Over the last three decades, first-in-class (FIC) drugs have become a driving force in pharmaceutical innovation, offering new therapeutic possibilities by targeting previously unexplored biological mechanisms. Enabled by advances in genomics, analytical technologies, and AI-driven discovery platforms, FIC development has steadily increased—even as the associated risks remain high. Cancer and rare diseases have emerged as dominant areas for FIC approvals, often aided by expedited regulatory pathways. At the same time, new modalities such as gene therapies, PROTACs, and bispecific antibodies are reshaping what’s possible in drug targeting. While success rates remain lower and returns less predictable than for follow-on drugs, the value of FIC therapies in addressing unmet needs continues to grow. Sustained investment in basic research and emerging technologies will be essential to keep expanding the frontiers of drug discovery.
First-in-Class Drugs: A Focus for Industry
First-in-class (FIC) drugs are drugs that function via novel mechanisms of action (MoAs), affecting newly identified biological pathways, often against new targets. In many instances, they are developed to treat diseases that lack effective medications. In the last several decades, increases in knowledge of the human genome and human biology, advances in analytical techniques, and growing digital capabilities, including artificial intelligen (AI) and machine learning are facilitate the development of FIC drugs.1
From 1980 to 2022, the U.S. Food and Drug Administration (FDA) approved 1,355 new drugs. The average number of new molecular entity approvals per year increased from 21.8 ± 6.4 before the 1992 Prescription Drug User Fee Act (PDUFA), to 24.7 ± 15.3 post-PDUFA, and to 32.1 ± 9.7 following the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA).2 Over half (788) of the new drugs approved over the entire period received approval with at least one special/expedited approval designation. In addition, from 2011 to 2020, as the number of approved drugs increased, so did the number of orphan and FIC drugs, with more than half of the FIC drugs also classified as orphan drugs.
One reason for the rise in first-in-class (FIC) drug approvals is the increasing pressure from payers, including insurance companies, for therapies that deliver clear advantages over existing treatments — whether in safety, efficacy, patient adherence, or overall value.3 Another key driver is the expanding focus on personalized medicine, which often necessitates novel mechanisms of action tailored to specific genetic or biological profiles.
Oncology Leads the Charge in FIC Innovation
The growing emphasis on oncology across all types of drug development has led to cancer treatments making up an increasingly large share of first-in-class (FIC) drug approvals over the past 30 years. Between 2000 and 2008, FIC drugs primarily targeted cardiovascular and neurological disorders, accounting for approximately 9% and 13% of approvals, respectively. From 2009 to 2017, those figures declined to around 5% and 10%, while cancer-related FIC approvals rose from about 12% to 17.5%.4 One study found that, from 1980 through 2022, antineoplastic and immunomodulating agents alone made up nearly 23% of all FDA drug approvals. When considering both oncology and orphan drug designations together, they represent roughly two-thirds of all FIC drugs approved with novel mechanisms of action.5 Many of these therapies also received expedited designations, including orphan status, priority review, accelerated approval, fast track, and breakthrough therapy status.
Shifting Targets: From GPCRs to Kinases and Beyond
The types of biological targets pursued for first-in-class (FIC) drugs have evolved significantly over time. From the 1930s through 2013, the most common target classes included G protein–coupled receptors (GPCRs), transporters, transcription factors, and enzymes.6 Another analysis found that GPCRs, kinases, ion channels, and nuclear receptors collectively account for nearly half of all known human drug targets.7
Between 1998 and 2017, GPCRs and kinases experienced the most substantial growth in popularity. GPCRs dominated the early part of this period, but interest in kinases surpassed that of GPCRs around 2013.8 Nevertheless, by 2020, ion channels and GPCRs once again accounted for the largest share of drug targets for several consecutive years.
The shift from GPCRs to kinases likely reflects broader changes in therapeutic focus — namely, a waning emphasis on cardiovascular diseases, for which GPCRs are often primary targets, and a growing concentration on oncology, where kinases play key roles in disease pathways. Notable kinase targets include receptor tyrosine kinases (RTKs) such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), and MET kinases, as well as RAF kinases, which relay intracellular signals to the nucleus.
