June 20, 2021

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Trend of drug development: Drugs approved by the FDA in 2010-2019

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Trend of drug development: Drugs approved by the FDA in 2010-2019

 

Trend of drug development: Drugs approved by the FDA in 2010-2019.  The drugs approved by the FDA in the past 10 years  (2010-2019). look at the trend and future of new drug development. 


The latest issue of the JMC journal, titled A Decade of FDA-Approved Drugs (2010–2019): Trends and Future Directions, publishes a review article that analyzes and summarizes the situation of new drugs approved by the FDA in the past 10 years, and has a great impact on the future. The outlook was carried out.

Trend of drug development: Drugs approved by the FDA in 2010-2019


From 2010 to 2019, the US FDA approved a total of 378 new drugs and 27 biosimilars, of which the oncology field accounted for 25%, the infection field accounted for 15%, and the central nervous system field accounted for 11%. Regulatory incentives are quite effective. With the increase of orphan drug indications, the clinical development time of the drug is prolonged. Small molecules still mainly follow the 5R rule, but with the approval of antisense oligonucleotides (ASO), siRNAs and ADC drugs, new models of innovative drugs are progressing rapidly.

 

Background

In the past ten years, forecasts of patent expiration, rising R&D costs, and declining approval numbers have brought huge challenges to the pharmaceutical industry. A 2009 report estimated that between 2010 and 2014, more than US$209 billion in annual sales would be at risk due to patent expiration.

For example, atorvastatin (peak sales of US$13 billion in 2006) lost in 2011 With exclusivity, both clopidogrel (peak annual sales of $7.1 billion) and montelukast (peak annual sales of $5.5 billion in 2012) lost their exclusivity in 2012. The introduction of the Biological Product Price Competition and Innovation Act (BPCIA) in 2009 encouraged generic competition of biological products, such as the number one-selling prescription drug Adalimumab (peak annual sales of $19.9 billion in 2018). Competition in four biosimilars (all approved in the past 4 years).

 

In addition to the loss of market share of best-selling drugs due to generic competition, as the number of innovative new drugs on the market continues to decrease, people are also worried that original innovative drugs (first in class, FIC) have stagnated, and new batches of drugs will not be able to compensate for the expiration of patents. The loss caused. For example, only 19 new molecular entities (NMEs) were approved in 2007, which is the lowest number since 1983; and FIC was only 29%, which dropped further to 17% in 2009. The “best-selling drug” mania and “Mee-to” drug concept that dominated the 1990s and early 2000s do not seem to be a viable model for maintaining the industry.


In summary, these factors make it necessary for the pharmaceutical industry to reform itself to prevent the expected decline in the number of new drugs and bring innovative drugs to the market. More important than the health of the pharmaceutical industry is that the unmet medical needs of patients urgently need to invent innovative drugs.

 


Number of drugs approved in 2010-2019

From 2010 to 2019, a total of 289 new molecular entities (NME), 89 biologic license applications (BLA) and 27 biosimilars were approved (Figure 1). In the past ten years, the median number of NME and BLA approvals per year was 40, the lowest in 2010 was 21, and the highest in 2018 was 59.


In contrast, during the ten years from 2000 to 2009, 25 new drugs were approved each year, with the highest in 2004 and the lowest in 2007 with 36. The proportion of BLA approvals has not changed in the past ten years (Figure 1), accounting for an average of 23% of all new drug approvals (excluding biosimilars). The lowest percentage of BLAs approved in 2013 was 8%, compared with 32% in 2015. Since the first FDA approval in 2015, the number of approvals for biosimilars has steadily increased.


Trend of drug development: Drugs approved by the FDA in 2010-2019

Figure 1 Number of NMEs and BLAs approved from 2010 to 2019


Number of New Molecular Entities (NME), Biologic License Applications (BLA) and Biosimilars approved from 2010 to 2019


Approve the time

This article compares the time from submission of IND (investigational new drug) application to final NDA (new drug application) approval for 268 new drugs from 2010 to 2019 (Figure 2).
Trend of drug development: Drugs approved by the FDA in 2010-2019

Figure 2 Time from IND application to drug approval

The average time from IND application to NDA approval was 8.7 years (±3.8), and the median was 8.1 years (range 2.2-23.2). The EGFR inhibitor osimertinib was approved by the NDA in 2.2 years, setting a record for the shortest approval period; deflazacort was 2.3 years. In contrast, Ibalizumab and flibanserin took 16 and 18 years from IND application to NDA approval, respectively.



