On April 2, 2018 Synlogic (Nasdaq:SYBX), a clinical-stage company applying synthetic biology to probiotic bacteria to develop novel living medicines, reported that the first patient was dosed in its Phase 1b/2a clinical trial of SYNB1020 (Press release, Synlogic, APR 2, 2018, View Source [SID1234525474]). SYNB1020 is a Synthetic Biotic medicine being developed for the treatment of hyperammonemia, associated with cirrhosis and urea cycle disorders (UCDs), which can result in severe and life-threatening consequences for patients. This randomized, double-blind, placebo-controlled study is designed to evaluate the safety and tolerability of SYNB1020, as well as its ability to lower blood-ammonia levels in patients with cirrhosis and elevated blood ammonia.

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"Our recently reported Phase 1 trial of SYNB1020 demonstrated that this Synthetic Biotic medicine was well tolerated and provided a dose-dependent proof of mechanism, functioning as designed in healthy volunteers. We look forward to evaluating the safety, tolerability and therapeutic potential of SYNB1020 in patients with liver disease who have developed cirrhosis," said Aoife Brennan, M.B., B.Ch., Synlogic’s chief medical officer. "There is unmet medical need for additional treatment options for patients with chronic liver disease and we are excited by the potential of SYNB1020 in this indication."

Synthetic Biotic therapies are designed to function in the gastrointestinal tract to convert metabolites that can build up to toxic levels in the blood into harmless metabolites that can be excreted from the body. Elevated blood ammonia levels are toxic to the brain and can have severe consequences, including neurologic crises requiring hospitalization and resulting in irreversible cognitive damage and death. SYNB1020 is designed to consume ammonia and convert it to arginine, an amino acid.

About Synlogic’s Phase 1b/2a Trial of SYNB1020 in Patients with Cirrhosis

This Phase 1b/2a study has two parts:

First, an initial sentinel open-label cohort of subjects with cirrhosis and a Model for End-Stage Liver Disease (MELD) score < 12 will receive orally administered SYNB1020 (5 x 1011 CFU TID) for six days. Subjects will be admitted to an inpatient facility for a run-in diet, baseline assessments, safety monitoring, and collection of blood, urine, and fecal samples for the evaluation of safety, tolerability, pharmacokinetics and pharmacodynamics of treatment. Once safety and tolerability have been established in these subjects, enrollment will be opened to subjects in Part 2.

Part 2 of the trial comprises a randomized, double-blinded, placebo-controlled study in patients with cirrhosis and hyperammonemia. Eligible subjects will be admitted to an inpatient facility for a run-in diet and 24-hour ammonia profile, and those with an elevated ammonia level will proceed with randomization and receive either placebo or orally administered SYNB1020 (5 x 1011 CFU TID) for six days. The primary endpoint of the study is safety and tolerability. In addition, the study will evaluate the effect of SYNB1020 administration on plasma ammonia levels as well as other exploratory endpoints.

Synlogic expects to report top-line data from this trial by year-end 2018. More information on this study can be found at View Source under the study ID NCT03447730.

About Hyperammonemia

Hyperammonemia is a metabolic condition characterized by an excess of ammonia in the blood. In healthy individuals, ammonia is primarily produced in the intestine as a byproduct of protein metabolism and microbial degradation of nitrogen-containing compounds. Ammonia is then converted to urea in the liver and is excreted in urine. However, if the liver’s ability to convert ammonia to urea is compromised, either due to a genetic defect such as UCDs or acquired liver disease that leads to cirrhosis, ammonia accumulates in the blood. Elevated blood ammonia levels are toxic to the brain and can have severe consequences, including neurologic crises requiring hospitalization, irreversible cognitive damage and death.

About Synthetic Biotic Medicines

Synlogic’s innovative new class of Synthetic Biotic medicines leverages the tools and principles of synthetic biology to genetically engineer probiotic microbes to perform or deliver critical functions missing or damaged due to disease. The company’s two lead programs, SYNB1020 and SYNB1618, target hyperammonemia as a result of liver damage or genetic disease, and phenylketonuria, respectively. Patients with these diseases are unable to break down commonly occurring by-products of digestion that then accumulate to toxic levels and cause serious health consequences. When delivered orally, Synthetic Biotic medicines can act from the gut to compensate for the dysfunctional metabolic pathway and have a systemic effect, with the potential to significantly improve symptoms of disease for affected patients. Synlogic has earlier-stage programs that apply the broad potential of its Synthetic Biotic platform in other disease areas, from inflammatory and immune disorders to cancer.

