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Asuragen NGS System for Streamlined Detection of RNA Lung Cancer Variants Demonstrates Superior Performance in Multisite Evaluation

On January 29, 2019 Asuragen, Inc., a molecular diagnostics company delivering easy-to-use products for complex testing in genetics and oncology, reported that the results of a five-site study using the QuantideX NGS RNA Lung Cancer Kit* have been published as an article in press by The Journal of Molecular Diagnostics (see View Source) (Press release, Asuragen, JAN 29, 2019, View Source [SID1234532947]). The peer-reviewed article, titled "Design, Optimization, and Multisite Evaluation of a Targeted Next-Generation Sequencing Assay System for Chimeric RNAs from Gene Fusions and Exon-Skipping Events in Non–Small Cell Lung Cancer," also describes the design and development of the assay system. This system includes controls, pre-analytical sample QC, targeted RNA-based enrichment, library clean-up and pooling, and companion bioinformatics software that analyzes the corresponding next-generation sequencing (NGS) data.

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Non-small cell lung cancer (NSCLC) accounts for more than 10% of all newly diagnosed cancers and is characterized by diverse molecular drivers ranging from point mutations and insertion-deletions to gene fusions and exon skipping events. NGS offers a multiplexed approach for detecting RNA chimera from many different fused genes and splice variants but it requires integrated reagents, controls, and interpretive software to standardize testing procedures and assure consistent results across laboratories. This study details the verification and external evaluations of the targeted RNA-seq panel across a total of >200 FFPE tumor biopsy materials representing common and rare RNA variants that are associated with NSCLC.

The QuantideX RNA Lung Cancer Kit is a cGMP manufactured, end-to-end, NGS-in-a-Box product solution that simultaneously interrogates over 100 known clinically-relevant gene fusions, 3’/5’ imbalance markers to detect rare or novel fusions, MET exon 14 skipping events, and mRNA expression levels from 23 genes in NSCLC samples. The kit is part of an integrated workflow that delivers sequencing-ready libraries in approximately half the time of comparable competitor methods and incorporates push-button analytics to standardize test results. The assay is optimized for use with low-quality and quantity samples such as FFPE and fine-needle aspirations and can generate libraries from approximately 10-20 ng RNA or total nucleic acid.

The targeted RNA-seq system was assessed for sensitivity, accuracy, alignment of results with alternative testing methods, and multi-laboratory concordance. Targeted fusions and exon skipping events were detected down to a 1% cell fraction in a wild-type background. Non-targeted fusions could be detected by 3’/5’ imbalance, with 100% of cases detected at 15% positivity and 50% at 5% positivity. Results of the Asuragen NGS assay were also compared to those generated by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and/or the nCounter Vantage Lung Gene Fusion Panel (Nanostring Technologies) using residual clinical specimens; all results reported by the Asuragen assay were consistent with those generated by these alternative methods. Lastly, a five-site precision study was conducted to evaluate assay reproducibility. Every fusion and exon skipping event in the cohort of nearly 250 sample libraries was correctly detected across sites, consistent with the reference results.

An accompanying commentary on the study, also pending publication in the journal, described the value of targeted RNA-based assays for limited nucleic acid inputs and for their focus on clinically actionable findings. "[The authors’] efforts at standardization and streamlining the workflow process were demonstrated by good concordance across a multisite implementation… the [QuantideX NGS RNA Lung Cancer Kit] demonstrated good accuracy, reproducibility, and analytic sensitivity for detecting fusions that were specifically targeted by design," noted the commentary’s author, Lauren Ritterhouse, MD, PhD, Co-Director, Molecular Diagnostics and Clinical Genomics Laboratories at the University of Chicago. "As such, they were able to produce a comprehensive approach to targeted RNA sequencing that addressed several quality control metrics that could ease the adoption of this assay into laboratories seeking an RNA-based assay for identifying fusions and splicing events in NSCLC."

*For Research Use Only. Not for use in diagnostic procedures.

