[Nature Sub-Journal] Review of FDA-Approved Drugs in 2021

On January 4, 2022, the journal Nat Rev Drug Discov published an article reviewing and commenting on the drugs approved by the FDA in 2021

The FDA has approved 50 new drugs in 2021 , including the first KRAS inhibitor for cancer and the first anti-amyloid antibody therapy for Alzheimer's disease

FDA approves 50 new drugs in 2021

Despite the ongoing impact of COVID-19, the number of FDA approvals last year was largely in line with recent years

Figure 1 | FDA-approved new drugs since 1993

The number of new molecular entities (NMEs) and biologics license applications (BLA) approved by the FDA's Center for Drug Evaluation and Research (CDER) each year

Products such as vaccines and gene therapies approved by the Center for Biologics Evaluation and Research (CBER) are not included in this drug count (see Table 2)

Table 1 | 2021 CDER Approvals

aApproved biologics

Additional FDA approvals for CBER include a landmark mRNA vaccine and CAR-T cell product (Table 2)

Table 2 | 2021 CBER Approvals

Emergency use authorizations (EUAs) also made news, including antibodies against COVID-19 and rapidly developing oral antivirals (Table 3)

Table 3 | Emergency Use Authorization for 2021

Cancer approvals still dominate, with 15 (30%) of new approvals (Figure 2)

Cancer approvals still dominate, with 15 new approvals

Figure 2 | CDER Approvals by Therapeutic Area

Indications that span multiple disease areas are grouped into only one area

CDER-approved drugs include the 100th antibody, two ADCs, a bispecific antibody, a constraint peptide, and two oligonucleotide drugs (Figure 3)

Figure 3 | CDER Approvals by Mode

"Small molecule" includes all peptides up to 40 amino acids in length

However, the sales potential of these products continued to be dragged down

Analysts expect only 8 CDER-approved products to reach blockbuster status

But new CBER approvals are compensating, and the COVID-19 vaccine is breaking records

Table 4 | Blockbuster contenders in 2021

a 2027 average sales forecast

A victory for vaccines

The vaccine (approved by CBER) is the star of the 2021 approval show

Pfizer and BioNTech's mRNA vaccine tozinameran (Comirnaty)

BioNTech began work on this mRNA vaccine for COVID-19 in January 2020 and partnered with Pfizer in March
.
A Phase II/III trial began in July, with safety and efficacy data for EUA by December 2020
.
Full approval was passed in August 2021, just 1.
5 years after the program began
.
The average time to vaccine discovery and development was 10.
7 years
.

Tozinameran is also breaking business records
.
Analysts forecast sales of more than $35 billion in 2021, surpassing the $21 billion in 2019 of No.
2 AbbVie's TNF blocker adalimumab
.
Previously, the antiviral combination of ledipasvir and sofosbuvir launched by Gilead earned more than $10 billion in hepatitis C virus treatment in its first year on the market
.

Tozinameran is also breaking business records
.
Analysts predict sales of more than $35 billion in 2021

High-income countries have been criticized for buying too much tozinameran, and Pfizer has also been criticized for its pricing and distribution policies
.

Moderna's elasomeran (Spikevax ) is a close second in both speed and profitability
.
It also received EU clearance for COVID-19 in December 2020
.
Full US FDA approval is expected by April 2022 (see Table 5 for additional drug candidates that will be approved in 2022)
.
Analysts forecast elasomeran sales to exceed $17 billion in 2021
.

Moderna's elasomeran (Spikevax ) is a close second in both speed and profitability
.

Table 5 | Some Approvals to Watch in 2022

a Designated Breakthrough Therapy

b Blockbuster forecast to 2027, according to Cortellis database

"These successes have fueled a wave of investment in mRNA technologies for influenza, other infectious diseases and cancer," said Uğur Şahin, CEO of BioNTech, "We now have funding to accelerate our cancer pipeline and make it even bolder
.

Pfizer's Prevnar 20 , a 20-valent conjugate vaccine against S.
pneumoniae serotypes, is expected to reach $4.
4 billion in sales by 2027
.
Prevnar 20 is the next-generation version of Prevnar 13, the world's best-selling vaccine prior to the advent of tozinameran
.