In the past, the study of the timetable from IND application to NDA approval is shown in Table 1. From 1987 to 1989, the median total time from IND to NDA approval was 7.7 years, the median development time was 4.2 years, and the regulatory time was 2.5 years. From 1990 to 1992, this time remained relatively stable (the median total time from IND to NDA approval was 7.8 years, the median clinical development was 4.9 years, and the median regulatory review was 2.0 years). From 1992 to 2002, the median time from IND application to NDA approval was reduced to 6.4 years, the median time for clinical trials was 5.1 years, and the median time for regulatory review was 1.2 years.


The significant acceleration in regulatory approval is attributed to the 1992 Prescription Drug User Fee Act (PDUFA), which uses user fees as a mechanism to fund regulatory review and reduce review time. Today, many rapid review determinations help reduce regulatory review time, including fast track (started in 1988), priority review and accelerated approval (1992), and breakthrough therapy (2012)


Therefore, from 2012 to 2016, the median time from IND to NDA for non-rapid review drugs was 8.0 years, and breakthrough therapy drugs were approved the fastest, with a median of 4.8 years. According to the latest data from the FDA, the approval time has remained consistent since the mid-1990s. The median priority review in 2016 was 8 months, while the standard review application was 10 months.
Although the approval time has been accelerated to a large extent due to accelerated review, clinical trial cycles (especially Phase II and Phase III trials) have increased in recent years. Martin et al. speculate that the increase in development time may be due to the increased complexity of the experimental design.

 


Quick review status

In order to accelerate the entry of drugs for the treatment of life-threatening or serious diseases into the market, the FDA has established four accelerated review channels: priority review, fast track, breakthrough therapy, and accelerated approval (Figure 4). These channels are not mutually exclusive, meaning that a drug can enter the rapid review state in more than one of the channels.


Each bar graph represents the percentage of each category relative to all drugs approved in a given year. A drug can be divided into multiple categories.


Figure 5 shows the rapid review status of FDA approved drugs from 2010 to 2019. For example, of the 48 drugs approved in 2019, 17 are fast track (35%), 13 are breakthrough therapies (27%), 28 are priority review (58%), and 9 are accelerated approval (19 %).


In the rapid review category, priority review names account for the majority. Since 2014, more than half of the drug approvals per year belong to this category (Figure 5). In the past ten years (except in 2010), the percentage of FDA-approved drugs with fast track names has remained relatively stable, with an average of 35%. Since the breakthrough category was introduced in 2012, more and more drugs have been awarded this designation, which currently accounts for 25% of approved drugs.


The most stringent channel is accelerated approval. On average, only 13% of new drugs receive accelerated approval. The accelerated approval designation grants early approval of the drug and requires further clinical studies to confirm the efficacy, so it is used with caution. For example, in 2019, only 9 compounds received accelerated approval, of which 7 were tumor indications; 3/4 of the drugs approved in 2018 were also used for tumors.


The same drug may enter multiple accelerated approval channels. For example, larotrectinib obtains breakthrough and priority evaluation at the same time, duvelisib obtains fast path and priority evaluation, lorlatinib obtains breakthrough and priority evaluation, and migalastat obtains fast path and priority evaluation.

 


Treatment field

The analysis of the 289 NME and 89 BLA treatment areas approved from 2010 to 2019 revealed that the top five treatment areas (NME and BLA) for new drugs approved by the FDA are oncology (25%) and infection (14%) , Central Nervous System (CNS) diseases (12%), metabolic disorders (7%) and cardiovascular diseases (6%) (Figure 7a). Approximately 4% of the new approvals are used in the integrated fields of hematology, respiratory, imaging/diagnostics, gastrointestinal and immunology ).

(A) Based on 378 approved NMEs and BLAs, the percentage of approvals divided by disease area from 2010 to 2019; (b) The treatment area approvals are divided into 2010-2014 (orange, 158) and 2015-2019 (green, 220)


Analysis of the therapeutic areas in 2010-2014 and 2015-2019 (Figure 7b) found that: approvals for hematology have increased in the past ten years; only 3 drugs were approved in 2010-2014 (1.9%), while 2015- In 2019, 14 drugs were approved (6.3%).


On the other hand, the proportion of new drug approvals in some disease fields has seen a small to moderate decline, including metabolic disorders (5.4% from 2015 to 2019, 10% from 2010 to 2014), respiratory diseases (2015 to 2019) 3.1% in the year, 6.3% from 2010 to 2014) and imaging/contrast agent (3.1% from 2015 to 2019, 6.3% from 2010 to 2014).


It is worth noting that no cardiovascular or diabetes drugs were approved in 2018, and only one drug in a specific disease field was approved in 2019. The slowing down of approvals may indicate that the current standard of care is sufficient to cover most patients. In addition, if many standard treatments are non-patented or will soon be non-patented, then a new drug needs to have clear patient benefits to prove that the benefits of the new treatment are higher than the non-patented therapies.


