Novartis Inks $1.16B Deal to Acquire Two AR-Targeting PROTAC Degraders from Arvinas

On April 11 local time, PROTAC leader Arvinas announced that it had reached an exclusive strategic licensing agreement with Novartis.Novartis will obtain the global development and commercialization rights for Arvinas' second-generation androgen receptor (AR) targeted PROTAC protein degrader ARV-766. The collaboration also includes an asset purchase agreement, under which Arvinas will sell another AR-targeted PROTAC degrader, AR-V7, currently in the preclinical stage, to Novartis.

Under the license agreement, Arvinas will receive a $150 million upfront payment. Additionally, the potential value in development, regulatory, and commercial milestones, as well as tiered royalties, could reach up to $1.01 billion. The total amount of this collaboration is up to $1.16 billion (approximately 8.39 billion yuan).

As the first pharmaceutical company focused on PROTAC, Arvinas was founded by Craig Martin Crews, the proposer of the PROTAC concept, and went public on NASDAQ in 2018 (NASDAQ: ARVN).

As early as 2001, Professor Crews' team and Professor Raymond J. Deshaies from the California Institute of Technology first proposed the concept of PROTAC and successfully designed and synthesized the first batch of PROTAC bifunctional molecules for the degradation of methionine aminopeptidase 2 (MetAP-2). The first publication describing PROTAC technology was also published by Professor Crews' team in July 2001.

Based on several years of scientific research and industry accumulation, Professor Crews founded Arvinas in 2013. Currently, Arvinas has established the PROTAC Discovery Engine and the PROTAC Targeted Protein Degradation Technology Platform, using these to develop multiple PROTAC pipelines. Over the years, the Arvinas PROTAC Discovery Engine has made breakthroughs in oral bioavailability, blood-brain barrier penetrance in preclinical studies, First-in-human safety data, human pharmacokinetics and pharmacodynamics data, and First-in-human efficacy data.

The key cooperative pipeline in this initiative, ARV-766, is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR).

Preclinical studies have shown that ARV-766 has demonstrated activity in both wild-type androgen receptor tumor models as well as in tumor models with AR mutations or amplifications. In October 2023, Arvinas presented positive efficacy and tolerability results from the Phase I/II clinical trial of ARV-766 in patients with metastatic castration-resistant prostate cancer (mCRPC) at the European Society for Medical Oncology (ESMO) conference. Based on the previous positive data, Arvinas is expected to initiate a Phase III clinical trial of ARV-766 in treating mCRPC this year, with plans to engage in regulatory discussions in the second quarter of 2024.

Besides the cooperative pipeline, the world's first PROTAC drug to enter clinical trials also came from Arvinas.In March 2019, Arvinas initiated clinical research on ARV-110, a targeted protein degrader, marking the world's first PROTAC drug to enter clinical trials for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Another key candidate product of Arvinas is ARV-471, an oral PROTAC protein degrader targeting estrogen receptor protein (ER), used for treating patients with locally advanced or metastatic ER-positive/HER2-negative breast cancer.Currently, ARV-471 is in Phase III clinical trials, being the most advanced molecule in Arvinas' pipeline and the most advanced PROTAC molecule globally. According to Endpoints, Arvinas expects the Phase III clinical trial of ARV-471 to be completed in the second half of 2024.

Previously, Arvinas achieved a significant collaboration with Pfizer through its ARV-471 pipeline. In July 2021, Arvinas announced a partnership with Pfizer to jointly develop and commercialize ARV-471. Arvinas received a $650 million upfront payment, $1.4 billion in milestone payments, and a $350 million equity investment from Pfizer, bringing the total transaction value to $2.4 billion.

In addition to partnerships with Pfizer and Novartis, in recent years, Arvinas has also reached collaborations with Merck and Roche, quickly regaining financial strength. As of 2023, Arvinas holds over $1.2 billion in cash, equivalents, restricted cash, and marketable securities, sufficient to support the advancement of its multiple PROTAC pipelines at clinical and preclinical stages.

Currently, about 80% of targets globally are considered undruggable by existing inhibitor drug development technologies and cannot be developed into targeted inhibitor drugs.The market for inhibitor-targeted drugs generated annually just from the 20% of targetable targets reaches 200 billion US dollars. If the remaining 80% of non-targetable targets could be utilized for drug development, the market potential would be immeasurable.To develop drugs targeting undruggable targets, PROTAC technology is a viable path.

Targeting this billion-dollar blue ocean, major MNCs began laying out the protein degradation field as early as 2015. Pfizer, BMS, Novo Nordisk, Merck, Eli Lilly, AstraZeneca, GSK, Bayer, Seagen, Roche, Biogen, Novartis, Astellas, and other pharmaceutical giants have been deploying in this area through collaborations in recent years. Overseas biotech companies, including Arvinas, C4 Therapeutics, Nurix Therapeutics, Kymera Therapeutics, and Vividion Therapeutics, are fiercely competing around protein degraders.

In China, dozens of companies such as CSPC Pharmaceutical Group, Hengrui Medicine, BeiGene, Haisco, Kintor Pharmaceuticals, Complix, LNK Therapeutics, Fendy Technologies, Wuyuan Biotech, Hengrui Medicine, HaiChuang Pharma, Biomarker, and HitGen have entered the field, making the protein degradation sector highly prosperous.

On the industry side, although no PROTAC drugs have been approved for marketing by regulatory authorities so far, several candidate drugs have entered the clinical development stage. There are 29 PROTACs under clinical research worldwide, of which 19 are in Phase I clinical trials, accounting for 66%; 9 are in Phase II clinical trials, accounting for 31%.

In terms of molecular glue drugs, the FDA has currently approved three: thalidomide, lenalidomide, and pomalidomide, which are used to treat multiple myeloma, myelodysplastic syndromes, etc., with lenalidomide achieving sales of $12.89 billion in 2021. In addition to these three approved drugs, more than 21 molecular glue drugs have now entered the clinical trial stage.

As mentioned earlier, ARV-471, currently in Phase III clinical trials, is the fastest-progressing PROTAC molecule globally, with its Phase III clinical trial expected to be completed in the second half of 2024. Once ARV-471 is approved first, the industrialization of PROTAC molecules will usher in a new era and open doors, and PROTAC will enter an even higher and larger风口.

References:
1. "$350 Million! Arvinas Announces Latest Financing, ARV-471 Phase III Trial Expected to Complete in the Second Half of Next Year"

2. "$4.8 Billion in Total! This Company Has Signed 8 Deals"