Merck Announces Second-Quarter 2019 Dividend

On January 29, 2019 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the Board of Directors has declared a quarterly dividend of $0.55 per share of the company’s common stock for the second quarter of 2019 (Press release, Merck & Co, JAN 29, 2019, View Source [SID1234532946]). Payment will be made on April 5, 2019 to shareholders of record at the close of business on March 15, 2019.

BIOGEN REPORTS RECORD REVENUES FOR BOTH THE FULL YEAR AND
Q4 2018, $13.5 BILLION AND $3.5 BILLION, RESPECTIVELY

On January 29, 2019 Biogen Inc. (Nasdaq: BIIB) reported full year and fourth quarter 2018 financial results (Press release, Biogen, JAN 29, 2019, View Source [SID1234532945]).

"In 2018 Biogen executed well against our strategic priorities and financial objectives," said Michel Vounatsos, Biogen’s chief executive officer. "We made significant progress developing and expanding our pipeline, as well as advancing multiple modalities to potentially deliver new therapies to patients. We also reported solid revenue growth for the year, led by continued strong global penetration of SPINRAZA, significant gains in our biosimilars business, and resilience in our core MS business. We believe our strong base business, including a deep and diversified neuroscience pipeline, positions Biogen well to take advantage of the opportunities before us. As always, we remain focused on allocating capital efficiently and appropriately with the objective of maximizing returns for our shareholders over the long term."

Financial Results

•Full year total revenues were $13.5 billion, a 10% increase versus the prior year. o Full year multiple sclerosis (MS) revenues, including $478 million in royalties on the sales of OCREVUS, were relatively stable versus the prior year at $9.1 billion.
▪ For the fourth quarter of 2018 MS revenues, including $152 million in royalties on the sales of OCREVUS, grew 2% versus the prior year to $2.3 billion.
o Full year revenue growth was driven primarily by the continued global launch of SPINRAZA, which contributed $1.7 billion in revenues compared to $884 million in the prior year.
• Full year GAAP net income and diluted earnings per share (EPS) attributable to Biogen Inc. were $4.4 billion and $21.58, respectively, compared to $2.5 billion and $11.92, respectively, in the prior year.

o Full year 2017 GAAP net income and diluted EPS attributable to Biogen Inc. were negatively impacted by $1.2 billion and $5.51, respectively, due to the transition toll tax and re-measurement of our net deferred tax assets related to the U.S. corporate tax reform legislation.

"We have shown strong momentum in building depth in our core growth areas beyond Alzheimer’s disease, as we continue to build multiple franchises within neuroscience," Mr. Vounatsos continued. "The positive data for BIIB067 in SOD1 ALS highlight the potential to leverage groundbreaking science to address previously untreatable diseases and exemplifies our strategy to build depth in neuromuscular diseases and movement disorders. Over the next 12-18 months, we expect to have several important data readouts across clinical programs in multiple sclerosis, progressive supranuclear palsy, and Alzheimer’s disease."

In the fourth quarter of 2018 channel inventory levels in the U.S. increased by approximately $115 million for TECFIDERA, AVONEX, PLEGRIDY, and TYSABRI combined. This compares to relatively stable inventory levels in the third quarter of 2018 and an increase of approximately $50 million in the fourth quarter of 2017.

• In the fourth quarter of 2018 SPINRAZA revenues comprised $236 million in sales in the U.S. and $234 million in sales outside the U.S. The number of commercial patients receiving SPINRAZA grew approximately 9% in the U.S. and approximately 18% outside the U.S. versus the third quarter of 2018. In the fourth quarter of 2018 Biogen recorded SPINRAZA revenues in over 40 countries. SPINRAZA revenues outside the 4 U.S. were negatively impacted by a combination of lower volumes in certain markets due to loading dose dynamics, the timing of shipments in certain distributor markets, and pricing dynamics in certain markets.

R&D expense in the fourth quarter of 2018 included $35 million related to the option exercise with Ionis Pharmaceuticals, Inc. (Ionis) to develop and commercialize BIIB067 (IONIS-SOD1Rx), an antisense oligonucleotide for ALS with superoxide dismutase 1 (SOD1) mutations.

• R&D expense in the fourth quarter of 2018 included $17 million related to the collaboration and research and development services agreement with C4 Therapeutics (C4T).

