Palleon Pharmaceuticals Announces IND Clearance for First-in-Class Cancer Immunotherapy Leveraging Glyco-Immunology

On January 20, 2022 Palleon Pharmaceuticals, a company pioneering the field of glyco-immunology to treat cancer and inflammatory diseases, reported that the U.S. Food and Drug Administration has cleared the company’s investigational new drug (IND) application for its lead candidate E-602 (Press release, Palleon Pharmaceuticals, JAN 20, 2022, View Source [SID1234605669]). This clearance paves the way for Palleon’s first-in-class cancer immunotherapy which targets immunosuppressive sialoglycans to enter clinical testing.

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"We are proud to have reached this milestone in advancing glyco-immunology from a promising, nascent scientific field to an entirely new class of medicines," said Jim Broderick, M.D., Chief Executive Officer and Founder of Palleon. "We continue to leverage our unrivaled expertise in glycobiology drug discovery and development to expand our product pipeline in the pursuit of better therapies for patients with cancer and inflammatory diseases."

E-602 is a first-in-class engineered human sialidase enzyme genetic fusion from Palleon’s EAGLE platform which is designed to desialylate both immune cells and tumor cells, potentiating an anti-tumor immune response. Palleon’s Phase 1/2 trial of E-602 is expected to begin enrolling patients with solid tumors refractory to standard of care in Q1 2022.

Elpiscience Announces First Patient Dosed in US Phase I Clinical Trial of Anti-CD39 Monoclonal Antibody ES002 for Treatment of Advanced Solid Tumors

On January 20, 2022 Elpiscience Biopharmaceuticals, Inc. ("Elpiscience"), a global clinical-stage biopharmaceutical company dedicated to discovering and developing next-generation cancer immunotherapies, reported that the first patient has been dosed in a U.S. multi-center, Phase I clinical trial, evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of ES002, the company’s proprietary anti-CD39 monoclonal antibody (mAb), that is being developed for the treatment of advanced solid tumors (NCT05075564) (Press release, Elpiscience, JAN 20, 2022, View Source [SID1234605667]). Elpiscience received U.S. Food and Drug Administration (FDA) IND clearance for ES002 in September 2021.

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"We are very pleased to see ES002 enter clinical trial testing in the United States," said Steve Chin, CMO of Elpiscience. "This is an important milestone for Elpiscience to develop innovative and differentiated cancer immunotherapies. We look forward to announcing additional clinical milestones throughout 2022 as Elpiscience expands its pipeline with a steadfast commitment to advance One World Class Molecule into the Clinic Each Year."

ES002 has demonstrated highly potent single-agent anti-tumor activity showing significant reduction in tumor size and weight in in-vivo pharmacology studies.

About ES002:

ES002 is an anti-CD39 mAb designed to promote anti-tumor immunity. CD39 is a key enzyme regulating the production of adenosine, a critical immune suppressor. By blocking CD39 function, ES002 also stabilizes pro-inflammatory extracellular ATP (eATP) and restores anti-tumor immunity within the tumor microenvironment. ES002 demonstrated highly potent single-agent anti-tumor activity in in-vivo pharmacology studies.

BeiGene Announces Acceptance of a Supplemental New Drug Application in China for BRUKINSA (zanubrutinib) in Waldenström’s Macroglobulinemia

On January 20, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted a supplemental new drug application (sNDA) for BeiGene’s BTK inhibitor BRUKINSA (zanubrutinib) as a treatment for adult patients with Waldenström’s macroglobulinemia (WM) (Press release, BeiGene, 20 20, 2022, View Source [SID1234605665]).

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"The ASPEN trial has supported BRUKINSA’s approval for patients with WM in the U.S., Canada, Australia, and the European Union. We look forward to continued discussions with the CDE and the opportunity to bring this potential best-in-class therapy to more people in the WM community in China."

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"The sNDA acceptance is welcoming news, and following BRUKINSA’s recent NMPA approval for patients with WM in the relapsed or refractory setting, this represents an opportunity to expand access to more WM patients in China, subject to NMPA approval. As demonstrated in the ASPEN trial, BRUKINSA can offer an efficacious treatment option with improved safety in regard to certain cardiovascular events, such as atrial fibrillation, for patients with WM," commented Jane Huang, M.D., Chief Medical Officer, Hematology, BeiGene. "The ASPEN trial has supported BRUKINSA’s approval for patients with WM in the U.S., Canada, Australia, and the European Union. We look forward to continued discussions with the CDE and the opportunity to bring this potential best-in-class therapy to more people in the WM community in China."

