On October 8, 2018 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported the successful animal testing of DNA-encoded monoclonal antibodies targeting the immune checkpoint molecule CTLA-4 as published in Cancer Research (Press release, Inovio, OCT 8, 2018, View Source;Monoclonal-Antibody-dMAb-Checkpoint-Inhibitor–and-Demonstrates-Tumor-Shrinkage-in-Preclinical-Studies/default.aspx [SID1234530270]). The breakthrough preclinical study demonstrated that highly optimized dMAbs targeting mouse CTLA-4 protein can be robustly expressed in vivo, and shrank tumors in mice. More importantly, Inovio’s dMAb constructs for anti-human CTLA-4 antibodies ipilimumab (YERVOY) and tremelimumab, achieved high expression levels in mice (approximately 85µg/ml and 58µg/ml, respectively). These dMAbs exhibited long-term expression with maintenance of serum levels >15µg/ml for over a year.

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This research publication is significant because it is the first to report on the use of Inovio dMAb technology to develop novel monoclonal antibody-based therapies targeting checkpoint inhibitors. Inovio is developing additional dMAbs targeting other checkpoint molecules including PD-1. When delivered directly into the body, the genetic instructions provided from the dMAb construct enable the patient’s own cells to become the factory which manufactures the therapeutic monoclonal antibody products. Inovio has previously published several papers demonstrating its dMAb product candidate’s ability to treat multiple virus targets such as flu, dengue, chikungunya, and HIV.

Laurent Humeau, Ph.D., Inovio’s Senior Vice President, Research & Development, said, "Even though conventional monoclonal antibodies represent one of the most successful segments of the biotechnology market, accounting for over $50 billion in sales today, manufacturing complexity and repeated dosing may limit a broader use of this technology. Inovio’s dMAb products may improve upon this class using our synthetic design and in vivo production. This newly published study further support that Inovio’s potent dMAb platform can be expanded to target cancer. We plan on advancing the first clinical dMAb candidate into the first-in-human study in 2019. Moreover, we expect to form partnerships to advance several dMAb products targeting cancers and infectious diseases."

David B. Weiner, Ph.D., the paper’s senior author and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, said, "Our work provides the first demonstration that we can use synthetic DNA technology to produce checkpoint inhibitor molecules in vivo to impact tumor growth in a preclinical setting. We showed that dMAbs may represent a valuable addition to the cancer immunotherapy toolbox: In our preclinical studies, dMAbs achieved antitumor activity comparable to that of traditional monoclonal antibodies, while being delivered through a simpler formulation that may provide a bridge to expand target populations for checkpoint inhibitors."

The study highlights that delivery of a synthetic, sequence-optimized DNA plasmid designed to encode anti-mouse CTLA-4 monoclonal antibodies, with the aid of an electroporation device to enhance uptake, resulted in significant and prolonged antibody expression with even a single dose. Importantly, this approach stimulated robust CD8+ T cell infiltration, achieving tumor clearance across multiple mouse tumor models. The researchers then went on to develop human checkpoint inhibitor molecules and demonstrated their production in mice and their ability to stimulate human T cell responses associated with antitumor activity. The study clearly demonstrates how optimized dMAbs encoding the human CPI’s ipilimumab and tremelimumab are potently expressed in vivo and enhance the activation of human effector T cells with the potential to destroy tumors. This strategy provides a novel approach to immune checkpoint therapy, with the potential to expand patient access to this breakthrough immunotherapy to treat cancer.

Funded with over $60 million in R&D support from top agencies like DARPA, NIH, and the Gates Foundation, Inovio dMAb products could extend the medical benefits that marketed monoclonal antibodies have already achieved, and even potentially address diseases that conventional monoclonal antibodies cannot.

