On November 30, 2021 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the U.S. Food and Drug Administration (FDA) has notified the Company that it plans to host a meeting of the Oncologic Drugs Advisory Committee (ODAC) in connection with its review of the pending Biologics License Application (BLA)/supplemental New Drug Application (sNDA) for the combination of ublituximab and UKONIQ (umbralisib) (combination referred to as U2) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, TG Therapeutics, NOV 30, 2021, View Source [SID1234596254]).

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Michael S. Weiss, Chairman and Chief Executive Officer of TG Therapeutics stated, "We appreciate the FDA’s efforts in reviewing the U2 BLA/sNDA and its interest in obtaining the perspective of the ODAC regarding the benefit-risk of UKONIQ and the U2 combination. We believe UKONIQ is a unique PI3K inhibitor, with a differentiated toxicity and tolerability profile and believe the data submitted thus far are supportive of approval of U2 in CLL."

Mr. Weiss continued, "We look forward to the ODAC meeting as we believe it will provide us an opportunity to highlight the important role U2 can play in the treatment of CLL. As we have noted previously, while many patients with CLL are well-served with currently available therapies, there exists an underserved population, which for a variety of reasons, including tolerability concerns, access issues, and treatment failure, would benefit from an alternative treatment option."

ABOUT THE ODAC MEETING
In general, the ODAC reviews and evaluates data concerning the safety and effectiveness of marketed and investigational human drug products for use in the treatment of cancer and makes appropriate recommendations to the Commissioner of Food and Drugs. Although the FDA will consider the recommendation of the ODAC Committee, the final decision regarding the approval of a product is made solely by the FDA.

The FDA has notified the Company that potential questions and discussion topics for the ODAC include: the benefit-risk of the U2 combination in the treatment of CLL or SLL, and the benefit-risk of UKONIQ in relapsed/refractory marginal zone lymphoma (MZL) or follicular lymphoma (FL). In addition, as part of the benefit-risk analysis, the overall safety profile of the U2 regimen, including adverse events (serious and Grade 3-4), discontinuations due to adverse events, and dose modifications, is expected to be reviewed. The FDA’s concern giving rise to the ODAC meeting appears to stem from an early analysis of overall survival from the UNITY-CLL trial.

Overall survival was designated as a secondary efficacy outcome in the UNITY-CLL protocol but was not part of the primary analysis in accordance with the study’s statistical analysis plan agreed upon via a Special Protocol Assessment (SPA), and therefore, was not analyzed or included in the BLA/sNDA. Additionally, the study was not powered for overall survival. As part of the ongoing review of the BLA/sNDA, the FDA requested an early analysis of overall survival from the UNITY-CLL trial. As of September 2021, the cut-off date for the overall survival analysis requested by the FDA during their review, there was an imbalance in favor of the control arm (HR: 1.23) though this result was not statistically significant. However, when excluding deaths related to COVID-19, the two arms were approximately balanced (HR: 1.04) with again no statistically significant difference between the treatment groups with regard to overall survival. The overall survival results are preliminary and the Company will continue to evaluate this endpoint over time as more events are available and will continue to analyze how COVID-19 may be impacting the analysis.

The date of the ODAC meeting has not yet been determined, although the FDA has stated that it is targeting holding the ODAC in March or April 2022. Given this timing, we believe it is unlikely that the FDA will make a decision on the BLA/sNDA by the PDUFA goal date of March 25, 2022.

ABOUT UNITY-CLL PHASE 3 TRIAL AND THE BLA/sNDA SUBMISSION
UNITY-CLL is a global, Phase 3, randomized, controlled clinical trial comparing the combination of ublituximab plus UKONIQ (umbralisib), or U2, to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL). The trial randomized patients into four treatment arms: ublituximab single agent, UKONIQ single agent, ublituximab plus UKONIQ, and an active control arm of obinutuzumab plus chlorambucil. A prespecified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm and allowed for the termination of the single agent arms. Accordingly, the UNITY-CLL Phase 3 trial continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of U2 and the control arm of obinutuzumab plus chlorambucil. Approximately 420 subjects enrolled to the two combination arms and approximately 60% of patients were treatment-naïve and 40% were relapsed or refractory. The primary endpoint for this study was superior progression-free survival (PFS) for the U2 combination compared to the control arm. The trial met its primary endpoint, with U2 significantly prolonging independent review committee (IRC) assessed PFS vs. control (median 31.9 months vs 17.9 months; hazard ratio 0.546 (p<0.0001)) at a median follow-up of 36.7 months, and results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. The UNITY-CLL Phase 3 trial is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).