The sNDA is supported by clinical results from the randomized, open-label, multicenter Phase 3 ASPEN trial (NCT03053400) comparing BRUKINSA to ibrutinib in patients with relapsed or refractory (R/R) or treatment-naïve (TN) WM.

As assessed by an independent review committee (IRC) based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the combined rate of complete response (CR) and very good partial response (VGPR) in the overall intention-to-treat (ITT) population was 28% with BRUKINSA (95% CI: 20, 38), compared to 19% with ibrutinib (95% CI: 12, 28). While this difference was not statistically significant (p=0.09), BRUKINSA did achieve numerically higher VGPR rates and trends towards increased response quality.1

In the ASPEN trial, BRUKINSA demonstrated a more favorable safety profile compared to ibrutinib with lower frequency of certain adverse events, including atrial fibrillation or flutter (2% vs. 15%) and major hemorrhage (6% vs. 9%). Of the 101 patients with WM treated with BRUKINSA, 4% of patients discontinued due to adverse events, and adverse events leading to dose reduction occurred in 14% of patients.4

About Waldenström’s Macroglobulinemia

Waldenström’s macroglobulinemia is a rare, slow-growing lymphoma, characterized by bone marrow infiltration with monoclonal immunoglobulin M (IgM) secreting lymphoplasmacytic cells, that occurs in less than two percent of patients with non-Hodgkin’s lymphoma (NHL).1 The disease usually affects older adults and is primarily found in the bone marrow, although it may also impact lymph nodes and the spleen.2 In China, there are an estimated 88,200 patients diagnosed with lymphoma each year. Approximately 91% of these cases are classified as NHL, amounting to ~1,000 newly diagnosed WM patients per year in China.3

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 MCL in patients who have received at least one prior therapy (Israel, January 2021);
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 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);
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021);
For the treatment of adult patients with WM who have received at least one prior therapy or first-line treatment of patients unsuitable for chemo-immunotherapy (European Union plus Iceland, Lichtenstein, and Norway, November 2021);
For the treatment of eligible adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy or for the first-line treatment of eligible patients unsuitable for chemo-immunotherapy (Great Britain, December 2021); and
For the treatment of adult patients with MCL who have received at least one previous therapy (Ecuador, December 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.

Transgene and BioInvent Joint JITC Publication Demonstrates the Potential of BT-001 Oncolytic Virus to provide therapeutic benefit beyond current anti-PD1/ anti-CTLA-4 immune checkpoint blockade

On January 20, 2022 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, and BioInvent International AB ("BioInvent") (Nasdaq Stockholm: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, jointly reported the publication of extensive preclinical proof-of-concept data for BT-001 in the Journal for ImmunoTherapy of Cancer (JITC) (Press release, Transgene, JAN 20, 2022, View Source [SID1234605652]). This peer-reviewed article demonstrates that their co-developed clinical stage product, based on Transgene’s patented oncolytic vector and encoding BioInvent’s proprietary anti-CTLA-4 antibody, has the potential to provide greater therapeutic benefit than systemically administered anti-CTLA-4 antibodies.

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Systemically administered anti-CTLA-4 antibodies, such as the approved ipilimumab, have demonstrated substantial efficacy but also clinically-limiting toxicity.

The JITC paper provides in vivo evidence that vectorized anti-CTLA-4 antibodies delivered intratumorally (i.t.) can improve safety by reducing their systemic exposure. Efficacy may also be improved, with evidence from the immunocompetent murine model showing that vectorized anti-CTLA-4 antibodies have anti-tumoral activity even against ‘cold tumors’ that are resistant to systemically-delivered checkpoint inhibitors. Furthermore, the precise targeting of the antibody to a unique functional epitope of CTLA-4 provides a higher level of regulatory T cells (Treg) depletion than ipilimumab.

"This strong preclinical data supports the development of our oncolytic virus BT-001 as an effective agent to treat solid tumors. We have vectorized a uniquely targeted anti-CTLA-4 antibody for intratumoral delivery and shown in vivo evidence that this reduces systemic toxicity, addresses ‘cold tumors’ and provides excellent tumor-selective Treg depletion. We are keenly anticipating progress in our ongoing Phase 1/2a clinical study with BT-001," said Bjorn Frendéus, Chief Scientific Officer of BioInvent.

