Scientists discover key enzyme in breast cancer proliferation, treatment resistance

Medical Xpress | March 12, 2019

Basal-like breast cancer is the most aggressive and difficult-to-treat subtype of breast cancer, and it largely overlaps with the triple-negative classification of the disease. Patients are in dire need of improved therapies that attack the underlying cellular features of these types of breast cancer. Now scientists at the UNC School of Medicine and the UNC Lineberger Comprehensive Cancer Center have uncovered a possible reason why these cancers are so aggressive. In lab experiments, the researchers found that an enzyme called USP21 promoted proliferation of basal-like breast cancer and is upregulated in a significant percentage of patient tumors. The discovery, published in Cell Reports, offers researchers a much-needed target for new therapies to battle aggressive subtypes of breast cancer. "We think USP21 could not only drive basal-like breast cancer in patients but could represent a new, future target for therapeutic intervention," said senior author Michael Emanuele, Ph.D., associate professor of pharmacology and UNC Lineberger member. "We also think targeting USP21 could sensitize cancer cells to therapies already in clinical use to treat patients with this disease."

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INDUSTRIAL IMPACT

Merakris and Dept. of Veterans Affairs Sign CRADA Agreement – Clinical Trial for Dermacyte® Wound Care Product To Begin Soon

Merakris Therapeutics | February 09, 2022

Merakris Therapeutics announced that it has entered into a Cooperative Research and Development Agreement (CRADA) with the United States Department of Veterans Affairs (VA) to test its investigational drug product, Dermacyte® Amniotic Wound Care Liquid. The VA plans to enroll patients, ages 18-75, in a two-part Phase II clinical study to evaluate Merakris’ first in class subcutaneous – or below the skin – injectable wound healing therapy. The study is designed to address the frequency of administration, safety and efficacy of Dermacyte Liquid in treating non-healing venous stasis ulcers. These types of ulcers are caused by problems with blood flow in the veins of the legs. The therapy consists of an acellular, sterile-filtered human amniotic fluid allograft. It works by stimulating skin cell migration and activating gene expression pathways that promote wound healing. “Wound care can be a huge issue for some of our veterans,” the VA said in a statement. “We are pleased to participate in studies like this one that are designed to contribute to the quality of life of veterans everywhere.” If approved, Dermacyte Liquid will be the first subcutaneous biologic indicated for VSUs, which account for between 60 and 80 percent of all leg ulcers. An estimated 500,000-600,000 people suffer from this condition in the United States each year. Fortune Business Insights forecasts that the global market for treatments will reach close to $5 billion annually by 2026. Merakris said prescreening will begin soon for patients with non-infected VSUs who haven’t improved after at least four weeks of conventional wound therapy. The clinical trial should be underway within the next several weeks. Participants will be randomized 1:1 to receive Dermacyte Liquid either weekly or biweekly in Part 1 of the study. That data will be used to determine dosing frequency for the double-blinded and placebo controlled second part of the study. The second stage will last 12 weeks. Reductions in participants’ VSU wound surface area will be measured against baseline in weeks 4, 8 and 12. Total wound closure also will be evaluated at the end of week 12. “This clinical trial marks a significant milestone for our biotechnology company. Dermacyte Liquid contains the natural biomolecules present in amniotic tissues and fluids, and our data suggest that these components may allow us to usher in a new era of precision wound healing.” Merakris CEO Chris Broderick Broderick said the company has filed patents covering Dermacyte Liquid and its unique mode of action and plans to conduct more clinical studies in the future. About Merakris Merakris Therapeutics – founded in 2016 and headquartered in Research Triangle Park, North Carolina – pioneers the use of commercially scalable stem cell-derived biotherapeutic technologies to promote the healing of damaged tissue. Its mission is to improve global patient care and outcomes through regenerative biotechnologies.

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MEDTECH

Pfizer to Acquire Trillium Therapeutics Inc.

