On November 5, 2019 eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, reported the dosing of the first subject in the phase 1/2 study of zotatifin (eFT226) being developed for advanced solid tumor malignancies (Press release, eFFECTOR Therapeutics, NOV 5, 2019, View Source [SID1234553137]). Zotatifin is a novel, potent and selective small molecule inhibitor of eukaryotic initiation factor 4A (eIF4A).

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The study will enroll patients with activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1, or FGFR2 receptor tyrosine kinases, or any KRAS mutation subtype. It will also include pancreatic adenocarcinoma with no molecular typing since the large majority of those patients harbor a KRAS mutation.

"There is an immediate need for more effective treatment options in patients with advanced cancers unable to respond to alternative therapies," said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. "Tumors treated with agents targeting specific RTKs frequently become resistant, and there are no available therapies targeting multiple KRAS mutation subtypes. The antitumor response observed in preclinical studies demonstrates the potential for zotatifin in the treatment of solid tumors with genetic modifications associated with aggressive disease, including RTK alterations such as FGFR1/2 and HER2 and KRAS, and provides direction for patient selection in our clinical trial."

In the open label, dose escalation and cohort expansion study, subjects will be assigned sequentially to increasing zotatifin doses until the maximum tolerated dose is reached. Zotatifin will be administered as a monotherapy in weekly intravenous infusions in subjects with advanced solid tumor malignancies. Treatment and study subject evaluations will be performed in 21-day cycles.

The primary endpoints of the study include safety and tolerability of zotatifin as monotherapy. Secondary endpoints include antitumor activity and survival, as well as pharmacokinetics of the drug. Exploratory endpoints include pharmacodynamics of zotatifin.

Scientists from eFFECTOR recently presented preclinical data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) – also known as the Triple Meeting. The data demonstrated that solid tumor cell lines driven by alterations in FGFR1, FGFR2 and HER2 treated with zotatifin showed decreased MAPK and AKT signaling, potent inhibition of cell proliferation and apoptosis and strong in vivo anti-tumor activity, indicating potential for zotatifin to treat FGFR1/2 or HER2-driven cancers.

About Zotatifin (eFT226)

Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A). eIF4A is located downstream from key oncogenic mutations and their common resistance mechanisms. Zotatifin inhibits the translation of mRNA encoding several important oncogenes and survival factors, including several RTKS, KRAS, Cyclin D, MCL1 and BCL-2 resulting in potent in vivo efficacy in multiple tumor models dependent on these factors, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. Since Zotatifin inhibits the translation of mRNA encoding KRAS and RTK, it is not limited to any mutation subtypes. The drug is currently being evaluated in a Phase 1/2 clinical trial in patients with solid tumors.

On November 5, 2019 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer, reported that the United States Food and Drug Administration (FDA) has granted AUTO1 orphan drug designation for treatment of acute lymphoblastic leukemia (ALL) patients (Press release, Autolus, NOV 5, 2019, View Source [SID1234550683]).

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According to the National Institute of Health’s National Cancer Institute, in the United States, there will be an estimated 5,930 new cases of ALL and an estimated 1,500 related deaths in 2019. Patients are predominantly children; approximately 60% of cases occur at age < 20 years. ALL occurs when the bone marrow makes too many immature lymphocytes, which are a type of white blood cell. Despite a high rate of response to induction chemotherapy, only 30–40% of adult patients with ALL will achieve long-term remission. Similarly, pediatric patients typically respond well to first-line treatment (combination chemotherapy) but 10 to 20% of total patients relapse with chemotherapy-resistant disease, leading to a significant unmet need in pediatric patients with high-risk relapsed or refractory ALL.

"We are pleased to receive orphan drug designation for AUTO1 for acute lymphoblastic leukemia," said Dr. Christian Itin, chairman and chief executive officer of Autolus. "From the data reported in our ongoing studies, we have seen strong remission rates and excellent CAR T cell expansion and persistence without inducing high-grade CRS, a serious adverse event affecting a significant number of patients on currently available CAR T treatments. We look forward to presenting data on AUTO1 at ASH (Free ASH Whitepaper) at the end of the year."

