**: Briana***
Author: Jiusi.
2023 is coming to an end, and so far the FDA's CDER (Center for Drug Evaluation and Research) has approved 54 new drugs. It is worth noting that among the 54 chemical drugs, there are 6 peptide drugs, accounting for 11%, up from 8% in 2022 (3 37).
6 new peptide drugs approved by the FDA in 2023
Table 1 New peptide drugs approved by FDA in 2023.
Source**: U.S. FDA official website, Brii Biosciences.
From the perspective of ** fields, there are 2 in the field of anti-tumor, anti-infection and rare diseases. The following is a brief introduction to these new peptide drugs approved by the FDA this year.
Daybue (trofinetide, trafinamide) was developed by Acadia Pharmaceuticals for the treatment of patients aged two years and older and with Rett syndrome in children. is a novel analog of IGF-1 N-terminal tripeptide designed to reduce neuroinflammation and support synaptic function as a core symptom of Rett syndrome. This is the first FDA-approved drug for Rett syndrome.
Rezzayo (Rezafungin) was developed by Cidara Therapeutics for the treatment of *** candidemia and invasive candidiasis. It is a novel echinocandinin that works by inhibiting -1, 3-glucose synthase thereby disrupting the integrity of the fungal cell wall. This is the first approved for invasive Candida infections in more than a decade**.
Posluma (Flotufolastat F 18) was developed by Blue Earth Diagnostics for PET with PSMA-positive lesions in men with suspected metastatic prostate cancer. The drug is an optimized PSMA-targeting molecule whose active ingredient is Flotufolastat F 18 Gallium bound to non-radioactive gallium. Among the parts responsible for binding to PSMA, the peptidoid plays an important role. The peptidomimetic structure in Flotufolastat F 18 molecule contains amino acid structures such as Glu, -Glu, Orn, 1,4-succinic acid, Lys, and Diaminopripionic Acid (DAP).
Paxlovid contains two active ingredients, Nirmatrelvir and Riton**IR, both of which are peptidoids. Nirmatrelvir acts as a protease inhibitor to block protease activity required for viral reproduction. It is an inhibitor of 3C-like protease (3ClPro, also known as mPro), which plays a key role in the replication of the SARS-CoV-2 virus. Riton**IR is a pharmacokinetic enhancer of nirmatrelvir, which improves the half-life and bioavailability of nirmatrelvir by inhibiting the degradation of CYP3A4.
Developed by Biolinerx, Aphexda (Motixafortide) is used in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells into peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. The drug is a synthetic cyclic peptide that targets the chemokine receptor CXCR4 and blocks the binding of its homologous ligand matrix-derived factor 1 (SDF-1) CXCL12. This is the first innovative drug for stem cell mobilization approved in the United States for the treatment of multiple myeloma in a decade.
Zilbrysq (ZilucoPlan) was developed by UCB for adult patients with generalized myasthenia gravis (GMG) who are positive for anti-acetylcholine receptor (ACHR) antibodies. The drug is a novel macrocyclic peptide C5 complement inhibitor administered subcutaneously once daily. As a complement C5 inhibitor, Zilbrysq inhibits complement-mediated neuromuscular junction injury through its targeted mechanism of action. Unlike monoclonal antibody C5 inhibitors, as a peptide, zilbrysq can be used concurrently with intravenous immunoglobulin and plasmapheresis without the need for supplemental administration.
Technology drives the development of peptide drugs
Peptide drugs have the advantages of low immunogenicity, good tissue permeability, easy synthesis and modification, good safety, and not easy to accumulate in tissues. In 1922, insulin was put into clinical practice, which changed the fate of many diabetic patients and opened the history of human peptide application. After 100 years of development, there are currently about 100 peptide drugs on the market, and hundreds of peptide drugs are in clinical trials.
The development of peptide drugs can be broadly divided into three stages:
Exploratory period before 1960: In 1922, insulin was discovered and extracted for diabetes**, but animal insulin was used at that time, which is different from human insulin in structure, which is easy to cause immune responses, and in 1954, the first in vitro chemical synthesis of oxytocin, people's knowledge and understanding of peptide drugs are gradually improving.
1960-2000 rapid development period: In 1963, the emergence of peptide solid-phase synthesis technology brought about a revolution in peptide organic synthesis, and human insulin was produced in large quantities. The invention of recombinant technology and phage display technology in the 80s made it possible to produce larger molecules of peptide drugs and to target the screening of peptide drugs with specific functions, and until the end of the twentieth century, peptides were still considered a niche field as a class of drugs.
After the maturity of technology in 2000, the explosion period: natural peptides continue to be enriched, and peptidemics from venom and new chemical modification methods promote the discovery of new peptide drugs. In recent years, the emergence of new technologies such as multifunctional peptides, confined peptides, conjugated peptides, oral peptides, and long-acting and delivery systems has greatly promoted the development of peptide drugs.
