On November 15, 2021 Instil Bio, Inc. ("Instil") (Nasdaq: TIL), a clinical-stage biopharmaceutical company focused on developing tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported poster presentations demonstrating pre-clinical data of the CoStimulatory Antigen Receptor (CoStAR) platform at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2021), held from November 10-14, 2021 (Press release, Instil Bio, NOV 15, 2021, View Source [SID1234595616]). Instil also presented a Trials-in-Progress poster detailing DELTA-1, the ongoing Phase 2 study of ITIL-168 in advanced melanoma.

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Pre-clinical data of the anti-FOLR1 CoStAR construct utilized in ITIL-306, Instil’s first genetically-engineered CoStAR-TIL product candidate, was shown in Poster 198. The results demonstrated that CoStAR broadly enhances effector function of T cells including cytolytic activity, cytokine secretion and proliferation of T cells. CoStAR did not stimulate T cells on its own, but only increased T-cell function in the presence of signals activating both the tumor-reactive TCR and the CoStAR molecule. Additionally, data were presented that showed CoStAR was transduced at high efficiency (greater than 40%) into primary ovarian cancer TILs and effector function of CoStAR-TIL was increased over untransduced TILs when cocultured with autologous tumor cells.

The proprietary CoStAR platform utilizes intracellular CD28 and CD40 domains to deliver novel synergistic costimulatory activity to T cells. Poster 199 showcased enhanced activity of T cells engineered with dual CD28/CD40-containing CoStARs, with greater proliferation, enhanced effector function, and a superior cytokine secretion profile compared to a CD28-only CoStAR. Importantly, CoStAR-expressing T cells proliferated exponentially after exposure to tumor antigen, even in the absence of exogenous interleukin (IL)-2, a key required growth factor for T cells in vitro.

"These data further support our excitement for the CoStAR platform, which addresses a major challenge for solid tumor cell therapy: the lack of effective costimulation within the tumor microenvironment," said Mark Dudley, Ph.D., Head of Research at Instil. "The optimized intracellular signaling domains of our CoStAR platform include CD28 and CD40, which demonstrate superior performance over CoStARs containing only CD28."

"With the encouraging preclinical data presented at SITC (Free SITC Whitepaper), we are optimistic that CoStAR may be able to enhance the activity of TILs in patients with cancer and may eliminate the need for high doses of post-infusion IL-2, which is a frequent cause of toxicity in unmodified TIL therapy," said Zachary Roberts, M.D. Ph.D., Chief Medical Officer of Instil Bio. "We continue to look forward to the upcoming Phase 1 first-in-human study of ITIL-306 which we expect to initiate in the first half of 2022."

The company also presented a trial-in-progress poster for DELTA-1, the ongoing Phase 2 study of ITIL-168 in advanced melanoma (Poster 544).

Details of the poster presentations are as follows:

Title: Costimulatory antigen receptor (CoStAR): a novel platform that enhances the activity of TILs
Authors: Sukumaran S, et al.
Poster/Abstract Number: 198 / DOI: 10.1136/jitc-2021-SITC2021.198

Title: Potent T cell costimulation mediated by a novel costimulatory antigen receptor (CoStAR) with dual CD28/CD40 signaling domains to improve adoptive cell therapies
Authors: Sykorova M, et al.
Poster/Abstract Number: 199 / DOI: 10.1136/jitc-2021-SITC2021.199

Title: A global, multicenter phase 2 study of ITIL-168, an unrestricted autologous TIL cell therapy, in adult patients with advanced cutaneous melanoma
Authors: Gastman B, et al.
Poster/Abstract Number: 544 / DOI: 10.1136/jitc-2021-SITC2021.544

The posters are available on the publications section of the Instil Bio website: www.instilbio.com/publications.