Orphan drug designation is granted by the FDA Office of Orphan Products Development to drugs and biologics which are intended for the treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. Under the Orphan Drug Act, the FDA may provide grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits, and seven years of market exclusivity in the United States following marketing approval by the FDA. For more information about orphan designation, please visit the FDA website at www.fda.gov.

About AUTO1
AUTO1 is a CD19 CAR T cell investigational therapy designed to overcome the limitations in safety – while maintaining similar levels of efficacy – compared to current CD19 CAR T cell therapies. Designed to have a fast target binding off-rate to minimize excessive activation of the programmed T cells, AUTO1 may reduce toxicity and be less prone to T cell exhaustion, which could enhance persistence and improve the T cells’ abilities to engage in serial killing of target cancer cells. In 2018, Autolus signed a license agreement under which Autolus acquired global rights from UCL Business plc (UCLB), the technology-transfer company of UCL, to develop and commercialize AUTO1 for the treatment of B cell malignancies. AUTO1 is currently being evaluated in two Phase 1 studies, one in pediatric ALL and one in adult ALL.

On November 5, 2019 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer, announced today pre-clinical data on AUTO6NG, the company’s next generation GD2-targeting CAR T cell therapy, at the 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) being held November 6-10, 2019, in Washington, D.C (Press release, Autolus, NOV 5, 2019, View Source [SID1234550682]). SITC (Free SITC Whitepaper) published the abstract today, which can be found at:

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View Source;ABSID=12038&CONF=SITC19&ssoOverride=OFF&CKEY=

"AUTO6NG builds on the clinically active AUTO6 GD2-targeting CAR and adds cell programming modules to improve persistence and render the product insensitive to several tumor defense mechanisms," said Dr Christian Itin, chairman and chief executive officer of Autolus. "This is the first program presentation illustrating our suite of advanced cell programming technologies."

Poster Presentation
Abstract #: P146
Abstract Title: "AUTO6NG: Next generation GD2-targeting CAR T-cell therapy with improved persistence and insensitivity to TGFBeta and checkpoint inhibition for relapsed/refractory neuroblastoma", Achkova, D., et al.
Session Date: Saturday, November 9
Session Time: Posters on display 7:00 am – 8:30 pm Eastern Time; author(s) will be at poster 12:35 – 2:05 p.m. and also during the poster reception 7 – 8:30 p.m.

About AUTO6NG
AUTO6NG is a next generation programmed T cell product candidate in pre-clinical development. AUTO6NG builds on preliminary proof of concept data from AUTO6, a CAR in clinical development for the treatment of neuroblastoma, which can target GD2-expressing cancers with a chimeric antigen receptor (CAR). AUTO6NG incorporates additional cell programming modules to augment its functions by extending persistence and rendering modified T-cells resistant to immune inhibition. With the enhanced properties of AUTO6NG, it may be suitable for the treatment of GD2-expressing solid tumors, including neuroblastoma, osteosarcoma, melanoma, small cell lung cancer, and soft tissue sarcoma.

AUTO6 is currently in a Phase 1 clinical trial for pediatric neuroblastoma conducted by Cancer Research UK in collaboration with University College London. Autolus has worldwide commercial rights to the GD2-targeting programmed T cell product candidate.

On November 5, 2019 Ambry Genetics (Ambry), a leading clinical genetic testing company, reported that it will present at this week’s National Society of Genetic Counselors Annual Conference in Salt Lake City, Utah, data from the first 2,500 patients that received +RNAinsight, paired RNA and DNA genetic testing for hereditary cancer risk (Press release, Ambry Genetics, NOV 5, 2019, View Source [SID1234550595]). Data revealed that +RNAinsight resulted in a substantial increase in diagnostic yield, identifying more patients with genetic mutations (disease-causing errors in our DNA) compared to DNA testing alone. This is the first major increase in diagnostic yield for hereditary cancer risk in over 10 years, since the adoption of deletion/duplication testing. Through +RNAinsight, Ambry is the first and only lab to offer paired RNA and DNA genetic testing for hereditary cancer as a commercially available clinical test.

