ADC research and development are normalizing, but Pfizer "quietly” changed hands to others!

On March 18, Pfizer and American biotechnology company Pyxis Oncology (hereinafter referred to as “Pyxis”) jointly announced that the two parties have reached a global licensing agreement for two ADC (antibody-drug conjugate) candidate products, but specific transactions The amount was not disclosed.

According to the license agreement, Pfizer will provide Pyxis with worldwide licensing, development and commercialization rights for two innovative ADC drug candidates, PYX-201 and PYX-203. At the same time, Pfizer will also provide Pyxis with a license for its ADC technology platform, including various payload categories, linker technologies, and ADC-specific conjugation technologies for the future development of other ADC drugs.

On March 18,  Pfizer (NYSE: PFIZN) and Pyxis Oncology (NYSE: PYXIS) announced that they have entered into a global licensing agreement for two ADC (Antibody Drug Conjugate) product candidates for an undisclosed amount.

Under the license agreement, Pfizer will provide Pyxis with worldwide licensing, development and commercialization rights for two innovative ADC candidates, PYX-201 and PYX-203.Pfizer will also license Pyxis’ ADC technology platform, which includes a variety of payload classes, linker technologies and ADC-specific conjugation technologies for future development of other ADC drugs.

Pfizer will also receive advance payments and equity from Pyxis, and will be eligible for milestone payments based on development and sales, as well as tiered royalties for potential sales.

01 R&D while giving up

The PYX-201 in this transaction is a world-first non-internalized ADC drug developed by Pfizer. It selectively kills tumor cells by targeting tumor-restricted antigens overexpressed in solid tumors while enhancing the anti-cancer immune response. . Compared with internalized ADC drugs, non-internalized ADC drugs can release cytotoxic drugs outside the cell without entering cancer cells, and play a role in the local microenvironment. PYX-203 is an ADC drug targeting hematomas, which reduces tumor drug resistance and prevents tumor recurrence through high-efficiency DNA disruptors.

After obtaining these two drugs, Pyxis will further develop and expand its ADC drug pipeline. At present, in addition to PYX-201 and PYX-203, Pyxis also has ADC drug PYX-202 and 4 monoclonal antibody drugs.

As a company only established in 2019, Pyxis has a lot of connections with Pfizer. Its CEO Lara Sullivan (Sullivan) worked for Pfizer for many years and became the president of Pfizer’s spin-off company SpringWorks in 2017. He left in 2019 and founded Pyxis. This also makes the cooperation between the two parties full of affection.

Dr. Ronald Herbst, Chief Scientific Officer of Pyxis, said: “Early ADC drugs have shown great potential, but there is still a lot of room for innovation to develop safer ADC drugs. PYX-201 and PYX-203 represent the use of innovative conjugation. Technology’s next-generation ADC. We are happy to advance the preclinical research conducted by Pfizer into the clinical trial phase.”

As the world’s first company to develop ADC drugs on the market, Pfizer’s ADC drug research and development road is also very tortuous.

In May 2000, the US FDA approved the listing of Pfizer’s ADC drug Mylotarg (gemtuzumab ozogamicin) for the treatment of patients over 60 years of age with CD33-positive acute myeloid leukemia (AML) who relapsed for the first time.

However, in subsequent trials, Mylotarg not only showed no obvious clinical benefits, but also had serious safety problems. The Mylotarg treatment group suffered severe fatal liver damage, and the death rate of the combination group was higher than that of the chemotherapy group alone. In 2010, Pfizer chose to take the initiative to delist Mylotarg. Until September 2017, Mylotarg was once again approved for marketing in the United States for the treatment of newly diagnosed adult patients with CD33-positive AML and patients with relapsed/refractory CD33-positive AML 2 years of age and older.

Today, Pfizer, which already has a number of ADC drugs on the market, is walking the path of giving up while developing.

In 2018, Pfizer terminated its five-year partnership with CytomX Therapeutics’ drug Probody for the development and commercialization of several ADC drug development platforms for cancer. Pfizer stated in the termination letter that it decided not to pursue the two ADC drug development goals previously selected.

While revenue fell 9% in the fourth quarter of 2019, Pfizer announced the termination of the development of ADC drug PF-06688992. PF-06688992 is a drug composed of anti-ganglioside GD3 monoclonal antibody, developed for the treatment of melanoma.

The sale of PYX-201 and PYX-203 is another “new move” of Pfizer in the ADC field.

02 Will the fiery ADC repeat the mistakes of PD-1?

Compared to the ADC market, which was quiet for a decade after Mylotarg went public in 2000, the ADC field is now very hot.