In a typical R&D strategy, patient needs, differentiation, and economic feasibility are all factors that need to be considered. Since new drug approval is a lagging investment indicator, given the long average time from preclinical development to approval, any new drug on the market reflects the research investment in the past few decades.

 

Tumor

In the past decade, a major breakthrough in cancer treatment has been the introduction of immuno-oncology (I-O) drugs. A major advance in this field is the discovery that T cells can be turned on or off through so-called “immune checkpoints.” The main regulator of this pathway was identified as CTLA-4. Ipilimumab, a CTLA-4 antibody, was approved for metastatic breast cancer in 2011, marking the first approval of an immuno-oncology drug. In 2014, the PD-1 blocker pembrolizumab was the first approved second-generation immuno-oncology drug.

In the past decade, another important new type of cancer treatment drug approved is PARP inhibitors (Figure 8). Mutations in BRCA make tumor cells sensitive to PARP inhibitors. The first PARP inhibitor, olaparib, was approved in 2014 for BRCA-mutated advanced ovarian cancer; other PARP inhibitors approved later are rucaparib 14 (2016), niraparib 15 (2017) and talazoparib 16 (2018).


Among 103 oncology drugs approved in 2010-2019, the first batch of indications was leukemia (Table 2, 17%), followed by breast cancer (12%) and non-small cell lung cancer (9%). Of the 18 leukemia approvals, 50% are FIC drugs, including: IDH1 inhibitor ivosidenib (2018), IDH2 inhibitor enasidenib (2017), KIT/FLT3) inhibitor midostaurin (2017), and BCL-2 inhibitor venetoclax (2017) ). Other new kinase inhibitors approved for leukemia include PI3Kδ inhibitor idelalisib (2014), BTK inhibitor ibrutinib (2013) and Bcr-Abl inhibitor ponatinib (2012). In addition, two BLA approvals are considered FIC: the CD22-ADC drug inotuzumab (2017) and the CD19/CD3 bispecific antibody blinatumomab (2014) (Table 2).


In the past decade, the FDA has approved more and more oncology drug companion diagnostics. Since the first trastuzumab companion diagnosis was approved in 1998, a total of 44 companion diagnoses have been approved. Among the 38 FIC oncology drugs from 2010 to 2019, the FDA approved 12 companion diagnostics.

 

 

New antiviral drugs

The decade 2010-2019 witnessed a variety of new mechanism drugs used to fight viral infections. In 2018, the CD4 antibody ibalizumab-uiyk was approved, which is the first monoclonal antibody against HIV and a new therapeutic mechanism in more than a decade. In addition, letermovir, a new drug for the treatment of cytomegalovirus (CMV), was approved in 2017 (Figure 11). It is a non-nucleoside CMV inhibitor that inhibits DNA terminal enzyme complexes. Its unique mechanism of action brings less Adverse reactions.

imageIn the past decade, the hepatitis C virus (HCV) treatment has been the biggest impact of antiviral drugs. In 2011, boceprevir was approved as the first NS3/4A serine protease inhibitor to be used in combination with peginterferon alpha and ribavirin. In 2013, the first NS5B polymerase inhibitor sofosbuvir was approved, followed by NS5A inhibitors such as daclatavir. In patients treated with Ledipasvir (also an NS5A inhibitor) and Sofosbuvir 29 for 12 weeks and 24 weeks, the remission rates of HCV were 94% and 99%, respectively. Another NS5A inhibitor, velpatasvir, was approved in 2016, and many other new HCV NS3/4A protease inhibitors include simeprevir, paritaprevir, grazoprevir, glecaprevir, and voxilaprevir .

 

 

 

New antibacterial and antiparasitic drugs

Approvals of antibacterial drugs are also increasing. Due to the emerging crisis of super bacteria and drug-resistant bacteria, as well as the large-scale divestment of many large pharmaceutical companies, the GAIN Act (“immediate antibacterial incentives”) was passed in 2011, providing new antibiotics with 5 years of market exclusivity and fast-track approval . Potential drugs for the treatment of life-threatening infections can obtain the title of qualified infectious disease products (QIDP) and allow the use of GAIN Act incentives.


Since 2014, a total of 15 new antibacterial drugs have obtained QIDP certification (Table 3). Although the GAIN Act encourages the development of new antibiotics, new antibacterial therapies are still elusive. The vast majority of approvals come from traditional therapies, such as tetracyclines, aminoglycosides and fluoroquinolones.