About CoStAR

CoStAR (Co-Stimulatory Antigen Receptor) is a novel platform technology used to create a new class of genetically engineered TIL therapies. These modified TILs rely on their native, patient-specific T cell receptors, or TCRs, for detection of tumor-specific antigens, with significantly enhanced effector function when the CoStAR molecule is simultaneously bound to its target in the tumor microenvironment. Submission of the IND for ITIL-306, Instil’s lead CoStAR-TIL product candidate which binds FOLR1 (Folate Receptor Alpha), is anticipated for the first half of 2022.

About ITIL-168

ITIL-168 is an investigational, autologous cell therapy made from tumor infiltrating lymphocytes, or TILs. Made from each patient’s digested and cryopreserved tumor, ITIL-168 is a TIL cell therapy manufactured to offer an unrestricted T cell receptor (TCR) repertoire. Instil’s proprietary, optimized, and scalable manufacturing process has been designed to capture and preserve the maximum diversity of each patient’s TILs. By collecting the patient’s tumor and immediately processing and then cryopreserving it, our process offers significant scheduling flexibility for patients and physicians at the time of both tumor resection and TIL treatment. In addition to DELTA-1, Instil plans to investigate ITIL-168 in additional solid tumor indications in Phase 1 clinical trials beginning in 2022.

About DELTA-1

DELTA-1 is a global, multicenter Phase 2 clinical trial of ITIL-168 in adult patients with advanced melanoma. Using an open-label, single-arm design, the main study cohort will evaluate the efficacy and safety of ITIL-168, when administered after a 5-day course of lymphodepleting chemotherapy and followed by up to 8 doses of high-dose interleukin-2 (IL-2), in patients whose cancer has progressed following a PD-1 inhibitor and, if positive for a BRAF-activating mutation, a BRAF inhibitor. Approximately 80 subjects are planned for enrollment and treatment in Cohort 1. Cohort 2 is anticipated to enroll approximately 25 subjects and is designed to evaluate the efficacy and safety of the regimen in patients who required discontinuation of PD-1 inhibitor(s) due to unacceptable toxicity, regardless of best overall disease response. Cohort 3 is also anticipated to enroll approximately 25 subjects and will evaluate efficacy and safety in patients whose best ongoing response to PD-1 inhibitor(s) is stable disease. Patients in Cohorts 2 and 3 whose cancer expresses a BRAF-activating mutation will be required to have experienced disease progression following BRAF inhibitor therapy. The primary endpoint of DELTA-1 is the objective response rate (ORR) according to RECIST v1.1 as assessed by independent central review. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, and safety.

On November 15, 2021 Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, reported the publication of a scientific paper in the peer-reviewed international scientific journal, ACS Pharmacology & Translational Science (Press release, Oryzon, NOV 15, 2021, View Source [SID1234595630]). The article reports a comprehensive comparison of iadademstat, the first LSD1 inhibitor to be developed in the clinic, with most of the LSD1 inhibitors in development.

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The manuscript, entitled "Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology", compares iadademstat with four LSD1 inhibitors in clinical development in oncology and with five commonly used compounds used in the academia as tool LSD1 inhibitors. Results show that iadademstat is consistently the most active compound across diverse cancer cell lines, that its capability to bind the target is superior, specially at low concentrations, and that the disruption of the transcriptional complexes implicated in the oncogenic programs is more efficacious in the case of iadademstat.

Dr. Jordi Xaus, Oryzon’s CSO, commented: "This set of head-to-head controlled comparisons have shown that iadademstat is clearly the most potent and selective LSD1 inhibitor among all tested clinical molecules. This correlates with the need for lower doses in the clinic, which greatly reduces the potential for idiosyncratic toxicity. A relevant result in this study is that at lower concentrations iadademstat is, by far, the most efficacious in binding LSD1. This may have clinical relevance in solid, dense and poorly vascularized tumors, where the access of drugs to tumoral cells is often an issue".

