On December 13, 2021 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported updated interim clinical data from the ongoing Phase 1/2 CIRLL (Cirmtuzumab and Ibrutinib targeting ROR1 for Leukemia and Lymphoma) clinical trial, that will be presented in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting (Press release, Oncternal Therapeutics, DEC 13, 2021, View Source [SID1234596937]). In the CIRLL study, zilovertamab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with MCL and CLL. The clinical trial is being conducted in collaboration with UC San Diego and is partially funded by the California Institute for Regenerative Medicine (CIRM).

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The updated interim data will be presented as a poster presentation at the Mantle Cell, Follicular and Oher Indolent B Cell Lymphomas Clinical and Epidemiological session on December 13, 2021 as part of the ASH (Free ASH Whitepaper) 2021 Annual Meeting:

Poster Title: Phase 1/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)
Publication Number: 3534
Session Name: 623, Mantle Cell, Follicular and Oher Indolent B Cell Lymphomas Clinical and Epidemiological
Session Date and Time: December 13, 2021 from 6:00-8:00 pm (Eastern Time)
Location: Georgia World Congress Center, Hall B5
"Our confidence in the differentiation of zilovertamab enabled therapy continues to build as we strengthen our MCL and CLL data set. The median PFS of 35.9 months for heavily pre-treated MCL patients is approximately three times longer than the previously reported median PFS of 12.8 months for ibrutinib monotherapy. The landmark PFS of 85% at 24 months and 65% at 36 months for patients with CLL, regardless of the number of prior lines of therapy, are also encouraging. The combination continues to be generally well tolerated, and we are encouraged by the low grade 3/4 neutropenia rate of 10% for the combination therapy, compared to 29% for ibrutinib alone from its registration study in MCL," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "We expect to provide an update regarding our dialogue with the U.S. FDA regarding Phase 3 study design later this month."

The results that will be presented in poster form at ASH (Free ASH Whitepaper) 2021 include 31 patients with relapsed/refractory MCL enrolled in the dose-finding and dose-expansion cohorts of the CIRLL clinical trial (Part 1 + Part 2), of whom 26 were evaluable for efficacy as of the October 1, 2021 data cut-off date.

Patients had high-risk factors and were heavily pre-treated at study entry, with 52% having high Ki-67 proliferative index (≥30%) and 45% with intermediate/high sMIPI prognostic score.
The ORR of 81% (21 of 26 evaluable patients), including recently enrolled patients with relatively short follow-up time, is comparable to the 83% ORR (15 of 18 evaluable patients) previously presented at the ASCO (Free ASCO Whitepaper) 2021 Annual Meeting.
Twelve of 26 (46%) evaluable patients achieved a partial response (PR) and three patients (12%) had stable disease (SD), for a total clinical benefit rate (CR, PR and SD) of 92%.
The complete response rate was 35% (9 of 26 evaluable patients). CRs have remained durable, for up to 32 months as of the data cutoff date.
The ORR and median duration of response were favorable in patients with high-risk features associated with difficult to treat disease:
Ki-67 ≥30%: ORR of 85%; median duration of response of 14 months (95% CI: 13.7, NE), and
>1 prior systemic therapy: ORR of 82%; median duration of response not reached for patients receiving two prior lines of systemic therapy and 34 months (95% CI: 13.8, 34.1) for patients with ≥ 3 prior lines of systemic therapy
Five patients had received prior treatment with ibrutinib, achieving two CRs and two PRs. One patient had SD.
Median PFS was 35.9 months after a median follow-up of 14.4 months (95% CI: 11.4, 19.3), regardless of number of prior systemic therapies. Further, median PFS had not been reached for patients achieving a CR.
Historical data published for single agent ibrutinib for 370 patients with relapsed/refractory MCL from three clinical trials showed an ORR of 66%, CR rate of 20% and median PFS of 12.8 months (Rule et al. 2017, British Journal of Haematology).
As of the October 1, 2021 data cut-off date, 34 patients with CLL have been enrolled in the dose-finding and dose-confirming cohorts of this clinical trial (Part 1 & Part 2), all of which were evaluable for efficacy. Patients had high-risk factors, and most were heavily pre-treated at study entry, with 71% having RAI staging ≥2 and a median of two systemic prior therapies (range 1-15).