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Standard DNA testing for hereditary cancer risk excludes large portions of DNA, thereby missing some mutations. In addition, DNA testing can produce inconclusive results and fail to determine that an error in our DNA increases cancer risk. These limitations impact patients and their families because doctors may not have the information needed to recommend appropriate preventive, early detection, or therapeutic steps. Additionally, relatives may not be referred for genetic testing and obtain the care they would otherwise have gotten if they had learned they had mutations.

Adding RNA to DNA testing overcomes these limitations for a substantial number of patients as it provides considerably more evidence than DNA testing alone about whether our DNA has mutations. Ambry will present data showing that paired testing with +RNAinsight both (1) identified new mutations that would have been missed with DNA testing alone, and (2) clarified inconclusive results as disease-causing. DNA testing alone would have found these latter results as inconclusive and left doctors without this crucial information.

"These findings further demonstrate that hereditary cancer panels should include both RNA and DNA genetic testing," said Rachid Karam, MD, PhD, lead study author and Director of the Translational Genomics Lab at Ambry Genetics. "By looking at regions of the gene that other tests don’t, +RNAinsight reduces false negatives, maximizing the number of patients who learn they have higher risks for hereditary cancer."

The data show an overall relative increase in diagnostic yield of 6.7 percent compared to DNA testing alone, increasing by as much as 19 percent for specific genes. For example, for BRCA1, 14 percent more patients learned they had a mutation that increased their cancer risks than would have if they had only received DNA testing. Moreover, by analyzing regions of DNA known as introns that standard DNA testing alone does not assess, paired RNA and DNA testing found completely new mutations that DNA-only testing would not have found or identified as disease-causing. Thus, patients who learn they have mutations from paired testing can get the appropriate medical treatment while those who undergo standard DNA testing alone might not because they may never learn they have those mutations.

RNA genetic testing also resulted in an overall 4.5 percent relative decrease in the number of patients that would have received inconclusive results with DNA testing alone, reducing inconclusive results by as much as 9 percent in specific genes. As with identifying entirely new mutations, clarifying results can let more patients with mutations learn they have them.

+RNAinsight is now available through doctors and genetic counselors around the country. For more information on RNA genetic testing, please go to www.ambrygen.com/RNAinsight.

In addition to this paired RNA and DNA testing data, Holly LaDuca, Senior Manager, Clinical Affairs Research at Ambry, will present data from a survey sent to clinicians assessing how genetic testing results inform patient care.

Since January 2018, Ambry Genetics has provided surveys to all clinicians ordering hereditary cancer testing through Ambry both before and after they receive their patients’ genetic test results. In the first few months of offering the survey, 131 providers completed pre-and post-test surveys for 469 patients who received genetic testing. When genetic testing found mutations, changes to preventive screening recommendations were made for 62.1 percent of patients and surgical recommendations were made for 37.9 percent of patients. In addition, 40.9 percent of clinicians recommended genetic counseling changes, such as the testing of family members and discussions of reproductive risks.

"Management guidelines have been developed for numerous cancer-predisposition genes. However, data is limited on how these guidelines and genetic testing results impact patient care in the real world," said Ms. LaDuca. "Preliminary data from this ongoing survey demonstrate that positive genetic test results frequently lead to changes in medical management."

For the full list of studies that will be presented at NSGC, please see below:

Featured Oral Presentations at 2019 NSGC

Date & Time

Presentation

Presenter

Session

Tues., Nov. 5,
2019

8:30 AM – 2:30
PM

Clarity in Chaos: Using somatic
genetic testing to inform germline
interpretation

Pia
Summerour

Session #A03: Pre-
Conference
Symposium

Wed., Nov. 6,
2019

12:30 PM

Unparalleled Clarity and Mutations:
Clinical RNA Testing Provides
Answers Beyond DNA

Rachid Karam

Level 2,

Room 250

Lunch Presentation

Thurs., Nov. 7,
2019

3:10 PM- 4:40
PM

The New GC in Town: Demystifying
the Role of Gene Curation in Variant
Interpretation, Clinical Reporting and
Case Reanalysis

Kelly Radtke

Session #C16:
Educational Breakout
Session

Featured Poster Presentations at 2019 NSGC

Date & Time

Presentation

Lead Author

Poster

Wed., Nov. 6,
2019

6:15 PM – 7:30
PM

A Nationwide Multi-Center Study Provides Insight
into the Increase in Clinically Actionable Results
from Concurrent DNA and RNA Genetic Testing

