On December 16, 2019 Organovo Holdings, Inc. ("Organovo") (Nasdaq: ONVO) and Tarveda Therapeutics, Inc. ("Tarveda"), a privately-held, clinical stage biopharmaceutical company developing a new class of potent and selective precision oncology medicines, which it refers to as Pentarin miniature drug conjugates, reported that they have entered into a definitive merger agreement under which Tarveda would merge with a wholly-owned subsidiary of Organovo in an all-stock transaction (Press release, Organovo, DEC 16, 2019, View Source [SID1234552406]). Upon completion of the merger, the merged company would operate under the name Tarveda Therapeutics, Inc. and trade on the Nasdaq Stock Market LLC under the ticker symbol "TVDA."

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Tarveda is primarily focused on the development of its pipeline of Pentarin miniature drug conjugates designed to selectively accumulate and retain anti-cancer payloads in solid tumor malignancies. Following the closing of the merger, Tarveda intends to continue to focus on advancing its two clinical stage oncology programs, PEN-866 and PEN-221, and on further development of novel conjugates from its proprietary miniature drug conjugate platform. At the closing of the merger, it is estimated that the combined company will have approximately $35 million of cash on hand that is expected to provide sufficient funding into the second half of 2021 to achieve key upcoming clinical data milestones on both clinical programs.

"After completing an extensive and thorough review of strategic alternatives, we are extremely pleased to announce this transaction with Tarveda, which we believe is in the best interest for our stockholders," said Taylor J. Crouch, President and Chief Executive Officer, Organovo. "Tarveda is advancing an innovative pipeline of clinical stage cancer therapies derived from the company’s proprietary miniature drug conjugate platform. Tarveda is supported by a strong syndicate of investors including Novo A/S, Versant Ventures and ND Capital (NanoDimension) and a highly seasoned management team with prior public company experience."

"Our growing portfolio of miniature drug conjugates has the potential to represent much needed new treatment options for patients with solid tumor malignancies," said Drew Fromkin, President and Chief Executive Officer of Tarveda. "We are encouraged by the activity and tolerability demonstrated in Phase 1 human studies of our two clinical programs, PEN-866 and PEN-221. Our Pentarin miniature drug conjugates are designed to incorporate the best properties of small molecule drugs and antibody drug conjugates to form miniature drug conjugates that are effective at rapidly and deeply penetrating solid tumors while minimizing damage to healthy tissue. We are excited about this merger with Organovo and believe that this is the right point in Tarveda’s trajectory to move forward as a publicly traded company given several upcoming clinical data milestones that we expect to be achieved in 2020 and 2021."

Tarveda expects the merger to provide the capital required to advance its two lead programs through the next set of clinical milestones and to generate novel conjugates from its Heat Shock Protein 90 (HSP90) binding miniature drug conjugate platform. PEN-866, the initial clinical program from Tarveda’s HSP90 binding miniature drug conjugate platform, is designed to bind to the activated form of HSP90 in solid tumors to accumulate and retain its potent topoisomerase 1 inhibitor (SN-38) payload. PEN-866 is completing the Phase 1 dose escalation and safety portion of its "all comers" trial in various types of solid tumors and has shown to be well tolerated and demonstrated early clinical activity in heavily treated, advanced patients with a range of solid tumor malignancies. Beginning in early 2020, it is expected that PEN-866 will be evaluated in a Phase 2a study both as a single agent and as a combination therapy across a range of solid tumors that are sensitive to topoisomerase 1 inhibitors. PEN-221 is a miniature drug conjugate in clinical evaluation for the treatment of patients with solid tumors expressing somatostatin receptor 2 (SSTR2) on the cell surface and is linked to the potent tubulin inhibitor payload, DM1. In a Phase 1 study, PEN-221 was well tolerated and demonstrated early clinical activity. PEN-221 is currently being evaluated in a Phase 2a study for the treatment of patients with neuroendocrine tumors and small cell lung cancer.

About the Proposed Merger

Under the terms of the merger, it is anticipated that Tarveda stockholders will own approximately 75% of the combined company and current Organovo stockholders will own approximately 25% of the combined company on a fully-diluted basis. The exchange ratio is based on valuation assumptions for both companies subject to potential adjustments for certain financial metrics prior to the completion of the merger.

The transaction has been approved by the boards of directors of both companies. The merger is anticipated to close in the first quarter of 2020, subject to the approval of Organovo and Tarveda stockholders as well as other customary closing conditions.