• SG&A expense in the fourth quarter of 2018 increased versus the third quarter of 2018 primarily due to timing of spend as well as certain investments across sales and marketing, worldwide medical, and general and administrative expense.

Other Financial Highlights

• For 2018 the Company’s effective full year GAAP tax rate was 24%, and the Company’s effective full year Non-GAAP tax rate was 21%. For the fourth quarter of 2018 the Company’s effective GAAP tax rate was 33%, and the Company’s effective Non-GAAP tax rate was 21%.

o In the fourth quarter of 2017 Biogen booked a GAAP-only tax charge of $1.2 billion related to the U.S. corporate tax reform legislation. o In the fourth qua 5

• As of December 31, 2018, Biogen had cash, cash equivalents, and marketable securities totaling approximately $4.9 billion, and approximately $5.9 billion in notes payable and other financing arrangements.

• The Company generated $6.2 billion in net cash flows from operations in 2018, including $1.9 billion in the fourth quarter of 2018.

• For 2018 the Company’s full year weighted average diluted shares were 205 million. For the fourth quarter of 2018 the Company’s weighted average diluted shares were 200 million.

2019 Financial Guidance

Biogen also announced its full year 2019 financial guidance. This guidance consists of the following components: • Revenue is expected to be approximately $13.6 billion to $13.8 billion.

• GAAP and Non-GAAP R&D expense is expected to be approximately 16% to 17% of total revenue. o This guidance does not include any impact from potential acquisitions or large business development transactions, as both are hard to predict.
• GAAP and Non-GAAP SG&A expense is expected to be approximately 16% to 17% of total revenue.
• GAAP tax rate is expected to be approximately 18.5% to 19.5%; Non-GAAP tax rate is expected to be approximately 18% to 19%. • GAAP diluted EPS is expected to be between $26.65 and $27.65.
• Non-GAAP diluted EPS is expected to be between $28.00 and $29.00. Biogen may incur charges, realize gains or losses, or experience other events in 2019 that could cause actual results to vary from this guidance.

Recent Events

• In January 2019 Biogen and Skyhawk Therapeutics, Inc. (Skyhawk) entered into a collaboration and research and development services agreement pursuant to which the companies will leverage Skyhawk’s SkySTAR technology platform with the goal of discovering innovative small molecule RNA splicing modifiers for MS, spinal muscular atrophy (SMA), and other neurological diseases. Biogen paid Skyhawk an upfront payment of $74 million and may also pay additional milestone payments as well as potential royalties. Biogen expects to record a research and development expense of approximately $35 million in the first quarter of 2019 related to this collaboration, with the remaining portion of the upfront payment to be allocated to future research services.

• In 2018 Biogen added six clinical programs to its neuroscience pipeline, including BIIB078 (IONIS-C9Rx) for C9ORF72-associated ALS, BIIB110 (ActRIIA/B ligand trap) for muscle enhancement in diseases such as SMA, an option to acquire TMS-007 for acute ischemic stroke, BIIB104 (AMPA receptor potentiator) for cognitive 6 impairment associated with schizophrenia (CIAS), BIIB074 (vixotrigine) for small fiber neuropathy, and BIIB095 for neuropathic pain.

• In December 2018 Biogen and C4T entered into a collaboration and research and development services agreement to investigate the use of C4T’s novel protein degradation platform to discover and develop potential new treatments for neurological conditions, such as Alzheimer’s disease (AD) and Parkinson’s disease. Biogen will pay C4T up to a total of $415 million in upfront and additional milestone payments as well as potential royalties. Biogen recorded a research and development expense of $17 million in the fourth quarter of 2018 related to this collaboration.

• In December 2018 Biogen enrolled the first patient in a global Phase 3b study evaluating the efficacy and safety of extended interval dosing (EID) for natalizumab compared to standard interval dosing (SID) in patients with relapsing MS. Currently commercialized under the brand name TYSABRI, natalizumab 300 mg dosed every four weeks is the only approved dosing regimen. The new study, NOVA, is a two-year, prospective, randomized, interventional, controlled, open-label, rater-blinded, international Phase 3b study that will assess the efficacy of six-week natalizumab dosing intervals in people with relapsing-remitting MS with a primary endpoint measuring the number of new or newly enlarging T2 hyperintense lesions at week 48. The NOVA study was initiated following analyses of observational data that showed that EID was associated with a significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection. The NOVA study aims to assess the efficacy of EID natalizumab to further evaluate the drug’s benefit-risk profile.