There have been some innovative developments in β-lactamase inhibitors. For example, Wabobactam (2017) is the first oxoboole β-lactamase inhibitor used in combination with meropenem (Figure 13). Another new type of β-lactamase inhibitor, Avibactam (a non-β-lactam), was approved for use in combination with ceftazidime in 2015.

Some drugs for the treatment of neglected tropical diseases have also been approved, such as pretomanid (2019) for the treatment of multidrug-resistant tuberculosis (TB), moxidectin (2018) for river blindness, and tafenoquine (2018) for the treatment of malaria. 2018) etc.

Charities and charitable foundations promote and facilitate the development of many tropical disease drugs. For example, pretomanid is developed by the Global Tuberculosis Drug Development Alliance (TB Alliance), and tafenoquine is a collaboration between Malaria Ventures and GlaxoSmithKline (GSK) developing. These types of foundations and collaborations are essential to address neglected tropical diseases, because these diseases lack significant economic benefits to incentivize investment in research, development, and commercialization of new drugs.

 

 

Central nervous system drugs

At the beginning of this century, there have been major changes in neuroscience drug development, and several major pharmaceutical companies including AstraZeneca, GlaxoSmithKline, Novartis and Pfizer have conducted large-scale divestments. Part of the reason for this sharp divestment is that the risk of developing psychiatric drugs is increasing, and biomarkers are not readily available. But surprisingly, in the context of a large number of R&D withdrawals, the number of approved central nervous system drugs has remained stable throughout the decade, accounting for 10% of the total approved amount.

Among them, edaravone is the first new treatment for amyotrophic lateral sclerosis (ALS) approved in 20 years (Figure 14). Nusinersen is the first approved treatment for spinal muscular atrophy (SMA).

SMA is a group of rare neuromuscular diseases characterized by the loss of motor neurons. SMA is a general term for several disease subtypes, defined by the age of onset and the severity of the disease. SMA is caused by mutations in the Survival Motor Neuron Gene 1 (SMN1) gene, which is one of two genes encoding Survival Motor Neuron (SMN). The loss of SMN protein is the driving factor of the neurodegenerative phenotype. The second gene, SMN2, has almost the same sequence as SMN1, but contains a single nucleotide substitution, resulting in exon 7 being excluded, leading to truncated protein expression.

Nusinersen is an antisense oligonucleotide (ASO) that can regulate the splicing of SMN2 precursor mRNA and promote the inclusion of exon 7 in SMN2, thereby increasing the expression of SMN2 and the production of functional SMN.

Migraine drugs have also been approved. Three new calcitonin gene-related peptide (CGRP) antagonists (fremanezumab, erenumab, and galcanezumab) were approved in 2018, all of which are monoclonal antibodies. These drugs mark the first new treatment for migraine in more than 20 years. They provide the prevention and control of migraine, and are importantly different from the existing oral generic drugs.

Other FIC CNS drugs approved between 2010 and 2019 are shown in Figure 14. Lofexidine is an alpha2-adrenergic agonist for opioid withdrawal (2018), isoproterenol is an adenosine receptor antagonist for Parkinson’s disease (2019), Palapa Nell is an AMPA receptor antagonist as an antiepileptic drug (2012), Brixanolone is a GABAA receptor modulator (2019), and suvorexant is an orexin-1 antagonist for sleep disorders (2014) ), dimethyl fumarate for multiple sclerosis (2013), sphingosine receptor modulator fingolimod for multiple sclerosis (2010), and hypnosis for narcolepsy Medicine 56 (2019).

 

 

Orphan Drug

The Orphan Drug Act of 1983 provides for a 7-year market exclusivity period and tax credits and subsidies to support clinical trials of drugs for orphan diseases. According to the data of 289 NMEs and 89 BLAs from 2010 to 2019, the number of NMEs approved under the Orphan Drug Act has increased in the past ten years, exceeding 40% in 2010 (Figure 15), and the 10-year average is 37%. The BLA approved by orphan drug is 48% of all approvals.


In 2018, migalastat (Figure 6), approved as an orphan drug, is used to treat adult Fabry disease. The life-threatening lysosomal storage disorder caused by α-galactosidase deficiency leads to globulin ceramide (GL-3). ) Toxicity accumulates, and the prevalence is 1 in 400,000 to 1 in 600,000.

burosumab was also approved as an orphan drug in 2018 for the treatment of adults and children 1 year and older with X-linked hypophosphatemia (XLH). XLH is an anti-vitamin D rickets with a prevalence of 1: 20000.

Ravulizumab is approved as an orphan drug for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), which is a very rare disease caused by the immune response of the complement system to defective red blood cells, leading to hemolysis, potentially life-threatening blood clots and For bone marrow, the prevalence is as low as 0.5-1.5 parts per million.