On April 2, 2018 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a clinical-stage biotechnology company that designs and develops innovative human enzyme therapeutics for patients with rare genetic diseases and cancer, reported treatment of the first patients with pegzilarginase in two small cell lung cancer (SCLC) trials, the single-agent Phase 1 cohort expansion and the Phase 1/2 combination trial with KEYTRUDA, an anti-PD-1 therapy marketed by Merck (known as MSD outside the United States and Canada) (Press release, Aeglea BioTherapeutics, APR 2, 2018, View Source [SID1234525379]). Aeglea expects to report topline safety and clinical activity data from both trials in the fourth quarter of 2018.

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The SCLC cohort expansion is one of three arms in a Phase 1 trial exploring pegzilarginase monotherapy in arginine dependent cancers. The combination therapy is part of the Company’s clinical collaboration to evaluate the use of pegzilarginase with KEYTRUDA, for the treatment of patients with SCLC. The multicenter Phase 1/2 study will evaluate overall response rate in patients with extensive disease SCLC who have relapsed or progressed after receiving platinum-based chemotherapy.

"Given Aeglea’s encouraging preclinical data in small cell lung cancer, we believe there is a strong rationale for arginine depletion in this cancer indication," said Anthony Quinn, M.B Ch.B, Ph.D., interim chief executive officer of Aeglea. "We are excited to be studying arginine depletion with pegzilarginase in both a monotherapy and combination setting, as the data from both trials will provide a broad understanding of the impact of arginine depletion in small cell lung cancer."

"Treating the initial patients with small cell lung cancer in both of these clinical trials is an important milestone for Aeglea as we develop innovative approaches for the management of arginine dependent cancers," said James Wooldridge, M.D., chief medical officer of Aeglea. "Small cell lung cancer is a challenging disease, and since the five-year survival rate is only about 6%, there is significant unmet need. Our intent is to confirm the safety profile and the Phase 2 dose as we look for signals of meaningful clinical activity."

In addition to the two clinical trials in cancer, the Company is conducting an open-label Phase 1/2 trial and a long-term extension trial in patients with Arginase 1 Deficiency, a rare genetic disease

On April 2, 2018 XBiotech USA, Inc. (NASDAQ:XBIT) reported that it has obtained an exclusive, worldwide license from CT Atlantic AG (CTA), a Swiss biotechnology company. Under the terms of the license agreement, XBiotech will use its proprietary manufacturing technology to advance the development of the True HumanTM anti-NY-ESO-1 monoclonal antibody, 12D7 (Press release, XBiotech, APR 2, 2018, View Source;p=RssLanding&cat=news&id=2340533 [SID1234525378]). Accordingly, XBiotech will now begin to establish the production capability to enable 12D7 clinical development.

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The 12D7 antibody targets NY-ESO-1, a cancer-related protein commonly found in many kinds of aggressive tumors. The therapeutic use of 12D7 offers the potential to target advanced tumors by activating cellular immunity or antibody directed immune responses against tumors. A 12D7 therapy may be combined with other therapies that unleash the immune system to produce anti-cancer responses.

John Simard, President & CEO of XBiotech, commented, "The 12D7 antibody was isolated from a human immune response against cancer and is therefore a logical fit with our pipeline of human-derived antibodies. 12D7 offers the potential to be used as a therapy with minimal side effects—and safely in combinations with other agents, including checkpoint inhibitors—to help direct a patient’s immune response against their cancer."

Simard further commented, "Although NY-ESO-1 has been the subject of an enormous amount of scientific investigation, pointing to its association with tumors and anti-tumor immunity, the 12D7 antibody has yet to be evaluated in clinical trials. 12D7 is a good example of how our unique manufacturing technology can be used to help advance promising candidates discovered elsewhere."

Prof. Alex Knuth, M.D., member of the Board of Directors at CTA, Medical Director and Chief Executive Officer of the National Center for Cancer Care and Research (NCCCR) and Chairman of Cancer Services at Hamad Medical Corporation, commented, "I am excited to bring this NY-ESO-1 specific True Human antibody to the clinic with the advanced technologies and expert guidance of XBiotech. NY-ESO-1 is the most immunogenic human cancer antigen known to date. The 12D7 antibody comes from a melanoma patient with a remarkably favourable disease course despite advanced metastasis. NY-ESO-1 immunity appears to predict a better response to immune checkpoint interventions and the 12D7 antibody has been shown to support conventional treatments like chemotherapy with better outcomes in animal models; and in combination with radiotherapy, 12D7 may also amplify immune responses against cancer cells."

