On March 17, 2020 Provectus (OTCQB: PVCT) reported that data from ongoing research into investigational lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) for the treatment of solid tumor and blood cancers had been accepted for presentation at the now terminated AACR (Free AACR Whitepaper) Annual Meeting 2020, which was originally scheduled to be held April 24-29 in San Diego, California (Press release, Provectus Biopharmaceuticals, MAR 17, 2020, View Source [SID1234555649]). Intratumoral injection with PV-10 yields immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

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The details of the previously accepted abstract were:

Title: Association of heat shock proteins as chaperone for STING: A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10
Abstract Control Number: 8165
Session Category: Clinical Research
Session Title: Inflammation, Immunity, and Cancer/Modifiers of the Tumor Microenvironment 1
Poster Board Number: 6
Permanent Abstract Number: 5393
This work was led by Aru Narendran, MD, PhD and his team of researchers at the Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC) Laboratory for Pre-Clinical and Drug Discovery Studies at the University of Calgary (Canada).

On March 10th, according to AACR (Free AACR Whitepaper)’s board of directors, the AACR (Free AACR Whitepaper) Annual Meeting 2020 was terminated based on their evaluation of currently available information related to the novel coronavirus (COVID-19) outbreak and a rescheduled meeting is being planned for later this year.

About PV-10

PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma). PV-10 is also undergoing preclinical study for pediatric solid tumor cancers (like neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).5,6

Tumor Cell Lysosomes as the Seminal Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.7 Cancer progression and metastasis are associated with lysosomal compartment changes8,9, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance10.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupts them, and causes them to die. The physicochemical properties of lysosomes trap PV-10. A lumenal pH of 4.5 to 5.0 is ideal for the conversion of the hydrophilic RB salt into the hydrophobic (lipophilic) lactone version. Provectus1,11, external collaborators5, and other researchers12-14 have independently shown that PV-10 (RB) triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via PV-10: PV-10 inducing autolytic cell death, or death by self-digestion, in Hepa1-6 murine HCC cells can be viewed in this Provectus video of the event (ethidium homodimer [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames; the event has a duration of approximately one hour). Exposure to PV-10 triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video; this event has a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators from POETIC using relapsed and refractory human pediatric neuroblastoma cells to show that lysosomes are disrupted upon exposure to PV-10.5

Immune Signaling Pathways: PV-10 causes acute oncolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways studied to date, such as the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Other mediated immune signaling pathways that have been identified include poly-ADP ribose polymerase (PARP) cleavage and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.15

Orphan Drug Designations (ODDs)

ODD status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Drug Product

Rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt) is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. PV-10 drug product is a formulation of 10% w/v RB in 0.9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and administered without dilution to solid tumors via intratumoral injection.

Intellectual Property (IP)

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which pharmaceutical grade RB and related xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Conference on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of PV-10 and systemic immunomodulatory therapy (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035.

On March 17, 2020 BioSpecifics Technologies Corp. (NASDAQ: BSTC), a biopharmaceutical company that originated and continues to develop collagenase-based therapies with a first in class collagenase-based product marketed as XIAFLEX in North America, reported its financial results for the fourth quarter and full year ended December 31, 2019 and provided a corporate update (Press release, BioSpecifics Technologies, MAR 17, 2020, View Source [SID1234555648]).

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"BioSpecifics generated strong growth in 2019. We reported a 16% increase in royalty revenue received from our partner Endo’s sales of XIAFLEX and our fully diluted earnings per share grew by 22%. Looking forward, we have a number of reasons to be enthusiastic about the future growth potential for XIAFLEX. First, the market for XIAFLEX in Dupuytren’s contracture and Peyronie’s disease continues to expand, second the FDA’s decision on Endo’s new BLA for the treatment of cellulite is expected in July 2020 and third Endo has announced the commencement of development programs in two new indications, adhesive capsulitis and plantar fibromatosis," said J. Kevin Buchi, chief executive officer of BioSpecifics. "Operating from a position of sound financial strength, we intend to explore opportunities beyond XIAFLEX."

Fourth Quarter and Full Year 2019 Financial Results

BioSpecifics reported net income of $7.3 million for the fourth quarter ended December 31, 2019, or $1.00 per basic share and $1.00 per share on a fully diluted basis, compared to net income of $6.2 million, or $0.85 per basic share and $0.84 per share on a fully diluted basis, for the same period in 2018. For the full year ended December 31, 2019, the Company reported a net income of $24.5 million, or $3.34 per basic share and $3.33 per share on a fully diluted basis, compared to a net income of $20.1 million, or $2.77 per basic share and $2.73 per share on a fully diluted basis for the same period in 2018.