 

 

Original Innovative Drug Approval (FIC)

Paul et al. believe that only 17% of approved drugs in 2009 were considered FIC, down from 29% in 2008, indicating that innovation and productivity in the entire pharmaceutical and biotechnology industries are declining. Here we analyzed the drugs approved by the FDA from 2010 to 2019 and determined the percentage of FIC based on the year of approval (Figure 16). We found that in the past ten years, an average of 37% of new drugs were FIC, with the lowest of 32% in 2013 and the highest of 49% in 2012. This shows that innovation (measured by FIC approval) has not stagnated throughout the decade.

 

Administration route and combination therapy of new molecular entities (NMEs)

From 2010 to 2019, oral administration is still the main route of administration for all over-the-counter drugs (201 kinds). Although compared with other routes of administration, the proportion of oral drugs has changed year by year, but in the past ten years, other routes of administration have not significantly increased or decreased (Figure 17a). In the past ten years, an average of 66% of newly approved drugs were administered orally and 15% were administered intravenously. Other routes of administration include inhalation, intramuscular injection, intra-aural administration, and topical administration. Only one intrathecal drug has been approved, the SMA drug nusinersen.


Figure 17 (a) The route of administration approved by the FDA from 2010 to 2019, (b) The single drug or fixed-dose combination approved by the FDA from 2010 to 2019


From 2010 to 2019, only 10% of NMEs were approved as fixed-dose combinations (Figure 17b), with the largest proportion of infectious drugs. In addition to HCV, four drug combinations for the treatment of HIV were approved in 2012. Of the 24 drugs in this category, 13 are used for viral or bacterial infections (Table 4). This is largely due to the fact that infectious diseases require drugs to act on multiple mechanisms to combat resistance.


Interestingly, in the past decade, only two fixed-dose oncology drugs have been approved. A fixed-dose combination of the HER2 antibody trastuzumab and hyaluronidase oysk was approved for breast cancer in 2019. In 2015, the combination of trifluridine and tepiracil (2015) was approved for colorectal cancer.

 

 

Black box warning

Many FDA-approved drugs receive a black box warning, which is a statement directly on the label indicating serious or life-threatening side effects. The black box warning was implemented in 1979 and can be attached when the drug is approved or during the post-marketing period. They can be specific to a drug or attached to an entire category of drugs.

We analyzed all 389 NMEs and BLAs from 2010 to 2019 to determine the initially approved NMEs and BLAs with black box warnings (Figure 21). Among New Molecular Entities (NMEs), 21% of approvals carry a black box warning, while almost half (42%) of BLA approvals carry a black box warning.


The number of approved BLAs with a black box warning may be caused by many factors. BLA is more approved for orphan indications. Given the lack of treatment options for orphan diseases, there is a greater willingness to bring the monitored risks into the clinic than with no-treatment alternatives. In addition, due to the disease indication itself, the mechanism of action of the biological agent or the route of administration, the risk of opportunistic infections in patients treated with biological agents is increased.

Inspections of the therapeutic areas of drugs approved from 2010 to 2019 showed that 31/103 (30%) of oncology drugs, 8/56 (14%) of infectious drugs, and 13/45 (28%) of central nervous system drugs , 7/28 (25%) of metabolic disease drugs and 11/22 (50%) of cardiovascular drugs approved black box warnings.

 

 

Characteristics of new chemical entity drugs

Ro5 is a set of drug-making rules, describing the characteristics of most known oral drugs. The rules are as follows: (1) No more than 5 hydrogen bond donors (HBD) in the molecule; (2) Hydrogen bond acceptors in the molecule (HBA) no more than 10; (3) molecular weight (MW) is less than 500; (4) cLogP<5.

In the original paper describing the 5 rules published by Lipinksi et al. in 2001, 90% of the known oral drugs met the rules. We checked the drugs approved from 2010 to 2019 to see if they meet these rules. From 2010 to 2019, a total of 192 approved drugs and oral drug combinations are expected to be absorbed orally. Since several of these approved drugs are used in combination with previously approved drugs, these combination partners were included in the analysis, and a total of 204 small-molecule oral drugs were used for evaluation.


We found that only 17% (35/204) of the drugs in the analysis violated more than one rule, while 83% (169/204) of the drugs violated one or more rules (Figure 22a). In addition, in the ten years from 2010 to 2019, the number of approved oral drugs that violated more than once did not change significantly over time (Figure 22b). Among these violations, most (62/73) were due to MW, followed by clogP (18/73), and then hydrogen bond acceptor (13/73) violations.

