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.

On September 20, 2019 Affibody AB ("Affibody"), a clinical stage biopharmaceutical company developing a pipeline of innovative drug projects, reported a strategic collaboration with GE Healthcare to develop and commercialize Affibody-based PET imaging tracers, with initial focus on HER2 and PD-L1 (Press release, Affibody, SEP 20, 2019, View Source [SID1234575701]). Financial terms were not disclosed.

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"The initiation of a strategic collaboration with GE Healthcare around PET imaging tracers reflects the commitment of Affibody to precision medicine and biomarker guided patient treatment. It also underlines the competitiveness of our technology and the value of the clinical data that has been generated with Affibody-based imaging agents", said David Bejker, CEO of Affibody. "We believe that our collaboration with GE Healthcare to develop and commercialize these imaging agents will make a significant contribution to enhance the treatment of cancer patients globally".

The Affibody technology is uniquely suited for the development of PET imaging tracers and ABY-025, a HER2-detecting Affibody-based PET imaging tracer, is currently in clinical development. ABY-025 provides a novel non-invasive and cost-effective approach to diagnose global HER2-expression in metastatic breast cancer patients using PET imaging. Affibody is currently working together with academic institutions to explore the clinical utility of ABY-025 further.

The PD-L1 binding Affibody molecule is being developed as a diagnostic tool to improve selection and monitoring of patients with immuno-oncology treatments. The collaboration with GE Healthcare will accelerate studies through to a stage of clinical proof of concept.

"We recognize that PET imaging plays a vital role in the development and use of cancer immunotherapies as it is a non-invasive way to measure patient response before, during and after treatment," said Sanka Thiru, Head of Molecular Imaging Oncology, in GE Healthcare’s Pharmaceutical Diagnostics business. "We are partnering with companies like Affibody to build a portfolio of molecular imaging agents for oncology, focusing on those disease biomarkers that will help accelerate the development of the next generation of cancer treatments."

On September 20, 2019 An Upstate Medical University professor is the lead investigator on a recently awarded National Institutes of Health grant to study how manipulating a gene could help people better tolerate and recover from chemotherapy (Press release, SUNY Upstate, SEP 20, 2019, View Source [SID1234551515]).

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William Kerr, PhD, is a professor of microbiology and immunology, biochemistry and molecular biology as well as pediatrics at Upstate. Kerr has spent much of his career studying the SHIP1 enzyme, which can affect how an immune cell detects and kills cancer cells. He is a co-founder of Alterna Therapeutics, a private biotechnology company. Kerr, Alterna Therapeutics and a Syracuse University professor are the recent beneficiaries of the one-year $225,000 NIH grant.

Kerr said research supported by the grant will be conducted at Upstate and at the Central New York Biotech Accelerator.

"This NIH grant at Upstate advances and showcases SUNY’s enduring commitment to medical discovery and innovation," said SUNY Chancellor Kristina Johnson. "This research has the potential to impact millions of people whose lives are upended by the devastating effects of chemotherapy. I applaud Dr. Kerr for his leadership on this work that may one day result in better therapeutics for people diagnosed with cancer."

The project is described this way: "While chemotherapy remains a mainstay in the treatment of cancer, some types of chemotherapy deplete bone marrow stem cells that are responsible for daily production of blood cells. The severely debilitating side effects of chemotherapy on daily blood cell production frequently result in hospitalization and treatment delays, and may compel dose reductions that compromise drug efficacy, with potentially fatal consequences. This project will develop a novel technology to significantly improve blood cell recovery following chemotherapy, thus reducing healthcare costs for cancer patients and saving lives."

Kerr’s initial study of this topic involved modulating the activity of the SHIP1 enzyme to enhance blood cell recovery after radiation exposure. Papers describing these findings have been cited in ongoing research more than 100 times and featured by the editors at the journal Science, he said. In 2015, Kerr received an investment from SUNY’s Technology Accelerator Fund (TAF) to systematically test more than 100 SHIP1 inhibitors to find the best candidates for a therapeutic product. TAF targets critical research and development milestones – such as feasibility studies, prototyping and testing – which demonstrate that an idea or innovation has commercial potential. Since its launch in 2011, TAF has invested over $2.6 million to successfully advance the commercial readiness of 49 SUNY-developed innovations.

This new study will apply modulating the activity of the SHIP1 enzyme but after chemotherapy rather than radiation, Kerr said.

