Domestic Innovative Drugs Shine at AACR 2022: Ten Promising Candidates Across Seven Key Therapeutic Tracks

Author: Shuye

As the 2022 AACR concludes, China's innovative pharmaceutical companies have unveiled their latest drug data and research advancements. Which new drug data caught your attention, and whose product pipeline has left you intrigued? Here, we provide a brief report on a few selected items based on their chosen targets for your reference.

NO.1 EGFR Succession

Two China-produced third-generation EGFR drugs have already been marketed, with another 4-5 in the approval process for market entry. As national medical insurance negotiations proceed, competition among third-generation drugs will intensify. Although the competition within the third-generation EGFR drug category has yet to be settled, the race for fourth-generation EGFR drugs appears to be heating up.

At the 2022 AACR conference, Qilu Pharmaceutical Co., Ltd. presented the preclinical data of the fourth-generation EGFR inhibitor QLH11811. The data shows that the enzymatic activity of QLH11811 is highly competitive.

It is not difficult to speculate that QLH11811 will also cover a variety of clinical medication scenarios. QLH11811 not only reverses the C797S mutation that confers osimertinib resistance but also exhibits inhibitory activity against common mutations such as ex19del, L858R, and T790M. Although it does not show selectivity for wild-type EGFR, compared to other fourth-generation products that can only target the C797S mutation, it represents significant progress. In preclinical tumor models, QLH11811 has indeed reduced tumor growth in multiple tumor xenograft models. Unfortunately, QLH11811 also seems to lack descriptions of activity data in the central nervous system.

In addition, Red Cloud Bio also announced the preclinical data of the fourth-generation EGFR inhibitor H002, which has received clinical approval, at the AACR conference. Professor Caihong Yun from Red Cloud Bio was one of the core members involved in the development of the allosteric inhibitor EAI045. However, the previously disclosed fourth-generation EGFR patent by Red Cloud Bio was also developed based on Brigatinib and did not continue the molecular framework of EAI045.

The preclinical data of H002 is also excellent, covering a combination of various drug-resistant mutations, and it has the potential for both first-line and later-line treatment. Meanwhile, H002 is one of the few fourth-generation EGFR products globally that can cross the blood-brain barrier, with significant clinical advantages and promising market prospects.

NO.2 China-produced KRAS Debuts for the First Time

KRAS is also one of the highly sought-after targets in China, with companies such as Innovent Biologics, Betta Pharmaceuticals, and Jacobio Pharmaceuticals actively pursuing its development and successively initiating clinical research.

2022 AACR: InnoCare Pharma Announced the Early Data of Phase I Clinical Study of KRAS G12C Inhibitor D-1553, Making D-1553 the First China-produced KRAS Inhibitor to Disclose Clinical Data.

Data show that at the PR2D dose, the ORR of D-1553 evaluated in 32 patients reached 40.6%, with a DCR of 84.4%. In terms of safety, D-1553 was well tolerated without reaching dose-limiting toxicity. In another concurrent safety evaluation study registered with AACR, among 22 patients, grade 3 anemia and hypokalemia as well as grade 4 hypertension adverse events occurred in 2 patients (9.1%). One patient (4.5%) discontinued D-1553 treatment due to cerebral hemorrhage. According to the investigator's assessment, this event was possibly unrelated to D-1553.

NO.3 PRMT5 Iterative Upgrade

In 2022, while announcing its 2021 performance, GlaxoSmithKline disclosed the termination of its collaboration with Epizyme, and will return the global rights to two drugs: the PRMT5 inhibitor GSK3326595 and the PRMT1 inhibitor GSK3368715. GSK3326595 is a key representative of first-generation PRMT5 inhibitors. Due to a lack of selectivity between tumor cells and normal cells, this class of drugs has shown varying degrees of grade 3 or 4 adverse events in clinical trials. MRTX9768 represents the second generation of such drugs, selectively binding to the PRMT5-MTA complex, killing tumor cells with MATP deficiency without affecting normal cells.