 

New types of drugs

Antisense oligonucleotides (AOS) and small interfering RNA (siRNA) are both RNA-targeted nucleotide therapies designed to regulate gene expression. ASOs are single-stranded modified deoxyribonucleic acids that bind to complementary RNA sequences. This may result in steric hindrance of translation, RNase H degradation of the DNA-RNA complex, or regulation of splicing. In contrast, siRNA is composed of double-stranded RNA molecules, which are dispersed within the cell. Single-stranded RNA also binds to complementary RNA target sequences and leads to mRNA degradation, resulting in expression silencing.

From 2010 to 2019, a total of 6 ASOs and 2 siRNAs were approved (Table 5). In contrast, before 2009, only two ASOs were approved, and no siRNA therapeutic drugs were approved. These include eteplirsen (2016), an ASO drug used to treat DMDM, and ASO nusinersen, used to treat SMA. Nusinersen is the only ASO approved for intrathecal administration in 2010-2019. Another ASO, inotersen (2018), is approved for the treatment of hereditary thyroxine-mediated amyloidosis polyneuropathy (hATTR).


In 2018, the first siRNA drug patisiran was approved by the FDA for polyneuropathy of hATTR. Aptamers are single-stranded oligonucleotides that can specifically bind target molecules such as polypeptides or small molecules. The first approved aptamer, pegaptanib, was approved for wet liver transplantation in macular degeneration in 2004, but it quickly lost market share because the monoclonal antibodies bevacizumab and ranibizumab (2006) are superior Efficacy. To date, the FDA has not approved other aptamers.

 

 

Antibody Drug Conjugates (ADC)

In 2019, the FDA approved 3 ADC drugs: trastuzumab-drutecan, enfutuzumab-vidotin and polatuzumab-vidotine, all of which are tumor indications. Drunotecan is a topoisomerase inhibitor used to treat previously treated HER2-positive breast cancer. Vidotin is a combination of microtubules targeting monomethylcalendula E and an antibody targeting connexin 4, and is approved for the treatment of metastatic urothelial cancer. Monomethylcalendula E66 itself is highly toxic (Figure 23). Combining with antibodies can reduce this toxicity, because the toxic payload directly acts on tumor cells.

 

 


Drug sales

Based on total sales, the 548 best-selling drugs in 2017 and 2018 were analyzed, and the sales of biological agents were higher than those of non-biological agents. The average annual sales of biologics is US$1.84 billion, while the average annual sales of NME is US$850 million.

The sales of biological products are mainly driven by 10 products, these products have created a total of 77 billion US dollars in sales, accounting for almost half of the total sales of biological products. Among these 10 products, only 3 are products approved in 2010-2019 (aflibercept, nivolumab, ustekinumab). Recent sales forecasts for 2019 show that the sales of two anti-PD-1 monoclonal antibody drugs pembrolizumab (approved in 2014) and nivolimumab (approved in 2014) will enter the top ten.


In 2018, more than $170 billion in sales came from drugs approved between 2010 and 2019 (Figure 25). On average, 30% of sales come from orphan drugs.

2013 and 2014 are the most representative years. Orphan drugs approved in these years accounted for more than 50% of sales in 2018 (for example, ibrutinib was approved for cancer treatment in 2013, and sales in 2018 were 62 In 2014, nivolumab was approved for tumor treatment, with sales of 7.5 billion U.S. dollars in 2018, and pembrolizumab was approved for tumor treatment in 2014, with sales of 7.1 billion U.S. dollars in 2018). The best-selling drugs in 2018 are listed in Table 6.

 

 

Future outlook

In the past decade, the number of approved FIC and new mode of action drugs has increased. As the next decade begins, there are still many opportunities.

 

Central Nervous System

Neurodegenerative diseases are one of the most important challenges in this field. The World Health Organization (WHO) predicts that by 2040, neurodegenerative diseases will surpass cancer and become the second leading cause of death after cardiovascular diseases.

Despite large investments, treatment options for neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer’s disease, are still few. Although the two ALS treatment drugs were approved, they had little impact on mortality and disease progression. To this day, Alzheimer’s disease is still a beluga in central nervous system drug research, and more than 190 researched new drugs have failed in clinical trials.

Although large pharmaceutical companies have made substantial divestments from the neuroscience field, the percentage of approved central nervous system drugs has remained the same over the past decade. Part of the reason for this seeming paradox may be the shift of investment from large pharmaceutical companies to CNS startups.

Due to increasing understanding of the molecular mechanisms of neurological diseases and high unmet medical needs, venture capital in this field has increased by 40% in the past 5 years. A recent report indicated that the development time of central nervous system drugs is 20% longer than that of non-central nervous system drugs, and the approval time is 38% longer than that of non-central nervous system drugs.

