On December 10, 2021 Exicure, Inc. (NASDAQ: XCUR) reported the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline (Press release, Exicure, DEC 10, 2021, View Source [SID1234596793]).

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The Audit Committee of the Board of Directors of the Company (the "Audit Committee") reported the findings of the internal investigation initiated and overseen by the Audit Committee and conducted by outside counsel in connection with alleged improprieties that Grant Corbett, Ph.D., the Company’s former Group Lead of Neuroscience, claimed to have committed with respect to the Company’s XCUR-FXN preclinical program.

The results of the investigation are summarized below.

Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;
Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;
The misreported data related solely to efficacy rather than safety of XCUR-FXN;
The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;
Dr. Corbett acted alone in misreporting the data, without the assistance or knowledge of anyone else at the Company, including Company management and other research and development employees and did not inform anyone at the Company of his actions until his resignation in November 2021;
Company management reasonably relied on Dr. Corbett’s analysis when making public statements that included Dr. Corbett’s misreported data; and
No other Company program was impacted by Dr. Corbett’s misreporting of the XCUR-FXN data.
After a review of the Audit Committee’s findings from the investigation and in combination with a previously initiated strategic review of the Company’s business plans and objectives and its existing cash resources, the Company’s Board of Directors has implemented the following approved plan:

A staggered workforce reduction of approximately 50%, expected to be completed by January 2022;
Discontinuation of further enrollment and the ethical wind down of the Company’s ongoing Phase 1b/2 cavrotolimod (AST-008) clinical trial in patients with solid tumors
Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia
Restructuring and realignment of the Company’s executive team as follows, effective today:
Brian C. Bock, the Company’s former Chief Financial Officer, has been appointed as the Company’s President and Chief Executive Officer, replacing David Giljohann, and was appointed as a member of the Board.
Dr. David Giljohann, the Company’s former Chief Executive Officer, has resigned from the Board and will serve as Chief Technology Officer through January 31, 2022.
Matthias Schroff, the Company’s former Chief Operating Officer, has assumed the new role of Chief Scientific Officer;
Sarah Longoria, the Company’s former Vice President of Human Resources has been appointed as the Company’s Chief Human Resources Officer and Chief Compliance Officer; and
Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.
Exicure expects to realize approximately $6.0 million in employee related cost savings in 2022, plus additional costs relating to the elimination of the cavrotolimod and XCUR-FXN programs. The Company estimates that it will incur total expenses relating to the restructuring of approximately $1.2 million, consisting of severance and termination-related costs and expects to record a significant portion of these charges in the fourth quarter of 2021.

The Company intends to align its research and development resources to support (i) the development of its preclinical program targeting SCN9A for neuropathic pain, (ii) the continued advancement of its partnered programs with Ipsen Biopharm Limited to develop SNA-based treatments in neuroscience targeting Huntington’s disease and Angelman syndrome, (iii) its continued advancement of its partnered program with AbbVie to develop SNA-based treatments for hair loss disorders, as well as (iv) the continued research and development of other undisclosed therapeutic product candidates.

The Company also announced a prepayment of $10.0 million of its outstanding loans under its senior secured term loan debt facility with MidCap Financial Trust, as agent, and Silicon Valley Bank (SVB), leaving a remaining outstanding balance of $7.5 million, which will remain subject to the existing terms under the loan facility.

"This has been a difficult time for all of our stakeholders and Exicure employees. I want to first thank the employees impacted by our workforce reduction for their significant contributions in pursuing treatments for patients with unmet medical needs and wish them success in their future endeavors. Although this unfortunate event will have residual effects, I strongly believe there is great value to be unlocked at Exicure with our proprietary Spherical Nucleic Acid (SNA) technology, and I look forward to advancing our promising programs in pain and other neuroscience diseases and continuing to closely work with our partners to develop innovative therapies for the treatment of genetic disorders," stated Brian Bock, President and Chief Executive Officer, Exicure.