Roth Capital Partners served as financial advisor, and Gunderson Dettmer Stough Villeneuve Franklin & Hachigian, LLP served as legal counsel to Organovo. Canaccord Genuity served as financial advisor, and Cooley LLP served as legal counsel, to Tarveda.

Management and Organization

Following the merger, the combined company will be led by the current Tarveda management team, including Drew Fromkin as President, Chief Executive Officer and Chairman; Jeffrey D. Bloss, M.D., Chief Medical Officer; Brian Roberts, Chief Financial Officer; Mark Bilodeau, Ph.D., Chief Scientific Officer; and Sudhakar Kadiyala Ph.D., Executive Vice President, Strategy.

The Board of Directors of the combined company will be comprised of eight directors, including six directors to be named by Tarveda and two directors to be named by Organovo. The corporate headquarters will be located in Watertown, MA.

Conference Call

Organovo and Tarveda will host a conference call at 8:30 a.m. ET on December 16, 2019, to discuss the proposed transaction. The conference call may be accessed by dialing (866) 405-4577 (domestic) or (602) 563-8680 (international) and using the conference ID 3679123. To help ensure the conference call begins in a timely manner, please dial in five minutes prior to the scheduled start time. The conference call will also be simultaneously webcast at View Source

Non-Solicitation

This communication does not constitute an offer to sell or solicitation of an offer to buy any securities, nor will there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction.

Important Information and Where to Find It

This communication may be deemed to be solicitation material in respect of the proposed transaction between Organovo and Tarveda. In connection with the proposed transaction, Organovo intends to file relevant materials with the SEC, including a registration statement on Form S-4 that will contain a proxy statement/prospectus/information statement. BEFORE MAKING ANY VOTING OR INVESTMENT DECISION, INVESTORS AND STOCKHOLDERS ARE URGED TO READ THESE MATERIALS CAREFULLY AND IN THEIR ENTIRETY WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT THE PROPOSED TRANSACTIONS. Stockholders may obtain, free of charge, copies of the definitive proxy statement and any other documents filed by Organovo with the SEC in connection with the proposed transactions at the SEC’s website (View Source) and at Organovo’s website.

Organovo and its directors and executive officers and Tarveda and its directors and executive officers may be deemed to be participants in the solicitation of proxies from the stockholders of Organovo in connection with the proposed transaction. Information regarding the special interests of these directors and executive officers in the merger will be included in the proxy statement/prospectus/information statement referred to above. Additional information regarding the directors and executive officers of Organovo is included in Organovo’s Definitive Proxy Statement on Schedule 14A relating to the 2019 Annual Meeting of Stockholders, filed with the SEC on July 26, 2019. This document is available free of charge at the SEC website (www.sec.gov) or at Organovo’s website.

On December 16, 2019 Mauna Kea Technologies (Paris:MKEA) (OTCQX:MKEAY) (Euronext: MKEA) inventor of Cellvizio, the multidisciplinary probe and needle-based confocal laser endomicroscopy (p/nCLE) platform, reported a strategic equity investment of 7.5 million euro by Johnson & Johnson Innovation – JJDC, Inc. (JJDC) (Press release, Mauna Kea Technologies, DEC 16, 2019, View Source [SID1234552405]). Pursuant to the agreement, JJDC, the strategic venture capital arm of Johnson & Johnson, will subscribe to 5,357,142 new ordinary MKEA shares for €1.40 per share, representing a total equity value of 7.5 million euro.

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"We are very proud to announce a strategic equity investment agreement with Johnson & Johnson Innovation – JJDC, Inc.," said Robert L. Gershon, Chief Executive Officer of Mauna Kea Technologies. "This agreement represents a significant strategic inflection point for Mauna Kea Technologies, particularly in that it provides a capital infusion that will help us execute our strategic growth initiatives."

Mr. Gershon continued: "This strategic investment will advance our collaboration with the Lung Cancer Initiative at Johnson & Johnson, which is working to develop new diagnostic and therapeutic approaches for this disease with significant unmet need. Our Cellvizio platform and AQ-Flex 19 Confocal Miniprobe (nCLE) is designed to be used through existing bronchoscopes, transbronchial needles and other bronchoscopic accessories, which makes it a viable option for use with the new emerging robotic and existing advanced navigation platforms."

Transaction Summary

JJDC will invest in the share capital of the Company an amount of 7.5 million euro, in consideration for 5,357,142 new ordinary shares, corresponding to an issue price per ordinary share equal to approximately €1.40. The new ordinary shares will be fungible with the existing shares of the Company. JJDC will own approximately 17.5% of the total ordinary shares outstanding following this transaction. JJDC will not have any board representation rights.