Another important unmet need is the increasing incidence of opioid addiction. From 1999 to 2018, opioid addiction has reached epidemic status in the United States, with more than 450,000 deaths due to opioid overdose. Recently, the first non-opioid drug for opioid withdrawal symptoms, the α2a antagonist lofexidine was approved for marketing (2018).

 

 

Infection

In the past ten years, 15 new antibacterial drugs have been approved as QIDP. This arrangement is designed to help new antibacterial drugs enter the market. This regulatory incentive seems to increase the number of new antibacterial drugs on the market.

But most approved bacterial infection drugs are similar to known drugs. The threat of bacterial resistance is growing, and WHO has made the development of drugs against carbapenem-resistant gram-negative bacilli Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae as its top priority.

As of the end of 2019, 53 antibacterial drugs are undergoing clinical evaluation worldwide. Tropical infectious diseases affect more than 1 billion people in the world and continue to cause a significant burden on developing countries. The Malaria Medicines Joint Venture (MMV) has made significant progress in developing the malaria drug pipeline, and the joint venture also supported the development of tafinoquine, which was approved in 2018.

The 21st century has witnessed some pandemics of viral epidemics threatening developing and developed countries, including SARS in 2002, Zika virus in 2015-2016, and Ebola virus in West Africa in 2013-2016 The epidemic and the yellow fever epidemic in 2016, as well as the recent ongoing COVID-19 pandemic caused by SARS-CoV-2, have infected 46 million people worldwide and have claimed nearly 1.2 million lives so far. .

The FDA has established an emergency plan to accelerate potential COVID-19 treatment, the Coronavirus Treatment Acceleration Plan (CTAP). Treatment methods include convalescent plasma, several types of antiviral drugs, including RNA polymerase inhibitors, protease inhibitors and virus entry inhibitors, and neutralizing antibodies. There are currently five treatment methods approved for emergency use (EUA).

 

Cardiovascular disease and metabolic syndrome

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are an active area of ​​clinical trials, with many different therapeutic mechanisms of action. Since there is no approved interventional therapy for the treatment of NAFLD, the clinical needs of the disease are seriously unmet. Drugs under study recently include the farnes X receptor agonist albendilic acid, the PPARα/δ dual agonist Ilabenol, the CCR 2/5 dual antagonist Senisilock, and the ASK1 inhibitor Celonceti Cloth etc.

Albendolic acid improved fibrosis in the phase III interim analysis, but neither elafibranor nor selonsertib reached their primary endpoints of NASH resolution and fibrosis. Cenicriroc’s Phase III clinical data is not expected to be available until the end of 2020.

So far, cardiovascular disease is still the number one cause of death in the world, claiming nearly 18 million lives every year. A major driver of cardiovascular disease is metabolic syndrome, a group of diseases that often occur simultaneously: obesity, hyperglycemia, dyslipidemia, and hypertension. Recently, two phase III clinical trials completed the study of patients with elevated low-density lipoprotein (LDL) cholesterol.

Tumor. Immuno-oncology (Immuno-oncology, I-O)

Tumor immunotherapy has changed the treatment options of cancer patients, and is one of the most important recent advances in cancer drug discovery and development. Since the first I-O drug, pembrolizumab, was launched, the number of patients taking these drugs has increased from 2500 in 2014 to more than 2 million in 2018.

In particular, PD-1 and PD-1L targeted I-O drugs are becoming the first-line therapy for solid tumors in the United States, such as metastatic NSCLC, metastatic melanoma, and metastatic renal cell carcinoma.

CD19 is expressed in a variety of B-cell malignancies, but the efficacy of traditional monospecific CD19 antibodies against CD19 is limited. The first CD19-targeting antibody, blinatumomab, was approved in 2014, and two new drugs targeting CD19 were approved in 2020 (tafaximab cxix and brexucabtagene autoleucel).

Brexucabtagene autoleucel is the third approved chimeric antigen receptor (CAR) T cell therapy that targets CD19-expressing tumor cells by reorganizing patient T cells.

Following PD-1 and CTLA-4, the third inhibitory receptor LAG3 has attracted attention as the target of I-O therapy. LAG3 also inhibits T cell activation and cytokine release. LAG3 can provide a synergistic effect on PD-1, so it is being studied in combination with anti-PD1 therapy. Three LAG3 targeting antibodies designed to inhibit signal transduction are currently being evaluated in clinical trials (BMS-986016, LAG525 and MK-4280).

