 Home > Active Ingredient News > Drugs Articles > The FDA has accelerated its approval, and Novartis, AstraZeneca, Roche, etc. are optimistic, and "alternative" conjugate drugs are on the rise!

The FDA has accelerated its approval, and Novartis, AstraZeneca, Roche, etc. are optimistic, and "alternative" conjugate drugs are on the rise!

 Last Update: 2021-09-12
 Source: Internet
 Author: User

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Antibody-conjugated drugs (ADC) have become one of the most important research areas at the moment, and many ADC products have been approved worldwide
.

At the same time, scientists are exploring more drug delivery methods, such as peptide drugs, protein-protein interaction inhibitors (PPIs), and drug delivery transporters

Among them, peptide-drug conjugate (PDC) is a relatively fast research progress

Up to now , two PDC products have been approved worldwide, and a number of PDC products have entered the clinical stage
.

This field has attracted the attention of many biopharmaceutical companies, including large pharmaceutical companies such as Novartis, AstraZeneca, Roche, etc.

, Two PDC products have been approved worldwide, and many PDC products have entered the clinical stage

Why can PDC stand out from many drug forms and be favored by the industry? What are the structural advantages and characteristics of PDC? What are the latest developments of PDC, and what are the future prospects and trends?

More friendly "magic missile"

PDC is a type of targeted therapy drugs, its structure is similar to ADC, but the design is different
.

PDC is composed of Homing Peptide (Cell Targeting Peptide), linker, and payload.

▲Schematic diagram of PDC structure (picture source: reference [1])

According to the definition of the US FDA, a polypeptide is a polymer composed of less than 40 amino acids
.

Compared with ADCs that use monoclonal antibodies to achieve targeting, PDC peptides have natural advantages : first, the peptides have a smaller molecular weight, which makes PDCs have better affinity, specificity and tissue permeability, and can be used in the treatment of certain solid tumors.

Compared with ADC using monoclonal antibodies to achieve targeting, PDC peptides have natural advantages

It is precisely because of these advantages that PDC is considered to be the most promising conjugate drug for therapeutic breakthroughs after ADC
.

However, the development of PDC has been relatively slow

According to a review published by Chemical Society Reviews in December 2020, as of the time of publication, there is only one type of therapeutic PDC approved in the world, namely 177Lu-dotatate (trade name Lutathera) from Novartis
.

Lutathera uses somatostatin as the attribution peptide, the load is the radionuclide 177Lu, and the approved indication is gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs)

Lutathera uses somatostatin as the attribution peptide, the load is the radionuclide 177Lu, and the approved indication is gastrointestinal pancreatic neuroendocrine tumors

▲ Structure of Lutathera

It is worth mentioning that in addition to being used as therapeutic drugs, PDC carrying radionuclides has also been successfully developed as a class of disease diagnostic tools
.

FDA accelerates approval, AstraZeneca, Roche, etc.
are optimistic

In 2021, the PDC product field ushered in new progress
.

On February 26, the biopharmaceutical company Oncopeptides announced that the FDA has accelerated the approval of its PDC drug Pepaxto (melphalan flufenamide, also known as melflufen) to be marketed for use in combination with dexamethasone.

The FDA has accelerated the approval of its PDC drug Pepaxto (melphalan flufenamide, also known as melflufen).

Recently, another biomedical company called Theratechnologies also announced the research progress of two PDCs in its R&D pipeline
.
Among them, TH1902 is a PDC with docetaxel as the payload, which is intended to be developed to treat triple-negative breast and ovarian cancer
.
The other TH1904 uses doxorubicin as a payload and is intended to be developed to treat ovarian cancer
.
Both PDCs target neurotensin receptor 3 (SORT1.
also known as NTSR3).
SORT1 has been confirmed to be expressed in a variety of cancers, including triple-negative breast cancer, ovarian cancer, lung cancer, and colorectal.
cancer, skin cancer and pancreatic cancer
.

Recently, another biomedical company called Theratechnologies also announced the research progress of two PDCs in its R&D pipeline.