About 12D7 Antibody
Work from the laboratories of Dr. Alexander Knuth and Dr. Steve Rosenberg previously showed that cellular immunity against NY-ESO-1 can be activated in cancer patients. The 12D7 antibody is expected to target the NY-ESO-1 antigen directly, as well as work to help direct the patient’s cellular immune response against NY-ESO-1 bearing tumors. 12D7 is the first True Human monoclonal antibody targeting NY-ESO-1.
NY‐ESO‐1 was discovered by researchers at the Ludwig Institute for Cancer Research and Weill Medical College of Cornell University in New York. Interestingly, NY‐ESO‐1 is encoded by the sex-linked X chromosome and is deregulated and expressed in a number of forms of cancer. NY‐ESO‐1 function is still not fully understood but may be involved in cell division in cancer. Consequently, expression of NY‐ESO‐1 is found in a wide range of metastatic tumors, including about 33% of all cancers of the bladder, esophagus, gut, liver, lung, ovaries, prostate and skin.
Natural antibody immunity against NY-ESO-1 is often seen in cancer patients but is absent in healthy individuals. The natural antibody 12D7 is thought to be capable of initiating cellular immune responses, a disease fighting mechanism that is now widely mobilized to fight cancer through the use of check point inhibitors.
The target of the 12D7 antibody, NY-ESO-1, is commonly found in high‐grade malignancies. The therapeutic use of 12D7 may therefore offer the potential to target these aggressive tumors in part by activating cellular immunity or antibody directed immune responses to the site of tumors. Anti-NY-ESO-1 antibody therapy may benefit from being combined with other therapies that reduce immune suppression. These combination therapies in particular offer hope that 12D7 could be a breakthrough approach to unleashing anti-cancer immunity against many forms of cancer
.
About True Human Therapeutic Antibodies
Unlike previous generations of antibody therapies, XBiotech’s True Human antibodies are derived without modification from individuals who possess natural immunity to certain diseases. With discovery and clinical programs across multiple disease areas, XBiotech’s True Human antibodies have the potential to harness the body’s natural immunity to fight disease with increased safety, efficacy and tolerability.

On April 2, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that NERLYNX (neratinib) has been included as a recommended treatment option in the latest National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Central Nervous System Cancers for Breast Cancer patients with brain metastases (Press release, Puma Biotechnology, APR 2, 2018, View Source [SID1234525377]). The NCCN designated NERLYNX in combination with capecitabine as a category 2A treatment option and NERLYNX in combination with paclitaxel as a category 2B treatment option. Use, as designated for breast cancer patients with brain metastases, is outside the FDA approved indication for NERLYNX and considered investigational.

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"Physicians use the NCCN Guidelines as the standard resource for determining the best course of treatment for patients," said Alan H. Auerbach, Chairman, Chief Executive Officer and President of Puma. "We believe the updated NCCN guidelines will increase awareness, which will help assist patients, their caregivers and their healthcare providers in making informed decisions while treating this significant unmet need in advanced breast cancer."

About Brain Metastases in Breast Cancer
Breast cancer is one of three types of cancers that are most likely to metastasize to the brain. Across all sub-types, approximately 10-15% of women with metastatic breast cancer develop brain metastases. This rate is as high as 30% for women with advanced HER2+ disease.

About National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 27 of the world’s leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

About HER2-Positive Breast Cancer
Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with a trastuzumab-based regimen experience recurrence.
IMPORTANT SAFETY INFORMATION
NERLYNX (neratinib) tablets, for oral use
INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:
Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:
Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.

USE IN SPECIFIC POPULATIONS:
Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.
The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.
To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

On April 2, 2018 OncoCyte Corporation (NYSE American:OCX), a developer of novel, non-invasive liquid biopsy diagnostic tests for the early detection of cancer, reported that strengthened its intellectual property portfolio as it filed global patent applications for 190 newly identified novel biomarkers (Press release, BioTime, APR 2, 2018, View Source;p=RssLanding&cat=news&id=2340627 [SID1234525371]). These new biomarkers may enhance OncoCyte’s lung cancer test and enable better differentiation of malignant from benign lung for improved lung cancer diagnosis.

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OncoCyte has created a preliminary algorithm by combining some of the new biomarkers with its previously identified biomarkers. This new algorithm was cross-validated on approximately 60 clinical samples and resulted in accuracy as measured by Area Under the Curve data at least equivalent to DetermaVu’s previously reported lung cancer test results. However, the results must be confirmed in studies using a larger sample set.

OncoCyte has initiated the larger sample set study, which includes the new biomarkers along with previously identified biomarkers. This study is being carried out on three of the commercial molecular diagnostic platforms being evaluated by OncoCyte. The Company expects to complete the study during the second quarter of 2018.