The ORR was 91% (31 of 34 evaluable patients), consistent with prior published results.
The CR rate was 6% (2 of 34 evaluable patients), twenty-nine patients (85%) achieved a PR and three patients (9%) had SD, for a total clinical benefit rate (CR, PR and SD) of 100%.
Median PFS in patients with ≤ 2 prior therapies had not been reached, and patients with > 2 prior therapies had a median PFS of ~36.1 months after a median follow up of 29.0 months (95% CI: 27.6, 31.6), in this high risk and mostly heavily pre-treated CLL population.
Based on the Kaplan-Meier curve, landmark PFS of ~ 85% and ~ 65% at 24 and 36 months, respectively, for CLL patients receiving > 2 prior lines of therapy compared favorably to historical ibrutinib monotherapy of ~ 65% and ~ 50%, respectively (Byrd 2019). Landmark PFS was 100% at 36 months for CLL patients with ≤ 2 prior lines of therapy, which compares favorably to historical ibrutinib monotherapy of ~ 75% (Byrd 2019).
Thirty-one patients with CLL have also been enrolled in the randomized efficacy cohort of this clinical trial (Part 3), of which 22 were evaluable for efficacy. Data on this cohort is maturing, and median PFS had not been reached as of the October 1, 2021 cut-off date.

The combination of zilovertamab plus ibrutinib has been well tolerated, with treatment emergent adverse events consistent with those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to zilovertamab alone.

About the CIRLL Clinical Trial
The CIRLL clinical trial (CIRM-0001) is a Phase 1/2 trial evaluating zilovertamab in combination with ibrutinib in separate groups of patients with CLL or MCL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and randomized Phase 2 cohort in CLL has been completed. Enrollment of the dose-expansion cohort in MCL is ongoing. Additional information about the CIRM-0001 clinical trial and other clinical trials of zilovertamab may be accessed at ClinicalTrials.gov.

About Zilovertamab (formerly Cirmtuzumab)
Zilovertamab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of MCL or CLL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine: (i) a Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, and (ii) a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically targeting ROR1 expressing tumors. This led to the development of zilovertamab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

On December 13, 2021 Novo Nordisk reported that initiated a share repurchase programme in accordance with Article 5 of Regulation No 596/2014 of the European Parliament and Council of 16 April 2014 (MAR) and the Commission Delegated Regulation (EU) 2016/1052 of 8 March 2016 (the "Safe Harbour Rules") (Press release, Novo Nordisk, DEC 13, 2021, View Source [SID1234596934]). This programme is part of the overall share repurchase programme of up to DKK 20 billion to be executed during a 12- month period beginning 3 February 2021.

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Under the programme initiated 5 November 2021, Novo Nordisk will repurchase B shares for an amount up to DKK 3.7 billion in the period from 11 November 2021 to 1 February 2022.

Since the announcement 6 December 2021, the following transactions have been made:

The details for each transaction made under the share repurchase programme are published on novonordisk.com.

With the transactions stated above, Novo Nordisk owns a total of 30,415,276 B shares of DKK 0.20 as treasury shares, corresponding to 1.3% of the share capital. The total amount of A and B shares in the company is 2,310,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 20 billion during a 12- month period beginning 3 February 2021. As of 10 December 2021, Novo Nordisk has since 3 February 2021 repurchased a total of 31,661,725 B shares at an average share price of DKK 565.96 per B share equal to a transaction value of DKK 17,919,256,493.

On December 13, 2021 NexImmune, Inc. (Nasdaq: NEXI), a clinical-stage biotechnology company developing a novel approach to immunotherapy designed to orchestrate a targeted immune response by directing the function of antigen-specific T cells, reported preliminary Phase 1/2 results from an ongoing study of NEXI-002, a patient-derived multi-antigen-specific CD8+ T cell treatment for patients with relapsed/refractory multiple myeloma who have failed ³3 prior lines of therapy (Press release, NexImmune, DEC 13, 2021, View Source [SID1234596933]). The data on low doses of NEXI-002, presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, showed a promising safety and tolerability profile and evidence of immunologic and clinical activity.