"On behalf of the Board of Directors, I want to thank David Giljohann for his discoveries and contributions to the development of our proprietary SNA architecture, commitment in building Exicure from the ground up and leadership during his time at the Company," said Tim Walbert, Chairman of the Board, Exicure. "We look forward to working closely with Brian Bock as he assumes leadership of the Company. The Board believes Brian’s disciplined approach as well as his financial and investment banking background make him well suited to develop the new strategic path for Exicure and navigate the Company through the next phase in the Company’s evolution."

On December 10, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the schedule of data presentations at the upcoming 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting and exposition, to be held December 11 – 14, 2021, virtually and also live at the Georgia World Congress Center in Atlanta, Georgia (Press release, TG Therapeutics, DEC 10, 2021, View Source [SID1234596765]).

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ASH Presentation Details:

Oral Presentations:
Oral Presentation Title: The Combination of Umbralisib Plus Ublituximab Is Active in Patients with Relapsed or Refractory Marginal Zone Lymphoma (MZL): Results from the Phase 2 Global Unity-NHL Trial

Session Date/Time: Saturday, December 11, 2021 / 10:00 AM ET
Session Name: 623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Targeted Therapy in Low Grade Lymphoma
Room: Georgia World Congress Center, A411-A412
Lead Author: Julio Chavez, MD, MS, Moffitt Cancer Center, Tampa, FL
Oral Presentation Title: Efficacy and Safety of Umbralisib, Ublituximab (U2), and U2 Plus Bendamustine in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Session Date/Time: Sunday, December 12, 2021 / 5:30 PM ET
Session Name: 626. Aggressive Lymphomas Prospective Therapeutic Trials: Novel Agents and Combinations
Room: Georgia World Congress Center, Thomas Murphy Ballroom 1-2
Lead Author: John Burke, MD, Rocky Mountain Cancer Centers / US Oncology Research, Aurora, CO
Oral Presentation Title: A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

Session Date/Time: Sunday, December 12, 2021 / 10:30 AM ET
Session Name: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological I
Room: Georgia World Congress Center, B401-B402
Lead Author: Lindsey E. Roeker, MD, CLL Program, Leukemia Service, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY
Poster Presentations:
Poster Presentation Title: The Selective Bruton Tyrosine Kinase (BTK) Inhibitor TG-1701 As Monotherapy and in Combination with Ublituximab and Umbralisib (U2) in Patients with B-Cell Malignancies

Date/Time: Saturday, December 11, 2021 / 5:30 PM – 7:30 PM ET
Session Name: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Location: Georgia World Congress Center, Hall B5
Lead Author: Chan Y. Cheah, MBBS, DMSc, Linear Clinical Research, Nedlands, Australia; Medical School, University of Western Australia, Perth, Australia; and Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia
Poster Presentation Title: Favorable Outcomes for Patients Treated with U2 with Co-Morbidities or Concomitant Medications: A Retrospective Analysis of Unity-CLL Phase 3 Trial

Date: Monday, December 13, 2021 / 6:00 PM – 8:00 PM
Session Name: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Location: Georgia World Congress Center, Hall B5
Lead Author: Javier Pinilla-Ibarz, MD, Lymphoma Section Head, Director of Immunotherapy, Malignant Hematology Division at the H. Lee Moffitt Cancer Center in Tampa, Florida
Poster Presentation Title: Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study

Date/Time: Monday, December 13, 2021 / 6:00 PM – 8:00 PM
Session Name: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Location: Georgia World Congress Center, Hall B5
Lead Author: Ryan Jacobs, MD, Department of Hematology, Lymphoma Division, Assistant Professor of Medicine, Levine Cancer Institute/Atrium Health, Charlotte, NC
Abstracts are now publicly available via the ASH (Free ASH Whitepaper) meeting website at www.hematology.org. Final presentations will be accessible at the above dates/times via the publications page of TG corporate website at View Source

On December 10, 2021 Abbott (NYSE: ABT) reported that its board of directors has increased the company’s quarterly common dividend, marking the company’s 50th consecutive year of dividend growth (Press release, Abbott, DEC 10, 2021, View Source [SID1234596746]).