"These data demonstrate the relevance of the approach which is based on combining our respective technologies to fully exploit the synergy between oncolytic vector, targeted delivery of a potent payload targeting immunosuppressive cells, and recruitment of effector T cells. The antitumor properties showed in this JITC publication give us great confidence in the results we expect from the further clinical development of BT-001," added Éric Quéméneur, Executive VP & Chief Scientific Officer of Transgene.

The safety-relevant data, published in JITC, show that a murine vector version of BT-001 delivered sustained levels of CTLA-4-receptor-saturating antibodies within tumors but low, sub-saturating exposure in blood and the non-tumor tissue. These antibody levels were associated with high depletion of Tregs in the tumor but the absence of systemic Treg depletion, notably in the spleen.

The study also provides several key insights into likely mechanisms underlying the efficacy of BT-001. Vectorized anti-CTLA-4:

triggered both Fcγ-receptor-dependent Treg depletion and antigen cross-presentation, mechanisms known to trigger and promote long-lasting, systemic, CD8+ T cell antitumor immunity;
showed broad antitumor activity, including activity against murine ‘cold tumor’ models which are resistant to systemic checkpoint inhibitors;
showed additive or synergistic anti-tumor activity when combined with anti-PD-1.
The JITC paper is titled "Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors" and can be accessed here.

Recruitment in the ongoing Phase I/IIa clinical study of BT-001 (NCT04725331) in Europe is progressing steadily. The trial assesses BT-001 as a single agent and in combination with the PD-1 checkpoint inhibitor pembrolizumab against solid tumors. Initial Phase I data are expected in the first half of 2022.

About BT-001

BT-001 is an oncolytic virus generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode both a Treg-depleting human recombinant anti-CTLA-4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, and the human GM-CSF cytokine. By selectively targeting the tumor microenvironment, BT-001 is expected to elicit a much stronger and more effective antitumoral response. As a consequence, by reducing systemic exposure, the safety and tolerability profile of the anti-CTLA-4 antibody will be greatly improved.

BT-001 is being co-developed as part of a 50/50 collaboration on oncolytic viruses between Transgene and BioInvent. To know more on BT-001, watch our video here.

LYSARC Partners with Veeva to Accelerate Innovation for Lymphoma Treatments

On January 20, 2022 Veeva Systems (NYSE: VEEV) reported that the Lymphoma Academic Research Organization (LYSARC) selected Veeva Development Cloud to improve operational efficiency across its lymphoma therapy research (Press release, LYSA Lymphoma, JAN 20, 2022, View Source [SID1234605648]). LYSARC will use applications in Vault Clinical, Vault Quality, and Vault Safety suites to build a robust, connected technology foundation that enables faster execution, higher quality data, and better trial oversight.

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"Partnering with Veeva will accelerate our digital transformation for greater scalability and speed in our pursuit to develop innovative lymphoma therapies or improve current therapies," said Franck Morschhauser, president of LYSARC. "Using Veeva Development Cloud gives us a single connected platform that can free our staff from time-consuming tasks and allow them to focus on what drives us every day: scientific excellence for the benefit of lymphoma patients."

The largest European academic organization devoted to lymphoma clinical research, LYSARC recruits more than 750 patients every year across Belgium, France, and Portugal. To expand its reach, the organization is collaborating with other academic groups in Europe or abroad, in partnership with pharma companies, and needed technology that can scale with its growth.

Veeva Development Cloud will bring together clinical, quality, and safety operations for end-to-end business processes and execution. With a digital and unified systems landscape, LYSARC can improve the patient trial experience, ensure alignment with SOPs across stakeholders, and reduce the costs and lead times of clinical trials.

"LYSARC is fully invested in empowering its teams with advanced technologies to evolve how they work together in a complex environment," said Jim Reilly, vice president of Vault R&D and Quality at Veeva Systems. "We’re proud to work with an organization dedicated to innovation, and we look forward to supporting their development of new lymphoma research and therapies."

LYSARC, the operational structure of the cooperative group LYSA, is standardizing clinical processes with Vault CDMS, Vault CTMS, Vault eTMF, Vault Study Start-up, and Vault Payments, streamlining quality processes with Vault QMS, Vault QualityDocs, and Vault Training, and mitigating risk with Vault Safety. The organization will also encourage its network of partners to adopt Veeva SiteVault Free to enable seamless information sharing with site investigators and sponsors.

Additional Information
For more on Veeva Vault Development Cloud, visit: veeva.com/DevelopmentCloud Connect with Veeva on LinkedIn: linkedin.com/company/veeva-systems Follow @veevasystems on Twitter: twitter.com/veevasystems