Total revenue for the fourth quarter ended December 31, 2019 was $11.8 million, compared to $9.9 million for the same period in 2018. For the full year ended December 31, 2019, total revenue was $38.2 million, compared to $33.0 million for the same period in 2018.

As of December 31, 2019, BioSpecifics had cash and cash equivalents and investments of $105.8 million, compared to $82.0 million as of December 31, 2018.

As of December 31, 2019, BioSpecifics had 7,339,578 million shares of common stock outstanding.

Commercial & Pipeline Highlights and Anticipated Upcoming Milestones

BioSpecifics’ Royalty Revenues from the XIAFLEX Commercial Franchise Grew by 16% Year-Over-Year for 2019: XIAFLEX royalty revenue growth was attributable to royalties associated with higher net sales of XIAFLEX by Endo International plc (Endo), in Dupuytren’s contracture and Peyronie’s disease.
Net Sales of XIAFLEX Expected to Continue to Grow in 2020: BioSpecifics’ partner, Endo, expects that XIAFLEX full year revenue growth will be approximately 20 percent in 2020.
Endo’s Biologics License Application (BLA) filing for CCH for Treatment of Cellulite Accepted by U.S. Food and Drug Administration (FDA) in November 2019: On November 19, 2019, the FDA accepted for review the original BLA for CCH for the treatment of cellulite in the buttocks. The Prescription Drug User Fee Act (PDUFA) date for the BLA, has been set for July 6, 2020.
Development in Two New Indications, Adhesive Capsulitis and Plantar Fibromatosis, Announced in 2020: Endo announced in 2020 that it expects to begin development in two new indications, adhesive capsulitis and plantar fibromatosis. Adhesive capsulitis, also known as frozen shoulder, is an inflammation and thickening of the shoulder capsule due to collagen which causes decreased motion in the shoulder. Plantar fibromatosis is a non-malignant thickening of the feet’s deep connective tissue or fascia. There are currently no FDA-approved pharmaceutical therapies available to treat either condition.

On March 17, 2020 Varian (NYSE: VAR) reported, Proton International at UAB has now treated its first cancer patient with the Varian ProBeam Compact proton therapy system (Press release, Varian Medical Systems, MAR 17, 2020, View Source [SID1234555646]). The center, a collaboration between The University of Alabama at Birmingham (UAB) and Proton International, opened in January 2020 and is the first proton therapy center in Alabama and one of only 35 proton therapy centers in the United States.

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"We celebrate this first of many patients who will be treated at UAB with this advanced technology," said Will Ferniany, Ph.D., CEO of the UAB Health System. "The Varian ProBeam system is one of the most advanced tools available and our physicians are now able to improve care and precision of treatment for their cancer patients. With this technology, we will improve the quality of life for many cancer patients and their families in Alabama and the Southeast."

Dr. James Bonner, chairman of the UAB Radiation Oncology Department added, "This is a landmark moment for the patients of Alabama. After so many years of planning, we have been able to bring this technologically advanced treatment to the UAB Cancer Center."

Proton therapy is the most sophisticated radiotherapy technology available today. It uses protons, accelerated to about two-thirds the speed of light, or more than 100,000 miles per second, to destroy cancer cells, while minimizing exposure to nearby healthy tissues.

"We are pleased to have reached this important milestone for the patients of Alabama and the region," said Chris Chandler, CEO of Proton International. "Together with Varian and UAB, this public – private approach has resulted in the development of a unique service that otherwise may not have been available to patients. Varian’s commitment has resulted in enhanced care for patients."

"One of our primary goals at Varian is to improve cancer care for patients around the globe," said Kolleen Kennedy, president, Proton Solutions and chief growth officer at Varian. "Through our partnership with Proton International and UAB, cancer patients in Alabama now have access to the most advanced, efficient and effective treatment, closer to home."

The Varian ProBeam Compact system is the only clinical single room system capable of fully rotational intensity modulated proton therapy (IMPT). Treatments can be delivered with an unmatched combination of speed, flexibility and cost efficiency. The full-featured ProBeam Compact includes a cyclotron, high-definition pencil beam scanning technology for IMPT, a fully rotational gantry, robotic patient positioning tools, and a comprehensive suite of motion management tools. It incorporates cone beam CT imaging for positioning the patient based on high quality anatomical images with excellent soft tissue resolution, and Varian’s world-class Eclipse and ARIA software systems for the planning and managing of treatments.