The paper has been published in the journal ACS Pharmacology & Translational Science as part of the special issue Epigenetics 2022 and is already accessible on-line. The paper can be accessed here: View Source

On November 15, 2021 BioAtla, Inc. (Nasdaq: BCAB), a global clinical-stage biotechnology company focused on the development of Conditionally Active Biologic (CAB) antibody therapeutics, reported financial results for the third quarter of 2021 and provided an update on its clinical progress and business (Press release, BioAtla, NOV 15, 2021, View Source [SID1234595646]).

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"BioAtla continues to advance the progress of the potentially registration-enabling Phase 2 clinical trials for our two lead CAB product candidates as well as our other preclinical and pipeline programs. The increase in our financial resources in the third quarter through our equity placement provides the funding into the first half of 2024 to develop these key assets and the several additional ADC and bispecific CAB candidates in our development pipeline," stated Jay M. Short, Ph.D., Chairman, Chief Executive Officer and co-founder of BioAtla, Inc. "We are aggressively advancing all of our clinical programs and are on track for a sarcoma Phase 2 interim data read out by year-end for BA3011, CAB-AXL-ADC. Additionally, a clinical trial for CAB-CTLA-4 is expected to be initiated by the end of the year," added Scott Smith, President of BioAtla.

Advancing clinical trials for lead candidates
Mecbotamab Vedotin (BA3011)
We are developing BA3011, CAB-AXL-ADC, a conditionally and reversibly active antibody drug conjugate targeting the receptor tyrosine kinase AXL, as a potential therapeutic for multiple solid tumor types, including soft tissue and bone sarcoma, non-small cell lung cancer (NSCLC) and ovarian cancer, with other potential indications in the future. The Office of Orphan Drug Products (OODP) at FDA granted Orphan Drug Designation to BA3011 for the treatment of soft tissue sarcoma, and Phase 1 results in sarcoma patients were presented at the recent Connective Tissue Oncology Society (CTOS) 2021 Annual Meeting. BA3011 was generally well tolerated in this refractory sarcoma population. Few patients discontinued due to an adverse event (2 patients out of 26 or 7.7%). No clinically meaningful on-target toxicity to normal AXL-expressing tissue was observed. Dose-limiting toxicities were limited to monomethyl auristatin E (MMAE) conjugate-associated toxicity at the highest dose tested, including reversible neutropenia.The degree of AXL tumor membrane expression correlated with response to treatment. Of the seven sarcoma patients who had an AXL tumor membrane percent score of greater than or equal to 70, four of these obtained a confirmed partial response, including patients with leiomyosarcoma, undifferentiated pleomorphic sarcoma, and Ewing sarcoma. Prolonged response to therapy was observed in this ongoing study with the duration of response ranging from 33 to more than 60 weeks. Overall, mecbotamab vedotin may have a favorable benefit-risk profile, and importantly this is one of the few studies with a putative biomarker which is not only highly expressed in sarcomas, but also may help select patients across multiple sarcoma subtypes who may benefit from therapy. In the ongoing potentially registration-enabling sarcoma Phase 2 study, patients are enrolled for therapy by prescreening for AXL expression. We also are conducting a Phase 2 study (BA3011-002) in AXL high NSCLC patients who have previously progressed on PD-1/L1, EGFR, or ALK inhibitor therapy. We currently expect to have enrolled more than 70 patients by year end in our sarcoma Phase 2 trial in the U.S. Interim analyses in the sarcoma and NSCLC trials are anticipated this year and in early 2022, respectively. In addition, a multi-center investigator-initiated Phase 2 clinical trial of BA3011 in combination with a PD-1 inhibitor in patients with platinum-resistant ovarian cancer is expected to begin enrollment by year end.