As part of the investment, JJDC agreed to customary lock up and stand still obligations for a period of 12 months. Pursuant to an agreement entered into as part of the investment, Mauna Kea has granted, for 24 months, to JJDC and its affiliates, a right of first refusal with respect to a transaction (other than change of control of Mauna Kea) on its pCLE (probe CLE) or nCLE (needle CLE) variants for use in endoluminal robotic procedures for lung applications and to the application of machine learning and artificial intelligence for lung applications. Mauna Kea has also granted, for 24 months, to JJDC and its affiliates, a right of first negotiation with respect to a transaction (other than change of control of Mauna Kea) on its pCLE (probe CLE) or nCLE (needle CLE) variants for use in endoluminal robotic procedures for GI and urology applications. In connection with this transaction, Piper Jaffray is acting as strategic advisor and McDermott Will & Emery is acting as legal advisor to Mauna Kea Technologies.

Use of proceeds

The Company’s management team expects that the net proceeds of the issue will be used to meet the financing needs of the current business in order to further develop the Cellvizio platform, pursue clinical studies and intensify sales and marketing efforts in the United States.

Cash position

The Company’s available cash position as of October 31, 2019 was approximately €4.1 million. Based on the Company’s current development plans, the Company expects the net proceeds from the share capital increase, combined with its current operating capital, to enable the funding of its operations until the end of 2020.

Legal framework

The new ordinary shares will be issued through a capital increase reserved to specified categories of person under the provisions of Article L. 225-138 of the French Commercial Code, pursuant to the decisions of the Company’s Board of Directors (Conseil d’Administration) dated December 13, 2019. Such decision by the Board of Directors is authorized pursuant to the 8th resolution adopted at the extraordinary meeting of the Company’s shareholders (Assemblée Générale Extraordinaire) held on October 5, 2018.

The closing of the transaction is expected to occur on December 19, 2019.

Application to list such new ordinary shares on the regulated market of Euronext Paris will be made pursuant to a listing prospectus subject to the approval by the Autorité des marchés financiers ("AMF") and comprising (i) the 2018 universal registration document, including the risk factors, which is expected to be filed with the AMF at the latest on December 17, 2019 (document d’enregistrement universel 2018), which will incorporate by reference the 2018 registration document (document de référence 2018) and the 2019 half-year financial report (rapport financier semestriel 2019), and (ii) a Securities Note (Note d’opération), including (iii) a summary of the prospectus. As from such filing with the AMF, copies of the Company’s 2018 universal registration document will be available free of charge at the Company’s head office located at 9 rue d’Enghien – 75010 Paris – France. The listing prospectus will be published on the AMF’s website at www.amf-france.org.

On December 16, 2019 Omeros Corporation (Nasdaq: OMER) reported new data directed to its novel cancer immunotherapy target GPR174 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Immuno-Oncology Congress in Geneva, Switzerland (Press release, Omeros, DEC 16, 2019, View Source [SID1234552404]). In addition to previously reported findings, which revealed enhanced anti-tumor immune responses in GPR174-deficient mice and synergism between adenosine receptor antagonists and GPR174 antagonists in promoting interleukin-2 (IL-2) and interferon-γ (IFN-γ) production from human T cells, this presentation included new data from human ex vivo studies demonstrating that GPR174 inhibition results in downregulation of checkpoint and tumor-promoting factors.

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The findings, presented by Marc Gavin, Ph.D., Omeros’ Director of Immunology, show that GPR174 suppresses T lymphocytes through the cyclic adenosine monophosphate (cAMP) signaling pathway. In addition to suppressing T-cell function, cAMP signaling is known to enhance production of both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and amphiregulin (AREG), both important drivers of tumor development. CTLA-4 is an immune checkpoint molecule targeted by FDA-approved drugs such as Yervoy (ipilimumab), and AREG is a cell growth factor involved in promoting tumor growth. The data demonstrate that, using either GPR174 small-molecule inhibitors or in GPR174-deficient mice, the T cell-suppressing effect of cAMP is blocked, resulting in enhanced "tumor-killing" T-cell activation. In addition, the new data show that GPR174 inhibitors reduce both CTLA-4 and AREG levels in T cells, suggesting that multiple pathways – including checkpoint and tumor-promoting factors – downstream of GPR174 inhibition may be inactivated, further augmenting anti-tumor immunity and blocking tumor growth.

