On October 9, 2020 Bold Therapeutics, a clinical-stage biopharmaceutical company, reported that the first patient for the company’s Phase 1b oncology clinical trial has been enrolled at the Cross Cancer Institute (Edmonton, Alberta) under Principal Investigator Dr. Jennifer Spratlin (Press release, Bold Therapeutics, OCT 9, 2020, View Source [SID1234568272]). This trial investigates the safety and tolerability of Bold Therapeutics’ first-in-class anti-cancer agent, BOLD-100, in combination with the current standard-of-care, FOLFOX (5-fluorouracil, leucovorin, oxaliplatin), for the treatment of patients with advanced gastric, pancreatic, colorectal and bile duct cancers. Five additional hospitals across Canada will also be enrolling patients: Princess Margaret Cancer Centre in Toronto, Ontario (PI Grainne O’Kane); Ottawa General Hospital in Ottawa, Ontario (PI Rachel Goodwin); Juravinski Cancer Centre in Hamilton, Ontario (PI Elaine McWhirter); and Jewish General Hospital and Royal Victoria Hospital in Montreal, Quebec (PIs Petr Kavan and Jamil Asselah, respectively).

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BOLD-100 is a first-in-class ruthenium-based therapeutic that selectively inhibits stress-induced upregulation of GRP78 and alters the unfolded protein response (UPR), mitigating resistance, survival and proliferation, with additional synergistic direct anti-cancer activity.

"Bold Therapeutics has achieved another key clinical development milestone. The current trial will provide data on not only the safety and tolerability of BOLD-100 in combination with FOLFOX, but also important efficacy measures to evaluate patient outcomes," stated Jim Pankovich, EVP of Clinical Development. "Bold Therapeutics is working with an experienced team of investigators across Canada – and, later, in the United States and South Korea – for this groundbreaking clinical trial. The dose-escalation portion of this adaptive-design study will enroll approximately 12 patients in cohorts of three after which the expansion-cohort portion will enroll up to 80 patients, with 20 patients in each arm."

In a previously completed 46-patient Phase 1 monotherapy study, BOLD-100 was well-tolerated with minimal hematological and neurological side effects, suggesting it could be combined favorably with other anti-cancer therapies. Preclinical data shows profound synergy in combination with numerous drug classes ranging from traditional chemotherapies to newer targeted therapies and immuno-oncology agents. The company received a No Objection Letter (NOL) from Health Canada earlier this year and has an open Investigational New Drug (IND) and an Orphan Drug Designation (ODD) in pancreatic cancer in the United States, with additional ODDs expected over the next six months.

"Cancer drug resistance remains a significant challenge for patients and physicians. We have deliberately chosen some of the most difficult-to-treat indications with the shortest mean survival times for this trial because this is where there is the greatest unmet medical need," said E. Russell McAllister, CEO. "Preclinically, BOLD-100 significantly improves outcomes in a wide range of different indications and combinations, acting through both anti-resistance but also direct anti-cancer pathways. We are now actively evaluating additional development options, some in partnership with other pharmaceutical companies, and we expect to initiate at least one additional oncology clinical trial in 2021. Areas of particular interest include triple-negative breast cancer; neoadjuvant therapy; first-line combinations with immuno-oncology agents; sarcomas; and various liquid tumors, including multiple myeloma – all of which are potentially viable development indications and combinations based on preclinical data and/or relevant literature."

On October 8, 2020 Invitae reported that Tumor-only genetic sequencing misses medically actionable genetic variants in cancer patients that germline genetic tests identify, according to a new study published this week in JAMA Network Open that included researchers (Press release, Invitae, OCT 8, 2020, View Source [SID1234568221]). The study also found that current clinical guidelines on who should be offered germline testing following tumor sequencing are too narrow, missing patients whose care could benefit from information about their germline genetic profile. Taken together, the study suggests the use of both tumor and germline testing provides the most complete and actionable genetic profiling to inform cancer treatment.