About Inovio’s DNA-based Monoclonal Antibody Platform

Traditional monoclonal antibodies are manufactured outside the body in bioreactors, typically requiring costly large-scale manufacturing facility development and laborious production. Inovio’s disruptive dMAb technology has the potential to overcome these limitations by virtue of their simplified design, rapidity of development, product stability, ease of manufacturing and deplorability, and cost effectiveness, thereby providing potential new avenues for treating a range of diseases. Another significant advancement seen in Inovio dMAb technologies is that the optimized genes for a desired monoclonal antibody is encoded in a DNA plasmid, which is produced using very cost effective and highly scalable fermentation techniques. These plasmids are delivered directly into cells of the body using electroporation and the encoded monoclonal antibody is then directly produced by these cells. Previously published studies show that a single administration of a highly optimized DNA-based monoclonal antibody targeting HIV virus produced a high level of expression of the antibody in the bloodstream of mice; Inovio similarly reported data showing that dMAb products against flu, Ebola, chikungunya and dengue protected animals against lethal challenge. Inovio Ebola dMAb product is being developed under a grant from the Defense Advanced Research Projects Agency (DARPA).

On October 8, 2018 Exact Sciences Corp. (Nasdaq: EXAS) reported that the company plans to release its third-quarter 2018 financial results after the close of the U.S. financial markets on Oct. 30, 2018 (Press release, Exact Sciences, OCT 8, 2018, View Source [SID1234529880]). Following the release, company management will host a webcast and conference call at 5 p.m. ET to discuss financial results and business progress.

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Third-Quarter 2018 Webcast & Conference Call Details

Date: Tuesday, Oct. 30, 2018

Time: 5 p.m. ET, 4 p.m. CT

Webcast: The live webcast can be accessed at www.exactsciences.com

Telephone: Domestic callers, dial 877-201-0168

International callers, dial +1 647-788-4901

Access code for both domestic and international callers: 6870368

An archive of the webcast will be available at www.exactsciences.com. A replay of the conference call will be available by calling 800-585-8367 domestically or 416-621-4642 internationally. The access code for the replay of the call is 6870368. The webcast, conference call and replay are open to all interested parties.

On October 8, 2018 Navidea Biopharmaceuticals, Inc. (NYSE American: NAVB) ("Navidea" or the "Company"), a company focused on the development of precision immunodiagnostic agents and immunotherapeutics, reported that its Chief Executive Officer, Jed Latkin, will present a corporate overview of the Company at the 2018 BIO Investor Forum, being held October 17-18, 2018 in San Francisco, California (Press release, Navidea Biopharmaceuticals, OCT 8, 2018, View Source [SID1234530337]).

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Conference Presentation Details:

Where: The Westin St. Francis Hotel, San Francisco, California
When: Thursday, October 18, 2018 at 11:15AM PDT
Room: Elizabethan C
Conference Website:
View Source

To schedule a meeting, investors can submit meeting requests through the conference one-on-one partnering system.

On October 6, 2018 Veracyte, Inc. (Nasdaq: VCYT) reported that new findings from six studies reinforcing the "real world" performance of the next-generation Afirma Genomic Sequencing Classifier (GSC) and the Afirma Xpression Atlas in thyroid cancer diagnosis were presented at the 88th Annual Meeting of the American Thyroid Association (ATA) (Press release, Veracyte, OCT 6, 2018, View Source [SID1234529797]). The meeting is being held October 3-7 in Washington, D.C.

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Researchers from leading institutions presented posters showing that use of the Afirma GSC at their respective centers significantly increased the identification of benign thyroid nodules among those deemed indeterminate – not clearly benign or malignant – following cytopathology review, compared to the original Afirma test.

