daiichi Sankyo

FLT3 inhibitor

Acute myelogenous leukaemia

May

Onasemnogene abeparvoveca,b

Novartis

Gene therapy

Spinal muscular atrophy

May

AR101a,b

Aimmune Therapeutics

Peanut flour

Peanut allergies

August

Erdafitiniba

Johnson & Johnson

Pan-FGFR inhibitor

Bladder cancer

September

Upadacitiniba,b

AbbVie

JAK1 inhibitor

Rheumatoid arthritis

December

Romosozumab

Amgen

Sclerostin antibody

Osteoporosis and osteopenia

2019 (second review)

Nature Reviews Drug Discovery 18, 85-89 (2019)

doi: 10.1038/d41573-019-00014-x

High-resolution versions of the figures for this article are available as supplementary information.

Supplementary Information

  1. Supplementary information
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