On January 7, 2020 Nuvo Pharmaceuticals Inc. (Nuvo or the Company) (TSX:NRI;OTCQX:NRIFF), a Canadian focused healthcare company with global reach and a diversified portfolio of commercial products, reported the Company will repay its Bridge Loan to Deerfield Management Company, L.P. (Deerfield) during the second week of January and will receive the full US$7.5 million annual minimum royalty payment due from the 2019 sales of Vimovo in the U.S (Press release, Nuvo Pharmaceuticals, JAN 7, 2020, View Source [SID1234552826]). The Company has received US$5.6 million to-date.

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Bridge Loan to Deerfield

The US$6.0 million Bridge Loan was one component of the financing provided by Deerfield in support of the acquisition of Aralez Pharmaceuticals Canada, the U.S. and International rights to Vimovo and other related assets as announced on December 31, 2018. The Company will repay its Bridge Loan (12.5% per annum) during the second week of January, ahead of its June 2020 maturity date. The Company’s remaining loans, US$52.5 million and US$60.0 million carry coupon interest rates of 3.5% per annum.

In June 2019, the Company announced its intention to reduce annual operating expenses by approximately $7.0 million due to identified synergies and the implementation of organizational changes. The Company began to realize these synergies during the second half of 2019.

In June 2019, Deerfield and certain of its affiliated funds, as lenders, and the Company agreed to an amendment to its financing agreement to provide, among other things, for a payment deferral mechanism in the event that Vimovo U.S. market exclusivity is lost. The amendment will allow Nuvo the option to defer a portion of the mandatory minimum quarterly prepayments by the difference between one quarter of the existing US$7.5 million annual minimum royalty due from Vimovo sales in the U.S. and the actual amount of royalties received in the applicable quarter in the event Vimovo U.S. market exclusivity is lost earlier than May 2022. The amount of any deferred prepayment would, until repaid in accordance with the amendment, be subject to an interest rate of 12.5% per annum.

Vimovo U.S. Royalty

As of December 31, 2019, no generic version of Vimovo had been launched in the U.S. during 2019 and, as of the end of business on January 6, 2020, the U.S. Food and Drug Administration (FDA) had not granted final approval for a generic version of Vimovo. As a result, the Company is entitled to the US$7.5 million annual minimum royalty due from the 2019 sales of Vimovo in the U.S., as per the agreement with its U.S. commercial partner.

The Company had previously disclosed its assumption that a generic version of Vimovo would be launched in the U.S. during the second half of 2019. The Company anticipates a generic version of Vimovo will launch in the U.S. during 2020. Upon launch of a generic version of Vimovo in the U.S., Nuvo Pharmaceuticals (Ireland) DAC’s (Nuvo Ireland) US$7.5 million annual minimum royalty from its partner ceases. The royalty rate for 2020 would be calculated as 10% of net sales of Vimovo in the U.S., subject to certain step-down provisions upon achievement of generic market share thresholds. A launch of a generic version of Vimovo in the U.S. does not impact Nuvo Ireland’s global Vimovo business in markets outside of the U.S. Nuvo Ireland will continue to receive royalty payments from its global partner, Grunenthal GmbH on global net sales of Vimovo.

Any launch of a generic version of Vimovo in the U.S. is considered "at risk" as Nuvo Ireland continues to hold U.S. Patent Nos. 8,858,996 and 9,161,920 (the ‘996 and ‘920 patents) covering Vimovo in the U.S. The ‘996 and ‘920 patents are currently the subject of patent infringement litigation against Dr. Reddy’s Laboratories Inc. The parties have mutually agreed on a pretrial litigation schedule with the U.S. District Court of New Jersey through to mid-2021. The term of the ‘996 and ‘920 patents extends to May 31, 2022. Nuvo Ireland, with its commercial partner, continue to work together to vigorously defend these patents.