Prevnar 20 by Pfizer

Analysts also predict that Merck's newly approved 15-valent pneumococcal vaccine Vaxneuvance will be a blockbuster
.

Merck's newly approved 15-valent pneumococcal vaccine Vaxneuvance

cancer moment

The approval of Amgen's KRAS-G12C inhibitor sotorasib is a momentous moment for the cancer community
.

Amgen's KRAS-G12C inhibitor sotorasib

Researchers discovered KRAS more than 40 years ago as a proto-oncogene and found it to be one of the most frequently mutated genes in cancer
.
However, due to the lack of an operational binding pocket, this GTP hydrolase was not discovered by drug developers for a long time
.
Then in 2013, chemical biologist Kevan Shokat of the University of California, San Francisco, provided a foothold by discovering a xenobiotic pocket on the G12C variant of the enzyme
.
Industry swarmed
.

"I knew there would be a lot of interest once someone cracked the RAS target directly, I just didn't know there would be that much interest," Shokat said
.

Amgen's sotorasib is the first approved in the KRAS population for KRASG12C-mutated non-small cell lung cancer (NSCLC)
.

But while sotorasib's activity could be approved in this case, it hasn't lived up to the highest hopes for this cancer target
.
Amgen is testing sotorasib in combination with other drugs for various cancers
.
Analysts forecast sales of $1.
6 billion by 2027
.

Other KRAS-targeted therapies are on the way
.
Mirati expects its KRAS-G12C inhibitor adagrasib to be approved in 2022
.

Other KRAS-targeted therapies are on the way
.
Mirati expects its KRAS-G12C inhibitor adagrasib

Merck's belzutifan drives another longstanding cancer story
.
FDA approves first class of hypoxia-inducible factor-2α (HIF-2α) inhibitors for the treatment of tumors associated with von Hippel-Lindau (VHL) disease, a hereditary tumor associated with well-developed blood vessels disease
.
Decades of research into the biology of VHL disease has shown that HIF-2α is a key driver of oxygen sensing, paving the way for a new class of antiangiogenic drugs and leading to William Kaelin et al at the Dana-Farber Cancer Institute won the Nobel Prize
.

belzutifan of Merck

HIF-2α, a transcription factor, is another class of target that medicinal chemists often grapple with
.
Belzutifan was also made possible by the discovery of a heterologous pocket in 2009
.
"There are now new ways to discover compounds that bind to various corners on proteins that aren't necessarily the active site, and some are using these to find allosteric inhibitors," Kaelin said
.

HIF-2α, a transcription factor, is another class of target that medicinal chemists often grapple with
.

With the approval of BMS' Idecabtagene viccleucel for multiple myeloma, oncologists also have access to BCMA-targeted CAR-T cell therapy
.
BCMA is expressed on the surface of B cells and has become a testing ground for antibodies, bispecifics, ADCs and cell therapies
.
The US FDA approved the first BCMA-targeted biologic (GSK's ADC belantamab mafodotin) in 2020
.
Idecabtagene viccleucel offers an alternative to cell therapy
.
T cells were harvested from a patient, engineered in vitro to target BCMA, and then reinfused into the patient
.

Other BCMA-targeted candidates coming to market include J&J's CAR-T therapy ciltacabtagene autoleucel , which is under FDA review
.

Other BCMA-targeted drug candidates coming to market include J&J's CAR-T therapy ciltacabtagene autoleucel

The FDA has approved five other CAR-T therapies, all of which hunt and destroy CD19-expressing blood cancer cells
.

The antibody model ushered in its 100th approval as the FDA gave the green light to GSK's PD1-targeting monoclonal antibody dostarlimab
.
Thirty-five years ago, the FDA approved the first antibody in 1986
.
Now, it approves about 10 antibody-based products a year
.

Dostarlimab is the seventh PD1/PDL1-targeting antibody to be marketed
.
Sales forecasts for this checkpoint inhibitor reflect its latecomer status
.
Analysts forecast sales of Merck's first-in-class product pembrolizumab to exceed $30 billion by 2027, while they forecast dostarlimab sales of just $270 million in 2025
.

The FDA is reviewing 4 additional PD1/PDL1 antibodies for approval in 2022
.
The FDA's Julia Beaver and Richard Pazdur recently wrote that checkpoint inhibitors have become a wild west in drug development, marked by "a stampede of developers, clinical trials, and redundant development programs.