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"Tumor sequencing alone is not sufficient to provide the full genetic picture needed to inform cancer care. Our study uncovered a high rate of actionable findings from germline testing following tumor sequencing, including some which were missed by tumor profiling, offering a strong rationale for further integrating germline genetics into routine care for cancer patients," said Robert Nussbaum, M.D., chief medical officer of Invitae and one of the team of authors of the study from Invitae. "Complete genetic information impacts prognosis, precision therapy selection, clinical trial qualification and surgical decisions. Importantly, a number of patients in our study were experiencing their second cancer, one which could have potentially been caught earlier had their full genetic risk profile been known and appropriate actions taken."

The retrospective study of 2,023 cancer patients who received germline testing following tumor DNA sequencing found that nearly a third (30.5%) harbored a pathogenic germline variant. Importantly, eight percent of pathogenic germline variants were missed by tumor sequencing results reviewed for the study and 11 percent of these variants were identified in patients experiencing a second cancer. Approximately 20% of patients with pathogenic germline variants did not meet criteria for germline testing.

"The genetics of both the person and the tumor play an important role in making cancer treatment decisions. Expanding germline testing guidelines will ensure all cancer patients who can benefit from comprehensive genetics in their care will receive this information," said Dr. Nussbaum. "By capturing genetic information on both tumor biology and a patient’s inherited risk of disease, we can develop more effective, personalized treatment plans and help inform family members of additional inherited risk, helping improve outcomes for both patient and family."

Germline testing assesses genetic changes carried in all the cells of the body, changes that a person already has from conception, while tumor profiling (somatic) sequencing analyzes alterations in DNA within a tumor that are often acquired and drive its growth, particularly for patients with advanced disease. While tumor sequencing can detect both somatic and some germline mutations, the most commonly ordered tests fall short in reporting pathogenic germline gene variants because of technical limitations and variant interpretation differences. This germline information can inform a wide range of clinical decisions, from prognosis to precision therapy selection, surgical decisions, reproductive choices and clinical trial qualification. In addition, germline genetic information has important implications for the families of cancer patients who may be at elevated risk of developing cancer themselves.

On October 8, 2020 ChromaDex Corp. (NASDAQ:CDXC) reported highlighted a new study from Nature Immunology that found nicotinamide riboside (NR) helped energize tumor infiltrating T-cells (TILs) in samples extracted from mice (Press release, ChromaDex, OCT 8, 2020, View Source [SID1234568239]. In a preclinical mouse model, NR was shown to improve T-cell function, which is a component of new cancer immunotherapies such as PD-1 and PDL-1 inhibitors. These findings lend further data to the potential role of NR in supporting healthy mitochondrial function.

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T-cells are immune cells tasked with recognizing and eliminating infected, damaged or cancerous cells. The researchers from the University of Lausanne and the Ludwig Institute for Cancer Research found that NR could prevent mitochondrial dysregulation and exhaustion in T-cells. By doing so, NR was also shown to improve T-cell mitochondrial function and responsiveness to anti-PD-1 cancer immunotherapy, a mainstay of cancer treatment approved for use against many solid tumor types. The tumor bearing mice fed with NR experienced less tumor growth, and an additive antitumor effect was observed when NR was combined with immunotherapy.

This research built upon a previous preclinical study, also conducted at the University of Lausanne, that found NR could promote hemopoietic stem cell (HSC) maturation in mice by stimulating mitochondrial function. Immune cells such as T-cells arise from these stem cells, as do essential red blood cells and platelets.

The prior study suggested that NR supplementation could facilitate cancer treatment by preventing myelosuppression in mice, (i.e. depletion of stem cells and all the cells they produce, caused by repeated chemotherapies).

This latest study from Nature Immunology indicates a new potential niche for NR supplementation by suggesting a synergistic effect with T-cell immunotherapies used for many solid tumors. NR has also been shown preclinically to possibly prevent neuropathy caused by paclitaxel, a common chemotherapy used for breast cancer treatment.