The BLA/sNDA submissions of U2 to treat CLL were based on the results of the UNITY-CLL trial. The FDA previously granted Fast Track designation to the U2 combination for the treatment of adult patients with CLL and orphan drug designation for ublituximab in combination with UKONIQ for the treatment of CLL. On May 25, 2021, FDA accepted the BLA for U2 as a treatment for patients with CLL and SLL and set a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022.

ABOUT CHRONIC LYMPHOCYTIC LEUKEMIA
Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. It is estimated there will be more than 20,000 new cases of CLL diagnosed in the United States in 2020 and approximately 45,000 new cases globally in 2020.1,2 Although signs and symptoms of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of malignant cells.

CONFERENCE CALL INFORMATION
The Company will host a conference call today, November 30, 2021, at 8:30 AM ET, to discuss the regulatory updates.

To participate in the conference call, please call 1-877-407-8029 (U.S.), 1-201-689-8029 (outside the U.S.), Conference Title: TG Therapeutics Update Call. A live audio webcast will be available on the Events page, located within the Investors & Media section, of the Company’s website at View Source An audio recording of the conference call will also be available for a period of 30 days after the call.

On November 30, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported that management will participate in the JMP Securities Hematology and Oncology Summit, a virtual presentation is scheduled for Tuesday, December 7, 2021 at 2:40 p.m. ET / 11:40 a.m. PT (Press release, Spectrum Pharmaceuticals, NOV 30, 2021, View Source [SID1234596274]).

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A live webcast of the presentation will be available from the Investor Relations section of the company’s website at View Source with a replay available shortly after the event.

On November 30, 2021 Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs (the "Company" or "Regulus"), reported the closing of its previously announced private placement of equity (Press release, Regulus, NOV 30, 2021, View Source [SID1234596294]). The Company received gross proceeds of approximately $34.6 million from the sale of 58,923,352 shares of the Company’s common stock ("Common Stock") at a purchase price of $0.36 per share. In addition, the Company sold 3,725,720 shares of non-voting Class A-4 convertible preferred stock, in lieu of shares of Common Stock, at a price of $3.60 per share. Each share of non-voting Class A-4 convertible preferred stock is convertible into 10 shares of Common Stock, subject to certain beneficial ownership conversion limitations. The Company expects to use the net proceeds from the transaction for non-clinical and clinical development activities for its product candidates and general corporate purposes. SVB Leerink acted as the lead placement agent for the financing. H.C. Wainwright and Co. acted as co-placement agent for the financing.

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The offer and sale of the foregoing securities were made in a transaction not involving a public offering and have not been registered under the Securities Act of 1933, as amended (the "Securities Act"), or applicable state securities laws. Accordingly, the securities may not be reoffered or resold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws.

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

Additional details regarding the private placement are included in the current reports on Form 8-K filed with the Securities and Exchange Commission on November 24, 2021 and November 30, 2021.

On November 30, 2021 Molecular Templates, Inc.(Nasdaq: MTEM, "Molecular Templates," or "MTEM" or "the Company"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs), reported a corporate update and outlined expected 2022 milestones (Press release, Molecular Templates, NOV 30, 2021, View Source [SID1234596311]).

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"2021 was a year of growth for MTEM as we advanced our multiple pipeline programs," said Eric Poma, Ph.D., Chief Executive and Chief Scientific Officer of Molecular Templates. "As we end the year and move into 2022, we look forward to generating further clinical data that builds on the unique biology we are seeing from three ongoing studies with MT-6402, MT-5111, and MT-0169. We expect to file an IND in 2H22 for our CTLA-4 program and will continue to advance our earlier stage pipeline with ETBs in preclinical development targeting TIGIT, TROP-2, and SLAMF7."

