On November 14, 2021 InnoCare Pharma (HKEX: 09969), a commercial-stage biotech company, reported the Investigational New Drug (IND) clearance of its SHP2 (Src Homology 2 domain containing protein tyrosine phosphatase) allosteric inhibitor ICP-189 by the US Food and Drug Administration (FDA) for starting clinical trial in the United States (Press release, InnoCare Pharma, NOV 14, 2021, View Source [SID1234595528]).

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This open, single-arm, multicenter study aims to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ICP-189 as a monotherapy and combined treatment in patients with advanced solid tumors.

ICP-189 is being developed for the treatment of solid tumors as a single agent and/or in combinations with other antitumor agents.

Preclinical study shows that ICP-189 is a potent oral allosteric inhibitor of SHP2 with excellent selectivity over other phosphatases. SHP2 is a non-receptor protein tyrosine phosphatase involved in mediating MAPK signaling pathway and immune checkpoint pathway for the regulation of cellular proliferation and survival.

Dr. Jasmine Cui, Co-Founder, Chairwoman and CEO of InnoCare, said, "In less than a month after clinical approval of ICP-189 in China, our ICP-189 got clinical approval in the U.S. This is our fourth innovative drug entering clinical stage in the U.S. This year, our innovative drug candidates have been continuously recognized by the FDA: Orphan Drug Designation to pan-FGFR inhibitor gunagratinib for the treatment of cholangiocarcinoma; Breakthrough Therapy Designation to orelabrutinib for the treatment of relapsed or refractory mantle cell lymphoma; clinical approval of the second-generation pan-TRK inhibitor ICP-723… InnoCare will continue to innovate to meet the unmet clinical needs of the entire world. "

On November 14, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, and NewBridge Pharmaceuticals, a specialty company in the Middle East and North Africa (MENA) regions established to bridge the access gap by partnering with global pharma and biotech companies, reported that BRUKINSA (zanubrutinib) has received approval from the Saudi Food and Drug Authority (SFDA) for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy (Press release, BeiGene, NOV 14, 2021, View Source [SID1234595524]). BeiGene and NewBridge Pharmaceuticals are working together to bring BRUKINSA to healthcare providers and people living with MCL in Saudi Arabia and other MENA markets following regulatory approvals.

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"Non-Hodgkin’s lymphoma is a leading cause of cancer incidence and mortality in Saudi Arabia, representing a significantly unmet need for those living with diseases, such as MCL. BRUKINSA is a next-generation BTK inhibitor designed to improve tolerability issues often associated with the class and has demonstrated efficacy in clinical trials for patients with relapsed or refractory MCL," said Dr. Ahmad Absi, Hematology Section Head at the National Guard Health Affairs in Jeddah, Kingdom of Saudi Arabia.

"We are delighted that MCL patients in Saudi Arabia will now have access to BRUKINSA, a potentially best-in-class BTK inhibitor. Driven by our belief—Cancer has no borders. Neither do we, BeiGene is committed to expanding access to high-impact medicines for all patients who need them. With approval in Saudi Arabia and in the United Arab Emirates earlier this year, we are working with NewBridge Pharmaceuticals to bring BRUKINSA to more patients in the MENA region," commented Mohammed Al-Kapany, Senior Director of New Markets in MENA at BeiGene.

"The approval of BRUKINSA in Saudi Arabia represents an important milestone in our ongoing collaboration with BeiGene. With this differentiated BTK inhibitor now approved in two markets in the MENA region, we are one step closer to reaching patients living with MCL with new treatment options," remarked Joe Henein, President and CEO of NewBridge Pharmaceuticals.

The recommended dose of BRUKINSA is either 160 mg twice daily or 320 mg once daily, taken orally with or without food. The dose may be adjusted for adverse reactions and reduced for patients with severe hepatic impairment and certain drug interactions.