BA3021 (Ozuriftamab Vedotin)
BA3021, CAB-ROR2-ADC, is a conditionally and reversibly active antibody drug conjugate directed against ROR2, a receptor tyrosine kinase that is overexpressed across many different solid tumors including lung, head and neck, melanoma and breast. We are developing BA3021 as a potential therapeutic for multiple solid tumor types, including NSCLC, melanoma, squamous cell cancer of the head and neck (SCCHN) and ovarian cancer. Based on Phase 1 data we believe BA3021 has broad potential as a cancer therapy for patients with advanced solid tumors that have previously progressed on a PD-1 inhibitor. We are enrolling a Phase 2 trial of BA3021 monotherapy or in combination with a PD-1 inhibitor in patients with ROR2 high melanoma who have previously progressed on PD-1/L1 inhibitor and patients with ROR2 high NSCLC who have previously progressed on PD-1/L1, EGFR or ALK inhibitor therapy. A Phase 2 study in patients with ROR2 high SCCHN is anticipated to enroll in early 2022. In addition, a multi-center investigator-initiated Phase 2 clinical trial of BA3021 in combination with a PD-1 inhibitor in patients with platinum-resistant ovarian cancer is expected to begin enrollment by year end.

BA3071
BA3071, is a CAB anti-CTLA-4 antibody that is being developed as an immuno-oncology agent with the goal of delivering efficacy comparable to the approved anti-CTLA-4 antibody, ipilimumab, but with lower toxicities due to the CAB’s tumor microenvironment-restricted activation. The development of BA3071 is the subject of a 2019 Global Co-Development and Collaboration Agreement between BioAtla and BeiGene, Ltd. Like BA3011, BA3021 and our other CAB candidates, BA3071 is designed to be conditionally and reversibly activated in the tumor microenvironment via the Protein-associated Chemical Switch or PaCS mechanism discovered by BioAtla scientists. This proprietary system enables reduction of systemic toxicity and potentially enables safer combination therapies, such as with anti-PD-1 antibody checkpoint inhibitors in the case of BA3071. BA3071 is being developed as a potential therapeutic for multiple solid tumor indications, including renal cell carcinoma, NSCLC, small cell lung cancer, hepatocellular carcinoma, melanoma, bladder cancer, gastric cancer and cervical cancer. We are currently in advanced discussions with BeiGene regarding the allocation of roles and responsibilities for global development and commercialization of BA3071 under our Global Co-Development and Collaboration Agreement with BeiGene. As part of these ongoing discussions, BeiGene is planning to initiate the transfer of the IND for BA3071 to BioAtla and BioAtla anticipates initiating the Phase I trial for BA3071 during 2021, with dosing commencing in the first half of 2022.

Plans to advance development of several bispecific CAB candidates
We have also leveraged our CAB technology to develop bispecific antibodies, which bind both a tumor-specific antigen and a T cell receptor (CD3) using CAB antigen-binding domains. With this design, bispecific antibodies can induce potent T cell responses against tumors expressing the tumor target antigen. We have shown in preclinical experiments that our CAB bispecific molecules meet or exceed the activity of conventional bispecifics and reduce systemic activation of potentially severe immune responses. We are conducting IND-enabling studies for two CAB bispecific antibody product candidates, EpCAM/CD3 and B7-H3/CD3, and presently plan to file INDs in mid-2022 and by year end 2022, respectively. We also are evaluating additional candidates including EGFR and Nectin-4 for CAB CD3 bispecific modalities. Nectin-4 is also progressing as a CAB ADC candidate. Overall, we are advancing multiple pre-clinical assets with the potential to submit up to four US INDs over the next 18 months for our CAB bispecific or ADC molecules.

Sheri Lydick joins to lead commercial strategy
BioAtla is building its capabilities to plan for and execute the commercial launches of its CAB portfolio of product candidates. A key element of this strategy is the recent hiring of Sheri Lydick as the company’s Senior Vice President, Commercial Strategy. Ms. Lydick will be leading commercial strategy, which includes long-range portfolio planning, assessing strategic business opportunities and delivering on these plans. Ms. Lydick has more than 20 years of leadership and commercialization experience in the biotechnology and pharmaceutical industry. In her most recent role at Bristol-Meyers Squibb Company, Ms. Lydick was responsible for building the sales and marketing teams and leading the commercial launch of Zeposia across multiple therapeutic areas (multiple sclerosis and ulcerative colitis). In her twelve years (2007-2019) at Celgene her leadership role expanded from Director of Global Marketing for the Inflammation and Immunology (I&I) Franchise to Executive Director, US Rheumatology Lead, to Vice President, US Commercial Lead for Zeposia. Among her accomplishments, she was instrumental in building Celgene’s Inflammation and Immunology franchise and led the planning and launch of the multi-billion dollar drug Otezla. BioAtla president Scott Smith commented, "Sheri has deep experience and success in global commercial marketing and sales and in building and leading multidisciplinary teams. We are excited for her to bring that expertise to BioAtla."