"The data show that GPR174 inhibitors enhance anti-tumor immune responses through multiple pathways, including increased production of tumor-fighting cytokines IL-2, IFN-γ, and TNF while suppressing expression of CTLA-4 and AREG," said Gregory A. Demopulos, M.D., Omeros’ chairman and chief executive officer. "Among our ongoing activities, we are exploring the effect of GPR174 inhibition on other checkpoints, including PD-1, and their inhibitors. We are increasingly confident in the role of GPR174 in immuno-oncology and look forward to moving our GPR174 inhibitors into the clinic as quickly as possible with the hope of improving survival for cancer patients."

Dr. Gavin’s recent presentation at ESMO (Free ESMO Whitepaper) can be accessed on the company’s website at View Source

On December 16, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported results from the Phase 3 ASPEN trial comparing its BTK inhibitor BRUKINSA (zanubrutinib) to ibrutinib for the treatment of Waldenström’s macroglobulinemia (WM) (Press release, BeiGene, DEC 16, 2019, View Sourcenews-releases/news-release-details/beigene-announces-results-phase-3-aspen-trial-zanubrutinib" target="_blank" title="View Sourcenews-releases/news-release-details/beigene-announces-results-phase-3-aspen-trial-zanubrutinib" rel="nofollow">View Source [SID1234552403]). While the trial did not achieve statistical significance on its primary endpoint of superiority in complete response (CR) and very good partial response (VGPR) rates for zanubrutinib compared to ibrutinib, zanubrutinib demonstrated a higher VGPR rate as well as improvements in safety and tolerability in this first randomized comparative trial to read out within the BTK inhibitor class.

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The ASPEN trial is a randomized Phase 3 trial in 229 patients with WM conducted in 61 centers in Europe, Australia, and the United States. The study includes two cohorts, a randomized cohort (cohort 1) consisting of 201 patients with a MYD88 mutation and a non-randomized cohort (cohort 2) in which 28 patients with MYD88 wild-type (MYD88WT) received zanubrutinib because they have historically responded poorly to ibrutinib therapy.

The randomized cohort 1 enrolled 102 patients (including 83 relapsed or refractory (R/R) patients and 19 treatment-naïve (TN) patients) in the zanubrutinib arm and 99 patients (including 81 R/R patients and 18 TN patients) in the ibrutinib arm. Patients in the zanubrutinib arm were assigned to receive zanubrutinib 160 mg twice daily (BID) and patients in the ibrutinib arm received 420 mg of ibrutinib once daily (QD).

Results from cohort 1 in the Phase 3 ASPEN trial, as of the data cutoff date of August 31, 2019 with a median follow-up of 19.4 months, include:

In R/R patients, the VGPR rate as assessed by independent review committee (IRC) was 28.9% in the zanubrutinib arm and 19.8% in the ibrutinib arm (no patients achieved a CR in either arm). The difference was not statistically significant (2-sided p=0.1160);

In the overall patient population, the VGPR rate as assessed by IRC was 28.4% in the zanubrutinib arm and 19.2% in the ibrutinib arm (no patients achieved a CR in either arm). The difference was not statistically significant (2-sided descriptive p=0.0921);

In the R/R patient population, the major response rate (MRR), which is the rate of partial response (PR) or better, as assessed by IRC was 78.3% in the zanubrutinib arm and 80.2% in the ibrutinib arm; in the overall patient population, the MRR was 77.5% in the zanubrutinib arm and 77.8% in the ibrutinib arm;

While the trial was not powered to detect a statistically significant improvement in progression free survival (PFS), and follow-up data for PFS is still short, early PFS and overall survival (OS) data for zanubrutinib were directionally consistent with the higher VGPR rates in the zanubrutinib arm:

° The 12-month PFS rate was 92.4% (83.8-96.5) in R/R patients and 89.7% (81.7-94.3) in all patients in the zanubrutinib arm, compared to 85.9% (75.9-91.9) in R/R patients and 87.2% (78.6-92.5) in all patients in the ibrutinib arm; and

° The 12-month OS rate was 98.8% (91.6-99.8) for R/R patients and 97.0% (90.9-99.0) for all patients in the zanubrutinib arm, compared to 92.5% (84.1-96.6) in R/R patients and 93.9% (86.8-97.2) in all patients in the ibrutinib arm;