On January 7, 2020 Sanford Burnham Prebys Medical Discovery Institute reported that identified a new way to boost the immune system’s ability to fight cancer (Press release, Sanford-Burnham Medical Research Institute, JAN 7, 2020, View Source [SID1234553267]). The study, which was performed in collaboration with NYU Langone’s Perlmutter Cancer Center, used a mouse model to identify the importance of the Siah2 protein in the control of immune cells called T regulatory cells (Tregs), which limit the effectiveness of currently used immunotherapies. The research, which offers a new avenue to pursue immunotherapy in cases where the treatment fails, was published today in Nature Communications.

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"While Siah2 is involved in control of activities that govern cancer development, this study offers the first direct evidence for its role in the immune system, namely in anti-tumor immunity," says Ze’ev Ronai, Ph.D., professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program and senior author of the study. "Our study shows that a PD-1 inhibitor can be used to treat tumors that currently do not respond to this therapy, when administered in mice lacking the Siah2 gene, thereby offering a means to expand the effectiveness of immunotherapy. The findings also provide further justification for our efforts to find a drug that blocks Siah2."

The development of cancer immunotherapies, which harness the power of an individual’s immune system to destroy tumors, has revolutionized the treatment of certain cancers. For some people with advanced melanoma, a deadly skin cancer, the treatment has extended survival to years instead of months. However, the treatment only works for about 40% of people with advanced melanoma. The study from the Ronai lab offers a new means to make this treatment effective in individuals who at present do not respond to anti-PD-1 therapy.

Ronai explains, "In our study, mice lacking the Siah2 gene were able to mount an immune attack against melanoma. Moreover, the effectiveness of Siah2 in immunotherapy was demonstrated for ‘cold’ tumors—those that do not respond to immunotherapy—which were effectively eliminated by a PD-1 blockade in Siah2-mutant mice."

"Understanding the basic mechanisms of tumor immunity will ultimately help us improve the effectiveness of immunotherapy," says Michael Rape, Ph.D., Howard Hughes Investigator and professor of Cell and Developmental Biology at University of California, Berkeley. "This study uncovers an important layer in the regulation of key immune cell components that impact the effectiveness of cancer immunotherapy, highlighting the need to develop inhibitors for Tregs, in which a Siah2 inhibitor holds promise."

Scientists have known for many years that Siah2 is involved in cellular responses to hypoxia (low oxygen) and the unfolded protein response—two processes that are exploited by tumors to keep growing. Ronai has studied the protein for nearly a decade in hopes of finding better cancer treatments: His team is currently working to develop a small molecule drug that blocks the protein. Now, Ronai’s study shows that the protein also plays an important role in regulating the immune system’s response to a tumor.

In the study, the scientists used genetically engineered mice that did not produce the Siah2 protein and then introduced BRAF-mutant melanoma—a mutation that occurs in about half of human melanomas. This approach allowed the researchers to study the role of Siah2 in the tumor’s microenvironment, of which the immune system is a major component. In the absence of the Siah2 gene, the melanoma tumors receded—a stark contrast to mice with the Siah2 gene, in which the tumor continued to grow. Giving these mice anti-PD-1 therapy effectively eliminated melanoma that otherwise resisted this therapy, demonstrating a new path to enhance the effectiveness of current immunotherapies.

Digging deeper into their findings, the scientists discovered that in the Siah2 mutant mice, the tumors were infiltrated by killer but not Treg immune cells—indicating the immune system was more active in clearing the tumors. The lack of the Treg cells was attributed to reduced proliferation and recruitment into the tumor due to the role of Siah2 and its control of cell cycle regulatory proteins.

"Our discovery only fuels our sense of urgency to find a drug that inhibits Siah2," says Ronai. "Using an arsenal of novel approaches should enable us to advance the targeting of Siah2 in both the tumors and their microenvironment."