Tumors. New biomarkers

Anti-PD-1 and -PD-L1 therapies have been shown to be effective against a variety of solid tumors and hematological tumors. However, different malignancies and clinical trials have different objective response rates. In addition, 7% to 34% of patients experienced high-grade immune-related adverse events. Currently, there are no effective biomarkers that can be used to select patients most sensitive to treatment.

In an encouraging development in the field of cancer therapy, the use of biomarkers to select the right patient population has steadily increased throughout the decade. As of 2018, 40% of cancer clinical trials use biomarkers. Identifying biomarkers to predict the responsiveness of PD-1/PD-L1 treatment and reduce the risk of adverse events is an important area. Biomarkers under consideration include tumor mutational burden, tumor infiltrating lymphocytes, mismatch repair defects, and intestine Road microbial components and so on.

Tumor. Research on Targeting DNA Damage Repair Pathways

Targeted DNA repair mechanism is a safe and effective method, and this discovery provides a new treatment method for cancer patients. Since the first PARP inhibitor, olaparib, was approved in 2014, three more PARP inhibitors have entered the market.

In addition, other DNA damage repair proteins are also being studied as therapeutic targets for a variety of tumors. The first ATR inhibitor M6620/berzosertib combined with gemcitabine showed efficacy in a phase II trial of platinum-resistant ovarian cancer patients. Several DNA-PK inhibitors have entered clinical treatment as single or combination. ATM inhibitors have also entered clinical trials to evaluate the safety of monotherapy or in combination with olaparib and chemotherapy.

 

Innovative new model

New treatment methods provide countless drug-making opportunities for previously thought to be non-drugable targets and signaling pathways. In the past decade, the number of approved RNA-targeted therapies has increased dramatically, and more drugs are in the late stages of clinical trials. ADC uses antibodies that recognize cancer cell antigens to target cytotoxic drugs to cancer cells, resulting in a rapid increase in the number of anti-cancer drugs.

Since the first bispecific antibody blinatumomab (CD9/CD13, Acute Lymphoblastic Leukemia) was approved in 2014, the share of bispecific antibodies has increased, rising to 25% of antibody drugs in 2018. There are 57 bispecific antibodies in clinical trials in 2019.

Using the ubiquitin-proteasome system (UPS) to target protein degradation to reduce the level of disease-related proteins is becoming a new area of ​​drug development. Since 2014, the investment in the field of protein degrading agents has exceeded 3.5 billion U.S. dollars, and the proteolytic targeting chimera (PROTAC) has accounted for a large share in the development of protein degrading agents. In 2019, ARV-110 became the first PROTAC to enter the clinic. It is an orally effective androgen receptor degrading agent for the treatment of metastatic castration to resist prostate cancer. Phase I clinical data show that the drug has acceptable safety and efficacy.

Gene editing is another area experiencing explosive growth. In 2012, the discovery that CRISPR-Cas9 can be used as a tool for efficient gene editing has greatly accelerated this growth. Some CRISPR therapies have been initiated, most of which focus on the in vitro editing of T cells or hematopoietic stem cells. However, in 2019, the first human CRISPR study was launched for the eye disease Leber Congenital Amatosis 10 (LCA) with a mutation in the CEP290 gene.

 

 

Summary

From 2010 to 2019, the median number of NME and BLA approvals increased by 60% compared to the previous ten years. The recent output of the pharmaceutical industry may be related to regulatory incentives, such as breakthrough treatments, fast-track designations, and orphan drugs and gains bills. In addition, the increased investment by the National Institutes of Health in basic neuroscience research has recently been related to the increase in investment in central nervous system ventures.

The emergence of new treatment models has further promoted the advancement of treatment fields and methods, while traditional drug-targeted treatment methods have not been affected. From 2010 to 2019, FIC approvals accounted for 37% of all drug approvals, up from 17% in 2009.

Major breakthroughs in new mechanisms such as I-O have changed the prognosis of patients and led to new and more effective clinical trial designs. As the industry enters new mechanisms and new patient populations, clinical trial design may become more complicated, leading to longer and more expensive development time costs. The use of companion diagnostics to predict the correct patient population will become increasingly important to reduce the cost of expensive or long-term clinical trials.

Finally, new drugs and diagnoses must be affordable and accessible to patients, products that are differentiated from existing drugs. The success of the past decade has brought hope to the entire industry. Drug R&D companies and institutions will meet new challenges and continue to provide patients with much-needed new drugs.

 

 

 

 

 

 

Trend of drug development: Drugs approved by the FDA in 2010-2019

Trend of drug development: Drugs approved by the FDA in 2010-2019

Trend of drug development: Drugs approved by the FDA in 2010-2019

 

(source:internet, reference only)


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