Rachid Karam

B-131

Investigating Variants of Uncertain Significance:
Reclassification Triggers and Drivers in Breast
Cancer Predisposition Genes

Kirsten Kelly

B-233

Thurs., Nov. 7,
2019

1:20 PM – 2:35
PM

Better than Guidelines? Pre & Post Genetic Testing
Data Suggests Change in Management Trends

Zöe Powis

C-132

What Should I Order? Genetic Testing Ordering
Trends for Autism Spectrum Disorder

Catherine
Schultz

C-294

On November 5, 2019 Boston Scientific Corporation (the "Company") (NYSE:BSX) reported the pricing terms of the previously announced cash tender offer (the "Tender Offer") for up to $1.0 billion aggregate principal amount (the "Aggregate Maximum Principal Amount") of the outstanding senior notes listed in the table below (the "Securities") (Press release, Boston Scientific, NOV 5, 2019, View Source [SID1234550505]).

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The table below summarizes certain information regarding the Securities and the Tender Offer, including the order of priority and purchase price information for the Securities.

(1) The offer with respect to the Securities is subject to the Aggregate Maximum Principal Amount. The Company will purchase up to the Aggregate Maximum Principal Amount of its Securities, subject to the Acceptance Priority Level as set forth in the table above (each, an "Acceptance Priority Level"). The Company reserves the right, but is under no obligation, to increase the Aggregate Maximum Principal Amount at any time, including on or after November 5, 2019 (the "Price Determination Date"), subject to applicable law.

(2) The Reference Yield was determined at 11:00 a.m. Eastern Standard Time (EST) on November 5, 2019 by the Lead Dealer Managers (identified below).

(3) The Total Consideration (as defined below) for Securities validly tendered prior to or at the Early Tender Date (as defined below) and accepted for purchase was calculated using the applicable Fixed Spread and is inclusive of the Early Tender Payment (as defined below). The Total Consideration takes into account the applicable par call date for each series of Securities, if any.

The Tender Offer is being made pursuant to an Offer to Purchase, dated October 22, 2019 (the "Offer to Purchase"), which sets forth the terms and conditions of the Tender Offer. The Tender Offer will expire at midnight EST, on November 19, 2019 (one minute after 11:59 p.m. EST on November 19, 2019), or any other date and time to which such Tender Offer is extended (such date and time, as it may be extended with respect to a Tender Offer, the "Expiration Date"), unless earlier terminated. However, because the aggregate principal amount of Securities validly tendered and not validly withdrawn would cause the Aggregate Maximum Principal Amount to be exceeded and the Company does not expect to increase the Aggregate Maximum Principal Amount, the Company does not expect to accept any further tenders of Securities.

Holders of Securities that validly tendered and did not validly withdraw their Securities prior to 5:00 p.m. EST on November 4, 2019 (the "Early Tender Date"), are eligible to receive the Total Consideration (as defined below), which is inclusive of the "Early Tender Payment" of $30 per $1,000 principal amount of validly tendered and accepted Securities.

The consideration (the "Total Consideration") offered per $1,000 principal amount of Securities of each series of Securities validly tendered and accepted for purchase pursuant to the Tender Offer was determined in the manner described in the Offer to Purchase by reference to the applicable "Fixed Spread" for such Securities specified in the table above plus the applicable yield to maturity based on the bid-side price of the applicable "U.S. Treasury Reference Security" specified in the table above as quoted on the applicable page on the Bloomberg Bond Trader at 11:00 a.m. EST on November 5, 2019.

All holders of Securities accepted for purchase will also receive accrued and unpaid interest on Securities validly tendered and accepted for purchase from the applicable last interest payment date up to, but not including, the settlement date.

