What is the charm of PDC drugs? Attracting many multinational pharmaceutical companies to hand over olive branches, Merck Sharp & Dohme, Eli Lilly...

Recently, PDC leader PeptiDream announced that it has entered into cooperation and licensing agreements with Merck and Eli Lilly to discover and develop novel peptidedrugconjugates (PDCs) for multiple drug targets, with a total value of more than $3.3 billion.

A number of multinational pharmaceutical companies extended olive branches

PeptiDream & Merck

On December 22, 2022, Merck and PeptiDream entered into an agreement to discover and develop new PDCs based on PeptiDream's drug discovery and development platform technology PDPS (Peptide Discovery Platform System), PeptiDream will receive an upfront payment and may receive a total of $2.1 billion in development, approval, and sales milestone fees totaling $2.1 billion in the future. In addition, the Company is entitled to royalties based on net sales after commercialization. Merck will be responsible for all development of PDCs in this program

PeptiDream & Eli Lilly

On December 26, 2022, Eli Lilly and PeptiDream signed an agreement under which PeptiDream will be responsible for peptide discovery and optimization based on the PDPS platform, while Lilly will be responsible for payload discovery and optimization and PDC product development in this collaboration. PeptiDream will receive an upfront payment and may receive a total of up to $1.235 billion in development, approval, and sales milestone fees. In addition, PeptiDream has the right to receive royalties for commercial sales.

Founded in 2006, PeptiDream has generated trillions of peptides based on its unique drug discovery and development platform, from which it efficiently screens out promising, highly selective non-standard cyclic peptides. PDC drugs are the focus of PeptiDream's layout, and there are currently a number of projects under development. PeptiDream has cooperated with a number of multinational pharmaceutical companies, including Eli Lilly, Merck, Roche, Novartis, Johnson & Johnson, Shionogi and others. We can't help but ask, why are PDC drugs so attractive, attracting many multinational pharmaceutical companies to extend olive branches?

What is PDC?

PDC is a peptide-conjugate drug, similar in structure to an antibody conjugate drug (ADC), consisting of three parts: peptide, cytotoxic drug and linker. Compared to ADCs, the difference is only that the homing device differs (swapping the antibody for a targeted peptide). PDC delivers cytotoxins to diseased tissues in the form of increased local concentrations, reducing the toxic effects in non-disease tissues, thereby reducing adverse reactions and achieving the purpose of synergy and toxicity. Since the antibody is replaced with a polypeptide, PDCs have the characteristics of small molecular weight, easier penetration of blood vessels and tissues, and low immunogenicity compared to ADCs.

In addition, PDCs offer a wider selection of cytotoxic drugs than ADCs. PDC can choose relatively low toxicity and commonly used clinical chemotherapy drugs such as doxorubicin and paclitaxel as toxic warheads, and the drug load is also higher. The cytotoxic molecules of ADC are mainly limited to a very small number of highly toxic candidates such as MMAE and DM-1.

In terms of safety, PDCs generally have a short half-life in the body, and because the molecular weight is small and hydrophilic can be quickly excreted through the kidneys, it is very beneficial to improve safety.

In terms of production process, compared with antibodies, the production process of peptides is simpler and cheaper, so the PDC production process based on peptide research and development is also simpler and easier to scale-up.

Despite the many advantages of PDC drugs, their track is still in its early stages, and only two PDC drugs have been approved for marketing worldwide. The first is Lutathera, developed by Advanced Accelerator Applications S.A, a subsidiary of Novartis, which is the first peptide receptor radionuclide therapy (PRRT) drug approved by the FDA in January 2018 for the treatment of somatostatin receptor-positive gastrointestinal and pancreatic neuroendocrine tumors.

Lutathera is a lutetium 177 (Lu-177) labeled somatostatin analog peptide. Its mechanism of action works by binding to cells of the somatostatin receptor, which can be present on certain tumors. After binding to these receptors, the drug enters the cells and damages tumor cells through radiation.

The second approved PDC drug is Pepaxto (melflufen) developed by Oncopeptides, which was approved by the FDA in February 2021 for the treatment of relapsed/refractory multiple myeloma (RRMM) in combination with dexamethasone. The approval is based on the results of a pivotal Phase II clinical trial (HORIZON). In the HORIZON trial, a total of 157 patients with relapsed/refractory MM received Pepaxto in combination with dexamethasone, and 97 of them were evaluated for efficacy in patients who had previously received at least four therapies (including proteasome inhibitors, immunomodulators, and monoclonal antibodies targeting CD38), with an overall response rate (ORR) of 23.7%, The median duration of response (DOR) was 4.2 months; safety was assessed in all 157 patients, with the most common adverse effects being fatigue, nausea, diarrhoea, fever, and respiratory infections.

In a phase III clinical trial called Ocean-3, the treatment group outperformed both progression-free survival (PFS) and ORR than the standard treatment pomalidomide, but Pepatxo performed worse than pomalidomide (Pepatxo vs. pomalidomide: 19.7 months vs. 25 months) in terms of survival. Moreover, the risk of death was 10% higher in the group of patients treated with Pepaxto and the steroid dexamethasone than in the pomalidomide group.

