On December 9, 2019 Australian life sciences company, QBiotics Group Limited (QBiotics) is reported the publication[1] of positive results from a first in-human Phase I clinical trial of its anticancer pharmaceutical, tigilanol tiglate (EBC-46) in EBioMedicine, a peer-reviewed translational biomedical research journal by The Lancet (Press release, QBiotics, DEC 9, 2019, View Source;efficacy-of-tigilanol-tiglate-in-solid-tumours-300971159.html [SID1234552170]).

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The key objectives of this Phase I, open-label, single-arm, non-randomised, dose-escalation study were to determine the safety profile, tolerability, pharmacokinetics (PK), and preliminary antitumour efficacy of tigilanol tiglate when administered once by intratumoural injection. Tigilanol tiglate was generally well tolerated and doses escalated from 0.06 to 3.60 mg/m[2], without reaching a maximum tolerated dose.

The study was conducted in 22 patients at four hospital sites in Australia[1]. Patients were recruited with a range of tumour types including squamous cell carcinoma, basal cell carcinoma, melanoma, breast adenocarcinoma, atypical fibroxanthoma, atypical myxoid fibrosarcoma, metastatic colorectal adenocarcinoma, adenoid cystic carcinoma and angiosarcoma. Signs of clinical activity were observed in all nine tumour types, even at the lowest doses.

"As this was a first-in-human, single dose safety study, the expectation of a strong anticancer response was low. However, the results revealed a 27% treatment response (in 6 patients), including an 18% complete response (in 4 patients) with full tumour destruction across a wide variety of solid tumour types.

"Solid tumours account for up to 80% of all tumour types,[3] so the results from this Phase I study indicate potentially broad applications for tigilanol tiglate in a range of tumours, and an important advancement for our pharmaceutical," said QBiotics Group CEO and Managing Director, Dr Victoria Gordon.

"Additionally, two patients with melanoma demonstrated an anenestic (or abscopal) response, where non-injected tumours at different locations in the body also reduced in size. These results were achieved despite many patients not receiving an optimal dose,[1]" added Dr Gordon.

The vast majority (96%) of adverse events (AEs) were mild to moderate, with the most commonly reported AE being injection site reaction related to the mode of action of tigilanol tiglate. AEs were generally managed with symptomatic therapy.[1]

"Given the very good safety profile, and positive antitumour responses observed, this study supports further development of tigilanol tiglate as a potential treatment of solid tumours," said Dr Gordon

"Results from this study also underpins selection of our initial lead indication and our recently announced Phase I/II trial of tigilanol tiglate in patients with Head and Neck Squamous Cell Carcinoma (HNSCC), in which the first patient was successfully dosed last week," Dr Gordon said.

The Phase I/II open label "QBC46-H03" study, is a dose escalation study in patients with HNSCC aimed at determining the maximum tolerated dose (MTD) and recommended dose level for further studies. The study will also investigate safety, tolerability and tumour response following single or multiple (two to three) doses of tigilanol tiglate. It will enrol up to 40 patients from the Tata Medical Centre in Kolkata, the Tata Memorial Hospital in Mumbai, and other clinical sites in Australia.

ISSUED BY

QBIOTICS GROUP LIMITED – www.QBiotics.com

FOR FURTHER
INFORMATION

DR VICTORIA GORDON, CEO & MANAGING DIRECTOR, QBIOTICS GROUP
[email protected] or + 61 418 453 737

On December 9, 2021 ADC Therapeutics SA, a clinical-stage oncology-focused biotechnology company pioneering the development of highly potent antibody drug conjugates (ADCs) for patients suffering from hematological malignancies and solid tumors, reported interim efficacy and safety data on 52 patients in the ongoing pivotal 145-patient Phase 2 clinical trial of ADCT-402 (loncastuximab tesirine), demonstrating its potential as a single agent for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Press release, ADC Therapeutics, DEC 9, 2019, View Source [SID1234596051]). Carmelo Carlo-Stella, MD, Section Chief, Lymphoid Malignancies and Cancer Therapeutics, Humanitas Cancer Center, Humanitas University, and an investigator for the trial, presented the data today during an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL.

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"The data continue to reinforce the significant single-agent, anti-tumor activity and manageable toxicity profile of ADCT-402 in patients with relapsed or refractory DLBCL, even in difficult-to-treat patients. Based on the encouraging data seen with this agent today, I believe ADCT-402 has the potential to be an integral part of the treatment paradigm for patients with DLBCL," said Dr. Carlo-Stella. "DLBCL is a common and aggressive cancer that can be challenging to treat due to its frequent resistance to available treatments. Patients who have failed established therapies are limited in their treatment options, creating a critical need for a new therapy."