Securities tendered prior to or at the Early Tender Date and accepted for purchase will be accepted based on the Acceptance Priority Levels noted on the table above, with 1 being the highest Acceptance Priority Level and 4 being the lowest Acceptance Priority Level, and will have priority over Securities tendered after the Early Tender Date, regardless of the Acceptance Priority Levels of the Securities tendered after the Early Tender Date. Because the aggregate principal amount of Securities validly tendered and not validly withdrawn prior to the Early Tender Date would cause the Aggregate Maximum Principal Amount to be exceeded, such Securities will be purchased subject to the Acceptance Priority Levels and subject to proration as described in the Offer to Purchase. The Company plans to accept all Securities tendered with Acceptance Priority Levels 1 and 2, Securities tendered with Acceptance Priority Level 3, using a proration factor of approximately 49.1% in accordance with the Offer to Purchase, and none of the Securities tendered with Acceptance Priority Level 4. Any tendered Securities not accepted for purchase will be promptly credited to the Holder’s account with DTC or otherwise returned to the Holder without cost.

The settlement date for the Securities that are validly tendered on or prior to the Early Tender Date is expected to be November 12, 2019, the fifth business day after the Early Tender Date, assuming the conditions to the satisfaction of the Tender Offer are satisfied.

Withdrawal rights for the Tender Offer expired at 5:00 p.m. EST on November 4, 2019, and, accordingly, Securities validly tendered in the Tender Offer may no longer be withdrawn except where additional withdrawal rights are required by law.

The Company’s obligation to accept for payment and to pay for the Securities validly tendered in the Tender Offer is not subject to any minimum tender condition but is subject to the satisfaction or waiver of the conditions described in the Offer to Purchase, including the financing condition that the Company shall have closed one or more debt financings resulting in net proceeds in an amount, together with cash on hand, not less than the amount required, upon the terms and subject to the conditions of the Tender Offer, to purchase all the Securities validly tendered and accepted for purchase in the Tender Offer and to pay accrued interest thereon and fees and expenses associated therewith. The Company reserves the right, subject to applicable law, to: (i) waive any and all conditions to the Tender Offer; (ii) extend or terminate the Tender Offer; (iii) increase or decrease the Aggregate Maximum Principal Amount; or (iv) otherwise amend the Tender Offer in any respect.

The Company or its affiliates may also from time to time, after completion of the Tender Offer, purchase additional Securities in the open market, in privately negotiated transactions, through tender or exchange offers or otherwise, or the Company may redeem Securities that are redeemable pursuant to their terms.

Information Relating to the Tender Offer
Barclays Capital Inc., BofA Securities and Goldman Sachs & Co. LLC are acting as the lead dealer managers (the "Lead Dealer Managers") for the Tender Offer. The information agent and tender agent for the Tender Offer is D.F. King & Co., Inc. (the "Tender and Information Agent"). Copies of the Offer to Purchase are available by contacting the Tender and Information Agent at (866)-406-2285 (U.S. toll-free) or (212)-269-5550 (banks and brokers) or email at [email protected]. Questions regarding the Tender Offer should be directed to Barclays Capital Inc., Liability Management Group at (212) 528-7581 (collect) or (800) 438-3242 (toll free), BofA Securities, Liability Management Group at (980) 387-3907 (collect) or (888) 292-0070 (toll-free) or Goldman Sachs & Co. LLC, Liability Management Group at (212) 902-6351 (collect) or (800) 828-3182 (toll-free). Citigroup Global Markets Inc., Deutsche Bank Securities Inc., J.P. Morgan Securities LLC and Wells Fargo Securities, LLC are acting as the co-dealer managers for the Tender Offer (collectively with the Lead Dealer Managers, the "Dealer Managers").

None of the Company, its affiliates, their respective boards of directors or managing members, the Dealer Managers, the Tender and Information Agent or the trustee with respect to any series of Securities is making any recommendation as to whether holders of Securities should tender any Securities in response to the Tender Offer, and neither the Company nor any such other person has authorized any person to make any such recommendation. Holders of Securities must make their own decision as to whether to tender any of their Securities, and, if so, the principal amount of Securities to tender.

This press release shall not constitute an offer to sell, a solicitation to buy or an offer to purchase or sell any securities. The Tender Offer is being made only pursuant to the Offer to Purchase and only in such jurisdictions as is permitted under applicable law.

The full details of the Tender Offer, including complete instructions on how to tender Securities, are included in the Offer to Purchase. The Offer to Purchase contains important information that should be read by holders of Securities before making a decision to tender any Securities.