Pfizer Inc | August 24, 2021

Pfizer Inc. and Trillium Therapeutics Inc. today announced that the companies have entered into a definitive agreement under which Pfizer will acquire Trillium, a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer. Under the terms of the agreement, Pfizer will acquire all outstanding shares of Trillium not already owned by Pfizer for an implied equity value of $2.26 billion, or $18.50 per share, in cash. This represents a 118% premium to the 60-day weighted average price for Trillium. Trillium’s portfolio includes biologics that are designed to enhance the ability of patients’ innate immune system to detect and destroy cancer cells. Its two lead molecules, TTI-622 and TTI-621, block the signal-regulatory protein α (SIRPα)–CD47 axis, which is emerging as a key immune checkpoint in hematological malignancies. TTI-622 and TTI-621 are novel, potentially best-in-class SIRPα-Fc fusion proteins that are currently in Phase 1b/2 development across several indications, with a focus on hematological malignancies. “Today’s announcement reinforces our commitment to pursue scientific breakthroughs with the addition of potentially best-in-class molecules to our innovative pipeline,” said Andy Schmeltz, Global President & General Manager, Pfizer Oncology. “The proposed acquisition of Trillium builds on our strong track record of leadership in Oncology, enhancing our hematology portfolio as we strive to improve outcomes for people living with blood cancers around the globe. Our deep experience in understanding the science of blood cancers, along with the diverse knowledge base we have developed across our growing hematology portfolio of eight approved and investigational therapies, provide us with a foundation to advance these important potential medicines to patients who need them.” Hematological malignancies are cancers that affect the blood, bone marrow, and lymph nodes. This classification includes various types of leukemia, multiple myeloma, and lymphoma. More than 1 million people worldwide were diagnosed with a blood cancer in 2020, representing almost 6% of all cancer diagnoses globally. In 2020, more than 700,000 people worldwide died from a form of blood cancer. “We’re delighted to announce Pfizer’s proposed acquisition of Trillium. Today’s announcement reflects Trillium’s potentially best in class SIRPα–CD47 status and contribution to immuno-oncology,” said Dr. Jan Skvarka, Chief Executive Officer of Trillium. “Trillium has the only known SIRPα–CD47 targeting molecules with clinically meaningful monotherapy responses as well as a strong basis for combination therapies, which is supported by preclinical evidence with a diverse set of therapeutic agents. With Pfizer’s global reach and deep capabilities, we believe our programs will advance more quickly to the patients we’ve always aspired to serve. We believe this is a good outcome for patients and our shareholders.” In clinical studies to-date, TTI-622 and TTI-621 have demonstrated activity as monotherapy in relapsed or refractory lymphoid malignancies, including Diffuse Large B-cell Lymphoma (DLBCL), Peripheral T-cell lymphoma (PTCL), Follicular Lymphoma (FL), and other lymphoid malignancies. As of July 26, 2021, Phase 1 data for TTI-622 in 30 response-evaluable patients have shown deep and durable responses in heavily pretreated patients, including two complete responses (CRs), one lasting over 114 weeks, with responses ongoing. TTI-622 and TTI-621 are currently the only known CD47-targeted molecules that have demonstrated meaningful single agent activity and CRs in multiple hematological malignancies. Thus far, adverse events (AEs) reported with TTI-622 and TTI-621 have been manageable. Related Grade 3 and 4 AEs with TTI-622 were rare and limited to transient cytopenias. In particular, the molecules demonstrate minimal red blood cell binding and few reported cases of anemia, an observed risk with other CD47-targeted approaches. Further data are expected to be shared at a forthcoming medical conference. “We are encouraged by the early clinical data for TTI-622 and TTI-621 monotherapy for patients with heavily pretreated lymphoid malignancies and early encouraging activity for TTI-622 in patients with multiple myeloma. Just as PD-1 and PD-L1 blockers have proven to be effective immuno-therapeutics for many solid tumors, the SIRPα-CD47 interaction defines a second key immune checkpoint for which disrupting agents are expected to become another important backbone immunotherapy for multiple types of cancer, especially hematological cancers,” said Chris Boshoff, MD, PhD, Chief Development Officer, Oncology, Pfizer Global Product Development. “Utilizing Pfizer’s leading research and global development capabilities, we plan to accelerate the clinical development of SIRPα fusion proteins as a potential new scientific breakthrough and explore combinations within our own portfolio and with innovative next-generation medicines for hematological malignancies.” In September 2020, as part of the Pfizer Breakthrough Growth Initiative (PBGI), Pfizer invested $25 million in Trillium and Jeff Settleman, Senior Vice President and Chief Scientific Officer of Pfizer’s Oncology Research & Development Group, was named to Trillium’s Scientific Advisory Board. Established in June 2020, PBGI’s goal is to provide funding for scientific research as well as access to Pfizer’s experts to ensure the continuity of clinical programs that could be of potential strategic interest for Pfizer. Pfizer has committed to providing up to $500 million in total funding to the PBGI. Additional Transaction Details The proposed acquisition of Trillium is to be completed by way of a statutory plan of arrangement under the Business Corporations Act (British Columbia) and subject to customary closing conditions, including approval of 66⅔% of the votes cast by Trillium shareholders, voting together as one class, at a special meeting of Trillium and approval of 66⅔% of the votes cast by Trillium shareholders and warrant holders, voting together as one class, at a special meeting of Trillium. Completion of the acquisition is also subject to court and regulatory approval, as well as certain other closing conditions customary for transactions of this nature. Pfizer’s financial advisors for the transaction are BofA Securities, Inc., with Ropes & Gray LLP and Norton Rose Fulbright Canada LLP acting as its legal advisors. Centerview Partners LLC served as Trillium’s financial advisor, while Goodwin Procter LLP and Baker McKenzie LLP (Canada) served as its legal advisors. About SIRPα/CD47 Accumulating data suggest that the SIRPα–CD47 axis is a key immune checkpoint in hematologic malignancies, similar to the PD-L1 / PD-1 checkpoint for solid tumors. CD47 is a protein that is overexpressed in numerous cancer cells, and in general, high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. SIRPα is an inhibitory receptor expressed on myeloid cells that binds to CD47, preventing the immune system from destroying cancer cells. Disruption of the CD47-SIRPα interaction has been proven to elicit tumor destruction through triggering of an innate immune response. About Pfizer Oncology At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma. About Pfizer: At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. About Trillium Therapeutics Trillium is an immuno-oncology company developing innovative therapies for the treatment of cancer. The company’s two clinical programs, TTI-622 and TTI-621, target CD47, a “don’t eat me” signal that cancer cells frequently use to evade the immune system.

