On September 21, 2019 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported preliminary results from the Phase Ia trial of the Company’s anti-CTLA-4 antibody in an oral presentation at the 22nd Annual Meeting of the Chinese Society of Clinical Oncology (CSCO, 2019 CSCO Annual Meeting) (Press release, CStone Pharmaceauticals, SEP 21, 2019, View Source;cstone-announces-preliminary-results-from-phase-i-trial-of-cs1002-demonstrating-characteristics-comparable-to-ipilimumab-300922880.html [SID1234539680]). This presentation marks the first data release on CS1002’s clinical development at a scientific meeting.

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CS1002-101 is an open-label, multi-dose, dose-escalation, and dose-expansion study conducted in Australia that aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD), and preliminary anti-tumor activity of CS1002 in patients with advanced solid tumors. The study has completed dose-escalation of CS1002 as a single agent.

The data were presented by Dr. Rasha Cosman, medical oncologist from the Oncology Department at St Vincent Hospital’s Kinghorn Cancer Center in Australia. "Data from this study demonstrate that CS1002 has a favorable tolerability profile. Dose-limiting toxicity was not observed up to 10 mg/kg of CS1002, and the maximum tolerated dose was not reached," said Dr. Cosman. "Additionally, these initial results of the safety, preliminary efficacy, pharmacokinetics and pharmacodynamics of CS1002 are comparable to those of ipilimumab."

Dr. Frank Jiang, Chairman and CEO of CStone, commented: "Ipilimumab is currently the only approved CTLA-4 inhibitor globally, and the product has not been launched in China. We are encouraged by the promising preliminary data from this Phase Ia study of CS1002. We are planning to initiate a dose-escalation study of CS1002 combined with CS1003 (an anti-PD-1 antibody) and a dose-expansion study of the combination therapy in selected tumor types. We hope these two of CStone’s backbone immunotherapy drug candidates in combination will produce favorable clinical results, and soon benefit tumor patients in need."

Dr. Archie Tse, Chief Translational Medicine Officer at CStone, noted: "In terms of mechanism of action, anti-CTLA-4 monoclonal antibodies stimulate the proliferation of immune cells by blocking the down-regulating immune effect of CTLA-4, thereby inducing or strengthening the anti-tumor immune responses. This mechanism of action suggests the wide-ranging potential of this class of therapies in cancer treatments. CS1001 is a fully human, full-length monoclonal immunoglobulin G1 (IgG1) that shares the same amino acid sequence with ipilimumab. We expect that CS1002 can potentially become another outstanding CTLA-4 inhibitor after ipilimumab."

An overview of results from CS1002-101 study
As of data cut off on April 25, 2019, 13 patients with advanced solid tumors were enrolled in the dose-escalation phase of the CS1002-101 study, of which 4 had colorectal cancer, 2 had metastatic adenocarcinoma, and 7 had other solid tumors. Among those patients, 6 patients were administered CS1002 at 1mg/kg, 3 patients at 3mg/kg, 4 patients at 10mg/kg. At data cut off, 2 patients remained on treatment.

Safety data on CS1002

No dose-limiting toxicity (DLT) was observed at 1mg/kg, 3mg/kg, and 10mg/kg, and the maximum tolerated dose (MTD) was not reached.
4 patients (30.8%) reported at least one 1 treatment-emergent adverse events (TEAEs) that included diarrhea (15.4%), fatigue (15.4%), elevated alanine aminotransferase (ALT) level (7.7%), and elevated aspartate aminotransferase (AST) level (7.7%). 2 of those patients (15.4%) developed TEAEs that were Grade 3 or higher, the rest had TEAEs between Grade 1-2.
2 patients reported immune-related adverse events (irAEs) that included diarrhea (7.7%) and fatigue (7.7%).
No serious TEAE was observed.
There was no death related to the treatment.
No discontinuation due to TEAEs.
Pharmacokinetics of CS1002

CS1002 has been shown in all three dose cohorts to have dose-proportional pharmacokinetic characteristics. The terminal half-life (T1/2) ranged from 12 to 15 days.
Pharmacodynamics of CS1002

Across all three dose cohorts, increase in absolute lymphocyte count (ALC) in peripheral blood were observed early during CS1002 treatment, indicating that the pharmacodynamics of CS1002 was comparable to that of the historical data of ipilimumab.
Preliminary efficacy data on CS1002

Of the 9 patients with evaluable efficacy, no patient has achieved complete response (CR) or partial response (PR). 2 patients were assessed as stable disease (SD).
One cholangiocarcinoma patient is still on treatment with SD for 11 months.
About CS1002 and the CTLA-4 pathway
CS1002 is an investigational anti-CTLA-4 monoclonal antibody being developed by CStone.

Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), also known as CD152, is a transmembrane protein encoded by the CTLA-4 gene that can down-regulate the activity of T cells when binding with its ligand, B7, a pathway also used by tumor cells to avoid T lymphocyte attack. Consequently, blockade of the CTLA-4 pathway can stimulate T cell activation and proliferation to induce or enhance anti-tumor immune responses. CTLA-4 provides a new immuno-therapeutic approach to a number of diseases, including tumors.

Presently, ipilimumab is the only anti-CTLA-4 antibody to gain a market approval worldwide, although ipilimumab has not yet been approved in China. Pre-clinical tests have shown that CS1002 has relatively high affinity to CTLA-4 and is expected to match ipilimumab in terms of efficacy.