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Poster Presentation:

Title: Preliminary Analysis of a Phase 1/2 Study of NEXI-002 Autologous Multi-Antigen-Specific CD8+ T cells for the Treatment of Relapsed or Refractory Multiple Myeloma (RRMM)

Abstract Number: 2824

Category: Poster Presentation

Authors: Maung Myo Htut, MD, Juan C. Varela, MD, PhD, Vineetha Edavana, PhD, Emily Lu, PhD, Sojung Kim, PhD, Lauren Suarez, PhD, Mathias Oelke, PhD, Daniel Bednarik, PhD, Robert D. Knight, MD, and, Andrew Kin, MD

Date & Time: Sunday, December 12, 2021; Poster Hall Hours 6-8 pm EDT

In this heavily pre-treated patient group (n=6 with an average of 7.6 lines of prior therapy), the clinical data suggests that NEXI-002 is well-tolerated without dose-limiting toxicities (no grade ³3 CRS or any grade of ICANS). Biomarker data show that the NEXI-002 product candidate contains CD8+ antigen-specific T cells with key memory phenotypes which, after administration, are detected in peripheral blood and bone marrow of treated individuals and proliferate and persist over time. Furthermore, TCR sequencing shows that the NEXI-002 product candidate contains CD8+ T cell clones that were undetectable in the peripheral blood of the patients at baseline and which expand in both blood and bone marrow over time. After receiving lymphodepleting therapy followed by NEXI-002 infusion, patients

experienced rapid lymphocyte recovery with reconstitution of both CD4+ and CD8+ T cell subtypes. Despite the infusion of very low numbers of NEXI-002 T cells (4-10x10e6 total T cells), these heavily pre-treated patients achieved stable disease for 2 to 3.5 months of duration. Importantly, despite receiving an average of 7.6 previous lines of therapy, the quality, functionality and in vivo persistence of all patient-derived NEXI-002 T cell products were comparable to those expanded from healthy donors. Strategies to yield higher product doses are underway, including evaluating patients with lower disease burden plasma cell dyscrasias.

"We are very encouraged by the initial Phase 1/2 results observed to-date with NEXI-002," said Scott Carmer, CEO of NexImmune. "We have now shown, in two separate clinical trials using apheresis material from either healthy donors or heavily pre-treated patients, that we can manufacture CD8+ T cell products with high target antigen specificity and with T cell phenotypes that promote in vivo proliferation, persistence and anti-tumor activity. Even at the very low doses of NEXI-002 administered in this ongoing trial, we’ve seen robust biomarker and immunological responses with evidence of clinical activity. These preliminary data provide further evidence of the NEXI-002 mechanism of action, and we are eager to continue assessing NEXI-002’s potential in this patient population and in additional patients with lower-disease-burden plasma cell dyscrasias."

On December 13, 2021 Midatech Pharma PLC (AIM: MTPH; Nasdaq: MTP), a drug delivery technology company focused on improving the bio-delivery and biodistribution of medicines, reported that its Investigational New Drug (IND) application for a Phase 1 study of MTX110, a panobinostat complex to be administered by convection enhanced delivery in patients with recurrent glioblastoma multiforme (rGBM), has been cleared by the US FDA (Press release, Midatech Pharma, DEC 13, 2021, View Source [SID1234596931]). The 30-day review period has expired and the IND has been judged safe to proceed. Accordingly, Midatech has initiated preparations for a study start in the first half of 2022.

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Employing the Company’s MidaSolve technology, MTX110 solubilises panobinostat, a histone deacetylase (HDAC) inhibitor currently used in the treatment of multiple myeloma. In a liquid formulation as MTX110, panobinostat can be delivered directly to a patient’s tumour under constant pressure via a catheter system (Convection Enhanced Delivery, or "CED") thereby bypassing the blood-brain barrier and allowing for high drug concentrations and broader drug distribution in and around the tumour while simultaneously minimising systemic toxicity and other side effects. Panobinostat has demonstrated high potency against patient-derived tumour cells in in vitro and in vivo models.

GBM is the most common and aggressive form of brain cancer in adults, usually occurring in the white matter of the cerebrum. Treatments include radiation, surgical resection and chemotherapy although, in almost all cases, tumours recur. There are approximately 2-3/100,000(1) diagnoses of GBM per annum. Survival with standard of care treatment ranges from approximately 13 months in unmethylated MGMT patients to approximately 30 months in highly methylated MGMT patients(2). Glioblastoma is an intractable brain cancer.