Grade >3 adverse events (AEs) were 58.4% in the zanubrutinib arm and 63.3% in the ibrutinib arm. In the zanubrutinib arm, four (4.0%) patients discontinued treatment due to AEs and there was one (1.0%) fatal adverse event; in the ibrutinib arm, nine patients (9.2%) discontinued due to AEs and there were four (4.1%) fatal adverse events;

For AEs of special interest for BTK inhibitors, atrial fibrillation/flutter of any grade was 2.0% in the zanubrutinib arm and 15.3% in the ibrutinib arm; minor bleeding was 48.5% for zanubrutinib and 59.2% for ibrutinib; major hemorrhage was 5.9% for zanubrutinib and 9.2% for ibrutinib; and diarrhea was 20.8% for zanubrutinib and 31.6% for ibrutinib; and

The rate of neutropenia was higher in the zanubrutinib arm (29.7%) as compared to the ibrutinib arm (13.3%).
Summary Tables:

"Our researchers sought to design a BTK inhibitor that would improve efficacy and decrease side effects in patients by maximizing BTK inhibition and minimizing off-target binding. We took a bold approach to our clinical development plan by evaluating zanubrutinib directly against ibrutinib in patients with WM and are encouraged by the improvements in VGPR rates and safety," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "The ASPEN trial, which was the largest prospective trial for patients with WM ever run, showed consistent safety advantages for patients treated with zanubrutinib compared to ibrutinib. While falling short of a statistically significant improvement in CR and VGPR, we believe the trial demonstrated that zanubrutinib is a highly potent BTK inhibitor that has clinical benefit and trends toward increased response quality."

Dr. Huang continued, "Today’s results are consistent with what we know about zanubrutinib from our broad clinical development program – that it is a more selective BTK inhibitor with beneficial pharmacokinetics designed to provide deep, meaningful responses for many patients. We plan to discuss our findings with regulatory authorities in the U.S. and Europe and plan to submit these data for presentation, with additional analysis, to an upcoming medical meeting. In addition, we will continue to evaluate zanubrutinib compared to ibrutinib in our ongoing Phase 3 ALPINE trial in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)."

"WM is a devastating and incurable disease with significant morbidity. These meaningful results help us advance the understanding of the role of BTK specificity and off-target effects during treatment," said Constantine S. Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia, and a member of the steering committee and principal investigator for the ASPEN trial. "Despite not reaching the primary endpoint, 28.4% of zanubrutinib patients achieved VGPR as compared to 19.2% in the ibrutinib arm, and zanubrutinib had a more favorable safety profile, suggesting improved clinical benefit for zanubrutinib over standard BTKi therapy in the treatment of patients with WM."

About the ASPEN trial

The Phase 3 randomized, open-label, multicenter ASPEN clinical trial (NCT03053440) evaluated BRUKINSA versus ibrutinib in people with relapsed/refractory (R/R) or treatment-naïve (TN) Waldenström’s macroglobulinemia. The primary objective was to establish superiority of BRUKINSA compared to ibrutinib as demonstrated by the proportion of people achieving complete response (CR) or very good partial response (VGPR). Secondary endpoints included major response rate, duration of response and progression-free survival, and safety, measured by incidence, timing and severity of treatment-emergent adverse events. The pre-specified analysis populations for the trial included the overall population (n=201) and R/R patients (n=164).

Results of cohort 2 were previously presented at the 24th Congress of European Hematology Association (EHA) (Free EHA Whitepaper) and showed an overall response rate (ORR) of 80.8%, a major response rate (MRR; partial response or better) of 53.8% and a VGPR rate of 23.1%.

The data from the study were masked and the results were first available for analysis this past week. The Company plans to submit the full ASPEN results for presentation to an upcoming medical congress.

BeiGene Conference Call and Webcast Information
Investors and analysts are invited to join the conference call on Monday, December 16 at 8:30 a.m. ET using the following dial-in information:
A live webcast of the conference call and the slides from the presentation can be accessed from the investors section of BeiGene’s website at View Source or View Source An archived replay will be available two hours after the event for 90 days.

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström’s macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;

Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);

Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);

Phase 2 trial in combination with GAZYVA (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);

Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);

Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);

Phase 2 ROSEWOOD trial (NCT03332017) in China comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;

Completed Phase 2 trials in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918); and

Completed enrollment in Phase 2 clinical trial in patients with WM (NCT03332173).
About BRUKINSA (zanubrutinib)

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 pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA was approved by the U.S. FDA to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy on November 14, 2019. 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.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States. BRUKINSA is not approved for the treatment of Waldenström’s macroglobulinemia.