2021 Accomplishments, Status Updates, and Expected 2022 Milestones

MT-6402 (PD-L1 ETB with Antigen Seeding)

MT-6402 is the first of the Company’s 3rd-generation ETBs to enter the clinic. It targets PD-L1 and incorporates the Company’s antigen seeding technology. MT-6402 was designed to directly destroy PD-L1+ tumor cells and alter the immunosuppressive tumor microenvironment through direct cell-kill of PD-L1+ immune cells. In addition, antigen seeding allows MT-6402 to induce the presentation of an MHC class I CMV antigen on tumor cells for pre-existing CD8 T-cell recognition and destruction in HLA-A2+ CMV+ patients. A Phase I study in relapsed/refractory patients with PD-L1-expressing tumors and/or immune cells in the tumor microenvironment was initiated in 2H21 at a starting dose of 16 mcg/kg. Highlights from the on-going Phase I study include:

4 patients have been treated (2 NSCLC, 1 melanoma, 1 ovarian) with no dose limiting toxicities (DLTs) to date
1 patient with stable disease (SD) at 5+ months with reduction in non-measurable bone metastasis
3 patients with progressive disease
Target-mediated, HLA type-independent pharmacodynamic effects after MT-6402 treatment observed in majority of patients including peripheral CD14+ monocyte depletion
One patient had monocyte depletion of >95% that was achieved in cycle 2 and is maintained and on-going at 5+ months of treatment, demonstrating potential for sustained effect with repeat dosing
One patient had monocyte depletion of 90% that was achieved in cycle 2 and sustained through two cycles of therapy before the patient discontinued the study for disease progression at the end of cycle 2
One patient had monocyte depletion of ~21% but discontinued at the end of cycle 1 for disease progression
One patient had no evidence of monocyte depletion but discontinued after 10 days on therapy for disease progression and did not complete cycle 1
Similar depletion was not observed in non-PD-L1-expressing cells (i.e., NK cells, B-cells, etc) nor was monocyte depletion noted in patients treated with other ETBs (MT-3724, MT-0169, or MT-5111)
Significant increases in key cytokines including IL- 2 and activated CD8+ T-cell markers including CD69 noted in patients
Comparable immune subset and/or cytokine changes not seen with approved PD-L1 agents
One HLA-A2 CMV+ patient (i.e., antigen-seeding eligible patient) has been treated to date
Patient is a NSCLC chemotherapy-ineligible patient whose disease had progressed following treatment with a combination of checkpoint inhibitors (ipilimumab and nivolumab); patient has non-measurable bone disease
On-going monocyte depletion of >95% observed at 5+ months of dosing
Initial increase of ~ 50% in CMV antigen-specific T-cells after dosing with MT-6402 with subsequent near-complete extravasation of CMV antigen-specific T-cells from the periphery despite a general increase in total peripheral CD8+ effector T-cells (effect not seen in non-HLA-A2 CMV-negative patients)
Multiple sites of bone disease had resolved on bone scan with only one remaining site which showed decreased uptake
Dose escalation continues as planned
In November, MT-6402 was granted Fast Track Designation for the treatment of patients with advanced NSCLC expressing PD-L1
"We are excited to see pharmacodynamic effects with MT-6402 this early in dose escalation in the Phase I study. No approved checkpoint agent has shown an ability to alter immune subset composition or induce cytokine changes in a PD-L1-targeted fashion," said Roger Waltzman, MD, Chief Medical Officer of Molecular Templates. "We believe that the actual clearance of PD-L1+ immune cells and not merely the steric inhibition of PD-L1 on immune cells may work to more potently alleviate tumor-mediated immunosuppression by removing immunosuppressive myeloid cells acting as a barrier to immunotherapy. Additionally, we are seeing early evidence supporting our unique antigen seeding approach to alter tumor immunophenotype. We are excited to see this unique biology potentially driving patient benefit and believe these data support both monotherapy treatment in relapsed/refractory patients as well as future combination studies in earlier lines of therapy with PD-1 antibodies or other therapies."