" They urged drug developers to cooperate better
.

FDA is reviewing 4 additional PD1/PDL1 antibodies

BMS has submitted relatlimab, the first LAG3-targeted checkpoint inhibitor, for FDA review
.
A decision will be made in 2022
.

The FDA approved two ADCs in 2021
.
ADC Therapeutics' loncastuximab tesirine is a CD19-directed ADC for B-cell lymphoma
.
Seagen and Genmab's tisotumab vedotin is a tissue factor-directed ADC for the treatment of cervical cancer
.
These bring the number of approved ADCs to 11
.
In the past 3 years, the FDA has approved 7 of them
.
AstraZeneca's HER2-targeting ADC, trastuzumab deruxtecan, was approved by the FDA in 2019, and emerging clinical data show that the new ADC could deliver considerable benefits over antibody and ADC "pioneers
.
"

FDA approves two ADCs in 2021

"The progress here is because we are now designing the ADC as a whole system," said Susan Galbraith, head of oncology research and development at AstraZeneca
.

J&J received approval for amivantamab, a bispecific antibody against EGFR and MET , for the treatment of NSCLC with EGFR exon 20 mutations, cancers that are resistant to small-molecule EGFR inhibitors
.
When amivantamab binds to the extracellular domain of either receptor, it blocks ligand binding, promotes endocytosis and degradation of receptor-antibody complexes, and triggers trogocytosis and antibody-dependent cytotoxicity
.

bispecific antibody

Amivantamab is the third bispecific antibody to market
.
This antibody format accounts for nearly 20% of the clinical-stage antibody pipeline
.

The FDA also approved Takeda's mobocertinib, a small-molecule kinase inhibitor designed to selectively target EGFR with mutations in exon 20, for the same indication
.

Small Molecule Kinase Inhibitors

Alzheimer's disease

The FDA approved Biogen and Eisai's amyloid beta-lowering antibody aducanumab in the most controversial decision of the year
.

The FDA approved Biogen and Eisai's amyloid beta-lowering antibody aducanumab in the most controversial decision of the year
.

In early 2019, an interim analysis of two phase III trials of aducanumab in Alzheimer's disease failed to find evidence of activity, prompting Biogen to halt development
.
But the company then reanalyzed the data, found a tinge of effect, and submitted it for approval
.

In November 2020, an independent FDA advisory panel voted 10-0, with 1 abstention, against approval
.
These experts questioned the clinical significance of Biogen's statistical methods and claimed effects
.
The FDA then used the accelerated approval pathway to give aducanumab the green light based on its ability to reduce amyloid levels, an unproven surrogate endpoint
.
The FDA gave Biogen until 2030 to confirm that the antibody provided clinical benefit
.

Using the accelerated approval pathway, the FDA gave aducanumab the green light based on its ability to reduce amyloid levels, an unproven surrogate endpoint
.

The approval has divided society and sparked multiple investigations into the FDA's decision-making process
.

Analysts still forecast that Biogen's blockbuster sales will reach $4.
1 billion by 2027
.
But sales started slowly, and some treatment centers in the U.
S.
refused to prescribe the antibody
.
Biogen initially priced aducanumab at $56,000 a year, but has since halved its cost
.
European regulators rejected the antibody, and Japanese regulators appear set to follow suit
.
The product's commercial success will depend on whether Medicare, the nation's national insurance plan for people 65 and older, will cover it
.
A draft decision is due in January
.

Two more anti-amyloid antibodies could arrive in 2022
.
Biogen and partner Eisai are completing the lenacumab application
.
Eli Lilly is also preparing to submit its donanemab and hopes to have confirmed evidence of benefit in 2023
.

Two more anti-amyloid antibodies could arrive in 2022
.

"Could the approval of aducanumab be done better? I think everyone agrees that this can be rolled out more efficiently," Mark Mintun, senior vice president of neuroscience research and development at Lilly, told Nature
.
"But as the data accumulates, people will increasingly believe, I think, that these differences will disappear
.
"

Other excellent products

With the approval of Novartis and Alnylam's inclisiran, a fourth siRNA-based drug has arrived
.
This approach uses RNA interference to reduce the expression of therapeutic targets
.

inclisiran inhibits PCSK9 to lower LDL-cholesterol
.
The FDA approved two PCSK9-targeting antibodies in 2015 (Regeneron and Sanofi's alirocumab, Amgen's evolocumab) for a subset of patients at increased risk of cardiovascular disease, but these products have yet to meet multiple blockbuster sales expectations
.
Inclisiran's convenience factor may help it get better grades
.
Antibodies are given every 2-4 weeks, while inclisiran can be given twice a year
.