More recently, attention has turned to Janus kinases (JAKs) — non-receptor tyrosine kinases involved in immune regulation through signal transducer and activator of transcription (STAT) proteins.8 JAKs have become important targets for new therapies treating autoimmune diseases like rheumatoid arthritis and are also being explored in treatments for neurological conditions.
The Rise of Biologics and Next-Generation Modalities
In addition to the increasing percentage of FIC drugs targeted cancer indications, there has also been a dramatic growth in the number of novel biologic FIC molecules and other advanced medicinal therapy products, particularly cell, gene, and RNA therapies, that operate via novel MoAs with novel drug targets.3 Small molecule drugs predominated from 2011 to 2014, with antibody-based therapies growing in noticeable importance from 2015 to 2018, and a wider array of antibody-based modalities and genetic medicines making inroads from 2019 until 2022.
Overall, during these three periods, GPCRs, transporters, and transcription factors were found to account for only small percentages of all target families, indicating that by 2011 they were no longer major FIC targets.3 Enzymes, while an important target class from 2011 to 2014, became much less important during 2019 to 2022. Classes that experienced increasing interest by the later period included secreted proteins/peptides, mRNAs, genes, and others, including metabolites, sugar chains, and structural proteins.
Some significant FDA approvals in the decade from 2010 to 2019 include the chimeric antigen receptor (CAR)-T cell therapies Kymriah and Yescarta to treat different types of lymphoma, the gene therapy Luxturna for an inherited eye disease, the cancer vaccine Provenge, and the monoclonal antibody immune checkpoint inhibitors Opdivo, Keytruda, and Tecentrique. Other notable new FICs receiving approval during that period included the RNA interference (RNAi) drug Onpattro for treatment of hereditary transthyretin-mediated amyloidos, Xadago for Parkinson’s disease, Ocrevus for multiple sclerosis, and Radicaba for ALS.9
There are many strategies for identifying drug targets, but target-based approaches have emerged as both effective and widely adopted. An analysis of the 113 first-in-class (FIC) drugs approved by the FDA between 1999 and 2013 found that 78 were discovered using target-based methods — 45 were small molecules and 33 were biologics.10 Among the remaining 33 drugs identified through non-targeted strategies, 25 originated from a chemocentric approach, which begins with compounds known to have pharmacological activity. Only eight were discovered through phenotypic screening. The study authors noted that high-throughput screening technologies were still in their early stages during that period but anticipated these tools would play an increasingly important role in future drug target discovery.
New Frontiers, New Hurdles
Identifying novel drug targets is becoming increasingly difficult.3 Many of the most accessible and well-characterized “druggable” targets have already been thoroughly explored, leaving behind more complex or “undruggable” targets that require innovative technologies to address. As a result, many pharmaceutical companies are investing in new therapeutic modalities — including bispecific antibodies, antibody fragments, antibody–drug conjugates (ADCs), gene and gene-editing therapies, proteolysis-targeting chimeras (PROTACs), and nucleic acid-based medicines.
Despite these advances, only about 20% of FDA-approved drugs act via novel mechanisms of action.5 This relatively low percentage reflects the higher risk profile associated with first-in-class (FIC) development. Success rates for FICs are lower — around 5%, compared with 8% for drugs built on validated targets — and they tend to generate less revenue on average ($2.8 billion vs. $3.6 billion).
Notably, the recent success of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss demonstrates that dramatic commercial gains can still be achieved through repurposing existing drug classes. Originally developed as FIC drugs for type 2 diabetes, GLP-1 agonists have found new and rapidly expanding applications in obesity treatment.
Finally, sustained investment in basic research is critical to the discovery of future drug targets. Cuts to funding for academic and government research institutions in recent years have raised concerns that progress in this area could slow significantly without renewed support.