The first author of the study is Marzia Scortegagna, Ph.D., of Sanford Burnham Prebys. Additional study authors include Yongmei Feng, Ph.D., Dennis C. Otero, Ph.D., Linda M. Bradley, Ph.D., and Yan Li, M.D., Ph.D., of Sanford Burnham Prebys; Kathryn Hockemeyer, M.D., Ph.D., Igor Dolgalev and Ioannis Aifantis, Ph.D., of NYU School of Medicine; Joanna Poźniak, Ph.D., Florian Rambow, Ph.D., and Jean-Christophe Marine, Ph.D., of VIB; Roberto Tinoco, Ph.D., of Sanford Burnham Prebys and the University of California, Irvine; Tongwu Zhang, Ph.D., and Kevin Brown, Ph.D., of the National Cancer Institute; and Marcus Bosenberg, M.D., Ph.D., of Yale School of Medicine.

On January 7, 2020 Tyme Technologies, Inc. (Nasdaq: TYME) ("TYME"), an emerging biotechnology company developing cancer metabolism-based therapies (CMBTs), and Eagle Pharmaceuticals, Inc. (Nasdaq: EGRX) ("Eagle"), reported the formation of a U.S. strategic collaboration focused on the co-promotion of TYME’s lead CMBT candidate oral SM-88 in advanced cancers (Press release, Eagle Pharmaceuticals, JAN 7, 2020, View Source [SID1234552776]). CMBTs are proprietary investigational compounds that are believed to disrupt cancer cells’ protein synthesis, leading to a breakdown of the cancer’s key defenses and cell death. In clinical trials, oral SM-88 has demonstrated complete or partial responses across 15 different cancers, including pancreatic, prostate, sarcoma, breast, lung, and blood cancers with minimal serious grade 3 or higher adverse events.

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"TYME’s approach is unique and transformational. Targeting cancer’s metabolism by disrupting protein synthesis has advantages over existing treatment approaches in terms of both efficacy and safety," said Scott Tarriff, Chief Executive Officer of Eagle Pharmaceuticals. "This collaboration provides an excellent opportunity to continue expanding our presence in the oncology space, as well as to evaluate potential combination opportunities with SM-88 in our existing pipeline. We look forward to leveraging our oncology sales infrastructure to maximize the commercialization of SM-88 in the U.S., if approved. As always, our goal remains to deliver innovative, next-generation therapeutics to address patient needs and to create value for our shareholders," concluded Tarriff.

Terms of the Agreements

Under the terms of the securities purchase agreements, TYME will receive a $20 million upfront cash payment for 10 million restricted shares of TYME common stock at $2.00 per share. In addition, TYME will receive a $20 million milestone payment upon the successful completion of the first to occur of the following three events: (1) achievement of the primary endpoint of overall survival in its TYME-88-Panc pivotal trial; or (2) achievement of the primary endpoint of overall survival in the PanCAN Precision PromiseSM SM-88 registration arm; or (3) U.S. Food and Drug Administration (FDA) approval of SM-88 in any cancer. This payment would be split into a $10 million milestone cash payment and a $10 million investment in TYME at a 15% premium to the then prevailing market price. Eagle’s shares will be restricted from sale until the earlier of three months following the milestone event or the three-year anniversary of the agreement.

Under the terms of the co-promotion agreement, Eagle Pharmaceuticals will undertake 25% of the promotional sales effort for SM-88 in the U.S. oncology market and receive 15% of the net U.S. revenues of SM-88, and TYME will be responsible for the remaining promotional effort. TYME will also be responsible for clinical development, regulatory approval, commercial strategy, marketing, reimbursement and manufacturing of SM-88. TYME retains the remaining 85% of net U.S. revenues and reserves the right to repurchase Eagle’s co-promotion right for $200 million.

As part of this partnership between TYME and Eagle, there is also the potential to evaluate oral SM-88 in combination therapy or as monotherapy through leveraging Eagle’s oncology pipeline and expertise in oncology settings, which may include trials in breast or lung cancers and other tumor types.