The primary objective of the Phase I study will be to assess the safety and tolerability of MTX110 in patients with rGBM. The study is expected to include two clinical centres in the US and to begin recruiting H1 2022.

Dmitry Zamoryakhin, Chief Scientific Officer of Midatech, said:

"Our solubilising technology in combination with a CED system offers the potential to deliver significantly higher doses of panobinostat, a potent HDAC inhibitor, directly to the tumour. Importantly, this targeting approach is designed to limit systemic circulation of drug and therefore toxicity. This signal finding Phase I study could point the way to a new treatment paradigm for this intractable brain cancer."

This announcement contains inside information for the purposes of Article 7 of Regulation (EU) 596/2014 (MAR).

1.American Association of Neurosurgeons

2.Radke et al (2019). Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients. Acta Neuropathologica Communications 7:89 Online: View Source org/10.1186/s40478-019-0745-z

On December 13, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported its inaugural issuance of a $1 billion sustainability bond, which was part of an $8 billion underwritten public offering of notes that closed on Dec. 10, 2021 (Press release, Merck & Co, DEC 13, 2021, View Source [SID1234596930]).

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Merck’s environmental, social and governance (ESG) efforts are grounded in the core values that have always guided the company’s mission to invent for life, with a responsibility to patients and animals in need of medicines and vaccines, and with respect, inclusion and accountability to its employees. The company’s 130-year legacy has been built on the understanding that operating responsibly, enabling access to health for the patients and communities it serves, investing in and cultivating the company’s employees, and reducing its impact on the environment underpins the success and long-term sustainability of its business.

"Today’s announcement is an important step to further integrate ESG into the core of our business, accelerate the achievement of our ESG goals, and measure and continue to be transparent about our progress," said Caroline Litchfield, chief financial officer, executive vice president, Merck.

Merck intends to use the net proceeds from this bond offering to support projects and partnerships in the company’s priority ESG areas and contribute to the advancement of the United Nations Sustainability Development Goals. These company projects and partnerships include:

Access to essential services – health care, such as medicines and vaccines, maternal health programs, health care system strengthening, product donations, medical outreach, disaster and emergency relief, and patient assistance programs
Infectious disease research and development that includes antimicrobial resistance, neglected and emerging diseases, and sexual and reproductive health
Socioeconomic advancement and empowerment, particularly for minority and women-owned business enterprise (MWBE) suppliers, employee diversity and inclusion initiatives, and health literacy programs which serve people of all ages, races, incomes and education levels
Renewable energy generation projects such as new onsite or offsite solar or wind generating capacity, as well as electricity generated from renewable sources
Energy efficiency expenditures related to the company’s operations, such as energy-efficient heating, ventilation, air conditioning, refrigeration, lighting, roofing or electrical equipment, energy monitoring, control solutions and energy assessments, including smart meters and control automation devices
Green buildings, including the design, development, construction and certification costs for new/existing facilities to meet LEED Gold or Platinum standards (or equivalent), as well as those which achieve at least a 30% improvement in energy use or GHG emissions
Sustainable water and wastewater management to improve water quality or water efficiency, such as wastewater treatment, recycling and harvesting, overall reductions and reuse
Pollution prevention and control projects to reduce and manage emissions to air or water, as well as recycling projects and efforts to divert non-hazardous and/or hazardous waste away from landfills
The bond transaction is in line with Merck’s newly introduced Sustainability Financing Framework, which facilitates the company’s use of sustainable capital markets to finance or refinance eligible projects that align with its ESG commitments. This framework addresses the core components and key recommendations of the Social Bond Principles (2021), Green Bond Principles (2021), and Sustainability Bond Guidelines (2021), all of which are administered by the International Capital Markets Association (ICMA). V.E., a Moody’s affiliate, provided a second party opinion (SPO) on Merck’s Sustainability Financing Framework.

Merck has committed to annual reporting on the allocation of bond net proceeds to actual spend by social and/or environmental category, along with the remaining balance of unallocated proceeds. Where feasible, Merck will report estimated social and/or environmental quantitative impact metrics and provide qualitative case studies on eligible projects. For eligible social projects, Merck will seek to report impact metrics by target population to show how expenditures are enhancing access to the stated target population.

For more information on Merck’s ESG performance, policies and initiatives, please view the company’s 2020/2021 ESG Progress Report.