Pfizer Leads, Hengrui and BeiGene Enter the Race: A Rising Star Emerges in Epigenetics

Following the emergence of EZH2, IDH1, PRMT5, etc. in the oncology field, the epigenetics field has once again...Potential TargetEmergence.

In May this year, Pfizer announced the latest Phase I clinical research data of KAT6 inhibitor PF-07248144 at the ASCO meeting. The product, in combination with fulvestrant for the treatment of CDK4/6 inhibitor-resistant breast cancer, demonstratedExcellent and Durable Antitumor Activity, among which the 5 mg dose group showed particularly outstanding efficacy. Pfizer plans to launch its Phase III clinical trial in the second half of this year.

PF-07248144 is the globally leading KAT6 inhibitor, and the initiation of its pivotal Phase III clinical trial signifiesKAT6 Target Drug Development Officially Enters the Fast Lane。

KAT6 Target: Three Decades of Exploration Finally Yield Breakthrough

KAT6 belongs toMYST Family(One of the three major families of histone acetyltransferases HATs), including KAT6A（MOZ、MYST3)、KAT6B（MORF、MYST4）Two subtypes. In 1996, KAT6A in acute myeloid leukemia（AML）It was first discovered in chromosomal translocations. In 1999, KAT6B was identified as a paralog of KAT6A. However, it was not until 2006 that the characteristics of the KAT6A/B complex were clearly defined.

KAT6A and KAT6B consist of 2004 and 2073 amino acids, respectively, with an N-terminal containing aDouble PHD Zinc Finger Domain(PHD1 and PHD2)And aMYST Domain, the C-terminal contains a richGlutamate/Aspartate AreaAnd a rich inSerine/Methionine RegionAmong them, the PHD zinc finger domain interacts with histone H3 and is essential for nuclear localization to chromatin. The N-terminal part is conserved in Drosophila Enok and is also known as the NEMM domain, while the C-terminal part possesses transcriptional activation activity.^[1]。

Source:Drug Resistance Updates

After research, scientists found that KAT6 can acetylate histone H3 and non-histone proteins.Cell Cycle Regulation, Stem Cell Self-Renewaland other aspects play an important role, with abnormal expression(Including mutations, genomic amplifications, deletions, or fusions)Often leads toBreast Cancer, Ovarian Cancer, Cervical Cancer, Glioblastoma, LeukemiaThe occurrence of various diseases such as...^[1]。

Source:Drug Resistance Updates

KAT6 has thus become a highly promising therapeutic target. In 2018, Professor Jonathan B. Baell's team published a study in Nature, in which they screened 240,000 small molecule compounds and carried out medicinal chemistry modifications, successfully developingGlobal First KAT6A/B Inhibitor WM-8041 and KAT6A Inhibitor WM-1119^[2]Although these inhibitors have been shown to induce cellular senescence and inhibit tumor growth, they may also affect many important normal cellular physiological processes in healthy tissues.

However, as an emerging cancer treatment, KAT6 inhibitors are promising.Addressing the Challenge of Drug Resistance in Existing Medications, still attracted a large number of pharmaceutical companies' attention. After 2020, pharmaceutical giants such as Pfizer and Bayer also successively joined the ranks of KAT6 target drug development.

Pfizer Takes the Lead, Chinese Companies Quickly Follow Up

Insight database shows that currently, there are 28 KAT6-targeted drugs under research and development globally.(Including items in both active and non-active states), of which 5 have entered the clinical stage, namely PF-07248144 (Pfizer), OP-3136 (Olema Oncology), HRS-2189 (Hengrui Pharma), ISM5043 (Insilico Medicine), and QLS1304 (Qilu). The initial indications are mostlyBreast Cancer, Prostate Cancer, Non-Small Cell Lung Cancer。

PF-07248144 is the world's first KAT6 inhibitor to enter clinical research. According to Pfizer's official website, PF-07248144 is an oral small-molecule inhibitor that selectively binds to KAT6A/B, inhibiting the acetylation modification of lysine 23 on histone H3.（H3K23Ac）, thereby affecting gene transcription to exert therapeutic effects.

In May this year, Pfizer announced PF-07248144 as a monotherapy and in combination with fulvestrant at the ASCO meeting.（FUL）First-in-Human Phase I Dose-Escalation/Expansion Study Data of the Combination in Heavily Pretreated ER+/HER2- Metastatic Breast Cancer Subjects(Registration Number: NCT04606446)。

As of October 11, 2024, a total of 107 patients who had previously received CDK4/6 inhibitors and endocrine therapy were administered the recommended expanded dose.（RDE）Treatment, where 35 patients received 5 mg PF-07248144 monotherapy, 43 patients received 5 mg PF-07248144 + FUL combination therapy, and 29 patients received 1 mg PF-07248144 + FUL combination therapy, with a follow-up of at least 6 months.