More research is required to validate this preclinical data and translate the findings into humans. Over 50 human trials investigating NR’s various health benefits are registered on ClinicalTrials.gov, 11 of which have been peer-reviewed and published through the ChromaDex External Research Program (CERP).

"We’re excited to see the discovery of so many potential applications for NR’s proven ability to promote mitochondrial function," said Dr. Andrew Shao, ChromaDex Senior Vice President of Global Scientific & Regulatory Affairs. "We know mitochondrial function is essential to the function of energy-expensive cells, including stem cells and immune cells. Their proper function, in turn, may play a key role in avoiding a wide array of diseases, including many cancers. We’re pleased to see that NR can support these essential cells and hope to elucidate its potential in human health and disease with further trials."

ChromaDex, the exclusive licensee of Dr. Charles Brenner’s patented NR, has invested over $35 million in investigating, manufacturing and offering NR in the form of Niagen and has secured more than 20 patents. ChromaDex has demonstrated the safety and efficacy of Niagen in 11 published human trials (and over 20 additional ongoing studies further evaluating its safety and efficacy) and has achieved government regulatory acceptance in the United States, Canada, the European Union, and Australia.

On October 8, 2020 Applied DNA Sciences, Inc. (NASDAQ: APDN) ("Applied DNA" or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing that enables in vitro diagnostics, pre-clinical nucleic acid-based therapeutic drug candidates, supply chain security, anti-counterfeiting, and anti-theft technology, reported that it entered into an agreement (the "Agreement") with the sole holder (the "Holder") of its outstanding July 16, 2019, secured convertible notes (the "Notes") for the repayment in full of the Notes, in an aggregate amount of approximately $1.7 million, representing the outstanding amount of the Notes plus interest through the scheduled maturity of the Notes (Press release, Applied DNA Sciences, OCT 8, 2020, View Source [SID1234568222]). In conjunction, affiliates of the Holder will exercise warrants issued as part of the Company’s November 15, 2019, underwritten public offering (the "2019 Warrants") for total proceeds to the Company of approximately $1.7 million. Not all of the Holder’s 2019 Warrants will be exercised in connection with the repayment of the Notes. As a result of the repayment of the Notes, approximately $1.5 million of debt and liabilities will be extinguished from the Company’s balance sheet, leaving the Company debt-free. In addition, the security interests in the Company’s property granted to secure the Notes will be released.

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In connection with a warrant exercise agreement with affiliates of the Holder, in addition to the shares of common stock issued upon exercise of the 2019 Warrants by such affiliates, the Company will issue replacement warrants (the "Replacement Warrants") to such affiliates of the Holder in an amount equal to one half the amount of the 2019 Warrants exercised in connection with the Notes repayment. The Replacement Warrants have an exercise price equal to the closing price of the Company’s common stock on October 7, 2020. In addition, until January 5, 2021, if affiliates of the Notes holder exercise additional 2019 Warrants, the Company will issue to such affiliates additional Replacement Warrants in an amount equal to one half the amount of such exercised warrants and with an exercise price equal to the closing price of the Company’s common stock on the date the related 2019 Warrants are exercised. The Replacement Warrants will not be registered nor listed on any exchange but will be the subject of a registration rights agreement pursuant to which the Company agrees to file a registration statement with respect to the common stock underlying the Replacement Warrants.

"The opportunistic elimination of our outstanding Notes preserves our cash balance to fund the execution of our COVID-19 diagnostics and testing strategy that we believe holds the potential to impact our growth trajectory positively," said Dr. James A. Hayward, president and CEO, Applied DNA Sciences. "Having built a solid strategic foundation and following the receipt of our first commercial contract for our COVID-19 diagnostic assay kits, we are working diligently to commercialize our testing-as-a-service program at our clinical laboratory subsidiary."

