Record-Breaking Upfront Payment in Biopharma Outbound Deal Signals a New Era for Breast Cancer Therapy

The record of Chinese innovative drugs going overseas is constantly being refreshed.

The latest record creator is Regor Therapeutics. On September 30, Regor Therapeutics announced that it had reached an acquisition agreement with Genentech, a subsidiary of Roche Group, for the next-generation CDK inhibitor.

According to the terms of the agreement, Regor Therapeutics will receive an upfront payment of $850 million and is eligible to receive additional cash payments based on the achievement of specific development, regulatory, and commercial milestones.

This deal also set a new record for upfront payments in the overseas licensing of China-produced innovative drugs. The previous record was held by Baili Tianhe's EGFR×HER3 bispecific antibody-drug conjugate (ADC) BL-B01D1 in its licensing deal with Bristol-Myers Squibb (BMS) (USD 800 million).

The continuous刷新 of records not only demonstrates the quality of innovative drugs produced in China but also reflects a trend from an industry perspective:

After more than a decade of intense effort, the development of the next generation of CDK inhibitors is reaching new heights.

Positioning the Next Generation of CDK Inhibitors

Since the discovery of cyclin-dependent kinases (CDKs), scientists have been attempting to target them to disrupt the division and proliferation of cancer cells.

Breast cancer, in particular, relies heavily on this process for growth. As a result, the first-generation CDK inhibitors targeting CDK4 and CDK6 have achieved significant success.

In February 2015, the first CDK4/6 inhibitor Palbociclib, developed by Pfizer, was approved for marketing in the United States for the treatment of HR+/HER2- locally advanced or metastatic breast cancer.

Breast cancer has a large patient population, with over 2.3 million new cases globally in 2020, making it the most common cancer worldwide. Based on the substantial patient scale, the sales volume of Palbociclib is also quite significant.

In 2016, the first full year of sales for Palbociclib reached $2.135 billion, making it a blockbuster drug without a doubt. Since then, CDK4/6 inhibitors from Eli Lilly, Novartis, Boehringer Ingelheim, and Hengrui Medicine have been successively approved for marketing.

In 2023, the total sales of CDK4/6 inhibitors from Pfizer, Novartis, and Eli Lilly alone approached $100 billion. Based on the successful commercial performance of CDK4/6 inhibitors in the breast cancer field, Nature Reviews Drug Discovery predicts that by 2029, CDK4/6 inhibitors are expected to contribute $20 billion, accounting for 42% of the breast cancer drug sales market share.

However, the currently marketed CDK4/6 inhibitors are not perfect, as they all have certain drawbacks to varying degrees. First, one issue that troubles CDK4/6 inhibitors is toxicity. At present, the most common adverse reaction of CDK4/6 inhibitors is neutropenia, with palbociclib and ribociclib having the highest incidence rates, where the proportion of grade 3-4 neutropenia reaches 60%-66%.

In addition, bone marrow suppression is also the most common toxic reaction of CDK4/6 inhibitors, with an incidence rate as high as 80% in women taking palbociclib or ribociclib, and up to 50% when taking abemaciclib.

These adverse reactions limit the dosing of CDK4/6, which to some extent affects the clinical application of CDK4/6 inhibitors. Precisely because of this, the research and development of next-generation CDK inhibitors is in full swing.

The Highly Anticipated CDK2

The potential of CDK inhibitors is not limited to targeting CDK4 and CDK6.

The CDK family has many members, and currently, 20 different subtypes have been discovered. According to their functions, they can be divided into two categories: one category of CDKs is involved in cell cycle regulation, such as CDK1, CDK2, CDK4, CDK6, etc.; the other category of CDKs is involved in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11, etc.

Among them, many family members are potential drug targets, and CDK2 is one of the current research hotspots.

Regor Therapeutics, which has reached a significant collaboration with Roche, has two CDK inhibitors in its pipeline, both targeting CDK2: one is the CDK2/4/6 inhibitor RGT-419B, and the other is the CDK2 inhibitor QR-6401.