MT-5111 (HER2 ETB)

MT-5111 is the Company’s 2nd-generation ETB targeting HER2. It is designed to avoid competition with and to overcome the primary mechanisms of tumor resistance to current therapies that target HER2. MT-5111 destroys HER2-positive tumor cells through a novel mechanism of action (enzymatic ribosomal destruction), targeting HER2 via a distinct epitope from trastuzumab and pertuzumab, and improving tumor penetration with a smaller size compared to HER2 antibodies (55 kDa vs 146 kDa). Dose escalation is on-going in the Phase I study with dose levels now at drug concentrations that are predicted to be active in metastatic breast cancer. Dose escalation will continue in solid tumor HER2-positive patients, and an expansion cohort in patients with metastatic breast cancer was initiated in 4Q21. Highlights from the on-going Phase I include:

27 patients have been treated to date with MT-5111 across 7 dose escalation cohorts ranging from 0.5 mcg/kg to 10 mcg/kg without any DLT’s
MT-5111 has been well-tolerated with no significant immuno- or cardiotoxicity observed
The expansion cohort for patients with metastatic breast cancer is open for enrollment
Dosing in the cohort is at 10 mcg/kg with the potential for dose-escalation
Dose levels of 10 mcg/kg or higher are expected to be required to achieve drug concentration levels that could drive efficacy in breast cancer
"We believe we are now at dose levels in the Phase I study that should be in the therapeutic range for MT-5111, and, with the opening of the breast cancer cohort, we are assessing the activity in the patient population we believe is most likely to respond," said Dr. Roger Waltzman. "We believe the tolerability to date supports further dose escalation."

MT-0169

MT-0169 is the Company’s 2nd-generation ETB targeting the CD38 receptor, found on the surface of multiple myeloma and non-Hodgkin lymphoma (NHL) cells. MT-0169 was designed to destroy CD38+ tumor cells through induced internalization of CD38 and cell destruction through a novel mechanism of action (enzymatic ribosomal destruction). MT-0169 is the most potent ETB developed to date and the study initiated with the highest starting dose for any ETB. Relevant pharmacodynamic data from patients treated in the first dose cohort show NK cell depletion consistent with maximal levels achieved with CD38 antibody therapy. MTEM assumed full rights to MT-0169 in August 2021 and is opening new sites for the Phase I study. As part of a protocol amendment, CD38+ NHL patients will be dosed in addition to myeloma patients. Highlights from the on-going phase I include:

5 multiple myeloma patients have been treated to date
No serious adverse events (SAEs) have been observed. Two cardiac adverse events were observed that meet criteria for DLT. Both evaluations were triggered by asymptomatic elevations in high-sensitivity troponin values. As previously disclosed, the first DLT was an asymptomatic, rapidly reversible episode of myocarditis that did not require treatment. The second DLT occurred recently and is an asymptomatic, nonischemic cardiomyopathy. We believe both DLTs may be due to activity against low CD38-expressing cells in the cardiac endothelium. We have not seen evidence of any clinically relevant cardiac adverse event such as myocarditis or cardiomyopathy in any other ETB program (MT-3724, MT-5111, MT-6402) at any dose.
Clearance of CD38+ NK cells noted in all patients with maximal levels of depletion occurring within 24 hours and consistent with maximal depletion seen with CD38 antibodies
Rapidity and depth of CD38+ NK cell-kill is substantially higher in humans than what was seen in non-human primate studies
One patient has shown symptomatic benefit with a reduction in myeloma-induced bone pain
A revised protocol will be submitted to explore dose reduction with MT-0169 to reduce the risk of toxicity caused by the destruction of low CD38-expressing cells and enable patients to continue MT-0169 therapy for a duration that may drive tumor benefit
"MT-0169 has shown potent and rapid pharmacodynamic activity against CD38+ NK cells with early signs of clinical benefit," said Dr. Roger Waltzman. "The pharmacodynamic activity of NK cell-kill at 50 mcg/kg exceeded what was expected based on the non-human primate data and is consistent with maximal achievable levels. In general, we have observed that MT-3724, MT-6402, and MT-0169 have all shown substantially more pharmacodynamic activity in patients compared to what was seen in NHPs at equivalent or higher doses. We will be exploring lower doses in the proposed revised protocol and expect to report additional data in 2022."

Preclinical Pipeline

MTEM continues to advance its pipeline with its CTLA-4 and TIGIT ETBs representing novel approaches to key immune-oncology targets and its TROP2 and SLAMF7 ETBs applying unique biology to validated targets. MTEM also continues to expand the capabilities of the ETB technology.