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Abbott’s quarterly common dividend has been increased to 47 cents per share, a 4.4% increase that follows a 25% increase to the company’s quarterly dividend in 2021. It will be the 392nd consecutive quarterly dividend to be paid by Abbott since 1924. The cash dividend is payable Feb. 15, 2022, to shareholders of record at the close of business on Jan. 14, 2022.

Abbott is a member of the S&P 500 Dividend Aristocrats Index, which tracks companies that have increased dividends annually for at least 25 consecutive years.

"Fifty years of dividend growth reflects the consistently strong performance of our diversified business model," said Robert B. Ford, president and chief executive officer, Abbott. "It exemplifies our longstanding commitment to delivering sustainable growth that fuels innovation as well as shareholder returns."

Abbott’s board also has authorized the repurchase of up to $5 billion of the corporation’s common shares. This new authorization is in addition to the unused portion of the previous program authorized by Abbott’s board in October 2019. The purchases may be made from time to time as market conditions warrant and subject to regulatory considerations.

On December 10, 2021 iTeos Therapeutics, Inc. (Nasdaq: ITOS), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of highly differentiated immuno-oncology therapeutics for patients, reported the presentation of new preclinical data for its anti-TIGIT monoclonal antibody, EOS-448, at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition and the TIGIT Therapies Digital Summit 2021 (Press release, iTeos Therapeutics, DEC 10, 2021, View Source [SID1234596766]).

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"The data we presented this week at the TIGIT Therapies Digital Summit provide further evidence of the multifaceted mechanism of our high affinity, potent anti-TIGIT monoclonal antibody, EOS-448. We presented preclinical data showing activation of immune stimulatory cells is dependent on activating via FcγR, and also show clinically that this activation is translating to depletion of immunosuppressive cells. Furthermore, the upcoming data presentations at ASH (Free ASH Whitepaper) demonstrate the synergistic effect of combining an FcγR active anti-TIGIT antibody with an IMiD in a preclinical model of multiple myeloma and provide strong rationale for our ongoing Phase 1/2 trial in this difficult to treat cancer," said Michel Detheux, Ph.D., president and chief executive officer of iTeos. "These results underscore our enthusiasm for EOS-448 as a potential therapy capable of harnessing the immune system to help improve outcomes for patients with advanced, aggressive cancers. We look forward to progressing our clinical development plan in 2022 in both multiple myeloma and solid tumors with several combinations."

ASH 2021:

The Combination of Anti-Tigit and Lenalidomide Promotes Synergistic Myeloma-Specific Immunity after ASCT
Presented by: Simone A. Minnie, Ph.D., Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Abstract #: 154087

Preclinical data demonstrating the efficacy of a mouse surrogate EOS-448 as a single agent and in combination with an immunomodulatory imide drug (IMiD) in a preclinical model of multiple myeloma was presented by our collaborator at the Fred Hutchinson Cancer Research Center. The Fc-enabled anti-TIGIT monoclonal antibody elicited effective control of multiple myeloma disease progression, while an Fc-disabled version was inactive, indicating the importance of engaging the FcγR. Furthermore, the Fc-enabled anti-TIGIT antibody demonstrated synergistic activity when combined with an IMiD, a class of drugs that has previously shown clinical activity in multiple myeloma.