According to the official information of Theratechnologies company, compared with traditional chemotherapy, TH1902 and TH1904 can selectively deliver anti-cancer active ingredients to SORT1 in cancer cells, and the anti-cancer active ingredients are quickly internalized and released by cancer cells
.
Pre-clinical studies have shown that TH1902, which combines a peptide targeting SORT1 receptor, a linker, and docetaxel, has better anti-metastatic activity and better tolerance than docetaxel alone
.

TH1902 and TH1904 can selectively deliver anti-cancer active ingredients to SORT1 in cancer cells, and the anti-cancer active ingredients are quickly internalized and released by cancer cells.

In addition, more forms of PDC have been designed
.
For example, Bicycle Therapeutics designed the peptides in PDC into bicyclic peptides, and has developed a variety of bicyclic peptide conjugates , including BT5528, BT8009 and BT1718
.

And has developed a variety of bicyclic peptide conjugates

According to Bicycle's official website, cyclic peptides are highly flexible and can be assembled and designed into more complex molecules
.
The company's bicyclic peptide conjugate is used as a drug delivery system to couple targeted immune activators and cytotoxic drugs, and accurately deliver them to solid tumors, targeting tumor cells without damaging normal tissues
.
Previous studies have shown that this type of conjugate not only has good pharmacokinetic characteristics, extensive tissue permeability and significant pharmacodynamic effects, but also has a short exposure time, which can be excreted by the kidneys instead of the liver to reduce liver toxicity, and There are currently no signs of immunogenicity
.

Cyclic peptides are highly flexible and can be assembled and designed into more complex molecules

Image source: Bicycle company official website

It is worth mentioning that the potential of PDC and Bicycle's innovative bicyclic peptide conjugates attracted the attention of AstraZeneca, Roche and other companies a few years ago
.
In December 2016, AstraZeneca and Bicycle signed an agreement to use the latter’s proprietary technology platform to develop bicyclic peptide drugs.
This cooperation amounted to more than US$1 billion
.
In February 2020, Roche's Genentech (Genentech) also reached an exclusive cooperation agreement with Bicycle to jointly develop and commercialize new tumor immunotherapy based on the latter's proprietary technology platform.
For this purpose, Bicycle received a down payment of 30 million US dollars.
And a later mileage of US$1.
7 billion
.

The potential of PDC and Bicycle's innovative bicyclic peptide conjugates have attracted the attention of AstraZeneca, Roche and other companies a few years ago.

China has already entered phase 3 clinical PDC products

According to public information, at least four pharmaceutical companies in China have been developing PDC products, namely Sheng Nuoji Pharmaceutical, Mainstream Biology, Tongyi Pharmaceutical and Taierkang Biology
.

They are Sheng Nuoji Pharmaceutical, Mainstream Biology, Tongyi Pharmaceutical and Taierkang Biological

Among them, the fastest progress is SGN1005 from Sheng Nuoji Medicine.
It has entered Phase 3 clinical trials
.
The product was developed by AngioChem, introduced by Sheng Nuoji Medicine and carried out clinical research in the field of new tumors in China
.
According to the public information of Sheng Nuoji Pharmaceutical, SNG1005 is a peptide-conjugated drug, which is formed by the combination of paclitaxel molecules and small peptide fragments that can specifically bind to the LRP-1 (low density lipoprotein receptor related protein) receptor
.
The LRP-1 receptor can mediate the endocytosis and exocytosis of SNG1005 by endothelial cells, and then be transported to the brain, and then SNG1005 is released in the brain tissue to play an anti-tumor effect
.
Paclitaxel is inactive when combined with polypeptides.
When SNG1005 enters tumor cells, the structure of the polypeptide is degraded by intracellular lysosomes, and paclitaxel molecules are released to exert cytotoxic effects
.