The results of Ocean-3's trial directly led to Pepaxto's delisting in October 2021. So far, Pepatxo has only been on the market for 8 months from the approval of the market to the "end of life".

Pepaxto's failure has not dampened the enthusiasm of many pharmaceutical companies at home and abroad. How is the PDC track progressing so far?

PDC track, how is the progress at home and abroad?

At present, most of the leading companies in the PDC track are overseas companies, in addition to PeptiDream and Oncopeptipes, there are Angiochem, Bicycle Therapeutics, Cybrexa Therapeutics and other representative enterprises.

SNG1005, jointly developed by Angiochem and domestic pharmaceutical company Sinokey, is currently in phase III clinical trial and has advanced progress. SNG1005 penetrates the blood-brain barrier, which conjugates paclitaxel to the amino acid short peptide to specifically deliver paclitaxel to the brain. The results of phase II clinical studies showed that the clinical benefit rate of SNG1005 in the treatment of intracranial and extracranial in patients with breast cancer brain metastases reached 77% and 86%, respectively.

BicycleTherapeutics has three PDC products under development, BT1718, BT5528 and BT8009, all of which are in clinical phase I/II development.

BT1718 is a PDC targeting matrix metalloproteinase type 1 (MT1-MMP), which is overexpressed in a variety of tumors. BT1718 is formed by the coupling of specific bicyclic peptide molecules to MD1 cytotoxins through cleavageable disulfide bonds and is currently in phase I/IIa clinical trials.

BT5528 is a modified PDC targeting EphA2 targets. EphA2 is abundantly expressed in prostate cancer, lung cancer, esophageal cancer and other tumors, and its expression is associated with poor prognosis, increased metastasis potential and reduced survival in tumor patients. The BT5528 is expected to overcome significant safety concerns caused by ADC-targeting of EphA2.

BT8009 is a nectin-4-targeting PDC that has demonstrated excellent anti-tumor activity in phase I clinical studies. However, its safety is questionable, and its advantages over direct competitor Padcev, an ADC drug targeting nectin-4, are not clear. It is currently in phase I/II clinical trials.

Cybrexa Therapeutics' CBX-12 is a PDC drug developed based on the company's proprietary alphalex platform technology. It targets acidic tissues by relying on pH insertion peptides (pHLIP). In general, one of the characteristics of tumors is the acidic microenvironment. CBX-12 specifically delivers exatecan, a potent cytotoxin, to cells in a low pH environment.

Preclinical studies have shown that CBX-12 shows more powerful tumor suppressors in a variety of tumor models than exatecan alone. In treatment with unbound exatecan, model animals consistently experienced significant weight loss or fluctuations, while CBX-12 had less effect on body weight, showing a tolerability advantage of CBX-12. Currently, CBX-12 is undergoing Phase I/II clinical studies.

Although the progress of domestic PDC drug research lags behind foreign countries, several companies have begun to emerge, such as Yi Pharmaceutical, Telcon Biotechnology, mainstream source biology, etc.

The PDC drug CBP-1008 developed by Tongyi Pharma with its core technology platform BESTTM is the world's first dual-ligand drug conjugate. At the 2021 ASCO meeting, Tongyi Pharma reported the Phase Ia study data of CBP-1008, and enrolled 18 patients with advanced solid tumors who failed standard therapy, the overall safety of CBP-1008 was predictable, controllable, manageable, and no adverse events beyond expectations were observed, and no adverse events of drug-induced death occurred. Phase Ia clinical trials are currently underway.

Telcon mainly develops PDC drugs targeting GPCRs, and the two fastest products at present, Tye-1001 and Tye-1002, are both developed for tumors. Among them, Tye-1001 is a broad-spectrum anti-tumor conjugate, and preclinical studies have shown that Tye-1001 can effectively inhibit the growth of tumor cells. Tye-1002 is a receptor-targeted conjugate, and studies have shown that Tye-1002 can effectively inhibit the growth of tumor cells, and animal tests are currently underway.

Mainstream Source Biotechnology has developed a series of peptide drugs with a class of new drug potential by using its advanced and unique PDC and multifunctional peptide drug screening and optimization platforms. Its core product, the peptide-conjugate drug MB1707, which targets CXCR4, is undergoing phase I clinical trials in the United States and Australia, which is expected to bring new hope to tumor patients with high CXCR4 expression.

epilogue

In summary, PDC drugs integrate the advantages of peptide drugs and have a broader industrial base and clinical value. Compared with ADC, PDC drugs have small molecular weight and high hydrophilicity, and are easily excreted quickly through the kidneys, which helps to improve the safety of drugs.

Compared with small molecule drugs, PDC drugs have the advantages of precise targeting and controlled release of drugs, which can significantly improve the therapeutic effect, reduce toxicity, and improve the treatment window.

However, PDC drugs also have challenges and thresholds, such as compared with monoclonal antibodies, the tissue specificity and tumor targeting of peptides are slightly inferior, which increases the difficulty of screening targeted peptides.

In addition, one of the defects of PDC is its poor circulatory stability, which will be quickly cleared by the kidneys; Therefore, the development of through-membrane peptide technology with targeted function and the improvement of cell penetration ability and stability of targeted peptide are urgent problems for PDC. In short, PDC has a promising future, but its technology still has room for further optimization.