On March 17, 2020 Pfizer Inc. (NYSE:PFE) reported investors and the general public to view and listen to a webcast of a conference call with investment analysts at 10 a.m. EDT on Tuesday, April 28, 2020 (Press release, Pfizer, MAR 17, 2020, View Source [SID1234555645]). The purpose of the call is to provide an update on Pfizer’s results, as reflected in the company’s First Quarter 2020 Performance Report, to be issued that morning.

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To view and listen to the webcast and view the Performance Report, visit our web site at www.pfizer.com/investors. Information on accessing and pre-registering for the webcast will be available at www.pfizer.com/investors beginning today. Participants are advised to pre-register in advance of the conference call.

You can also listen to the conference call by dialing either (866) 669-8582 in the United States and Canada or (702) 495-1304 outside of the United States and Canada. The password is "First Quarter Earnings".

On March 17, 2020 NGM Biopharmaceuticals, Inc. (NGM or the Company) (Nasdaq: NGM), a biotechnology company focused on developing transformative therapeutics for patients, reported financial results for the fourth quarter and year ended December 31, 2019 and business highlights (Press release, NGM Biopharmaceuticals, MAR 17, 2020, View Source [SID1234555644]).

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"2019 was a year of significant growth and productivity for NGM. We completed a successful IPO and achieved several milestones furthering our goal to operate one of the most productive R&D engines in the biopharma industry and enabling strong momentum as we entered 2020," said David J. Woodhouse, Ph.D., Chief Executive Officer at NGM. "We now have multiple clinical programs underway across cardio-metabolic and liver disease, ophthalmic disease and cancer. Each of our programs tackles an area of significant unmet medical need and has the potential to deliver a transformative impact for patients while enhancing shareholder value."

Dr. Woodhouse continued, "As we, along with our industry colleagues and our nation as a whole, navigate these uncertain times around the COVID-19 spread, we remain focused on delivering on our ambitious plans, while being mindful of the safety and well-being of our employees, patients and collaborators, and the broader community."

Hsiao D. Lieu, M.D., Chief Medical Officer of NGM, commented, "Following last month’s data readout from the final cohort of our adaptive Phase 2 study of aldafermin in NASH patients, we are very excited about aldafermin’s potential as a potent monotherapy to help patients with advanced disease. The results of our clinical trials in NASH patients have demonstrated aldafermin’s meaningful effect on all key liver histology and biomarker measures of the disease, accompanied by a favorable tolerability profile. We look forward to the continued progress of our aldafermin Phase 2b development program, where we hope to gain important clinical experience with this drug across a broader number of NASH patients and in different stages of the disease."

Key 2019 Accomplishments and Recent Highlights

Our Pipeline

Cardio-metabolic and liver disease

Reported positive preliminary topline liver histology and biomarker data from 24-week Phase 2 study of aldafermin 1 mg in patients with NASH (Cohort 4). In February 2020, NGM announced positive preliminary topline results from a 24-week double-blind, randomized, placebo-controlled Phase 2 clinical study (Cohort 4) of aldafermin (formerly NGM282) in NASH patients with Stage 2 or 3 (F2-F3) fibrosis. Cohort 4 was powered to demonstrate the effect of aldafermin treatment versus placebo on the primary endpoint of change in absolute liver fat content (LFC), which achieved statistical significance. In addition, the study assessed secondary and exploratory endpoints of liver histology and biomarkers of disease activity. The histology results revealed that

treatment with aldafermin led to clinically meaningful improvements at 24 weeks versus placebo in fibrosis improvement of ≥1 stage with no worsening of NASH and in resolution of NASH with no worsening of liver fibrosis. In addition, the study demonstrated a statistically significant impact on the composite endpoint of both fibrosis improvement and resolution of NASH (22% in aldafermin-treated patients vs. 0% placebo). In the study, aldafermin continued to demonstrate a favorable tolerability profile. Cohort 4 was the final reported cohort from NGM’s adaptive phase 2 clinical study of aldafermin in NASH. NGM has exclusive worldwide commercial rights to aldafermin.

Initiated Phase 2b study of aldafermin in NASH patients with F2-F3 fibrosis. In May 2019, NGM announced that it dosed the first patient in the Phase 2b ALPINE 2/3 clinical study evaluating aldafermin in patients with biopsy-confirmed NASH and F2-F3 liver fibrosis. This 24-week study is expected to enroll approximately 150 patients and will assess the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg of aldafermin compared to placebo. NGM expects to announce topline data from ALPINE 2/3 in the first half of 2021.