The Ohio State University – Researchers compared results of 113 indeterminate samples that were tested with the Afirma GSC to those of 403 samples using the earlier version of the test (the Afirma Gene Expression Classifier, or GEC). The Afirma GSC identified 74.1 percent of the nodules as benign, compared to 48.4 percent with the GEC, an increase of 53 percent. The overall surgery rate among all patients who underwent genomic testing decreased by more than half – from 42.2 percent with the GEC to 20.2 percent with the GSC.
Cleveland Clinic – Comparing results of 46 samples tested with the Afirma GSC between July 2017 and December 2017 with 182 samples tested with the original test between December 2011 and July 2017, researchers found that the GSC identified 67.4 percent as benign, compared to 41.8 percent with the GEC – an increase of 61 percent. The overall surgery rate for nodules tested with the GSC was 32.6 percent, compared to 47.3 percent with the original test, a decrease of 31 percent.
Brigham and Women’s Hospital – Researchers evaluated results for 583 thyroid nodules tested with either the Afirma GSC (n=97) or GEC (n=486) between 2011 and 2018. They found that the Afirma GSC identified 64.9 percent of nodules as benign, compared to 47.9 percent with the GEC, an increase of 35 percent.
"Our results show that with the improved testing, we sent significantly fewer patients to surgery," said Dr. Christian Nasr, medical director of the Thyroid Center in the Endocrinology & Metabolism Institute at Cleveland Clinic in Cleveland, Ohio. "Additionally, when patients went to surgery following ‘suspicious’ results, we were more likely to find cancer. Our findings suggest that the next-generation test can help more patients avoid unnecessary thyroid surgery, while focusing healthcare resources on the patients who are more likely to need them."

Additionally, in two oral presentations, researchers shared the first "real world" Afirma Xpression Atlas data, providing insights into the distribution of a wide range of gene variants and fusions across key categories of indeterminate thyroid nodules and Afirma GSC results. For example, among 13,549 indeterminate thyroid nodules evaluated using the Afirma GSC and Xpression Atlas, more than a quarter (25.9 percent) of GSC-suspicious nodules (in primary risk categories known as Bethesda III/IV) contained RAS variants. Additionally, RET, NTRK, BRAF and ALK fusions were only found in GSC-suspicious, versus GSC-benign, cases (in all Bethesda categories).

"Having detailed genomic information about thyroid nodules that are malignant or suspicious for cancer may in some cases help inform surgical decision-making for these patients," said Dr. Allan C. Golding of Memorial Healthcare System in Hollywood, Fla. "Additionally, the wide range of gene alterations detected by the Xpression Atlas may provide further insights into pathway activation and potential cancer treatment targets for patients with thyroid cancer."

The field of precision medicine is progressing rapidly, and multiple targeted therapies are in clinical trials or have been approved for treatment of advanced cancers that harbor specific genomic alterations. In the new data presented at the ATA conference, genomic changes (or alterations) targeted by these new therapies were identified in Afirma GSC-suspicious cases by the Xpression Atlas.

"The new data shared at the ATA annual meeting add to the growing library of real-world evidence demonstrating the Afirma GSC’s performance across multiple institutions in reducing unnecessary surgeries in thyroid cancer diagnosis," said Bonnie Anderson, Veracyte’s chairman and chief executive officer. "Additionally, these new study data for the Afirma Xpression Atlas demonstrate the ability of our robust RNA sequencing platform to provide rich genomic content that may help inform surgery decisions and treatment options for patients with suspected or confirmed thyroid cancer. The extensive gene alteration data that it provides becomes increasingly important in the era of targeted therapies."

For more information, please visit the Veracyte Booth #201 or www.afirma.com/ATA2018.

About Afirma

Veracyte’s Afirma solution provides a comprehensive offering in thyroid cancer diagnosis for physicians evaluating patients with thyroid nodules. The Afirma Genomic Sequencing Classifier combines RNA sequencing data with machine learning to identify patients with benign thyroid nodules among those with indeterminate cytopathology results in order to avoid unnecessary surgery and preserve the thyroid. Since the commercial introduction of Afirma in 2011, Veracyte has performed over 100,000 genomic tests, and estimates it has saved more than 40,000 patients from unnecessary thyroid surgery and removed an estimated $800 million in surgery costs from the healthcare system. The Afirma classifier is proven in over 20 published clinical studies, is included in most leading clinical guidelines and is covered as medically necessary by Medicare and all major U.S. health plans. The company’s Afirma Xpression Atlas platform, introduced in May 2018, provides extensive genomic data that may inform surgery strategy and treatment options for patients with thyroid nodules that are suspicious for cancer or cancerous. The RNA sequencing-based platform measures 761 DNA variants and 130 RNA fusions in over 500 genes shown to be associated with thyroid cancer on thyroid nodule fine needle aspiration samples.