With the development and maturity of small molecule toxin, ligon and coupling technology, the safety and effectiveness of ADC technology platform have been greatly increased and the therapeutic window has been greatly expanded after several iterations.According to data analysis, the global ADC drug market capacity will reach US $10 billion in 2026 and exceed US $15 billion in 2030.As a result, the ADC field has become an important track for major pharmaceutical enterprises to compete for the layout.

Currently, there are 11 ADC drugs on the market worldwide.In 2019 alone, three ADC drugs were approved for market in the United States, apparently, the development of “biological missile” ADC drugs has been pushed to a climax.

And domestic pharmaceutical enterprises for ADC research and development enthusiasm is no less than foreign.

According to ClinicalTrials.gov, as of March 19, 2021, 155 ClinicalTrials for ADC drugs are ongoing worldwide, of which 29 are domestic.According to incomplete statistics, more than 20 companies have developed ADC drugs in China.

List of ADC drug research and development of some companies

At present, RC48 (vidisetuximab) of Rongchang Biotech is the fastest developing HER2 antibode-drug conjugation (ADC) drug in China, which has been submitted to the State Drug Administration of China for marketing as a new drug for gastric cancer indications in August 2020, and has been included in the priority review and approval procedure.In addition to the new drug application for gastric cancer, Vaticetuumab is also conducting pivotal clinical trials in urothelial carcinoma (Ⅱ), in breast cancer with low HER2 expression, and in lung cancer and cholangiocarcinoma (I). In addition, Vaticetuumab has also been licensed for clinical trials in urothelial carcinoma (UI) in the United States.

Dongyao Pharmaceutical Co., Ltd. is in the first echelon of ADC pharmaceutical companies in China, and its candidate core product TAA013 has entered the Phase III clinical stage.TAA013 is an investigational antibody-conjugated drug containing a trastuzumab-mettan derivative (trastuzumab-MCC-DM1) and is intended to be an affordable alternative to Kadcyla for the treatment of HER2-positive breast cancer.

As a leading domestic innovative drug research and development enterprise, Hengrui Pharmaceutical not only joined the ADC war, and is a multi-pronged.At present, Hengrui Pharmaceutical has disclosed the development progress of four ADC drugs.ADC drugs targeting c-Met, SHR-A1403, and HER2-targeted SHR-A1201 and SHR-A1811 are all in the clinical stage.In January this year, the clinical trial application of the fourth ADC drug SHR-A1904 of Hengrui Pharma was also accepted by NMPA.

In April 2020, Trodelvy, a drug developed by Immunomedic for TROP-2 ADC, was approved in the U.S.Trodelvy has become a high-profile treatment for triple-negative breast cancer, claiming to be far more effective than conventional treatments.In 2019, Genting acquired the exclusive license to develop, register and commercialize Trodelvy for all cancer indications in Greater China, South Korea, and certain Southeast Asian countries and regions.Genting is currently conducting a phase IIb clinical trial of Trodelvy in patients with metastatic triple-negative breast cancer who have received at least two previous treatments.

As can be seen from the meeting minutes of the research activity recently published by Kelun Pharmaceutical, Kelun Pharmaceutical will focus on the distribution of ADC drugs in 2021.A166 targeting HER2 has submitted a critical Ⅱ phase application to CDE;Phase I clinical data have been obtained for SKB264 targeting TROP-2;ADC drugs targeting Claudin 18.2 will enter the clinic in 2021.

The Claudin 18.2 targeted ADC drug SYS1801 independently developed by CSPC is the first ADC drug targeted by Claudin 18.2 in a domestic pharmaceutical company. It was approved by the FDA as an orphan drug in November last year. CSPC also plans to submit clinical trial applications in China and the United States this year.

However, such a hot ADC track may face the problem of “crowding” and “being unable to make ends meet”.

In early March of this year, Biotech announced that it would abandon the clinical development of its ADC drugs BAT8003 and monoclonal antibody BAT1306. In February, Biotech announced that another ADC drug, BAT8001, had failed the Phase III clinical trial. According to calculations in the 2020 annual report published by Biotech, the three drugs caused Biotech to lose 340 million yuan in research and development investment costs.

Biotech’s BAT8001 was the first ADC drug targeting HER2 to enter clinical phase III in China, and has always been high hopes. BAT8003 is also an ADC drug targeting the popular target Trop2. However, the two popular drugs withdrew one after another, which undoubtedly poured “cold water” on Biotec and even ADC drugs.

Regarding the suspension of the research and development of BAT8003, Biotech stated that it is to rationally allocate the company’s research and development resources and focus on advantageous projects in the research and development pipeline.

Biotech’s “timely stop loss” also shows a serious imbalance between investment and income. Behind the hot track means the increase in research and development costs, and it also hides the “price war” under a lot of future competing products.

And will the “crowded” PD-1 monoclonal antibody track become the “tomorrow” of ADC?