• In December 2018 Biogen received feedback from the U.S. Food and Drug Administration (FDA) on its proposed Phase 3 development plan for BIIB074 (vixotrigine) in trigeminal neuralgia (TGN). Biogen is now planning to initiate a Phase 3 program for the development of vixotrigine in TGN by the end of 2019.

• In December 2018 Biogen and Alkermes plc (Alkermes) announced that Alkermes has submitted a New Drug Application (NDA) to the FDA for diroximel fumarate (BIIB098), a novel oral fumarate in development for the treatment of relapsing forms of MS. Alkermes is seeking approval of diroximel fumarate under the 505(b)(2) regulatory pathway, and the NDA submission includes data from EVOLVE-1, a Phase 3 pivotal trial that evaluated long-term safety in relapsing-remitting MS with approximately 700 patients dosed with diroximel fumarate. If approved, Biogen intends to market diroximel fumarate under the brand name VUMERITY. This name has been conditionally accepted by the FDA and will be confirmed upon approval.

• In December 2018 Biogen notified Applied Genetic Technologies Corporation (AGTC) of the termination of its collaboration agreement related to the development of AAVbased gene therapies for the treatment of rare ophthalmologic diseases, including Xlinked retinoschisis (XLRS) and X-linked retinitis pigmentosa. This portfolio prioritization decision followed topline interim six-month data from a Phase 1/2 clinical trial in XLRS which demonstrated no signs of clinical activity. The termination will be effective in March 2019. 7

• In December 2018 Biogen reported positive Phase 1 data from an interim analysis of a randomized, placebo-controlled single-and multiple-ascending dose study (n=70) that achieved proof-of-biology and proof-of-concept for BIIB067, an investigational treatment for ALS with SOD1 mutations. At the highest dose tested (n=10), treatment with BIIB067 over a three month period resulted in a statistically significant lowering of SOD1 protein levels in the cerebrospinal fluid (p=0.002) and numerical trends across three efficacy endpoints: slowing of clinical decline as measured by the ALS Functional Rating Scale-Revised, slowing of decline in respiratory function as measured by slow vital capacity, and slowing of decline in muscle strength as measured by handheld dynamometry, all compared to placebo (n=12). Biogen paid Ionis a $35 million one-time upfront payment to exercise its option to obtain a worldwide, exclusive, royalty-bearing license to develop and commercialize BIIB067. The Company plans to add an additional cohort to this study with the potential to support registration.

• In December 2018 Biogen dosed the first patient in the Phase 2b study of BIIB104, an AMPA receptor potentiator, in patients with CIAS.

• In December 2018 Biogen dosed the first patient in a bioequivalence study to test whether exposure levels of PLEGRIDY are maintained with intramuscular administration as compared to subcutaneous administration. Biogen is pursuing an intramuscular formulation of PLEGRIDY with the goal of reducing injection site reactions.

• In November 2018 Biogen was awarded the 2018 International Prix Galien as Best Biotechnology Product for SPINRAZA, the first and only treatment for SMA. The prestigious honor marks the seventh Prix Galien for SPINRAZA, following country recognitions in the U.S., Germany, Italy, Belgium-Luxembourg, the Netherlands, and the U.K. The International Prix Galien is given every two years by Prix Galien International Committee members in recognition of excellence in scientific innovation to improve human health.

