Frequent Side Effects and Resistance Challenge in CDK4/6 Inhibitors; New CDK Inhibitor Market Potential Over $2 Billion

On September 30, Genentech, a division of Roche, made headlines by entering into a significant agreement with Rueger, acquiring Rueger's portfolio of next-generation CDK inhibitors for $850 million in upfront cash and other potential milestone payments. This transaction not only sets a new benchmark for the foreign authorization of domestic molecules but also signifies a pivotal moment in the partnership between the two entities. Previously, Benefi Tianheng's agreement with BMS for the BL-B01D1 molecule, valued at $800 million, held the record.

The previous deal between Benefi Tianheng and BMS involved a single molecule, BL-B01D1, already in the later stages of clinical development, with both parties sharing subsequent overseas clinical costs. In contrast, the collaboration with Genentech encompasses a broader portfolio of next-generation CDK inhibitors, including the Phase I CDK2/4/6 inhibitor RGT-419B and the preclinical CDK2 inhibitor QR-6401. Under the terms of the agreement, Genentech will take charge of the global clinical development, manufacturing, and commercialization of these products following the completion of the existing Phase 1 clinical stage.

The field of CDK inhibitors has recently garnered significant attention from numerous companies. Besides Genentech, Beigene also announced in November last year the introduction of ETX-197, a CDK2 inhibitor from Onsun Pharma. Although the upfront payment amount was undisclosed, considering potential future milestone payments and sales sharing, the overall value of the deal could reach $1.33 billion.

With the entry of generic CDK4/6 inhibitors into the market, some investors have questioned whether the competitive landscape for CDK inhibitors has reached saturation. However, leading companies like Roche and Beigene continue to actively develop next-generation CDK inhibitors, highlighting a compelling scientific and commercial rationale.

Cyclin-dependent kinases (CDKs) are crucial members of the serine/threonine protein kinase family, playing vital roles in cell cycle regulation. These kinases are mainly divided into two categories: those involved in cell cycle regulation, such as CDK1, 2, 4, and 6, and those primarily involved in transcriptional regulation, such as CDK7, 8, 9, and 11. Among them, CDK4/6 and CDK2 have attracted considerable attention due to their significant roles in tumor development.

CDK4/6 is a key protein in the human cell division and proliferation cycle, triggering the transition from the growth phase (G1 phase) to the DNA replication phase (S phase). In many cancer cells, CDK4/6 is overexpressed, promoting uncontrolled cell proliferation by over-phosphorylating and inhibiting the Rb protein. Therefore, CDK4/6 inhibitors can block the cell growth cycle in the G1 phase, inhibiting tumor cell proliferation. CDK2 plays a critical role in the early and synthesis phases of the cell cycle, and its overexpression is closely linked to abnormal cell cycle regulation and excessive cancer cell proliferation.

From a market perspective, breast cancer, the world's most prevalent malignant tumor (accounting for about 24.5% of all malignancies), offers significant application potential for CDK inhibitors. Especially in HR+/HER2- advanced breast cancer patients (about 60%-70%), endocrine therapy combined with CDK4/6 inhibitors is a first-line treatment. This partly explains why CDK4/6 inhibitors hold a crucial position in breast cancer treatment and command a substantial market share.

Despite the emergence of blockbuster drugs, existing CDK4/6 inhibitors have notable shortcomings, primarily drug toxicity and resistance. Hematotoxicity is the most common side effect, with neutropenia, leukopenia, anemia, and thrombocytopenia being prevalent. Additionally, gastrointestinal adverse reactions are also significant concerns. In terms of drug resistance, 15-20% of patients exhibit primary resistance to CDK4/6 inhibitors at the start of treatment, while 30-40% develop resistance over time due to mechanisms like ESR1 gene mutation, upregulation of PI3K/AKT/mTOR signaling, and BRCA2 gene mutation.

The urgency to address toxicity and drug resistance issues has opened new development opportunities for next-generation CDK inhibitors. Roche's RRT-419B, a next-generation CDK2/4/6 small molecule inhibitor developed by Rueger Pharmaceutical, is not yet commercially available worldwide. It has shown promising preliminary validation in existing breast cancer clinical data by aiming to increase CDK2 inhibition, thereby reducing resistance to CDK4/6 inhibitors and achieving long-term efficacy.

In December 2023, Rueger presented promising Phase 1a clinical trial data for RGT-419B at the SABCS Conference. The drug demonstrated safety and tolerability, with three patients achieving partial response and six patients continuing treatment for over 24 weeks.

Given the potential of next-generation CDK inhibitors in second-line breast cancer monotherapy and the success of second-line endocrine drugs like fluvestrant, the global market for these inhibitors is expected to reach $2-3 billion. This prospect has driven Roche to make substantial investments.

Domestic pharmaceutical companies are also actively researching and developing new-generation CDK2/4/6 inhibitors. Companies like Hengrui Pharmaceutical and First Sound Pharmaceutical are expanding their development of CDK2 inhibitors based on CDK4/6 inhibitors. Meanwhile, firms like Ruge Pharmaceutical, Stone Pharmaceutical Group, and Homology Kang Pharmaceutical are making significant strides in the CDK inhibitor field.

Most CDK2/4/6 inhibitors in clinical stages in China are still in early clinical stages and lack comprehensive clinical validation. However, AI technology has played a crucial role in optimizing molecules for these projects. The AI pharmaceutical platform has been instrumental in identifying key binding pockets and screening CDK targets, driving the clinical trial process.

Investors may need to pay more attention to biotech companies leveraging AI technology to address challenges in drug development, particularly in the evolving landscape of CDK inhibitors.