"We are pleased that the data from our oral presentation at ASH (Free ASH Whitepaper) support the potential of ADCT-402 to be an important treatment option for heavily pretreated patients with DLBCL," said Jay Feingold, MD, PhD, Senior Vice President, Chief Medical Officer and Head of Oncology Clinical Development at ADC Therapeutics. "We look forward to completing the pivotal Phase 2 clinical trial and submitting a Biologics License Application to the U.S. Food and Drug Administration for accelerated approval of ADCT-402 for the treatment of relapsed or refractory DLBCL patients who have failed two or more treatment regimens in the second half of 2020."

The oral presentation included data, as of October 4, 2019, on 52 patients from the pivotal Phase 2 clinical trial of ADCT-402 (loncastuximab tesirine) who were a median age of 63 years (range 24-84) and had received a median of three previous therapies. Key data include:

The overall response rate (ORR) was 46.2% (24/52 patients), comprising 19.2% complete responses and 26.9% partial responses. Comparably, the ORR in the Phase 1 trial of ADCT-402 (loncastuximab tesirine) at the initial dose used in Phase 2 was 41.4% (29/70 patients), comprising 21.4% complete responses and 20% partial responses. The primary endpoint in the pivotal Phase 2 clinical trial is ORR.
For complete responders, the median duration of response has not yet been reached. For complete and partial responders, the preliminary median duration of response is 5.7 months.
Stable disease was attained in 19.2% of patients.
ADCT-402 (loncastuximab tesirine) demonstrated manageable toxicity in patients with relapsed or refractory DLBCL. The most common grade ≥3 treatment-emergent adverse events in at least 5% of patients were: gamma-glutamyltransferase increased (25%), hypokalemia (5.8%), platelet count decreased (21.2%), neutrophil count decreased (32.7%) and anemia (11.5%).
The ongoing single-arm, multi-center, open-label Phase 2 clinical trial is evaluating the safety, efficacy and pharmacokinetics of ADCT-402 (loncastuximab tesirine) as a monotherapy in patients with relapsed or refractory DLBCL. Patients received 30-minute intravenous infusions of ADCT-402 (loncastuximab tesirine) once every three weeks at a dose of 150 μg/kg for the first two cycles, followed by 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurred first.

The presentation will be available on the Posters and Presentations page and a video of the investor event ADC Therapeutics hosted on Sunday, December 8 will be available on the Videos page of the Company’s website: View Source

About ADCT-402 (loncastuximab tesirine)
ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Once bound to a CD19-expressing cell, ADCT-402 (loncastuximab tesirine) is designed to be internalized by the cell, following which the warhead is released. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies. ADCT-402 (loncastuximab tesirine) is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (NCT03589469), a Phase 1b trial in combination with ibrutinib in patients with R/R DLBCL or mantle cell lymphoma (MCL) (NCT03684694) and a Phase 1b trial in combination with durvalumab in patients with R/R DLBCL, MCL or follicular lymphoma (NCT03685344). The U.S. Food and Drug Administration granted orphan drug designation to ADCT-402 (loncastuximab tesirine) for the treatment of R/R DLBCL and MCL.

On December 9, 2019 STORM Therapeutics, the biotechnology company focused on the discovery of small molecule therapies modulating RNA epigenetics reported, that its collaborator Dr. Konstantinos Tzelepis, Sir Henry Wellcome Fellow and Visiting Scientist at the Wellcome Sanger Institute, received the ASH (Free ASH Whitepaper)-BSH Abstract Achievement Award for his work on STORM Therapeutics’ lead programme, METTL3, at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) held on 7th-10th December 2019 in Orlando, Florida (Press release, STORM Therapeutics, DEC 9, 2019, View Source [SID1234561038]).

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Dr. Tzelepis received the meritorious award for his abstract entitled ‘Pharmacological Inhibition of the RNA m6a Writer METTL3 As a Novel Therapeutics Strategy for Acute Myeloid Leukemia’ at the Abstract Achievement Award Ceremony which was held on Saturday, 7th December 2019 at 3:30pm (EST) at the Orange County Convention Center in Exhibit Hall B2-B4.

Dr. Tzelepis’s work, which was carried out in collaboration with the Wellcome Sanger Institute and the University of Cambridge, was presented in an oral presentation during the "802. Chemical Biology and Experimental Therapeutics: Novel Compounds and Mechanisms of Action" session on Sunday, 8th December 2019 at 9:30am-11:30am (EST) at the Orange County Convention Centre. The abstract and talk encapsulated the ground-breaking work made on targeting RNA modifying enzymes for cancer treatment and described the recent progress made with the METTL3 inhibitor.