"We’re very interested in exploring the potential to expand stem cell production to help promote recovery of blood cell populations," said Alterna Therapeutics co-founder and CEO Chris Meldrum. He noted that Kerr’s breakthrough could be especially helpful to patients who undergo chemotherapy or other treatments that severely deplete or suppress production of blood cells by the bone marrow. Some of those treatments cause severe deficiencies in neutrophil and platelet counts, which can make a patient very sick requiring hospitalization. That in turn can slow down or halt their treatments, which puts the patient at a higher risk for the cancer to return. The discovery from Dr. Kerr’s lab additionally has the potential to be a treatment used in improving blood cell recovery following bone marrow transplant procedures.

"It’s taken us about a year to get some of these grants and now that we have the first one we’ll be applying for others," Kerr said, noting this is a "phase one grant" to test the initial science and could lead to Phase 2 funding from the NIH for further clinical development and testing.

"I’m excited. This bodes well that the review committees of the NIH see research conducted by Alterna Therapeutics as valuable and thus something that the NIH should support because it could lead to next generation cancer therapies."

On September 20, 2019 Delos Capital reported that it has launched Curamir Therapeutics Inc., a Woburn, MA-based biotechnology company pioneering micro RNA (miRNA) based cancer therapeutics, with a $10 million Series A financing (Press release, Curamir Therapeutics, SEP 20, 2019, View Source [SID1234539679]).

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Curamir is incubated through a licensing collaboration with the State University of New York (SUNY) and co-founded by veterans in the field of gene regulation and translational medicine: Dr. Jingfang Ju, Professor of Department of Pathology at Stony Brook University; Dr. James D. Watson, co-discoverer of the DNA structure and a 1962 Nobel Laureate; and Dr. Lan Bo Chen, Professor Emeritus of Pathology at Harvard Medical School and an Academician of the Academia Sinica of Taiwan.

Curamir is developing innovative therapeutics based on its proprietary miRNA engineering platform and insights into cancer biology, aiming to address unmet needs to overcome drug resistance and toxicity associated with current oncology therapies.

"Curamir is founded with the vision to extend and improve patients’ lives by the discovery and development of innovative miRNA-based oncology therapeutics," said Mr. Henry Chen, a co-founder and the CEO of Curamir and the Managing Partner of Delos Capital. "We appreciate the significant contribution and strong support from our scientific co-founders, who bring unparalleled knowledge of miRNA therapeutics and a proven track record of discovering and developing transformative therapies. We look forward to further advancing our miRNA pipeline into clinical studies with the Series A financing."

"I am thrilled to have the strongest support from Delos Capital and our scientific co-founders and advisors to develop innovative and transformative miRNA-based medicine to defeat cancer," said Dr. Ju. "Our miRNA drug development platform technology has the potential to revolutionize cancer medicine by eliminating resistant cancer stem cells."

Curamir is led by a world-class team of scientists and industry veterans at the forefront of cancer biology and genetics. Dr. Ju has more than 25 years of research expertise on chemoresistance in cancer research. His lab at SUNY studies miRNAs in cancer stem cell resistance, epithelial to mesenchymal transition, autophagy, and apoptosis in various cancers. Dr. Watson is the co-discoverer of the DNA structure and the Nobel Laureate in 1962 in Physiology / Medicine. He also helped establish the Human Genome Project. Dr. Lan Bo Chen is the author of over 250 publications. He founded several successful biotech companies and led the development or consulted for more than a dozen drugs and drug candidates.

On September 20, 2019 CStone Pharmaceuticals ("CStone" or the "Company", HKEX: 2616) reported the preliminary data from the Phase I bridging study of the Company’s investigational anti-PD-1 monoclonal antibody CS1003 for the first time, 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 20, 2019, View Source;cstone-releases-preliminary-results-from-the-phase-ia-trial-of-cs1003-in-chinese-patients-with-advanced-tumors-300922487.html [SID1234539678]).

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CS1003-102 is a multi-center, open-label, dose-escalation and indication-expansion Phase I clinical trial being conducted in China. Initiated in November 2018, the trial is designed to evaluate the safety, pharmacokinetics, immunogenicity, and preliminary anti-tumor efficacy of CS1003 in patients with advanced tumors.

Professor Lin Shen, Vice President of Beijing Cancer Hospital and the presenter of the results, commented: "Data from the dose escalation phase of the trial demonstrated CS1003’s favorable safety and tolerability in Chinese patients with advanced tumors. Furthermore, preliminary yet noticeable anti-tumor activities were also observed in multiple tumor types."