Highlighting a Few Important Discoveries
Selected FIC Advances over the Last 50 Years11
Hydroxymethylglutaryl coenzyme A (HMG- CoA) reductase inhibitors (statins) for cholesterol control
Beta blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors (“prils” and “sartans”) for prevention of cardiac events
GLP-1 receptor agonists, dipeptidyl peptidase (DPP)-4 inhibitors (gliptins), and sodium-glucose co-transporter (SGLT)-2 inhibitors (gliflozins) for treatment of type 2 diabetes mellitus (T2DM)
Renin–angiotensin–aldosterone system (RAAS) inhibitors for delaying nephropathy progression in T2DM in patients
B-Raf proto-oncogene 1 (BRAF) protein inhibitors for the treatment of malignant melanoma
EGFR inhibitors for the treatment of small-cell lung cancer
Immune checkpoint inhibitors that target immune rather than cancer cells, providing durable responses in many previously-difficult-to-treat oncology indications
Anti-tumor necrosis factor (TNF)-alpha agents for treatment of autoimmune/inflammatory disorders
Selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression and anxiety disorders
“Atypical” antipsychotics for the treatment of schizophrenia and related psychotic disorders
Beta-adrenoceptor agonists, long-acting beta-adrenoceptor agonists (LABAs), and long-acting muscarinic receptor antagonists (LAMAs) for treatment of chronic obstructive pulmonary disease (COPD)
Cystic fibrosis transmembrane conductance regulator (CFTR)-directed therapeutics for the treatment of cystic fibrosis
Recombinant enzyme replacement therapies for metabolic disorders caused by enzyme deficiencies
Vascular endothelial growth factor A inhibitors for treatment of many eye diseases that can result in vision loss
Antiretroviral therapies (ARTs) for treatment of acquired immunodeficiency syndrome (AIDS)
Gene therapies for multiple rare and increasingly more prevalent diseases
Cell therapies, including adoptive cell therapies such as CAR T-cell treatments, for cancer and many other indications.
Our parent company, That’s Nice, is committed to supporting the companies and innovators driving the next wave of pharma and biotech innovation. To celebrate That’s Nice’s 30th anniversary, Pharma’s Almanac is diving into 30 groundbreaking advancements, trends, and breakthroughs that have shaped the life sciences, highlighting the industry-defining milestones our agency has had the pleasure of growing alongside. Here’s to 30 years of innovation and the future ahead!
References
1. Gu, Jinying, Qiuyu Wu, Qiuyue Zhang, Qidong You, and Lei Wang. “A decade of approved first-in-class small molecule orphan drugs: Achievements, challenges and perspectives.” European Journal of Medicinal Chemistry. 243: 114742 (2022).
2. Seoane-Vazquez, E, R Rodriguez-Monguio, and JH Powers. “Analysis of US Food and Drug Administration new drug and biologic approvals, regulatory pathways, and review times, 1980–2022.” Sci. Rep. 14: 3325 (2024).
3. Okuyama, Ryo. “Chronological Analysis of First-in-Class Drugs Approved from 2011 to 2022: Their Technological Trend and Origin.” Pharmaceutics. 15; 1794 (2023). h
4. Batta, Angelika, Bhupinder Singh Kalra, and Raj Khirasaria.“Trends in FDA drug approvals over last 2 decades: An observational study.” J. Family Med. Prim. Care. 9:105–114 (2020).
5. Falaguera, Maria J, et al. “Temporal trends in novel drug target discovery reveal the increasing importance of human genetic data.” 20 Dec. 2024.
6. Kinch, MS, D Hoyer, E Patridge, and M Plummer. “Target selection for FDA-approved medicines.” Drug Discov. Today. 20: 784–789 (2015).
7. Santos, R,. et al. “A comprehensive map of molecular drug targets.” Nat. Rev. Drug Discov. 16: 19–34 (2017).
8. Zdrazil, B, et al. “Moving targets in drug discovery.” Sci. Rep. 10: 20213 (2020).
9. Hogg, Peter. “The most significant FDA approvals of the decade (2010-2019).” Proclinical Blog. 1 Sep. 2020.
10. Eder, J, R Sedrani, and C Wiesmann. “The discovery of first-in-class drugs: origins and evolution.” Nat. Rev. Drug Discov. 13: 577–587 (2014).
11. Peters, Dene C. “50 Years of Drugs.” Drugs. 81: 3–5 (2020).