Third quarter 2021 financial results
Cash and cash equivalents as of September 30, 2021 were $269.9 million. We expect current cash and cash equivalents will be sufficient to fund planned operations into the first half of 2024. In September 2021, we executed a private placement of common stock yielding gross proceeds of $75.0 million before deducting placement agent fees and other offering expenses. The investors included both current and new institutional investors.

Research and development (R&D) expenses were $16.6 million for the quarter ended September 30, 2021 compared to $4.9 million for the same quarter in 2020. We expect our R&D expenses to increase substantially for the foreseeable future as we continue to invest in R&D activities to advance our product candidates, and our clinical programs and expand our product candidate pipeline.

General and administrative (G&A) expenses were $7.1 million for the quarter ended September 30, 2021 compared to $3.3 million for the same quarter in 2020. We expect our G&A expenses to increase as a result of operating as a public company. In addition, we expect our intellectual property expenses to increase as we expand our intellectual property portfolio.

Net loss for the third quarter ended September 30, 2021 was $22.9 million compared to a net loss of $11.6 million for the same quarter in 2020. Net cash used in operating activities for the first nine months of 2021 was $41.3 million compared to net cash used in operating activities of $22.3 million for the same period in 2020.

On November 15, 2021 Sirnaomics, Inc., a biopharmaceutical company engaged in the discovery and development of RNAi therapeutics against cancer and fibrotic diseases, reported that it will be presenting positive results from a Phase 2a clinical study of the company’s lead drug candidate, STP705, for treatment of squamous cell skin cancer in situ (nonmelanoma skin cancer) at the 2021 TIDES Europe event (Press release, Sirnaomics, NOV 15, 2021, View Source [SID1234595670]). The hybrid conference is taking place digitally and in person at the Sheraton Brussels Airport Hotel in Belgium from November 15-17, 2021.

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Title: Novel Dual Targeting siRNA Therapeutic Offers Innovative Solution for Derm-Oncology Treatment
Presenter: David Evans, PhD., Sirnaomics Chief Scientific Officer
Presentation Overview: Clinical trial results showing STP705, used to target TGF-β1 and COX-2 siRNAs for the treatment of nonmelanoma skin cancer, has demonstrated rates of histological clearance that rival surgical excision combined with improved cosmetic appearance.
Time/Date: November 16, 2021 at 16:30; available on demand after the presentation to TIDES delegates

About STP705

Sirnaomics’ product candidate, STP705, is a siRNA (small interfering RNA) therapeutic that takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. The product candidate has received multiple IND approvals from both the US FDA and Chinese NMPA, including for the treatment treatments of cholangiocarcinoma and other solid liver tumors, nonmelanoma skin cancer and hypertrophic scar, and Keloid scarring. STP705 has also received Orphan Drug Designation for treatment of cholangiocarcinoma, primary sclerosing cholangitis, and hepatocellular carcinoma. A Phase 2a study of STP705 for treatment of squamous cell skin cancer (isSCC) in adult patients demonstrated positive efficacy and safety results, with 76% of all patients (19/25) achieving complete histologically clearance and the two optimal dosing ranges achieving 90% histological clearance of tumor cell in the lesion. No significant or serious adverse events, including no significant cutaneous skin reactions, were reported in the study, and the company was able to define a clear therapeutic window in advance of later stage studies.

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.