Figure 1: Key milestones in the development of the peptide** field and historical timeline for drug approval.
*: Reference 2
Peptide drugs have shown advantages in many fields
At present, peptide drugs have been used in many disease fields, including tumors, infectious diseases, rare diseases, chronic metabolic diseases, cardiovascular diseases, gastrointestinal diseases, orthopedic diseases, immune diseases, etc.
Peptides and chronic diseases.
Insulin is the most representative type of peptide drug, which has changed the fate of many diabetics.
In recent years, a second class of revolutionary peptides in the field of diabetes has been born, GLP-1 receptor agonists. Moreover, follow-up clinical studies have proved that not only diabetes, but also GLP-1 peptides have good efficacy in other chronic diseases such as obesity, cardiovascular, NASH, Alzheimer's disease, etc., attracting the layout of major pharmaceutical companies around the world. Tianfeng** reported that at present, there are more than 160 weight-loss-related pipelines in the global GLP-1 pipeline, and more than 70 domestic R&D pipelines, involving Eli Lilly, Novo Nordisk, Roche, Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, Amgen and other multinational pharmaceutical companies. The GLP-1 pipeline under development in China has made rapid progress in the company's Innovent Biologics' Mastotide Peptide, Yinnuo Pharmaceutical's Supaglutide, Hongyun Huaning's Glutazumab, Paige Biotech's PB-119, Changshan Biochemical's Ebenatid Peptide, Xianweida Biotech's Enoglutide, and Hengrui Pharmaceutical's Noli Glycopeptide.
Peptides and tumors.
Compared with small molecule chemical drugs, peptide drugs have the advantages of good selectivity, specificity, low toxicity, and low cost, good tissue permeability, and easy modification compared with monoclonal antibody drugs, so they have received extensive attention in the research of tumor drugs. Previously, peptide drugs marketed in the field of oncology were mainly concentrated in ** tumors and prostate cancer, and were used as hormones ** tumors and castration**. With the continuous deepening of research, there has been a significant breakthrough in the indication range of peptide drugs in the field of tumors in recent years.
For example, Aphexda is a synthetic cyclic peptide that targets the chemokine receptor CXCR4 and blocks the binding of its homologous ligand matrix-derived factor 1 (SDF-1) CxCl12. This year, the FDA approved the use of filgrastim (G-CSF) in combination with hematopoietic stem cells to mobilize hematopoietic stem cells into peripheral blood for the collection and subsequent autologous transplantation of patients with multiple myeloma.
In addition to their drug uses, peptides can also be used as molecular probe tools for molecular diagnosis and imaging of tumors.
For example, Posluma, a high-affinity PSMA-targeted radiodiagnostic reagent based on a novel radiohybridization technology, was approved by the FDA this year for PET with PSMA-positive lesions in men with prostate cancer suspected of metastasis.
Peptides and infectious diseases.
Infectious diseases are one of the major challenges facing clinical medicine, and certain peptides can achieve the purpose of infection by inhibiting the growth and reproduction of bacteria, viruses or other pathogens.
For example, rezzayo, a new, once-weekly echinocandin-like drug, works by inhibiting -1, 3-glucose synthetase thereby disrupting the integrity of fungal cell walls.
Paxlovid contains two active ingredients, Nirmatrelvir and Riton**IR, both of which are peptidoids. Nirmatrelvir acts as a protease inhibitor to block protease activity required for viral reproduction. Riton**IR is a pharmacokinetic enhancer of nirmatrelvir. In December 2021, Paxlovid received its first Emergency Use Authorization (EUA) in the U.S., and in May 2023, the U.S. FDA officially approved Paxlovid for adult patients with mild to moderate COVID with high-risk factors for progression to severe disease, including hospitalization or death.
Peptides and rare diseases.
Rare diseases are also the main battlefield of peptide drugs. At present, a number of peptide drugs have been approved for various rare diseases, including glatiramer for multiple sclerosis, pegcetacoplan for paroxysmal nocturnal hemoglobinuria, and terlipressin for hepatorenal syndrome (HRS). Among them, glatiramer, developed by Teva and launched in 1996, was once the largest peptide drug, with global sales of 42 percent in 2014$3.7 billion for multiple sclerosis (MS). On June 28, 2023, glatiramer acetate injection (trade name: Gupaisone) was officially approved in China for patients with multiple sclerosis (MS)**.