"We are extremely pleased to establish this collaboration with Eagle Pharmaceuticals who shares our passion and commitment to improving the lives of patients with advanced cancers. After a thorough due diligence process by both parties, each came away with great respect for each organization’s capabilities and potential," said Steve Hoffman, Chairman and Chief Executive Officer of TYME. "This alliance provides TYME with the commercial and capital resources to advance our leadership position in the field of cancer metabolism and the potential to expand our capabilities and accelerate clinical programs that will create value for all of our stakeholders, most importantly for the patients we serve."

About SM-88

SM-88 is an oral investigational modified proprietary tyrosine derivative that is believed to interrupt the metabolic processes of cancer cells by breaking down the cells’ key defenses and leading to cell death through oxidative stress and exposure to the body’s natural immune system. Clinical trial data have shown that SM-88 has demonstrated encouraging tumor responses across 15 different cancers, including pancreatic, lung, breast, prostate and sarcoma cancers with minimal serious grade 3 or higher adverse events.

Clinical results of SM-88, based on data as of April 25, 2019, from the Phase II portion of the TYME-88-Panc study, were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 21st World Congress on Gastrointestinal Cancer in Barcelona, Spain on Wednesday, July 4, 2019 (TYME-88-Panc poster). The study demonstrated a median overall survival in evaluable patients (38 of 49) of 6.4 months. These survival results compare very favorably to the analysis of 19 prospective pancreatic cancer trials where the median reported survival after progressing on second-line therapy was 2.0 – 2.5 months1 based on reported historical trials. In the Phase II portion of the TYME-88-Panc study, a RECIST CBR of stable disease or better was achieved by 44% of patients (11 of 25) with available imaging. Patients achieving stable disease or better demonstrated a statistically significant (p=0.02) improvement in survival with a 92% reduction in risk of death (hazard ratio=0.08). The CBR was durable with a majority of patients remaining in stable disease or better for more than 7 months after receiving treatment with SM-88. The study showed a median reduction of 63% in CTC burden in evaluable patients. Patients (10 of 24) with available results reaching an 80% reduction or greater in CTCs demonstrated a 60% decrease in risk of death (hazard ratio=0.40).

The Phase II portion of the TYME-88 Panc study reported that SM-88 was well tolerated with only 4.0% of patients (2 of 49) who experienced serious adverse events (SAEs) deemed at least possibly related to SM-88 (abdominal pain, arthralgia, and hypotension). One patient with reported SAEs continued on treatment.

About Advanced Pancreatic Cancer

Advanced pancreatic cancer is a difficult-to-treat cancer with the lowest survival rates among all cancer types. Across all patients with pancreatic cancer, relative 5-year survival is 8% and is less than 3% for those with advanced disease.2 The median survival for patients in end-stage of the disease is approximately 3 months. There are two main types of pancreatic cancer – adenocarcinomas, which accounts for approximately 90% of all pancreatic cancer, and neuroendocrine tumors. Pancreatic cancer is relatively uncommon with new cases accounting for only 2.1% of all newly diagnosed cancers.

However, pancreatic cancer is the fourth most common cause of cancer death for men and women in the United States.

About Precision PromiseSM

Precision PromiseSM is an adaptive randomized Phase III registration-ready clinical trial. The objective of Precision PromiseSM is to expedite the study and approval of promising therapies for pancreatic cancer by bringing multiple stakeholders together, including academic, industry and regulatory entities. The primary goal of SM-88’s inclusion is to study SM-88 as a monotherapy treatment arm for patients who have failed one prior line of chemotherapy. Additionally, it is planned that SM-88 will be evaluated in combination with gemcitabine (Gemzar ) and nab-paclitaxel (Abraxane ) for first-line patients. The primary end point of these randomized trials is overall survival.