SNG1005 is a peptide-conjugated drug, formed by combining paclitaxel molecules with small peptides that can specifically bind to the LRP-1 (low density lipoprotein receptor related protein) receptor

In February 2020, the authoritative oncology journal Clinical Cancer Research published online the results of a phase 2 clinical study of SNG1005: Intracranial and extracranial clinical benefits of patients with evaluable breast cancer brain metastases treated with SNG1005 The rates were 77% and 86%, respectively, and the intracranial objective response rate (iORR) was 15% (investigator assessment) or 8% (independent radiology assessment)
.
In terms of safety, SNG1005 is similar to ordinary paclitaxel and has no severe allergic reactions
.
Further, Sheng Nokia medicine still exploring SNG1005 anti-PD-1 antibody in combination with treatment of triple negative breast cancer (including brain metastasis), non-small cell lung cancer with brain metastasis effect
.

, The patient’s intracranial and extracranial clinical benefit rates were 77% and 86%, respectively, and the intracranial objective response rate (iORR) was 15% (investigator assessment) or 8% (independent radiology assessment)

Another company is Taierkang Biology, the founder of the company has accumulated rich experience in the field of peptide technology and targeted drug research and development
.
According to the official website of Taierkang, Taierkang uses specific peptides and specific protein targeting carriers to develop related targets based on the small molecule compounds AP-3 (Ansamectin-3) and FK-506 (Tacrolimus).
Drugs
.
Among them, AP-3 is one of the small molecule compounds with strong anti-tumor activity in the world, but it is difficult to prepare medicines
.
FK-506 is a very classic immunosuppressant, but due to its large side effects, it is limited to organ transplantation and cannot be used for dozens of other autoimmune diseases
.

Taierkang uses specific peptides and specific protein targeting carriers to develop related targeted drugs based on small molecule compounds AP-3 (Ansamcin-3) and FK-506 (Tacrolimus)

In addition, PDC drugs targeting CXCR4, the core product of mainstream biology, are undergoing preclinical studies for triple-negative breast cancer
.
Tongyi Medicine’s CBP-1008 is undergoing a phase 1a clinical study for breast cancer, ovarian cancer and squamous cell carcinoma
.

Prospects can be expected

Compared with small molecules and biological products, although PDC has made less progress in clinical trials, its versatility and many advantages mean that PDC is a promising research field
.
It is worth noting that peptides also have obvious limitations.
One of the most notable limitations is the extremely limited oral bioavailability of peptides, which makes them only available through intravenous injection
.
There have also been studies trying to solve the limitations of PDC
.
For example: using different nanoparticles to enhance the stability of PDC, to prevent the early release of cytotoxic payloads and lead to systemic exposure; through different modifications to enhance its chemical and enzymatic stability, and so on
.

Although PDC products still have many challenges, advances in chemistry and biology have expanded the scientific community's further understanding of PDC
.
It is expected that with the advancement of related platforms and technologies, more innovative biopharmaceutical companies will join in, enabling the rapid development of PDC drugs and benefiting more patients!

Reference materials:

[1] Bethany M Cooper, et al (2021).
Peptides as a platform for targeted therapeutics for cancer: peptide–drug conjugates (PDCs).
Chem Soc Rev, DOI: 10.
1039/D0CS00556H

[2]FDA approves Oncopeptides' PEPAXTO® (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma.
Retrieved February 28.
2021.
from https:// --melphalan-flufenamide-for-patients-with-relapsed-or-refractory-multiple-myeloma-301236751.
html

[3] Beijing Sheng Nuoji Pharmaceutical Technology Co.
, Ltd.
Science and Technology Innovation Board IPO prospectus (application draft) (Beijing Sheng Nuoji Pharmaceutical Technology Co.
, Ltd.
).
Retrieved May 28.
2020.
from http://guba.
eastmoney.
com/news,gs81048210.
933994725.
html

[4] Advanced Accelerator Applications Receives US FDA Approval for LUTATHERA for Treatment of Gastroenteropancreatic Neuroendocrine Tumors, Jan 26.
2018.
from https://#axzz55NkMXJoh

[5] Official website and public information of each company

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