Dr. Frank Jiang, Chairman and CEO of CStone, commented: "CS1003 is one of CStone’s three backbone immuno-oncology drug candidates. I am very pleased about the encouraging initial data from this Phase Ia trial, as it provides a solid foundation for the continued development of this asset. We will continue to vigorously advance the clinical development of CS1003 around the world. In addition to the on-going programs in China and Australia, we have received IND approval for CS1003 in the U.S. With a robust pipeline and core strategy centering on combination cancer immunotherapy, we will further exploit CS1003’s unique advantages and its vast application potential in combination with multiple drugs."

Dr. Archie Tse, Chief Translational Medicine Officer at CStone, noted: "CS1003 is a high-affinity monoclonal antibody that potently blocks the binding of PD-1 to its ligands. It is worth noting that CS1003’s ability to cross-react with both human PD-1 and mouse PD-1 will allow us to significantly accelerate the preclinical proof-of-concept of CS1003 in combination with new targeted drugs in syngeneic tumor models. Through clinical development, we will further explore the potential of CS1003 as cancer immunotherapy."

CS1003-102 study results

The CS1003-102 study data presented at this year’s CSCO Annual Meeting was generated from 19 patients with advanced tumors, who were enrolled during the dose escalation phase of the study. As of June 15, 2019, 3 patients with gastric adenocarcinoma, 2 with esophageal squamous cell carcinoma, 2 with leiomyosarcoma, and 12 with other advanced tumors were enrolled. 7 patients were administered with CS1003 once every three weeks, at a fixed dose of 60 mg; 12 patients were administered with CS1003 once every three weeks, at a fixed dose of 200 mg. The median treatment duration was 9.1 weeks (range, 3.0-29.3) and 9.0 weeks (range, 4.9-21.7) at 60 mg and 200 mg dose, respectively.

Preliminary safety data on CS1003

No dose-limiting toxicity was observed at either 60 mg or 200 mg, and the maximum tolerated dose was not reached.
Of the 18 patients (94.7%) who developed treatment-related adverse events (TRAEs), 3 reported Grade 3 or higher TRAEs, and the rest were all Grade 1-2 in severity. The common TRAEs included fatigue (26.3%), elevated serum bilirubin levels (15.8%), hypothyroidism (15.8%), and anemia (15.8%).
Nine patients reported at least one immune-related adverse event (irAE), and the most common irAEs included fatigue (15.8%), hypothyroidism (15.8%), hyperthyroidism (10.5%), and rash (10.5%).
The pharmacokinetic characteristics of CS1003

In the on-going Phase I trial in China, CS1003 demonstrated dose-proportional systemic exposure. Comparable pharmacokinetic characteristics were observed between patients in China and Australia.
The immunogenicity of CS1003

The preliminary analysis of anti-drug antibody (ADA) data suggests CS1003 has relatively low immunogenicity. No treatment-induced and enhanced ADA responses (ADA-positive) were observed.
Preliminary efficacy data on CS1003

Of the 16 efficacy-evaluable patients, 7 remained on the treatment, with a median treatment duration of 21.3 weeks (range, 5.6–29.3).
At 60 mg, 1 patient with esophageal squamous cell carcinoma and 1 patient with uterine leiomyosarcoma had a confirmed partial response (PR) per RECIST v1.1; At 200 mg, 1 patient with laryngeal squamous cell carcinoma was determined to be in PR awaiting confirmation.
One patient treated at 200 mg was evaluated as having disease progression per RECIST v1.1 during the first post-baseline tumor assessment and continued to receive CS1003 beyond progression; Noticeable tumor reduction compared to baseline was observed during the following tumor assessment, and the patient remained on treatment as of the data cut-off date.
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About CS1003 and the PD-1/PD-L1 pathway

CS1003 is a humanized IgG4 anti-PD-1 monoclonal antibody developed by CStone using a state-of-the-art hybridoma platform. CS1003 has shown good tolerability and efficacy profile in preclinical in vivo studies. Unlike other anti-PD-1 mAbs, CS1003 recognizes both human and murine PD-1, providing a unique competitive advantage during efficacy evaluation in syngeneic mouse tumor models and the development of combination therapies.

PD-1, or programmed death-1, is an inhibitory checkpoint receptor expressed on T cells. Under normal conditions, PD-1 binds to its ligands, programmed death ligand-1 or ligand-2 (PD-L1/PD-L2), inhibiting T cell and cytokine activation, serving to dampen the immune response in order to prevent damage to healthy tissues. However, studies have shown that PD-L1 can be abundantly expressed on the surface of many solid tumors as well as hematological malignancies. Cancer cells utilize the PD-1/PD-L1 pathway to avoid immune system recognition. Targeting of the PD-1/PD-L1 checkpoint by anti-tumor drugs can block the "tumor immune evasion mechanism" and restore anti-cancer immunity in patients.