On October 6, 2018 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported the presentation of updated data from the ongoing Phase 1 ARROW clinical trial of BLU-667, an investigational precision therapy targeting RET alterations, including resistance mutations (Press release, Blueprint Medicines, OCT 6, 2018, View Source [SID1234529798]). The new results showed that BLU-667 was highly active and well-tolerated in patients with advanced RET-altered medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC), with increased activity observed with higher dose levels and longer treatment durations.

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The reported data showed 90 percent of evaluable patients with MTC and PTC had radiographic tumor reductions, regardless of RET alteration type or prior multi-kinase inhibitor (MKI) therapy. In addition, the response rate was 62 percent in patients with MTC treated once daily (QD) with BLU-667 at doses of 300 to 400 mg for at least 24 weeks. In the MTC and PTC populations, all responders across dose levels and all patients treated at 400 mg QD remain on study. Safety results were consistent with prior data, and the majority of adverse events (AEs) were Grade 1. These results were as of a data cutoff date of September 14, 2018 and were reported today in an oral presentation at The 88th Annual Meeting of the American Thyroid Association (ATA).

"Existing treatment of medullary and papillary thyroid cancer with multi-kinase inhibitors is limited by frequent dose modifications or interruptions due to off-target toxicities, reducing the opportunity for a meaningful or sustained response," said Andy Boral, M.D., Ph.D., Chief Medical Officer of Blueprint Medicines. "These new data showed selectively targeting RET alterations with BLU-667 was well-tolerated and enabled durable responses. Importantly, response rates were high for patients with prolonged time on therapy at higher dose levels, demonstrating that potent and sustained target inhibition leads to improved patient outcomes. We believe these results begin to reveal the potential of BLU-667 to transform the care of patients with RET-altered thyroid cancer, and we look forward to seeing the data continue to mature as additional patients are treated at the recommended phase 2 dose for longer durations."

Based on the encouraging data reported to date, Blueprint Medicines has expanded enrollment targets for the ARROW trial to further evaluate the safety and efficacy of BLU-667 in a broader patient population and, ultimately, to support potential registration.

Data Highlights from the Ongoing Phase 1 ARROW Clinical Trial

The data presented included all patients enrolled in the Phase 1 ARROW clinical trial as of May 9, 2018 and included follow-up on these patients through the data cutoff date of September 14, 2018. Of the 69 patients who had been treated with BLU-667 in the dose escalation and expansion portions of the trial, 42 had RET-altered thyroid cancer, including 37 with MTC and five with PTC. In the dose escalation portion, patients were treated at dose levels ranging from 30 mg to 600 mg QD or up to 300 mg twice daily. In the expansion portion, patients were treated at the recommended phase 2 dose of 400 mg QD.

Clinical Activity Data

As of the data cutoff date, 35 patients with MTC and four patients with PTC were evaluable for response assessment by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Overall, 90 percent of MTC and PTC patients with measurable target lesions had radiographic tumor reductions.

In patients with MTC, response assessments showed increased clinical activity with higher dose levels and longer treatment durations. Across all evaluable MTC patients, the overall response rate (ORR) was 49 percent, including one patient with a confirmed complete response (CR) and 16 patients with a partial response (PR; two pending confirmation). In patients with MTC treated with 300 to 400 mg QD for at least 24 weeks, the response rate was 62 percent, including one patient with a confirmed CR and seven patients with a confirmed PR.

In patients with PTC, two of four evaluable patients had a confirmed PR, and all evaluable patients with PTC had radiographic tumor shrinkage.

The data also showed encouraging evidence of durable activity. All patients with MTC and PTC who responded to BLU-667 remain on treatment as of the data cutoff date. In addition, all patients treated at 400 mg QD are continuing on therapy. Patients with the longest treatment durations remain on therapy for more than 15 months.