About Mantle Cell Lymphoma (MCL)

Non-Hodgkin’s lymphoma (NHL) is the third most common cancer in Saudi Arabia,1 with approximately 1,700 new cases in 2020.2 MCL is rare form of NHL, accounting for five percent of all cases. It develops in the outer edge of a lymph node called the mantle zone. Mantle cell lymphoma occurs more often in men than in women. It is usually diagnosed in people in their early 60s.3 MCL has a poor prognosis, with a median survival of three to four years, and is often diagnosed at a later stage of disease.4

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is approved in the following indications and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021);
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021);
For the treatment of adult patients with WM who have received at least one prior therapy (China, June 2021)**;
For the treatment of MCL in adult patients who have received at least one prior therapy (Canada, July 2021);
For the treatment of MCL in adult patients who have received at least one prior therapy (Chile, July 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Brazil, August 2021);
For the treatment of adult patients with WM (United States, August 2021);
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (United States, September 2021)*;
For the treatment of adult patients with MCL who have received at least one previous therapy (Singapore, October 2021);
For the treatment of MCL in patients who have received at least one prior therapy (Israel, October 2021);
For the treatment of adult patients with WM who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one prior therapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Russia, October 2021); and
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021).
To date, more than 20 marketing authorization applications have been submitted for BRUKINSA for various indications.

* This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients, most commonly pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse reactions

The most common adverse reactions, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf.

BeiGene Oncology

BeiGene is committed to advancing hematology, immuno-oncology and targeted therapies in order to bring impactful and affordable medicines to patients across the globe. We have a growing R&D team of approximately 2,300 colleagues dedicated to advancing more than 90 clinical trials involving more than 13,000 patients and healthy subjects. Our expansive portfolio is directed by a predominantly internalized clinical development team supporting trials in more than 40 countries or regions. We currently market three medicines discovered and developed in our labs: BTK inhibitor BRUKINSA in the United States, China, Canada, Australia and additional international markets; and non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab and PARP inhibitor pamiparib in China. BeiGene has a high quality, innovative science and medicine organization and is a leader in China with a large oncology focused commercial team.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On November 13, 2021 NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune-related diseases, reported new data from two clinical studies and one research study presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting in Washington, D.C., and on a virtual platform (Press release, NextCure, NOV 13, 2021, View Source [SID1234595603]). The data come from clinical studies evaluating NC318, a Siglec-15 (S15) antibody, and NC410, a fusion protein of LAIR-2, in patients with advanced/metastatic solid tumors, as well as from a research study evaluating NC410’s impact on T cell activation and myeloid cell polarization conducted in collaboration with the National Cancer Institute at the National Institutes of Health.

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"We are pleased to share promising data from our NC318 and NC410 programs at this year’s SITC (Free SITC Whitepaper) annual meeting," said Han Myint, MD, NextCure’s chief medical officer. "Results from our ongoing Phase 1 and Phase 2 trials suggest that NC318 may have a clinical benefit in patients. Retrospective analysis of patient biopsies from the Phase 1 and Phase 2 trials showed better outcomes in S15+ patients compared to S15- patients receiving NC318. Selecting for patients with S15+ expression coupled with a higher and more frequent dosing regimen that increases overall drug exposure is anticipated to impact clinical outcomes. Additionally, data from our NC410 program show that NC410 is safe and well-tolerated in patients and demonstrates early indications of immune modulation. We look forward to continuing the advancement of both programs to improve the treatment landscape for cancer patients."

Details of the oral and poster presentations are below:

Clinical benefit through S15 targeting with NC318 antibody in subjects with S15 positive advanced solid tumors

Combined Phase 1 and Phase 2 data from the NC318 study show early evidence of possible clinical benefit in patients with lung cancer, squamous cell carcinoma of the head and neck and breast cancer and other advanced/metastatic solid tumors with dosing once every two weeks during dose escalation and with the 400mg dose selected for the Phase 2 studies. Highlights include:

Data are derived from patient cohorts in both Phase 1 (n=49) and Phase 2 (n=47) of these studies.
One NSCLC CR and one NSCLC PR patient from the Phase 1 study remain on therapy for 2.8 and 2.2 years, respectively.
NC318 appears to show evidence of disease control with better outcomes in S15+ patients compared to S15- patients.
The disease control rate across all tumors in both studies was 37% with a median progression-free survival (PFS) of 5.0 months.
Patients in the lung cohort from both studies showed 45% disease control rate with a median PFS of 5.2 months.
Data indicate that soluble S15 (sS15) level may serve as a biomarker for patient selection.
Pharmacokinetic and pharmacodynamic modeling predict that a dose of 800 mg once a week results in nearly 10 times greater drug exposure which may impact drug activity and clinical outcomes.
NC410, a fusion protein of LAIR-2 (Leukocyte Associated Immunoglobulin-like Receptor) fused to human IgG1 Fc domain appears safe and well-tolerated with evidence of immune modulation in subjects with advanced solid tumors

Interim data presented from the Phase 1 dose-escalation study show that NC410 appears to be safe and well-tolerated in patients with advanced tumors and show evidence of immune modulation. Highlights include:

The data come from the first five patient cohorts (n=19), who received doses of NC410 up to 60 mg once every two weeks.
There were no dose-limiting toxicities.
Data show a transient reduction in peripheral C1q, suggesting target binding of NC410.
LAIR-2 levels in peripheral blood increase in a dose-dependent fashion and may suggest mechanistic evidence of immune normalization.
Early evidence of extracellular matrix (ECM) remodeling and immune activation was shown by an increase in serum C4G, a Granzyme B-mediated collagen fragment, and a reduction in serum Pro-C3 and Pro-C6 fragments.
Time-dependent increase in CD4+ and CD8+ T cells without an increase in LAIR-1 expression provides further early evidence of immune activation.
Safety, tolerability, efficacy, and biomarker analyses are ongoing in higher dose cohort patients.
Blockade of the inhibitory collagen receptor LAIR-1, PD-L1, and TGF-β promotes anti-tumor activity through T cell activation and myeloid cell polarization

Non-clinical data from a research study conducted in collaboration with the National Cancer Institute at the National Institutes of Health show NC410’s impact on T cell activation, myeloid cell polarization and anti-tumor activity. Highlights include:

NC410 and bintrafusp alpha, a TGF-beta trap molecule, synergize for effective tumor control in a mouse model of colon cancer.
Tumor control is mediated by an increase in activated CD8+ T cells and a reduction in M2 tumor-associated macrophages in tumor infiltrates.
Collagen remodeling is demonstrated in tumors treated with NC410.
About NC318
NC318 is a first-in-class immunomedicine against Siglec-15 (S15), a novel immunomodulatory target found on highly immunosuppressive cells called M2 macrophages in the tumor microenvironment and on certain tumor types including lung, ovarian and head and neck cancers. In preclinical research, it was observed that S15 promoted the survival and differentiation of suppressive myeloid cells and negatively regulated T cell function, allowing cancer to avoid immune destruction. In preclinical studies, NC318 blocked the negative effects of S15. NextCure believes NC318 has the potential to treat multiple cancer types.

About NC410
NC410 is a first-in-class immunomedicine designed to block immune suppression mediated by LAIR-1, an immunomodulatory receptor expressed on T cells and myeloid cells, including dendritic cells, a type of antigen presenting cell. In preclinical research, it has been shown that LAIR-1 inhibits T cell function and myeloid activity. In preclinical studies, NC410 blocks the negative effects of LAIR-1 and promotes T cell function and myeloid cell activity. NextCure believes NC410 has the potential to treat multiple cancer types.

On November 13, 2021 Intensity Therapeutics, Inc. ("Intensity"), a clinical-stage biotechnology company focused on the discovery and development of proprietary immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported the Company made two presentations on novel lead asset, INT230-6, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 36th Annual Meeting (SITC) (Free SITC Whitepaper) in Washington, D.C (Press release, Intensity Therapeutics, NOV 13, 2021, View Source [SID1234595530]).