TIG-007: Study of EOS884448/GSK4428859A Alone, and in Combination with Iberdomide with or without Dexamethasone, in Participants with Relapsed or Refractory Multiple Myeloma
Presented by: Philippe Moreau, M.D., Hematology Department, Nantes University Hospital, Nantes, France
Abstract #: 152395

The presentation highlighted TIG-007, an ongoing open-label, multicenter, dose-escalation/expansion Phase 1/2 trial evaluating the safety, tolerability, and preliminary activity of EOS-448 as monotherapy and in combination with Bristol Myers Squibb’s IMiD, iberdomide, with or without dexamethasone, in adults with relapsed or refractory multiple myeloma. The preclinical data presented from the preclinical model of multiple myeloma provide a strong rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent the progression of myeloma, and previous studies have shown notable clinical activity and acceptable tolerability with iberdomide in combination with dexamethasone or other antimyeloma agents in heavily pre-treated patients with relapsed or refractory multiple myeloma. The study aims to assess the therapeutic opportunity of EOS-448 alone or in combination with iberdomide, with or without dexamethasone to amplify myeloma-specific T cell anti-tumor responses in patients with difficult-to-treat relapsed or refractory multiple myeloma.

TIGIT Therapies Digital Summit 2021:

Targeting TIGIT: Which cell populations are modulated by FcγR engagement?
Presented by: Gregory Driessens, Ph.D., Senior Director, Project Head, iTeos Therapeutics

The presentation featured both preclinical and clinical evidence for the multifaceted mechanism of action of EOS-448, including activation of T cells, modulation of antigen-presenting cells and depletion of regulatory T cells (Tregs) and terminally exhausted T cells. Preclinical data demonstrated that FcγR engagement activated professional antigen-presenting cells either alone or synergistically with anti-PD1, both in the tumor and within the tumor draining lymph node. This effect was only evident when using a fully functional anti-TIGIT antibody, providing support for the design of EOS-448 as an IgG1 antibody. An update on the pharmacodynamic effect of EOS-448 in the blood of treated patients from the Phase 1 trial showed strong depletion of Tregs, an increase in the CD8/Treg ratio and a transient increase in proliferation (as assessed by the Ki67 marker), in line with previous observations with pembrolizumab.

On December 10, 2021 Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) reported an update on Phase 1 dose escalation data of ARV-471, a novel PROTAC estrogen receptor (ER) degrader, which is being co-developed for the treatment of patients with locally advanced or metastatic ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (ER+/HER2-) (Press release, Arvinas, DEC 10, 2021, View Source [SID1234596747]). These data were presented as a virtual spotlight poster session at the 2021 San Antonio Breast Cancer Symposium (SABCS) and showed:

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ARV-471 demonstrated antitumor activity in CDK4/6 inhibitor-pretreated patients with a clinical benefit rate (CBR) of 40% in 47 evaluable patients. This heavily pretreated patient group had a median of four prior therapies.
Three patients exhibited confirmed partial responses (PR) among the 38 patients with response evaluation criteria in solid tumors (RECIST) measurable lesions and at least one on-treatment tumor assessment.
ARV-471 continues to demonstrate a favorable tolerability profile. Robust ER degradation was observed at all dose levels, reaching 89% reduction of ER.
Erika P. Hamilton, MD, Director of the Breast Cancer and Gynecologic Cancer Research Program and Principal Investigator, Sarah Cannon Research Institute, provided an overview of these data.

"These results continue to suggest that ARV-471 has the potential to become a first-in-category treatment, and a new standard of care, for ER+/HER2- breast cancer patients," said John Houston, Ph.D., Chief Executive Officer at Arvinas. "The profile we see emerging for this drug candidate continues to validate our PROTAC protein degrader platform, with ARV-471 showing clear signals of clinical benefit in a heavily pretreated patient population, including tumor shrinkage and good tolerability."

These data support and further validate the evaluation of ARV-471 as a potential treatment for metastatic breast cancer that is ongoing in a Phase 1b combination study with IBRANCE (palbociclib) and a Phase 2 monotherapy dose expansion study.

"We are excited by these results and believe ARV-471 is a promising ER-targeting investigational medicine," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "It is encouraging to see ARV-471 continuing to show durable efficacy and tolerability in heavily pre-treated patients with ER+ breast cancer who have limited treatment choices."

ARV-471 Clinical Update

Enrollment

As of the data cut-off date of September 30, 2021, 60 adult patients with locally advanced or metastatic ER+/HER2- breast cancer were treated in the Phase 1 dose escalation portion of the study with total daily ARV-471 doses ranging from 30 mg to 700 mg. This patient group is heavily pretreated, with a median of four prior therapies. All patients were previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors; 80% of patients received prior fulvestrant; and 78% received prior chemotherapy.