On January 7, 2020 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium") reported that Sandesh Seth, Actinium’s Chairman and CEO, will present at the 2020 Biotech Showcase being held on January 13-15 (Press release, Actinium Pharmaceuticals, JAN 7, 2020, View Source [SID1234552793]). The conference will be at the Hilton San Francisco Union Square. Details of Actinium’s presentation are as follows:

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Date: Monday, January 13, 2020
Time: 2:30 pm PT
Track: Yosemite C (Ballroom Level)
Venue: Hilton San Francisco Union Square

Members of Actinium’s Executive and Corporate Development teams will be available for 1-on-1 meetings during the conference. Those interested in scheduling a meeting with Actinium may do so by contacting David Gould, MD, Actinium’s SVP, Corporate Development & Corporate Affairs via email at [email protected].

About Biotech Showcase

Biotech Showcase, produced by Demy-Colton and EBD Group, is an investor and networking conference devoted to providing private and public biotechnology and life sciences company with an opportunity to present to, and meet with, investors and executives in one place during the course of one of the industry’s largest annual healthcare investor conferences, J.P. Morgan Annual Healthcare Conference.

On January 7, 2020 Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for cancer, reported the launch of the NeXT Dx Test to help oncologists identify potential therapies and clinical trial options for cancer patients (Press release, Personalis, JAN 7, 2020, View Source [SID1234552810]). The Personalis NeXT Dx Test is one of the first cancer diagnostic platforms to profile approximately 20,000 genes in both the tumor exome and transcriptome, providing a comprehensive genomic testing solution that goes beyond many existing cancer diagnostic panels that focus on a few hundred genes. The Personalis NeXT Dx Test includes advanced analytics to provide a diagnostic report on genetic alterations in medically-important cancer genes, as well as emerging immunotherapy composite biomarkers of medical importance. Additionally, immunotherapy-related biomarkers such as microsatellite instability (MSI) status and tumor mutational burden (TMB) are included in the clinical report.

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"With new cancer immunotherapy and combination therapies, there is an increasing need for the development of more advanced composite biomarkers that can model the complex biology driving the response and resistance to cancer therapy. Our NeXT Dx Test provides oncologists with clinical reports on key diagnostic markers driving therapies today as well as provides information that can support the identification of new, advanced biomarkers. With the NeXT Dx Test, we look forward to expanding engagements with both leading clinical cancer centers as well as biopharmaceutical companies looking to push forward cutting-edge precision medicine in cancer," said Dr. Richard Chen, MD, Chief Scientific Officer at Personalis.

About NeXT Dx Test

The NeXT Dx Test, optimized for formalin-fixed, paraffin-embedded tumor samples, is a laboratory-developed test performed at Personalis’ CAP-accredited and CLIA’88-certified laboratory. The test utilizes ImmunoID NeXT, a high-accuracy, clinical-grade, next-generation sequencing and analysis platform, to report base substitutions, insertions/deletions, gene fusions, and copy number alterations in cancer driver genes of clinical significance. Additionally, MSI status is reported based on five canonical loci (BAT25, BAT26, NR-21, NR-24, and NR-27), and TMB status is reported by leveraging the exome-wide analysis of non-synonymous somatic mutations. Based on the tumor’s molecular profile, the report delivers relevant therapy recommendations and appropriate clinical trial matches. Each case is reviewed by a team of board-certified molecular geneticists and genetic counselors. Test results are electronically delivered to the ordering clinician.

About ImmunoID NeXT Platform

ImmunoID NeXT is a universal cancer immunogenomics platform that consolidates multiple biomarker assays into one, providing a multidimensional view of the tumor and its tumor microenvironment from a single sample. The platform represents an end-to-end solution for immuno-oncology and supports precision oncology biomarker discovery applications. It combines the pioneering NeXT assay (whole exome and transcriptome sequencing), sophisticated analytics engines, and quality support to provide researchers with comprehensive immunogenomic data to drive their drug development programs.