In China, Shenghe Pharmaceutical has begun clinical research on related drugs, while Simcere Pharmaceutical and CSPC have also obtained clinical permits respectively. At the 2022 AACR, Simcere Pharmaceutical, as a representative of domestic PRMT5 inhibitor development, delivered an oral presentation at the conference. However, the PRMT5 inhibitor reported by Simcere Pharmaceutical this time was SCR-6277, not SCR-6920, which was submitted for clinical trials.

Data show that SCR-6277 has the potential for intratumoral specific distribution, with a significantly better tumor-to-plasma drug concentration ratio (T/P) compared to GSK3326595, and demonstrates growth inhibition in tumor cells or grafts such as CLL (Z-138).

In addition to PRMT5, Simcere Pharmaceutical also announced preclinical data for MAT2A inhibitor SCR-7952, RAD51 inhibitor SCR-6992, and CDK2/4/6 inhibitor SCR-8079 at the conference.

NO.4 BTK Is Not Willing to Fall Behind

Bruton's Tyrosine Kinase (BTK) is an important signaling molecule in the B-cell receptor pathway, expressed at all stages of B-cell development, and involved in regulating the proliferation, differentiation, and apoptosis of B cells. It has become a highly regarded target in the fields of tumor treatment and immune diseases and is also a typical representative of China's innovative drug exports.

With the clinical application of non-covalent inhibitors, the C481S mutation has become a common known resistance mechanism for these products. Merck and Eli Lilly took the lead in this field, and domestic companies in China are certainly not willing to lag behind. Similar products from Hutchmed and BrightGene Bio-Medical have already entered clinical research, while Haibeibio Pharma has completed its IND filing.

2022 AACR: Fosun Pharma Presented Preclinical Data of BTK C481S Inhibitor FCN-589. Compared to ARQ531, FCN-589 Achieves Higher Tumor Growth Inhibition at Similar or Lower Dose Levels.

Moreover, pirtobrutinib made another appearance at AACR, continuing to demonstrate strong tumor suppression and clinical potential.

NO.5 PD-L1 Adds Another Small Molecule Player

Immune therapies represented by PD-1/L1 have significantly extended the survival period of tumor responders, especially in the field of lung cancer, and have become the new standard therapy. However, in the PD-1/L1 field, only antibody drugs are currently on the market, while small-molecule PD-1/L1 is still in the clinical exploration stage.

2022 AACR: Ascletis Pharma, Hebec Pharma, and Betta Pharmaceuticals respectively presented preclinical data on their clinical-stage small-molecule PD-L1 drugs. ASC61, a small-molecule PD-L1 drug developed by Ascletis Pharma, demonstrated in preclinical in vivo studies that at a dose of 100mg/kg, ASC61 achieved tumor inhibition comparable to that of atezolizumab (5mg/kg).

ABSK043 from Hebao Pharmaceuticals primarily conducted animal in-vivo efficacy comparisons with chemotherapy drugs, while BPI-371153 from Betta Pharmaceuticals conducted in-vivo efficacy comparisons with Durvalumab. Compared to Durvalumab (10mg/kg), BPI-371153 demonstrated similar tumor inhibition effects at a dose of 100mg/kg.

Small-molecule drugs are considered capable of penetrating tumor tissues, particularly in achieving the killing of tumor cells distant from blood vessels. Coupled with the advantages of convenient oral administration and more, they are also regarded as a promising field. However, the final efficacy, and whether they can replace antibody drugs, still needs to be clinically verified.

