R&D ADC vs PDC——Inventory of current status of ADC-PDC drug R&D at home and abroad

With the continuous efforts of the Chinese pharmaceutical industry and the increasing attractiveness of the Chinese pharmaceutical market to global innovative drugs, more innovative drug projects have begun to make listing on the Chinese market a mandatory item in their projects
.

Among these innovative drugs, ADC drugs are favored by innovative drug companies because of their combined therapeutic effects, and are also continuously concerned by industry investors

The first in a series of articles listed on the Chinese market

Introduction to ADC Drugs

Introduction to ADC Drugs

In recent years, ADC drugs have been the key direction of global anti-tumor drug technology development, as well as the research and development hotspots in the field of biomedicine, known as "intelligent biological missiles" and "magic bullets
.

" ADC drugs, antibody drug conjugates (ADC), are composed of three parts: monoclonal antibody (mAb), linker, and cytotoxin/payload.

PDC (peptide-drug conjugate), or peptide-drug conjugate, is a new type of conjugated drug that has also begun to attract attention in the field of research and development
.

Figure 1 The mechanism of action of ADC drugs (picture source ADC Drug Research and Development Report 2020)

ADC drugs on the global market

ADC drugs on the global market

Since Pfizer’s first ADC drug Mylotarg was launched in 2000, a total of 14 ADC drugs have been approved worldwide (see Table 1 for details)
.

ADC drug research and development focus on the disease areas, which are basically solid tumors and hematological tumors.

Figure 2 ADC drug solid tumor antigen target (picture source British Journal of Cancer, 2016)

Table 1 ADC drugs approved worldwide

Since ADC entered the pharmaceutical market, its drug development technology has been continuously improving; from the perspective of drug composition and development technology, ADC drugs that have been on the market have undergone three generations of technological changes.
The first generation ADC drugs have low antigen specificity and insufficient toxic load.
Strong and unstable joint, the representative drug is Pfizer’s Mylotarg; the second-generation ADC drug is represented by Adcetris jointly developed by Seagen/Takeda and Roche’s Kadcyla, which generally uses more toxic small molecules, which overcomes the first-generation toxic load The disadvantage of not enough, but still uses traditional chemical coupling and the linker stability is not good, it is easy to lyse in the blood and cause serious toxic side effects
.

The third-generation ADC drugs solve the problem of poor coupling ratio of the previous generation of antibodies.

The first generation ADC drug The second generation ADC drug The third generation ADC drug

ADC drugs have significant clinical effects.
From market feedback, ADC drug sales are increasing year by year.
Roche’s Kadcyla (enmetrastuzumab) is currently one of the most popular products in the ADC field.
The global sales in 2020 will be 1.
745 billion Swiss francs (approximately 1.
946 billion US dollars), entered the global top 100 sales list for the first time, and was also the first ADC drug to be included in the list
.

ADC drugs on the domestic market

ADC drugs on the domestic market

Currently, there are 3 ADC drugs on the market in China: Roche’s Kadcyla (Enmetrastuzumab (trade name: Hercelium)) was approved for marketing in China in January 2020; Adcetris, a subsidiary of Takeda Pharmaceuticals, in May 2020 (Vibtuximab (trade name: Anshili)) was approved in China; in June 2021, Rongchang Bio's vedicitumumab was approved for marketing, which is the third ADC antibody drug approved in China , And also the first domestically produced ADC
.

In addition, in January 2021, Pfizer’s Besponsa (inotuzumab ozolamicin) submitted a marketing application in China, and was subsequently included in the priority review scope by CDE; Genting Pharmaceutical’s Gosartor group list in May 2021 Anti (targeting Trop2) also submitted a listing application in China
.

It is worth mentioning that in August 2021, Rongchang Biotechnology and Seagen reached an exclusive global license agreement for the development and commercialization of vedicitumumab.
Seagen will pay a US$200 million down payment and a milestone of up to US$2.
4 billion.
The payment set a record for Chinese pharmaceutical companies' single-variety overseas authorized transactions
.

Rongchang Bio is a pioneer in the domestic ADC track.
It started to develop ACD drugs more than ten years ago.
From the R&D pipeline of Rongchang Bio, we can see that the company has a variety of ADC drugs (Figure 3)
.

In August 2014, Rongchang Biotechnology completed the RC48 clinical trial application; in August 2015, Rongchang Biotechnology obtained the clinical approval issued by the National Drug Administration, and its new anti-tumor drug RC48 with independent intellectual property rights became the first domestic human clinical trial.

Figure 3 Rongchang Biological R&D pipeline (source: Rongchang Biological official website)

Although the research and development of ADC drugs in China started late, the market competition is quite fierce.
At present, many domestic companies have deployed ADC drugs, such as Hengrui Pharmaceutical, CSPC, Kelun Pharmaceutical, Junshi Bio, Zhejiang Pharmaceutical, Fudan Zhangjiang , Lepu Biological, Hausen Pharmaceutical, Biotech, Toyo Pharmaceutical, Duoxi Biological and Shanghai Meyac and so on
.