On October 8, 2020 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that the US Food and Drug Administration (FDA) has granted two Orphan Drug Designations (ODDs) to two of the company’s apoptosis-targeting assets: the MDM2-p53 inhibitor, APG-115, for the treatment of acute myeloid leukemia (AML); and the Bcl-2/Bcl-xL inhibitor, APG-1252, for the treatment of small-cell lung cancer (SCLC) (Press release, Ascentage Pharma, OCT 8, 2020, View Source [SID1234568240]). With these two latest designations, Ascentage Pharma has obtained a total of six ODDs from the FDA for four of the company’s investigational drug candidates .

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The term "orphan drugs" refers to pharmaceutical products developed for the prevention, diagnosis, and treatment of rare diseases or conditions. In the United States, an orphan disease is defined as a disease or condition with a prevalence of less than 200,000 patients in the country. Since the Orphan Drug Act was passed in 1983, the US government has provided incentives and policy support to encourage development of orphan drugs. Drug candidate granted ODDs by the FDA will qualify for various development incentives, including a tax credit on expenditures incurred in clinical studies, a waiver of the New Drug Application (NDA) fee, research grant awarded by the FDA, and, most importantly, 7 years of US market exclusivity upon approval.

The MDM2-p53 inhibitor APG-115 for the treatment of AML

AML is a highly heterogenous hematologic malignancy that is more common in the elderly population with a median age at diagnosis of 68 years[1]. The most recent data from the Surveillance, Epidemiology, and End Results Program (SEER) of the US National Cancer Institute (NCI) estimates that there will be 19,940 new cases of AML and an estimated 11,180 deaths from this disease in the United States in 2020. Despite the recent advances in therapeutics, the 5-year survival rate of AML remains at 25%–30%, which still represents a significant unmet medical need.

APG-115 is an orally administered, selective, small-molecule inhibitor of MDM2. APG-115 has strong binding affinity to MDM2 and is designed to activate the tumor-suppressing activity of p53 by blocking the MDM2-p53 protein-to-protein interaction (PPI). APG-115 is the first MDM2-p53 inhibitor entering clinical development in China, with multiple ongoing clinical studies in solid tumors and hematologic malignancies in China and the US.

The Bcl-2/Bcl-xL inhibitor APG-1252 for the treatment of SCLC

Lung cancer remains the leading cause of cancer death in the United States[2]. Lung cancer is divided into two main histopathological types: non-small cell lung cancer (NSCLC) and SCLC, with 13-15% of lung cancers classified as SCLC[2],[3]. SCLC is a rare and highly aggressive cancer with a low 5-year survival rate[3]. Patients with relapsed/refractory SCLC have few treatment options, all of which offer modest response rates.

Being developed by Ascentage Pharma, APG-1252 is a novel small-molecule drug candidate that restores apoptosis by selectively inhibiting Bcl-2 and Bcl-xL proteins simultaneously. APG-1252 is currently being investigated in Phase I dose-escalation studies in patients with advanced cancers in the US and Australia, a Phase Ib/2 study of APG-1252 plus paclitaxel in patients with relapsed/refractory SCLC in the US, and a Phase I dose-escalation study of APG-1252 single agent in patients with SCLC in China. The clinical data of APG-1252 generated thus far have shown a favorable safety profile and preliminary efficacy in patients with SCLC and other advanced solid tumors.

"AML and SCLC are both devastating and life-threatening diseases which have high unmet clinical needs globally. For APG-115, this designation marks the second ODD of the molecule from the FDA, while it is the very first time for APG-1252 to obtain an ODD," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "All the ODD-related supporting policies in the US will help us to accelerate the global clinical development and commercialization of these two drug candidates, and allow more patients to benefit as soon as possible."

References

[1] DeSantis CE, Lin CC, Mariotto AB, et al. Cancer Treatment and Survivorship Statistics, 2014. CA Cancer J Clin 2014;64:252-271.

[2] Siegel R, Miller K, Jemal A. Cancer Statistics, 2020. American Cancer Society. CA Cancer J Clin 2020;70:7–30.

[3] Lu T, Yang X, Huang Y, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res. 2019; 11: 943–953.