STORM has identified small molecule inhibitors of METTL3 that are orally bioavailable and show pronounced anti-tumour efficacy in physiologically relevant, proof of concept animal models of Acute Myeloid Leukaemia (AML). The talk demonstrated that small molecule inhibition of METTL3 produces the same phenotype and effects previously described in one of STORM’s founder scientists’ publications using genetic models and validates METTL3 as a druggable target for cancer.

Keith Blundy, CEO of STORM Therapeutics, said: "STORM is progressing fast in its preclinical work with our multiple programmes to showcase the capabilities of our novel platform. STORM is a pioneer in RNA epigenetics and we are very pleased to hear that our collaborator is being recognized for the partnership research of METTL3. As the first company in the world to demonstrate in vivo activity of an RNA methyltransferase inhibitor, we are excited to be leading the field as we look to develop these highly innovative new treatment options for cancer patients."

On December 9, 2019 ArQule, Inc. (Nasdaq: ARQL) reported final results from the phase 1 study for ARQ 531, an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting & Exposition in Orlando, Florida (Press release, ArQule, DEC 9, 2019, View Source [SID1234552104]).

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"The final phase 1 data set confirms the potential utility of ARQ 531 for the treatment of these heavily pretreated CLL patients. We were excited to observe such deep and durable responses at a well-tolerated dose in this highly refractory population," commented Dr. Brian Schwartz, Chief Medical Officer of ArQule. "In addition, the three responses we observed in Richter’s Transformation patients were a welcome outcome and allowed several patients to transition to potentially curative therapies."

"ARQ 531 was selected and extensively tested preclinically to address the emerging therapeutic needs of patients who have become resistant to covalent BTK inhibitors in a broad set of hematologic malignancies," commented Dr. Jennifer Woyach, Associate Professor of Medicine at The Ohio State University and the Principal Investigator of the study. "It is tremendously gratifying to witness the emergence of a potential therapeutic for patients with such a high degree of unmet need, such as C481S-mutant CLL and Richter’s Transformation, and beyond. The data presented in this poster provide compelling proof-of-concept for this novel class of reversible BTK inhibitors."

The reported data are from the phase 1, open label, single arm dose escalation study and include patients (n=47) initially dosed at levels of 5, 10, 15, 20, 30, 45, 65 and 75 mg once a day with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), Richter’s Transformation, Waldenström macroglobulinemia and other B-cell Non-Hodgkin lymphomas.

Key Findings:

65 mg QD was selected as the Recommended Phase 2 Dose (RP2D) for further studies
Across all disease subsets, ARQ 531 showed a low incidence of associated toxicities, including one grade three DLT and no atrial fibrillation or bleeding observed
At 65 mg QD, ARQ 531 has a steady state mean Cmin above 1 µM and long plasma half-life of 56 hours resulting in complete pBTK inhibition
Clinical Anti-Tumor Activity:
In CLL, an Overall Response Rate (ORR) of 89% (8/9 responses in evaluable patients) was achieved in heavily pretreated R/R CLL patients (7/8 harboring BTK-C481S mutation) dosed at ≥65 mg QD. Eleven of 19 patients treated at 65 mg QD remain on study
In Richter’s Transformation, an ORR of 50% (3/6 responses in evaluable patients) was achieved at 65 mg QD
Two additional PRs were observed including one patient with Follicular Lymphoma (FL) and 1 patient with Diffuse Large B-cell Lymphoma (DLBCL)
Durability:
100% (5/5) evaluable CLL patients that received a third scan (cycle 9) are durable confirmed PRs and remain on therapy
67% (2/3) of Richter’s patients that achieved PRs came off study after becoming eligible for CAR-T therapy
The Follicular Lymphoma patient that achieved a PR has been on study for 120 weeks and remains a PR and on therapy
The poster at ASH (Free ASH Whitepaper) presenting these data entitled, "Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies," is available on the company’s website at www.arqule.com/publications-presentations/.

In addition, earlier today Merck and ArQule announced that the companies have entered into a definitive agreement under which Merck, through a subsidiary, will acquire ArQule. A copy of the joint press release is available on ArQule’s website, www.arqule.com.

ArQule will host a conference call and webcast for investors on Monday, December 9, 2019 at 8:15 a.m. EST to discuss the ARQ 531 clinical data. The live webcast can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events & Presentations" or by visiting click here. You may also listen to the call by dialing (877) 868-1831 within the U.S. or (914) 495-8595 outside the U.S. and providing conference ID 4573858. A replay will be available two hours after the completion of the call and can be accessed in the "Investors & Media" section of our website, www.arqule.com, under "Events and Presentations."

ArQule management will host an Investor Event to answer questions and discuss these data in Orlando tonight, Monday, December 9, 2019 from 8:00–10:00 p.m. EST. Investors, sell side analysts, and industry representatives are welcome to attend. For event details and to RSVP, please email [email protected].