Two more peptides have been approved for rare diseases this year**. Daybue, a novel synthetic analogue of the N-terminal tripeptide of insulin-like growth factor I (IGF-1), is the first and only FDA-approved drug for RTT syndrome**. The approval of DAYBUE for patients with RETT syndrome, a rare progressive neurodevelopmental disorder that causes severe intellectual disability, loss of exercise capacity, and autism-like symptoms, is an important milestone for people with RETT syndrome. Zilbrysq is a novel macrocyclic peptide C5 complement inhibitor administered subcutaneously once daily that provides a simpler dosing option for patients with generalized myasthenia gravis.
Other. In addition, peptide drugs are also used in gastrointestinal, orthopedic, immunological and other fields.
The gastrointestinal tract mainly includes somatostatin analogues and vasopressin analogues, and the main varieties are somatostatin, desmopressin, octreotide, linaclotide, etc.
Orthopedics mainly focuses on osteoporosis, mainly for postmenopausal women and elderly patients, and the representative drugs are salmoncalcitonin, teriparatide, etc.
Peptide drugs in the field of immunity are similar to adjuvant drugs, and the main varieties include thymus pentapeptide and thymus fasin.
Future development trends and challenges of peptide drugs
Peptide drugs have been widely used in chronic diseases, tumors, infections, rare diseases and other fields, and with the deepening of scientific research and clinical practice, their application fields will continue to expand. However, it should also be noted that there are still many limitations to the development and utilization of peptide drugs.
At present, peptide drugs are mainly administered by injection (intravenous, intramuscular, subcutaneous) or non-injection (**oral, nasal, etc.) to reach their tissues or targets, and patients prefer oral administration, but the oral bioavailability of peptides is low, and reasonable modification, transformation of dosage forms and delivery methods, and reduction of administration frequency will still be the direction of peptide drugs in the future.
For example, Rybelsus (oral semaglutide tablets) with the help of the high-efficiency penetrant agent SNAC, can not only locally increase the pH to create an alkaline environment for the drug and avoid its degradation by pepsin, but also enhance the permeability of the gastric mucosa, promote transmembrane transport, and increase the intragastric absorption of the drug, so as to achieve oral administration.
Pegylated loxenatitide increases the relative molecular weight of the drug through pegylation, thereby reducing renal filtration and achieving long-term effect. Exenatide microspheres prolong the release time of drugs in the body through drug-loaded microspheres to achieve long-term effect. Hongyun Huaning tried to extend the half-life by tandem GLP-1 peptide analogue and GLP-1R monoclonal antibody fusion protein, and the current indication for glutazumab hypoglycemic has reached bi-weekly or even monthly administration, and the drug is currently in phase 3 clinical trial.
With the research and development of peptide drugs, people's demand for peptides is rising, especially the industry demand brought by GLP-1 peptides, which poses challenges to peptide pharmaceutical process research and production capacity. At present, the world's major pharmaceutical companies are frantically expanding their production capacity.
In the 50s of the 20th century, American scientists synthesized the first polypeptide - oxytocin. Peptide synthesis has developed rapidly over the past few decades, and the current peptide synthesis methods can be divided into biosynthesis and chemical synthesis.
With the development of gene recombination technology, in addition to the traditional natural extraction method, the commonly used enzymatic hydrolysis method and fermentation method, the gene recombination method has also been gradually applied in peptide synthesis.
The peptide chemical synthesis method uses the protective group to protect the temporarily unreacted group in the raw material amino acid, to ensure that the reaction is carried out in accordance with the design direction, and the amino acid connection is extended through the condensation reaction between amino acids to obtain a specific sequence of polypeptides.
There are liquid phase synthesis and solid phase synthesis methods for peptide chemical synthesis, and the main difference between the two is whether to use solid phase support. At present, most of the peptide drugs on the market are prepared by chemical synthesis, and the solid-phase synthesis process is dominant.
However, there are many problems and challenges in the peptide pharmaceutical process, such as the large amount of reagents, the difficulty of purification, and the high requirements of process control, and many problems such as output scale, equipment demand, production cost, quality management, and environmental protection requirements need to be considered in the industrial production of peptides. Therefore, enterprises usually choose to cooperate with CDMO CRO companies in the early stage of R&D. With the increase in domestic R&D investment in peptide drugs, local CDMO service providers are also a good choice.
In the future, with the development of a new generation of drug design technology, modification technology, formulation technology and in-depth research on disease physiology, more types of peptide drugs will be developed, the proportion of innovative peptide drugs will be further increased, and peptide drugs will become one of the most important forms of drugs.
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2.trends in peptide drug discovery.
3.peptide therapeutics: current status and future directions.
4.The birth of a nuclear explosive, Pluvicto Rise Apocalypse (36K).
5.Yiwen first learned about "peptide" drugs and their development (Yingyang Pharmaceutical).
6.China Securities Construction Investment and Tianfeng**, FDA official website and other online public information.
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