Anti-tumor activity was observed regardless of prior MKI therapy or RET alteration. Similar response rates were observed in MTC patients who were MKI-experienced (47 percent; 8/17 patients) and MKI-naïve (50 percent; 9/18 patients). In addition, clinical responses were observed in patients with common activating mutations in MTC (e.g., M918T) and fusion partners in PTC (e.g., NCO4A and CCDC6). A clinical response was also observed in the one evaluable MTC patient with a germline V804M gatekeeper mutation.

Safety Data

The reported data showed that across 69 patients, BLU-667 was well-tolerated as of the data cutoff date. Most AEs were Grade 1, and only two patients discontinued therapy due to a treatment-related AE (Grade 3 increased alanine aminotransferase in a patient with liver metastases and Grade 2 pneumonitis). Treatment-emergent AEs (regardless of relationship to BLU-667) reported by investigators (≥15 percent) most commonly were constipation (35 percent), increased aspartate aminotransferase (33 percent), anemia (30 percent), hypertension (30 percent), decreased white blood cell count (29 percent), diarrhea (28 percent), neutropenia (28 percent), increased alanine aminotransferase (25 percent), increased blood creatinine (23 percent), fatigue (19 percent) and headache (17 percent). Grade 3 or higher treatment-related AEs occurring in two or more patients included anemia, hypertension, decreased white blood cell count, diarrhea and neutropenia.

About the Phase 1 ARROW Clinical Trial of BLU-667

ARROW is a Phase 1 clinical trial designed to evaluate the safety, tolerability and efficacy of BLU-667 in multiple ascending doses in adults with RET-altered non-small cell lung cancer (NSCLC), MTC and other advanced solid tumors. The trial consists of two parts: a dose escalation portion and an expansion portion. Enrollment in the dose escalation portion is complete, and the expansion portion has been initiated and is actively enrolling patients in six defined cohorts at the recommended phase 2 dose of 400 mg QD: (1) RET-altered NSCLC patients previously treated with an MKI, (2) RET-altered NSCLC patients who have not previously received any MKI treatment, (3) MTC patients previously treated with an MKI, (4) MTC patients who have not previously received any MKI treatment, (5) patients with other RET-altered solid tumors and (6) RET-altered solid tumor patients with prior selective RET tyrosine kinase inhibitor. Trial objectives include assessing response, pharmacokinetics, pharmacodynamics and safety. The trial is designed to enroll approximately 190 patients across all six expansion cohorts, at multiple sites in the United States, European Union and Asia.

Patients and physicians interested in the ARROW clinical trial can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. Additional details are available at www.arrowtrial.com or www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03037385).

About RET-Altered Solid Tumors

RET activating fusions and mutations are a key disease driver in many cancer types, including NSCLC and MTC. RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC and approximately 10 percent of patients with PTC, while RET mutations are implicated in approximately 60 percent of patients with MTC. In addition, oncogenic RET alterations are observed at low frequencies in colorectal, breast, pancreatic and other cancers, and RET fusions have been observed in patients with treatment-resistant, EGFR-mutant NSCLC.

Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved MKIs with RET activity being evaluated in clinical trials. Thus far, clinical activity attributable to RET inhibition has been uncertain for these inhibitors, likely due to insufficient inhibition of RET and off-target toxicities. There is a need for precision therapies that provide durable clinical benefit by selectively targeting RET alterations and resistance mutations.

About BLU-667

BLU-667 is an investigational, once-daily oral precision therapy specifically designed for highly potent and selective targeting of oncogenic RET fusions, mutations and resistance mutations. In preclinical studies, BLU-667 consistently demonstrated sub-nanomolar potency against the most common RET fusions, activating mutations and resistance mutations. In addition, BLU-667 demonstrated markedly improved selectivity for RET compared to approved MKIs, including more than 80-fold improved potency for RET versus VEGFR2. By suppressing primary and secondary mutants, BLU-667 has the potential to overcome and prevent the emergence of clinical resistance. This approach is expected to enable durable clinical responses across the range of RET alterations, with a favorable safety profile.

BLU-667 was discovered by Blueprint Medicines’ research team based on its proprietary compound library. The company is developing BLU-667 for the treatment of people with RET-altered NSCLC, MTC and other solid tumors. Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of BLU-667 and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for BLU-667 in the rest of the world.