• In October 2018 Biogen presented results at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting, in Barcelona, Spain, from the recent 36-and 48-month analyses of the ongoing long-term extension (LTE) of the Phase 1b PRIME study of aducanumab, an investigational treatment for mild cognitive impairment (MCI) due to AD and mild AD. A late-breaking oral presentation and a poster included data from patients treated with aducanumab for up to 36 and 48 months. Data from both analyses showed a reduction in amyloid plaque levels in a dose-and time-dependent manner, as measured by positron emission tomography (PET). In addition, analyses of exploratory clinical endpoints, Clinical Dementia Rating Sum of Boxes (CDR-SB) and the Mini-Mental State Examination (MMSE), suggested a continued slowing of clinical decline over 36 months and 48 months. The results in each dosing arm were generally consistent with previously reported analyses of this study, and there were no changes to the risk-benefit profile of aducanumab.

• In October 2018 Biogen’s collaboration partner Eisai Co., Ltd. (Eisai) presented the latest data from the Phase 2 clinical study (Study 201) of BAN2401, an anti-amyloid beta protofibril antibody, in 856 patients with early AD, at a symposium session titled "Clinical and Biomarker Updates from BAN2401 Study 201 in Early Alzheimer’s Disease" held on October 25 at CTAD. The study did not achieve its primary outcome measure which was designed to enable a potentially more rapid entry into Phase 3 development based on Bayesian analysis at 12 months of treatment. From conventional statistical analysis of the topline 18-month final results, the highest treatment dose demonstrated a statistically significant reduction in brain amyloid measured by PET at 18 months (p<0.0001). This dose also showed a statistically significant slowing of clinical decline on the Alzheimer’s disease composite score (ADCOMS) of 30% compared to placebo at 18 months (p=0.034). Eisai also presented analysis of clinical outcome measures in pre-specified subgroups, including in APOE4 positive versus APOE4 negative patients. Conference Call and Webcast The Company’s earnings conference call for the fourth quarter will be broadcast via the internet at 8:00 a.m. ET on January 29, 2019, and will be accessible through the Investors section of Biogen’s website, www.biogen.com. Supplemental information in the form of a slide presentation is also accessible at the same location on the internet and will be subsequently available on the website for at least one month. Note about Earnings Releases and Calls Starting with the second quarter 2018 earnings release, Biogen has ceased publishing press releases relating to future earnings calls, earnings releases, and investor events via newswire services. The Company will post these materials on the Investors section of Biogen’s website, www.biogen.com, and issue a statement on Twitter (@biogen) when they become available

Propanc Biopharma to Present at the 2019 BIO CEO & Investor Conference

On January 29, 2019 Propanc Biopharma, Inc. (OTCQB: PPCB) ("Propanc"), a clinical stage biopharmaceutical company focused on development of new and proprietary treatments for cancer patients suffering from solid tumors such as pancreatic, ovarian and colorectal cancers, reported that its Chief Executive Officer, James Nathanielsz, will be presenting at the 2019 BIO CEO & Investor Conference on Tuesday, February 12, 2019, at 9:45 am EST (Press release, Propanc, JAN 29, 2019, View Source [SID1234532944]). The conference will be held at the New York Marriott Marquis.

"The BIO CEO & Investor Conference is one of the largest investor conferences, focused on established and emerging publicly traded and select private biotech companies, and I am honored to be selected to present at this year’s conference. As we prepare to transition our lead technology into human trials, this is a great opportunity for us to meet with investors and potential partners to provide a company update for 2019, focusing on the advancement of our lead product, PRP," said James Nathanielsz, CEO and Executive Chairman of Propanc. "PRP is a solution for intravenous administration of a combination of two pancreatic proenzymes trypsinogen and chymotrypsinogen. Progressing towards a first-in-human study, PRP seeks to prevent recurrence and metastasis from solid tumors by targeting and eradicating cancer stem cells."

Investors and potential partners attending the conference who wish to meet with Propanc’s management can reach out through the BIO One-on-One Partnering system to request a meeting. For those not planning to attend the meeting, please contact Lisa DeScenza to set up a call with Mr. Nathanielsz to learn more about Propanc.

A live audio webcast of Mr. Nathanielsz’s presentation will be accessible within the Investor Relations section of Propanc’s website at View Source An archived version of this webcast will be available for 90 days following the conclusion of the live presentation.