Efficacy

Of 47 patients who were evaluable for clinical benefit (confirmed complete response, PR, or stable disease ≥ 24 weeks) the CBR was 40%. As of the data cutoff date, 14 patients were continuing to receive study treatment, including two patients who had been on treatment for over 18 months. Three confirmed PRs were observed among the 38 patients with baseline RECIST measurable disease and at least one on-treatment tumor assessment.

Safety

Patients were treated in the monotherapy escalation at total daily doses of 30 mg (n=3), 60 mg (n=3), 120 mg (n=7), 180/200 mg (n=11), 360 mg (n=15), 500 mg (n=17), and 700 mg (n= 4). All patients in the 700 mg cohort received ARV-471 twice-daily, a subset of patients who received 500 mg as a total daily dose received ARV-471 twice-daily, and other all doses were administered once-daily. A maximum tolerated dose was not reached and no dose limiting toxicities or Grade ≥4 treatment-related adverse events (TRAEs) were observed. Of the 60 patients, 37% had Grade 1 TRAEs and 57% had Grade ≤2 TRAEs, and the most common TRAEs were nausea (29%), fatigue (20%), and vomiting (10%). No Grade 1 or 2 TRAEs led to discontinuation or dose reduction of ARV-471. Four patients experienced six Grade 3 TRAEs that were potentially related to ARV-471, including: headache lasting 1-day, single occurrence of asymptomatic increased amylase and lipase, nausea and asymptomatic QTc prolongation, and post-biopsy venous embolism. The patient with the venous embolism was the only Grade 3 patient who discontinued ARV-471 due to a TRAE, and the patient with Grade 3 nausea was the only patient with a dose reduction due to a TRAE (reduced from 500 mg to 400 mg daily).

ER Degradation

In paired biopsies from 14 patients across all doses up to 500 mg daily, robust ER degradation of up to 89% was observed, regardless of ESR1 mutation status. Median and mean ER degradation across dose levels were 67% and 64%, respectively.

Pharmacokinetics

ARV-471 demonstrated a dose-related increase in plasma exposure, with doses from 30 mg to 500 mg daily, resulting in steady-state Cmax and AUC24 that exceeded the exposure associated with tumor regression in preclinical breast cancer models. Mean exposure on day 15 exceeded the nonclinical efficacious range at doses ≥60 mg daily.

Anticipated 2021/2022 Milestones

ARV-471 currently is being evaluated as a treatment for metastatic breast cancer in a Phase 1 dose escalation study, a Phase 1b combination study with IBRANCE (palbociclib), and a Phase 2 monotherapy dose expansion study.
In 2022, we expect to:
Initiate Phase 3 studies across lines of therapy in metastatic breast cancer, as both monotherapy and in combination.
Initiate two additional trials of ARV-471, including a Phase 1b combination trial with everolimus in 2L/3L metastatic breast cancer, potentially as part of a planned umbrella study to explore multiple combination agents, and a Phase 2 neoadjuvant trial in early breast cancer.
Present data from the ongoing Phase 1b combination study with IBRANCE (palbociclib) and from the ongoing Phase 2 monotherapy dose expansion study.
Investor Conference Call Details
Arvinas will host a conference call and webcast at 8:30 AM ET on Friday, December 10, 2021, to discuss these data. Pfizer Oncology executives will also participate in this call. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode 9122219.

Supporting materials for the conference call and webcast will be available on the Arvinas’ website at www.arvinas.com under Events + Presentations. A replay of the webcast will be archived on the Arvinas website following the presentation.

About ARV-471
ARV-471 is an investigational orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer.

In preclinical studies, ARV-471 demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed superior anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of ARV-471; Arvinas and Pfizer will equally share worldwide development costs, commercialization expenses, and profits.