Similarly, on November 21 last year, BeiGene collaborated with Oncostem Pharmaceuticals to obtain the global exclusive rights to the latter's investigational oral CDK2 inhibitor, ETX-197.

It is no surprise that CDK2 has drawn attention, given its tremendous potential.

For example, CDK2 may help address the resistance issues associated with CDK4/6 inhibitors. As a first-line treatment, whether combined with aromatase inhibitors or fulvestrant, 15%-20% of patients exhibit primary resistance to CDK4/6 inhibitors, and almost all patients develop secondary resistance in the later stages of using CDK4/6 inhibitors. Once resistance occurs, the treatment options for patients become very limited.

It appears that CDK2 is a potential breakthrough. Studies have shown that after CDK4 is inhibited, CDK2 takes over its function and promotes cancer cell proliferation. These cancer cells not only continue to grow but may also develop resistance to previous CDK inhibitor treatments. This suggests that CDK2 could be one of the mechanisms behind CDK4/6 resistance.

This has also been preliminarily validated by Pfizer. In clinical trials, among 16 patients with metastatic breast cancer who had previously received second-line CDK4/6 inhibitor plus endocrine monotherapy, three patients achieved partial response and six patients achieved stable disease after treatment with PF-07104091, a selective CDK2 inhibitor developed by Pfizer. Initial results indicate that PF-07104091 demonstrates promising efficacy in HR+/HER2- breast cancer patients resistant to CDK4/6 inhibitors.

This means that the combination of CDK2 with CDK4/6 may help address drug resistance issues.

Regor Therapeutics' RGT-419B, which is progressing rapidly, also aims to address resistance to CDK4/6 inhibitors and other hormone receptor modulating therapies. Preclinical data show that in ER+ breast cancer cells resistant to currently approved CDK4/6 inhibitors, RGT-419B demonstrated complete inhibition of cancer cell proliferation. In these experiments, the inhibitory effect of RGT-419B on tumor cells was further enhanced when combined with selective estrogen receptor degraders or PI3K pathway inhibitors.

Team Formation in Progress

Facing the huge temptation of the CDK inhibitor market worth tens of billions of US dollars, quite a few pharmaceutical companies in China and abroad have begun to show great interest.

Currently, the pharmaceutical industry has extensively laid out strategies targeting CDK2 as well as CDK4/6. In China, companies such as Chenxin Pharmaceutical, CSPC Pharmaceutical Group, Qilu Pharmaceutical, and Tongyuan Kang Pharmaceutical are conducting clinical trials for CDK2/4/6 inhibitors.

Outside of China, Pfizer's R&D is progressing the fastest. At last year's ASCO conference, Pfizer had already announced the Phase 1/2a clinical data of its candidate drug PF-07104091 and is currently conducting a three-year study. Additionally, CDK2 inhibitors such as Incyte's INCB123667 and Blueprint's BLU-222 are also in the clinical research stage.

Now, with Roche's entry, the competition surrounding the new generation of CDK inhibitors will undoubtedly become even more intense. For biotech companies, while developing superior molecules, they may also need to consider issues related to strategic choices.

After all, the entry of large pharmaceutical companies will constantly change the competitive landscape. On the one hand, the core of giants like Roche introducing projects is essentially to leverage their "clinical development capabilities, manufacturing capacity, and commercial influence" to create more value in transactions. In these three aspects, biotech does not have the upper hand.

On the other hand, some large pharmaceutical companies have formed the ability to achieve ecological breakthroughs in the field of breast cancer. The most typical example is Roche, which has led the research and development wave of targeted drugs in the breast cancer field from HER2 to PI3K targets, and is still pushing this field to develop to a higher level. In other words, the competitiveness of these large pharmaceutical enterprises in these specific fields will be further strengthened.

For biotech, it is necessary to act faster and ensure the realization of commercial expectations. In this context, strategic choices may be the most critical.

So, in this field, will domestic biotech create new BD records?

This article is from the WeChat Official Account"Amino Observation" (ID: anjiguancha), Author: Zheng Xiao, 36Kr authorized release.