IMPORTANT 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 bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% 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 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was 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 (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 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 0.6% 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 at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 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 in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

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.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is 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.

On December 16, 2019 NantKwest Inc. (Nasdaq: NK), a clinical-stage natural killer cell-based therapeutics company, and ImmunityBio, a privately held immunotherapy company, reported results from their Phase 1b trial investigating a novel, first-in-human immunotherapy protocol consisting of NantKwest’s off-the-shelf, antibody-targeted NK cells (haNK) combined with ImmunityBio’s IL-15 superagonist (N-803), low-dose metronomic chemoradiation therapy, adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA) and a PD-L1 checkpoint inhibitor in patients with metastatic triple negative breast cancer (TNBC) who had relapsed after prior therapy (Press release, NantKwest, DEC 16, 2019, https://ir.nantkwest.com/news-releases/news-release-details/nantkwest-and-immunitybio-present-results-landmark-trial-first?field_nir_news_date_value[min]=2019 [SID1234552402]).

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The results were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) on December 13, 2019, in San Antonio, Texas, in a poster titled "Safety and efficacy from first-in-human immunotherapy combining NK and T-cell activation with off-the-shelf, antibody-targeted CD16 NK cell line (haNK) in patients with 2nd-line or greater metastatic triple-negative breast cancer (TNBC)."

This landmark study is the world’s first trial to combine cellular therapy with checkpoint inhibitors and IL-15 cytokine stimulation, as well as with adenoviral vectors, all acting in concert to induce immune simulation of both NK cells and T cells.

"We are extremely pleased that the FDA granted us IND authorization to initiate this novel immunotherapy trial enabling the safety and efficacy study of multiple novel biological agents administered as a single protocol in the outpatient setting," said Dr. Patrick Soon-Shiong, Chairman and CEO of NantKwest. "This important trial forms the basis of our approach to induce immunogenic cell death and long-term memory, and avoid the ravages of high dose chemotherapy."

"Achieving durable, complete responses in metastatic TNBC patients that have failed all current standards of care is a promising finding and further validates our approach to orchestrate both the innate and adaptive immune system," continued Soon-Shiong. "TNBC is a highly aggressive cancer, with limited treatment options and poor prognosis. These results are important proof-of-concept supporting our hypothesis that comprehensively activating the immune responses of the NK, T and Dendritic cells would induce immunogenic cell death leading to durable responses, even among this challenging patient population. We are thrilled with the safety and efficacy data from this first-in-human clinical trial of combination NK cell therapy, cytokine fusion protein, chemoradiation and checkpoint inhibitor, and look forward to advancing this exciting off-the-shelf cell therapy approach to randomized clinical trials in this setting."

Data Highlights Include:

Of 9 patients treated, efficacy results include a disease control rate of 78% (7/9 patients) and an overall response rate of 67% (6/9 patients).
2 out of 9 patients to date have ongoing complete responses with durations ranging from 8 to 11 months, with a 3rd patient demonstrating a partial response (near complete response) in the target lesion after initiation of targeted and endocrine therapy off-study.
To date, 7 patients are alive with durations of response ranging from 2 to 12 months with 4 patients remaining on study. Median progression-free survival rate is 13.7 months.
All patients were treated in an outpatient setting with treatment generally safe and well tolerated and no observed cytokine release syndrome.
No immune related SAEs were attributed to the immunotherapy investigational agents
All patients had at least 1 grade ≥ 3 TRAE, primarily chemotherapy-related neutropenia or anemia. Grade ≥ 3 haNK-related AEs, namely fever and fatigue, were observed in 2 patients.
Early data from peripheral blood analysis demonstrate clonal selection occurs with the immunotherapy regimen enabling targeted therapy tailored to patient specific mutations identified via next generation sequencing.
"The approximately 10-20% of breast cancer patients who are triple negative are faced with a grim prognosis with limited treatment options. These results are clinically significant, with overall response rates and complete response rates in this highly refractory, advanced metastatic patient population," said Dr. Chaitali Nangia, a Hematologist/Oncologist with the Chan Soon-Shiong Immuno-Oncology Network and study co-author. "Importantly, these responses to treatment are also durable, with median progression free survival exceeding 13 months compared to historical controls of approximately 3 months in this heavily pretreated population. We also observed a positive safety and tolerability profile, with no cytokine release syndrome. Taken together, these efficacy and safety results point to the emergence of a new treatment paradigm for TNBC."