About BTK and ARQ 531

Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. ARQ 531 has demonstrated a manageable safety profile, predictable PK, convincing pharmacodynamic effects and signs of clinical activity.

On December 9, 2019 Merck (NYSE: MRK), known as MSD outside the United States and Canada, and ArQule, Inc. (Nasdaq: ARQL) reported that the companies have entered into a definitive agreement under which Merck, through a subsidiary, will acquire ArQule for $20 per share in cash for an approximate total equity value of $2.7 billion (Press release, Merck & Co, DEC 9, 2019, View Source [SID1234552121]). ArQule is a publicly traded biopharmaceutical company focused on kinase inhibitor discovery and development for the treatment of patients with cancer and other diseases. ArQule’s lead investigational candidate, ARQ 531, is a novel, oral Bruton’s tyrosine kinase (BTK) inhibitor currently in a Phase 2 dose expansion study for the treatment of B-cell malignancies.

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"ArQule’s focus on precision medicine has yielded multiple clinical-stage oral kinase inhibitors that have novel and important properties," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "This acquisition strengthens Merck’s pipeline with the addition of these strategic assets including, most notably, ARQ 531, a compelling candidate for the treatment of B-cell malignancies."

BTK inhibition has been shown to prevent B-cell receptor signaling that is critical for the survival and proliferation of leukemic cells in many B-cell malignancies. ARQ 531 is a highly selective, reversible inhibitor that blocks both wild-type BTK and the C481S mutant form of the enzyme that is commonly associated with resistance to other BTK inhibitors. In early clinical trials, ARQ 531 demonstrated a manageable safety profile and early signs of anti-tumor activity for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and Richter’s Transformation. Final data from the Phase 1 study of ARQ 531 will be presented on Dec. 9, 2019 at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Orlando, Florida.

"We are proud that Merck has recognized the contributions that ArQule, together with its scientific collaborators, has made to the field of precision medicine in oncology with ARQ 531 for the treatment of B-cell malignancies and with the rest of our clinical-stage pipeline," said Paolo Pucci, CEO, ArQule. "With this agreement, ArQule’s pipeline will benefit from Merck’s vast capabilities and determined engagement to benefit the patients who we have always strived to serve."

Under the terms of the acquisition agreement announced today, Merck, through a subsidiary, will initiate a tender offer to acquire all outstanding shares of ArQule. The closing of the tender offer will be subject to certain conditions, including the tender of shares representing at least a majority of the total number of ArQule’s outstanding shares, the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions. Upon the successful completion of the tender offer, Merck’s acquisition subsidiary will be merged into ArQule, and any remaining shares of common stock of ArQule will be canceled and converted into the right to receive the same $20 per share price payable in the tender offer. The transaction is expected to close early in the first quarter of 2020.

BofA Securities acted as financial advisor to Merck in this transaction and Covington & Burling LLP as its legal advisor. Centerview Partners acted as exclusive financial advisor to ArQule and Skadden, Arps, Slate, Meagher & Flom LLP as its legal advisor.

Important Information About the Tender Offer

The tender offer described in this press release (the "Offer") has not yet commenced. This press release is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell any shares of the common stock of ArQule, Inc. ("ArQule") or any other securities. At the time the planned tender offer is commenced, a tender offer statement on Schedule TO, including an offer to purchase, a letter of transmittal and related documents, will be filed by Merck Sharp & Dohme Corp. ("Merck") and Argon Merger Sub, Inc., a wholly-owned subsidiary of Merck, with the Securities and Exchange Commission (the "SEC"), and a solicitation/recommendation statement on Schedule 14D-9 will be filed by ArQule with the SEC. The offer to purchase shares of ArQule common stock will only be made pursuant to the offer to purchase, the letter of transmittal and related documents filed as a part of the Schedule TO.

INVESTORS AND SECURITY HOLDERS ARE URGED TO READ BOTH THE TENDER OFFER STATEMENT AND THE SOLICITATION/RECOMMENDATION STATEMENT REGARDING THE OFFER, AS THEY MAY BE AMENDED FROM TIME TO TIME, WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION.

Investors and security holders may obtain a free copy of these statements (when available) and other documents filed with the SEC at the website maintained by the SEC at www.sec.gov or by directing such requests to the Information Agent for the Offer, which will be named in the tender offer statement. Additional copies of the tender offer materials may be obtained at no charge by contacting Merck at 2000 Galloping Hill Road, Kenilworth, N.J., 07033 or by phoning (908) 423-1000. In addition, Merck and ArQule will file annual, quarterly and current reports and other information with the SEC. Merck’s and ArQule’s filings with the SEC also will be available to the public from commercial document-retrieval services and at the SEC’s website at www.sec.gov.