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CELL AND GENE THERAPY

Neurophth and AAVnerGene Announces Strategic AAV Capsids Partnership for Next-Generation Ophthalmic Gene Therapy

Neurophth | January 19, 2021

Neurophth Therapeutics, Inc., a subsidiary of Wuhan Neurophth Biotechnology Ltd. gene therapy organization, and AAVnerGene Inc., a practicing AAV innovation organization, reports a strategic partnership to provide Neurophth with overall rights to commonly choose adeno-associated virus (AAV) capsids for the next generation ophthalmic gene therapy. AAVnerGene's Tissue-specific, Highly-transductive and Expressive New AAVs (ATHENA) screening stage can productively choose the best AAV vector for every cell type in a high-throughput (HTP) way. Significant difficulties in AAV-based gene therapy are the transduction productivity, conceivable resistance to the capsid and complex assembling measures. The capacity to distinguish appropriate cutting edge AAV vectors that could beat the limits of before generation AAV vectors is basic to a patient for accomplishing adequate helpful articulation of the moved gene in the most minimal portion dose regular strategy, for example, intravitreal (IVT) injection with reasonable cost. "AAVnerGene's proprietary technology may create capsid libraries derived from artificial intelligence machine learning, DNA shuffling or directed evolution allowing a significant increase in AAV genetic payload capacity, production, and transduction with the ability to penetrate through the inner limiting membrane of the retina, thus potentially enhance the overall transduction efficiency of capsid library-derived AAV vectors," said Alvin Luk, Ph.D., M.B.A., Chief Executive Officer of Neurophth. "Importantly, if proven successful, the administration of the selected AAVnerGene capsid variant(s) in gene therapy may enable repeated dosing AAVs in both adults and pediatric patients, potentially improving the clinical efficacy at a lower vector dose with better penetration of the barriers in eyes using a safer and less invasive procedure such as intravitreal injection which lower the risk of immune response to the capsid."

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