ARTICLE COMPARING SURVIVAL OUTCOMES OF ISOLATED LIMB INFUSION VERSUS PV-10 FOR IN-TRANSIT MELANOMA PUBLISHED IN JOURNAL OF SURGICAL ONCOLOGY

On January 29, 2019 Provectus (OTCQB: PVCT) reported that the Journal of Surgical Oncology (JSO) has published results from an investigator-conceived and led, single-center study of in-transit melanoma (ITM) patients receiving either regionally-administered isolated limb infusion (ILI) or intratumoral (aka intralesional) PV-10 to assess and compare the effect of these treatments on survival (Press release, Provectus Biopharmaceuticals, JAN 29, 2019, View Source [SID1234532943]). The JSO article detailed the work of investigators at the Princess Alexandra Hospital (PAH) in Brisbane, Australia, where ILI represents the historical standard of care for ITM and PV-10 was used to treat ITM under expanded access. Intratumoral injection of PV-10 can yield immunogenic cell death in solid tumor cancers and stimulate tumor-specific reactivity in circulating T cells.1,2,3,4

This article, entitled "Patients with in-transit melanoma metastases have comparable survival outcomes following isolated limb infusion or intralesional PV-10 – A propensity score matched, single center study," may be accessed via the JSO’s website at View Source

Key Results from the JSO Article:

Baseline and disease characteristics:

Patients matched for key covariates: age, gender, primary disease site, and Breslow thickness
ILI: 36 patients; 56% men; median age of 76.5 years (interquartile range 69-83); 100% Stage IIIB/IIIC
PV-10: 36 patients; 56% men; median age of 74.5 years (65-81); 89% Stage IIIB/IIIC (11% Stage IV)

Treatment response (patient-level best overall response):

ILI: 22% complete response and 50% overall response rate
PV-10: 25% complete response and 83% overall response rate

Survival outcomes:

ILI
progression-free survival (PFS): median of 5.0 months (interquartile range 2.7-10.7)
disease-free survival (DFS): median of 16.5 months (8.9-48.4)
overall survival (OS): median of 29.7 months (12.3-88.5)
melanoma-specific survival (MSS): median of 74.4 months (24.3-NA); 12‐, 24‐, 36‐, and 60‐month MSS rates of 85%, 75%, 60%, and 60%, respectively
PV-10
PFS: median of 3.9 months (9.6-47.9)
DFS: median of 14.1 months (4.5-20.9)
OS: median of 27.1 months (14.3-48.6)
MSS: median of 36.4 months (16.6-65.3); 12‐, 24‐, 36‐, and 60‐month MSS rates of 83%, 70%, 54%, and 36%, respectively
Differences in PFS, DFS, and MSS comparing ILI with PV‐10 were not statistically significant
Among the authors’ conclusions:

"Overall these results demonstrate that demographically similar patients with in-transit melanoma metastases treated with ILI or PV-10 have comparable long-term survival rates,"

"Propensity score matching is a useful statistical technique for examining relative treatment effects within complex patient groups, particularly when larger randomized controlled studies are impractical,"

"A complete response to either treatment was the only independent factor identified that significantly predicted long-term survival,"

"These findings suggest that both ILI and PV‐10 can be considered as a suitable standard of care," and

"These treatments are relevant and likely to remain of value in the near future, particularly for the treatment of symptomatic or refractory metastases following the discontinuation of systemic therapies due to serious drug-related side-effects or exhaustion of other systemic options."
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "Despite the advances made by targeted therapies and checkpoint inhibitors, these comparative survival data highlight the important role that investigational PV-10 may have for the treatment of advanced melanoma. The Australian investigators place PV-10’s role in the context of relatively more expensive systemic agents that have substantial toxicity profiles and similar response rates."

Mr. Rodrigues added, "Furthermore, these comparative survival data substantiate the Company’s historical work in melanoma and provide more validation of PV-10 in a single-agent setting for a challenging patient population. The key focus of Provectus’ drug development program now is to demonstrate PV-10 activity in both single-agent and combination therapy settings for the treatment of both hot and cold tumor types."

About PV-10

Provectus’ lead investigational oncology drug, PV-10, the first small molecule oncolytic immunotherapy, can induce immunogenic cell death. PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver, and preclinical study for pediatric cancers.