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"Patients with metastatic and refractory cancers continue to have poor survival. Response rates remain low in most tumor types even with the use of immunotherapies such as checkpoint inhibitors," said Jacob S. Thomas, M.D., Assistant Professor of Clinical Medicine, Keck School of Medicine at the University of Southern California (USC) and oncologist at USC’s Norris Comprehensive Cancer Center, part of Keck Medicine of USC. "INT230-6 demonstrates direct tumor killing in injected lesions. In addition, analysis shows increases of immune cells in tumors and the shrinkage of uninjected tumors or abscopal results. These data suggest dosing INT230-6 may activate a T-cell mediated immune response. Results presented at SITC (Free SITC Whitepaper) indicate that use of intratumoral INT230-6 appears to be a viable approach in treating metastatic disease alone or in combination with immunotherapies."

"Sarcoma continues to be a very challenging cancer to treat and has proven resistant to checkpoint blockade. Novel immunotherapy-based approaches are still needed, and sarcoma is an attractive cancer for intratumoral injection of INT230-6, which is a direct tumor killing agent," said Matthew Ingham, M.D., Assistant Professor of Medicine in the Division of Hematology and Oncology, Columbia University Irving Medical Center. "Biopsies from tumors treated using INT230-6 showed substantial tumor necrosis, reduction of viable cancer, a decreased cancer proliferation as measured by Ki67, and increased tumor infiltrating lymphocytes such as CD4 and CD8 T-cells. An exploratory analysis suggests promising survival for subjects receiving INT230-6 compared to historical standards."

"Our Phase 1/2 data show INT230-6 alone or in combination with checkpoint inhibitors was well tolerated with no severe toxicities," remarked Dr. Ian Walters, Intensity’s Chief Medical Officer. "We now have promising early results from 115 patients with this drug, and the safety remains favorable even with injections into multiple deep tumors. The most common adverse event related to the drug is pain at the injection site. We have also demonstrated rapid tumor necrosis and promotion of systemic immune responses."

These presentations illustrate three different treatment regimens of INT230-6; as monotherapy, with pembrolizumab, or with ipilimumab. The results showcase the broad treatment potential of our locally-delivered anti-cancer product candidate in a variety of tumor types," stated Lewis H. Bender, President and Chief Executive Officer of Intensity Therapeutics. "Extended survival is the goal of any new cancer treatment, and these data show the potential for longer survival using INT230-6 when compared to historical results. Survival also appears to be improved with higher INT230-6 loading into tumors and treating more tumors over the course of therapy. Based on these encouraging early results, we are planning to initiate a randomized Phase 3 study with INT230-6 in patients with advanced soft tissue sarcomas next year."

The posters are accessible on the "Publications, Papers and Posters" section of Intensity’s website at: View Source

Highlights from the presentations are as follows:

Abstract Number: 501 "Survival and Immune Response Data from Intratumoral INT230-6 Alone (IT-01) and with Pembrolizumab [KEYNOTE-A10] in Subjects with Locally Advanced, Unresectable and Metastatic Solid Tumors"

Authors: Jacob Thomas, MD; Anthony El-Khoueiry, MD; Anthony J. Olszanski, MD, RPh; Nilofer Azad, MD; Giles F. Whalen, MD; Diana Hanna, MD; Matthew Ingham, MD; Syed Mahmood, MD; Lewis H. Bender, MS, MA, MBA; Ian B. Walters, MD, MBA; Lilian L. Siu, MD