IND filing of CTLA-4 program expected in 2H22
Lead selection for TIGIT, TROP-2 with antigen seeding, and SLAMF-7 is ongoing
Additional target selection and scaffold improvements expected in 2022
"We continue to move forward with programs against new targets using the unique biology of ETBs, and we continue to advance the biology of the ETB scaffold," continued Dr. Poma. "We believe MT-6402 and our CTLA-4 and TIGIT programs represent a new way of altering the immune environment in patients with cancer through targeting and destroying myeloid-derived suppressor cells and regulatory T cells (Tregs). Additionally, we believe that new mechanisms of action against validated targets like TROP-2 and SLAMF-7 are needed in these diseases with high unmet medical need."

Key Milestones for 2022

"We believe that 2022 will be another exciting year for the Company with potentially transformational data across our three ongoing clinical programs, an IND filing expected for our CTLA-4 ETB and continued preclinical development," concluded Dr. Poma. "We have substantial cash reserves into 4Q23 to drive development of a broad range of compounds at MTEM."

Continued data read-outs on all three clinical programs
IND filing for ETB targeting CTLA-4
Advancement of ETBs targeting TROP2, TIGIT, SLAMF-7
The Company has cash runway into 4Q23
Participation in Evercore ISI 4th Annual HealthCONx

The Company will participate in a fireside chat and hold 1-on-1 investor meetings at the Evercore ISI 4th Annual HealthCONx, to take place November 30 – December 2, 2021.

On November 30, 2021 IMV Inc. (NASDAQ: IMV; TSX: IMV), a clinical-stage company developing a portfolio of immune-educating therapies based on its novel DPX platform to treat solid and blood cancers while preserving patients’ quality of life, reported that the first patient with hormone receptor positive/HER2-negative (HR+/HER2-) breast cancer has been dosed with its lead compound, maveropepimut-S (MVP-S, formerly known as DPX-Survivac) (Press release, IMV, NOV 30, 2021, View Source [SID1234596257]). In this trial, MVP-S is being administered in combination with an aromatase inhibitor, with or without radiotherapy or cyclophosphamide prior to surgery.

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"We are excited to see maveropepimut-S evaluated in this new clinical study and in an indication where survivin is known to play a critical role in resistance to treatment," said Jeremy Graff Ph.D., Chief Scientific Officer at IMV. "This is a new opportunity not only to explore the clinical benefit of MVP-S in breast cancer patients but also to deepen and enrich our understanding of the MVP-S therapeutic mechanism of action".

Kristina H. Young, M.D., Ph.D., Principal investigator of the study, and Assistant Member, Tumor Microenvironment Lab in the Earle A. Chiles Research Institute, a division of the Providence Cancer Institute commented, "Upregulation of survivin expression in HR+/HER- breast cancer is known to be associated with resistance to aromatase inhibitors. The combination of MVP-S may help overcome this mechanism of resistance and provide benefit to these women while limiting adverse events." She added that "Women with HR+/HER2- breast cancer are in need of treatments that are effective and allow a good quality of life."

About the Study

This investigator-initiated clinical study is a Phase 1b, non-randomized, open-label study to evaluate the combination of maveropepimut-S (MVP-S, formerly named DPX-Survivac) and an aromatase inhibitor with/without radiotherapy or cyclophosphamide (CPA) prior to surgery. Across the three arms of this study, MVP-S will be evaluated in 18 subjects with resectable, non-metastatic HR+/HER2- breast cancer.

The primary objective is to evaluate the safety in this neoadjuvant trial of the combination of maveropepimut-S with an aromatase inhibitor and with/without radiation, or CPA in each arm. The generation of survivin-specific T cells in PBMCs and in tumor tissue both pre and on treatment will be evaluated as secondary objectives. Extensive translational studies will be conducted to explore further the MVP-S mechanism of action in the tumor, the tumor environment and in peripheral circulation. The study is being conducted at the Providence Cancer Institute in Portland, Oregon, and is expected to be completed in 2026 with primary results in 2023. For more information, refer to ClinicalTrials.gov Identifier: NCT04895761.