The results showed that the 5 mg dose combined with FUL group and the 1 mg dose groupObjective Response Rate (ORR) was 37.2% and 24.1%, respectively.，Median Duration of Response (mDOR)15.8 months and 4.6 months, respectively, with clinical benefit rates (CBR) of 55.8% and 37.9%, respectively,Median Progression-Free Survival (mPFS)10.7 months and 3.6 months, respectively.

In terms of safety, the most common TRAE in the combination therapy were in the 5 mg and 1 mg dose groups.Taste Disorder, with incidence rates of 83.7% and 89.7%, respectively. The most common ≥3 grade TRAE was neutropenia.（G3：39.5% vs 20.7%；G4：7.0% vs 0.0%）Neutropenia is reversible and can be controlled by dose adjustment. No febrile neutropenia was observed. The safety of 5 mg monotherapy is consistent with the safety of the 5 mg combination therapy group. No pneumonia events were reported.

Based on the above data, 5 mg QD PF-07248144 was determined to be the recommended Phase III dose for use in combination with FUL.（RP3D）Pfizer will also launch the pivotal Phase III clinical trial of this product this year, further solidifying the company's leading position in the breast cancer field.

Hengrui'sHRS-2189 is currently in Phase II clinical trials for prostate cancer and Phase I/II clinical trials for breast cancer, with no clinical data disclosed publicly yet. Qilu'sQLS1304 is currently undergoing Phase I clinical trials for solid tumors in China. Notably, the product successfully obtained clinical trial authorization from the U.S. FDA at the end of April for the indication of ER+/HER2- breast cancer and was granted Fast Track Designation (FTD) in early May.

Deals Have Been Made, Huge Potential for Overseas Expansion

Although only 5 products have advanced to clinical trials,KAT6 Target Has Already Seen BD Deals, once again demonstrating the enormous potential in this field.

In January 2024, Insilico Medicine will ISM5043(At that time, it was in the preclinical stage)The global exclusive development and commercialization rights have been granted to Menarini,Total amount up to 500 million US dollars, including a $12 million upfront payment, as well as subsequent development, regulatory, and commercial milestone payments.

ISM5043 is a KAT6 inhibitor designed and developed by Insilico Medicine using an AI-powered platform. In preclinical studies, this product demonstrated efficacy in multiple cell line xenograft models.(CDX) Human Xenograft Model(PDX) Displayed potent activity against KAT6A in ChinaInhibitory effect, with good efficacy and safety.

Source:Insilico Medicine

In October 2024, Menarini launched ISM5043 treatment in the United States.Advanced Breast CancerTheFirst-in-Human Phase I Clinical StudyThis study plans to enroll 124 subjects and complete the primary endpoint analysis in October this year.

Turning the focus to China, apart from Hengrui Pharma and Qilu Pharma,BeiGene, Henlius Biotech, Renfu Pharmaceutical, Innovent BiologicsOthers also have KAT6 inhibitors under research, but they are still in the preclinical stage for now. Fosun Henlius and Renfu Pharmaceutical bothKAT6 Inhibitor First Disclosed at This Year's AACR ConferencePreclinical data.

Compared with PF-07248144, HenliusHLX97-053 Demonstrates Significantly Stronger Synergistic Effects with Fulvestrant and Palbociclib in CDK4/6 Inhibitor-Resistant Patient-Derived Xenograft (PDX) ModelsIn addition, the hematological toxicity of HLX97-053 was also significantly reduced, showing best-in-class potential.

PersonFu PharmaHW321005 In the ZR-751 (breast cancer) xenograft model, it also showedPowerful Antitumor Efficacy and Pharmacodynamic Response。

Currently, under research in ChinaKAT6 inhibitors mostly targetPost-line Therapy for Breast Cancer. In recent years, althoughCDK4/6 InhibitorThe emergence of new drugs such as 等 has significantly improved the prognosis of breast cancer patients, but the issue of drug resistance still exists, which undoubtedly poses a challenge.KAT6 Inhibitors Create a Huge Market Gap.

The existing data on the KAT6 inhibitor under research in China has preliminarily demonstrated its clinical potential.As more data is released, combined with the broad commercial prospects, the likelihood of related products going overseas is very high.

Conclusion

In summary, KAT6 has become a popular development target, with several advancements just this year.Publication of 11 Early R&D DataIn the future, as more and more clinical data is disclosed, perhaps more pharmaceutical companies will join the competition. The differentiation potential of products and the selection of indications will become the core winning factors for pharmaceutical companies to stand out in the track competition.

Cover Source:ZCOOL Hello

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