This presentation reports results from 78 subjects summarizing the preliminary efficacy and safety of either INT230-6 alone (n=60) or in combination with the anti-PD-1 therapy, pembrolizumab (n=18) from an ongoing open-label, multi-arm Phase 1/2 clinical trial. Patients had a variety of relapsed, refractory metastatic solid tumors and progressed following a median of four prior therapies. INT230-6 was administered at doses of 0.3 to 175mL (86 mg CIS, 17.2 mg VIN) in a single session, which are higher amounts than typical IV doses, with repeated intratumoral injections in multiple tumors.
The median overall survival (mOS) of 373 days for all monotherapy (n=53) patients compares favorably to results seen in studies with similar Phase 1 solid tumor populations. An exploratory analysis of dose relative to total tumor burden (TTB) showed that subjects receiving a dose of INT230-6 to <40% of their reported TTB had a mOS of 96 days, while in subjects receiving a dose of INT230-6 to ≥40% of TTB, had a mOS of 570 days (HR=0.104, 95% CI(0.038, 0.29)). Patients receiving the pembrolizumab combination had a mOS of 376 days (n=16). Comparison of the survival data of INT230-6 monotherapy to the pembrolizumab combo was not made due to different cancer types in the two cohort populations.
As of July 31, 2021, six patients in the monotherapy arm who received an INT230-6 dose of ≥40% of the TTB demonstrated abscopal effects (i.e., shrinkage of multiple non-injected tumors), further emphasizing the importance of dosing sufficient amounts to cause substantial tumor necrosis. Together with the immunohistochemistry biomarker findings, the results suggest a systemic immune system activation.
INT230-6, either as monotherapy or in combination with pembrolizumab, was well tolerated. The most common adverse events (AEs) were localized tumor-related pain, nausea, fatigue and vomiting. AEs were mainly mild to moderate with no Grade 4 or 5 AEs.
Abstract Number: 16284 "Intratumoral INT230-6 Shows a Favorable Safety Profile and Early Signs of Efficacy in Advanced Soft Tissue Sarcoma with Monotherapy and in Combination with Ipilimumab [Intensity IT-01; BMS#CA184-592]"

Authors: Matthew Ingham, MD; James Hu, MD; Giles F. Whalen, MD; Jacob Thomas, MD; Anthony El-Khoueiry, MD; Diana Hanna, MD; Anthony J. Olszanski, MD, RPh; Christian F. Meyer; Nilofer Azad, MD; Syed Mahmood, MD; Lewis H. Bender, MS, MA, MBA; Ian B. Walters, MD, MBA; Lilian L. Siu, MD; Albiruni R. Razak

The poster reports preliminary efficacy and safety results from 19 subjects treated with either INT230-6 alone (n=10) or in combination with checkpoint inhibitors primarily ipilimumab from an ongoing Phase 1/2 clinical trial. Patients had a variety of relapsed, refractory sarcoma types and progressed following a median of three prior therapies. Demographics were similar in subjects enrolled in monotherapy and checkpoint inhibitor combination arm. The cumulative dose of INT230-6 injections given every 2 weeks over 56 days ranged from 20 to 530mL with repeated intratumoral injections in multiple tumors. Pharmacokinetic (PK) profile analysis from 18 sarcoma subjects were analyzed for cisplatin, SHAO and vinblastine and showed that greater than 95% of the active drugs remains in the tumor.
Kaplan Meier estimates that approximately 60% of those of sarcoma subjects receiving INT230-6 monotherapy a dose volume greater than 40% of their total tumor burden will be alive at 1 year. These results compare favorable to results of survival data in studies of mixed refractory sarcoma patients with similar prognostic factors scores (ECOG, LDH, # of metastatic sites) where the median survival is estimated to be 3 to 8 months
Biopsies showed substantial tumor necrosis, reduction of viable cancer, a decreased cancer proliferation as measured by Ki67, and increased Tumor Infiltrating Lymphocytes (CD4 and CD8 T-cells). Monotherapy patients had abscopal effects (i.e., shrinkage of multiple non-injected tumors).
INT230-6 safety data showed that INT230-6 is well tolerated as monotherapy and preliminary data suggests that INT230-6 is well tolerated in combination with ipilimumab in sarcoma subjects. Most adverse events were low grade and transient. There were no grade 4 or 5 treatment emergent AEs and no events that were dose limiting.
About INT230-6

INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In addition to local disease control, direct killing of the tumor by INT230-6 creates neoantigens leading to engagement of the immune system and systemic anti-tumor effects in the tumor. Importantly, these effects are mediated without the immunosuppression of concomitant systemic chemotherapy.