The layout of domestic companies' ADC drugs is dominated by HER2 and TROP2 targets, and the internal volume is serious

In addition, we should also pay attention to the R&D risks of innovative drugs.
Biotech’s ADC drug R&D process once took the lead.
The drug BAT8001 under investigation has entered clinical phase III.
In February 2021, due to clinical phase III results, it did not reach the preset value.
As the goal of superior efficiency, Biotech announced the termination of the development of HER2 ADC (BAT8001).
In March 2021, Aotei again disclosed that it had terminated the development of Trop2ADC (BAT8003)
.

It is reported that BAT8001 has invested a total of 226 million yuan in research and development, and the BAT8003 project has invested a total of 61.

The success and failure of PDC drugs

The success and failure of PDC drugs

PDC (peptide-drug conjugate) is a new type of conjugated drug.
Its structure mainly contains three elements-linker, homing peptide, and cytotoxicity.
Payload, homing peptides can specifically target protein receptors overexpressed on the surface of tumor cells to deliver cytotoxins to induce tumor cell apoptosis
.

The structure of PDC drugs is similar to ADC drugs.

From the perspective of the global market, only two PDC drugs have been approved for listing.
One is Lutathera from Advanced Accelerator Applications SA, a subsidiary of Novartis, which is the first peptide receptor radionuclide therapy (PRRT) drug, January 2018 26 was approved by the FDA; the other is Pepaxto (melphalan flufenamide) from Oncopeptides AB, which was approved by the FDA on February 27, 2021
.

On October 22, Oncopeptides announced the withdrawal of its peptide-conjugated drug Pepaxto (melphalan flufenamide) for the treatment of relapsed or refractory multiple myeloma in the US market, mainly because Pepaxto failed to reduce the ITT population in the confirmatory phase III OCEAN study The risk of death (HR=1.
104)
.
From the accelerated approval of the FDA in February this year to the withdrawal, Pepaxto has been on the market for less than 8 months
.

PDC drug failure lesson-Pepaxto collapse

PDC drug failure lesson-Pepaxto collapse

In February 2021, Pepaxto was approved by the FDA for accelerated listing, and used in combination with dexamethasone to treat patients with triple refractory/relapsed multiple myeloma
.
The FDA accelerated the approval of Pepaxto combined with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma (RRMM), based on the results of a pivotal phase II clinical trial (HORIZON), these patients have previously received at least four previous therapies, including proteases Body inhibitors, immunomodulators, monoclonal antibodies targeting CD38
.
Similarly, as a requirement for accelerated marketing approval, Oncopeptides needs to perform post-marketing Phase III clinical trials (OCEAN)
.

In May 2021, Oncopeptides announced the preliminary results of a head-to-head Phase III clinical trial (OCEAN) of Pepaxto combined with dexamethasone and pomalidomide combined with dexamethasone for the treatment of patients with relapsed and refractory MM.
Pepaxto combined with dexamethasone improved The patient’s PFS and ORR
.
But when the results were updated again in July this year, it showed that the OS data of the pomalidomide combined with dexamethasone control group was better
.

In July 2021, the FDA issued a safety warning against Pepaxto
.
The warning stated that Pepaxto's Phase III clinical trial (OCEAN, Study OP-103) results analysis showed that Pepaxto combined with dexamethasone in the treatment of relapsed and refractory multiple myeloma (RRMM) increased the risk of death
.
The FDA has recommended that medical personnel should review and analyze the disease progression of patients after taking Pepaxto, and then discuss with patients the risk of changing other treatment options to continue treatment
.
At the same time, patients taking Pepaxto should discuss the risks and benefits of taking Pepaxto with the attending doctor
.
At the same time, the FDA requested that OCEAN and Pepaxto other clinical trial patient recruitment be suspended
.

In the end, Oncopeptides chose to withdraw Pepaxto from the US market
.
This failure case should make more companies dedicated to the research and development of such drugs begin to think deeply about the safety of drugs
.

summary

summary

Based on the above information and data, it can be seen that ADC drugs have entered the super hot spot that the industry is highly concerned about
.
The continuous efforts in the field of drug research and development have also made the research and development technology and evaluation standards of ADC drugs clearer
.
It can be predicted that this field will continue to attract R&D investment, and there will also be more excellent products appearing, providing more choices for patients
.

Although there are not many PDC drugs currently on the market, there have recently been cases of withdrawal from the market due to serious safety issues
.
However, the author believes that with the resolution of related technical problems and breakthroughs in supporting technologies, PDC drugs will also become a hot spot for research and development and a crowded track for investment in the next ten years
.

In the next ten years, PDC drugs will also become a crowded track for research and development hotspots and investment
.

Reference materials:

References: References:

1-The oncology market for antibody–drug conjugates

1-The oncology market for antibody–drug conjugates

2-FDA official website

2-FDA official website

3-NMPA official website

3-NMPA official website

4- Official websites of major pharmaceutical companies

4- Official websites of major pharmaceutical companies

5-Oncopeptides official website information

5-Oncopeptides official website information