Alnylam anticipates that long-acting siRNAs could be transformative in multiple therapeutic areas
.
"We're in an extraordinary period of renaissance in terms of where this technology is going," said John Maraganore, Alnylam's outgoing CEO
.

Alnylam anticipates that long-acting siRNAs could be transformative in multiple therapeutic areas
.

If the FDA approves Anlyam's vutrisiran in 2022, it would be the fifth RNAi approval in as many years
.

If the FDA approves Anlyam's vutrisiran in 2022, it would be the fifth RNAi approval in as many years
.

Regeneron achieved another first in the cardiovascular field (with its first-in-class ANGPTL3-targeting evinacumab)
.
Regeneron genetically validated this target in atherosclerotic cardiovascular disease in 2017
.
It has now received approval for homozygous familial hypercholesterolemia (HoFH), a genetic disorder characterized by extremely high LDL cholesterol levels
.
Another phase III trial for the prevention of acute pancreatitis is underway
.

AstraZeneca and Amgen's tezepelumab is a TSLP-directed mAb (first-in-class) for the treatment of severe asthma
.
TSLP is an IL-7-like cytokine that regulates multiple inflammatory cascades and can trigger allergic, eosinophilic, and other forms of inflammation associated with lung disease
.
Tezepelumab is the only biologic approved for severe asthma without any phenotypic or biomarker limitations on its label
.
Analysts expect sales to reach $1.
4 billion by 2027
.

AstraZeneca and Amgen's tezepelumab

AstraZeneca's anifrolumab is the first new drug approved for systemic lupus erythematosus (SLE) in a decade
.
Many patients with systemic lupus erythematosus have elevated levels of type I interferon, and mutations in interferon signaling are associated with susceptibility to the disease
.
Anifrolumab blocks the activity of these cytokines by binding to type I interferon receptors
.

Anifrolumab by AstraZeneca

Apellis' pegcetacoplan is the first approved complement protein C3 inhibitor, demonstrating continued interest in complement-regulating drugs
.
The U.
S.
Food and Drug Administration approved the constrained cyclic peptide for paroxysmal nocturnal hemoglobinuria, a rare and potentially fatal blood disorder
.

Apellis' pegcetacoplan

ChemoCentryx's avacopan , approved by the FDA in 2021 for ANCA-associated vasculitis, is the first approved complement 5a receptor antagonist
.

avacopan by ChemoCentryx

"We're going to see a lot of complement modulator activity, especially if drug developers can succeed outside of rare indications," said immunologist John Lambris of the University of Pennsylvania
.

While COVID-19 vaccines, antibodies and antivirals show how quickly drug developers can move under pressure, Takeda's maribavir offers a negative lesson
.
Phase I data for this antiviral drug were first presented in 1996
.
The antiviral drug went through deprioritization and licensing, failed Phase III trials and two company acquisitions before it was approved this year to treat cytomegalovirus (CMV) infection
.

If it doesn't work at first

The FDA also rejected several applications last year (Table 6)
.
Some of these may soon be resubmitted to the FDA for review
.
For example, Provention Bio is working to resubmit its CD3-targeted teplizumab for delayed type 1 diabetes in high-risk populations
.
Teplizumab was first tested in clinical trials in 1997 for the treatment of transplant rejection and has led a line of T-cell modulation therapies for autoimmune diseases
.

The FDA also rejected several applications last year (Table 6)
.
Some of these may soon be resubmitted to the FDA for review
.

Table 6 | Drugs Rejected in 2021

a to be approved later this year

Other rejected treatments have also come to an end
.
Pfizer and Eli Lilly stopped development of their NGF-targeting tanezumab this year after the FDA issued a full response letter to its use in osteoarthritis pain
.
The FDA placed once-promising anti-NGF drugs on clinical hold in 2010 after Phase III data showed the painkillers could cause joint destruction
.

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