INT230-6 is currently being evaluated in several Phase 2 cohorts (NCT03058289) in patients with various advanced solid tumors as part of Study IT-01. In 2019, the Company signed a clinical collaboration agreement with Merck Sharpe & Dohme (Merck) to evaluate the combination of INT230-6 and KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, in patients with advanced pancreatic, colon, squamous cell and bile duct malignancies. In 2020, the Company executed a clinical collaboration agreement with Bristol-Myers Squibb Company to evaluate the combination of INT230-6 with Bristol-Myers Squibb’s anti-CTLA-4 antibody, Yervoy (ipilimumab), in patients with advanced liver, breast and sarcoma cancers. In 2021, the Company executed agreements with the Ottawa Hospital Research Institute and the Ontario Institute of Cancer Research to study INT230-6 in a randomized controlled neoadjuvant Phase 2 study in women with early stage breast cancer (the INVINCIBLE study) (NCT04781725).

On November 13, 2021 CG Oncology, Inc., a clinical-stage biotechnology company focused on developing oncolytic immunotherapies for patients with advanced cancer, reported preliminary Phase 2 study (CORE1) results for CG0070 in combination with KEYTRUDA (pembrolizumab), for the treatment of patients with Non-Muscle-Invasive Bladder Cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) (Press release, CG Oncology, NOV 13, 2021, View Source [SID1234595526]).

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The preliminary Phase 2 results showed that a combination of CG0070 and pembrolizumab was well tolerated with encouraging early efficacy data in 9 patients. The results (Abstract #955) were presented as a late-breaking oral presentation at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2021 Annual Meeting.

"We are excited to announce these preliminary results toward CG0070’s safety, tolerability and clinical efficacy in patients with bladder cancer unresponsive to BCG who have limited treatment options," said Arthur Kuan, Chief Executive Officer, CG Oncology. "We hope to see continued responses as the study progresses, as CG0070’s dual mechanism of action has shown to be highly effective in this difficult-to-treat patient population."

Summary of Preliminary Clinical Results

The analysis, based on a data cutoff on November 8, 2021, reported that 100% of patients evaluable for efficacy (n=9) have achieved complete response (CR) at the initial 3-month timepoint. Of those patients that have reached additional timepoints, 100% (n=6) have also maintained a CR through 6 months and 100% (n=3) at the 9-month assessment.
Treatment related adverse events (AEs) were limited to transient grade 1-2 local genitourinary symptoms and immune-related adverse events including urinary frequency, bladder spasm, fatigue, chills, autoimmune thyroiditis, blood discharge, dysuria, and flu-like symptoms. No treatment-related grade 3 or higher AEs or severe adverse events (SAEs) have been observed.
"These preliminary results are exciting," said Dr. Roger Li, M.D., lead study investigator and Urologic Oncologist at Moffitt Cancer Center. "If similar trends hold moving forward, we may have a game changer to combat BCG-unresponsive bladder cancer for patients with significant unmet medical need."

About the CORE1 Study

Under a previously announced clinical collaboration with Merck (known as MSD outside the US and Canada) relating to the investigation of CG0070 used in combination with pembrolizumab, the goal of CORE1, which will enroll up to 35 patients, is to evaluate the safety and efficacy of CG0070 plus KEYTRUDA for the treatment of NMIBC unresponsive to BCG.

More information about the study can be found at www.clinicaltrials.gov (NCT04387461).

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About CG0700

CG0070, a selective oncolytic immunotherapy based on a modified adenovirus type 5 backbone that contains a cancer-selective promoter and a GM-CSF transgene, destroys bladder tumor cells through their defective retinoblastoma (Rb) pathway. CG0070 was designed to replicate inside tumor cells with dysfunctional Rb pathways, causing tumor cell lysis and immunogenic cell death. The rupture of cancer cells releases tumor-derived antigens and GM-CSF, which stimulates a systemic anti-tumor immune response. In advanced clinical trials, CG0070 is a safe and efficacious agent in NMIBC following BCG failure. CG0070 is currently in late-stage clinical trials across a variety of solid cancers, as a monotherapy or in combination with immune checkpoint inhibitors.