NO.6 PI3K Rebirth

By the end of 2021, the wave of AA indication withdrawals initiated by PI3K inhibitors began, with duvelisib being the first to withdraw its indication for relapsed or refractory follicular lymphoma (FL). In 2022, other marketed PI3K drugs also became embroiled in indication withdrawals or investigations. Gilead announced the withdrawal of FL and SLL indications in the U.S. market, the FDA launched a safety investigation into umbralisib, Bayer withdrew its marketing application for MZL in the EU, Incyte withdrew its marketing applications for FL, MZL, and MCL from the FDA, and MEI Pharma was required by the FDA to conduct additional clinical trials before submitting a marketing application. It can be said that PI3K inhibitors in the field of hematological tumors, whether selective or not, were all affected in this round, reflecting the regulatory authorities' concerns about the efficacy or safety of such drugs.

In China, through authorized introduction and independent research and development, a vast PI3K pipeline has been established, with 25 active PI3K clinical products (excluding MNCs, including INDs). At the 2022 AACR, Hansoh Pharma, Hutchison MediPharma, Zhejiang Medicine, and Fochon Pharma, among others, showcased related products. Among them, Hansoh announced clinical data for the selective PI3Kα inhibitor HS-10352 in breast cancer research.

Preliminary results showed that HS-10352 had acceptable safety potential, with the maximum tolerated dose being 6mg QD. The most common (≥ 30%) treatment-related adverse events (TRAEs) were hyperglycemia (88.9%, n=16), weight loss (61.1%, n=11), elevated insulin C-peptide and diarrhea (each 33.3%, n=6). Grade 3-4 TRAEs included hyperglycemia (8 mg, n=2), weight loss (6 mg, n=2), fatigue (8 mg, n=1), blurred vision (8 mg, n=1), hyperkalemia (8 mg, n=1), and hypocalcemia (8 mg, n=1). The overall response rate and disease control rate for all patients (n=18) were 27.8% and 55.6%, respectively. Among six patients with PIK3CA mutations, ORR was 50.0% (3 PR at 6 mg), and DCR was 100.0% (6 mg, n=4; 8 mg, n=2). At the tolerable dose (6 mg), the ORR in four PIK3CA-mutated patients reached 75.0%.

NO.7 CCR8 New Opportunity Arrives

CCR8 is highly expressed specifically on tumor-infiltrating regulatory T cells (Treg), while the levels of CCR8+ Treg cells in blood and normal tissues are low. Targeting CCR8 may be more selective compared to other methods of depleting Treg. Meanwhile, CCR8 is also a target for new drug development opportunities at this year's AACR selected by PharmaCube.

At the 2022 AACR, Genor Biopharma and Zai Lab both disclosed preclinical data for their CCR8 antibody drugs. GB2101, a CCR8 antibody drug developed by Genor Biopharma through hybridoma technology, demonstrated effective binding to CCR8-expressing cells in both in vitro and in vivo studies. It was able to effectively block CCL1 binding and CCL1-induced signaling. Additionally, the afucosylation modification of GB2101 enhanced ADCC response and exhibited ADCC activity against target cells.

GB2101 demonstrated preliminary inhibition of tumor growth in a syngeneic xenograft model, and its clinical potential remains to be further validated.

ZL-1218 is a humanized therapeutic antibody developed by Zai Lab. It binds to human CCR8 with high affinity and specificity and can induce potent ADCC activity, thereby enabling strong NK cell-mediated killing of CCR8-expressing Tregs.

Disclosed preclinical data show that in human CCR8 knock-in mouse models bearing syngeneic tumors, ZL-1218 can reduce intratumoral Treg cells, thereby significantly inhibiting tumor growth in a dose-dependent manner. Particularly, when used in combination with a PD-1 antibody, it achieves enhanced and significant anti-tumor activity.

The international voice of China's innovative drugs is increasing. In addition to the seven major tracks and ten products mentioned above, many innovative drugs from Chinese pharmaceutical companies were showcased at this year's AACR, including various ADC drugs, differentiated bispecific antibody drugs, or cell therapies, etc. Due to space limitations, they will not be listed one by one. As for this year’s AACR, if there are any research advances or interesting report contents worth special attention, feel free to leave a comment for discussion.