Initiated Phase 1 study of NGM395 in overweight healthy adults. In March 2020, NGM dosed the first patient in a Phase 1 single ascending dose clinical study evaluating the safety, tolerability and pharmacokinetics of NGM395, a long acting GDF15 (growth differentiation factor 15) analog, in obese but otherwise healthy adults. NGM395 is wholly-owned by NGM.

Ophthalmic disease

Initiated Phase 1 study of NGM621 for the potential treatment of geographic atrophy, an advanced dry form of age-related macular degeneration (AMD). In August 2019, NGM announced that it dosed the first patient in a Phase 1 clinical study to evaluate the safety, tolerability and pharmacokinetics of up to two intravitreal doses of NGM621 in patients with geographic atrophy. NGM621 is an inhibitory antibody binding complement C3, a key node of all three complement pathways.

Cancer

Initiated Phase 1a/1b study of NGM120 for the potential treatment of cancer and cancer anorexia/cachexia syndrome (CACS). In February 2020, NGM announced that it dosed the first patient in a Phase 1a/1b clinical study to evaluate NGM120, a first-in-class antagonistic antibody that binds glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) and inhibits GDF15 signaling, for the potential treatment of cancer and CACS. CACS is the uncontrolled wasting of both skeletal muscle and fat that is a common co-morbidity of cancer and is associated with shortened survival in cancer patients. The Phase 1a/1b study initiation followed the successful completion of a Phase 1 safety, tolerability and pharmacokinetics study of NGM120 in healthy adult subjects in 2019.

Merck has a one-time option to license NGM pipeline programs, other than aldafermin and NGM395, following human proof-of-concept trials, under the terms of the companies’ ongoing strategic collaboration. Upon exercising any such options, Merck would lead global product development and commercialization for the resulting products, if approved. Prior to Merck initiating a Phase 3 study for a licensed program, NGM may elect to either receive milestone and royalty payments or, in certain cases, to co-fund development and participate in a global cost and revenue share arrangement of up to 50%. The agreement also provides NGM with the option to participate in the co-promotion of any co‑funded program in the United States.

Corporate

Raised $173.7 million in net cash proceeds from initial public offering (IPO) and concurrent private placement with Merck. Commenced trading on the Nasdaq Global Select Market under the ticker symbol "NGM" on April 4, 2019.

Extended strategic collaboration with Merck to 2022. In March 2019, NGM and Merck announced that Merck exercised its option, under the terms of its original agreement with NGM, to extend the initial five-year research and early development phase of the collaboration for an additional two-year period from March 2020 to March 2022. The collaboration, originally announced in February 2015, is focused on discovering, developing and commercializing novel biologic therapeutics across a wide range of therapeutic areas. During the two-year extension period, Merck will continue to fund NGM’s research and development efforts at levels similar to those funded under the original collaboration terms and will make additional payments totaling up to $20 million in support of NGM’s research and development activities in 2021 and 2022. Merck retains one additional two-year extension option that is exercisable in March 2021, which would extend the collaboration from March 2022 to March 2024.

Expanded leadership with key management team and board appointments. NGM announced the appointment of two new executive leadership team members in 2019, Hsiao D. Lieu, M.D., as Senior Vice President, Chief Medical Officer and Valerie Pierce as Senior Vice President, General Counsel and Chief Compliance Officer. Last year, NGM also announced the appointment of Shelly Guyer to its Board of Directors. Ms. Guyer currently serves as Chief Financial Officer of Invitae Corporation.

Fourth Quarter and Full Year 2019 Financial Results

For the quarter ended December 31, 2019, NGM reported a net loss of $15.9 million compared with net income of $14.2 million for the corresponding period in 2018. For the year ended December 31, 2019, net loss was $42.8 million compared with a net loss of $0.5 million for the year ended December 31, 2018.

Related party revenue from our collaboration with Merck for the quarter and year ended December 31, 2019 was $31.1 million and $103.5 million compared to $47.1 million and $108.7 million for the quarter and year ended December 31, 2018. The decrease in related party revenue was primarily attributable to a one-time license fee received from Merck in the fourth quarter of 2018, partially offset by year-over-year increases in reimbursable research and development expenses for ongoing clinical activities and clinical material purchases, as well as additional upfront revenue recognized as a result of the adoption of ASU 2014-09, Revenue from Contracts with Customers (Topic 606) which was effective January 1, 2019.

Research and development expenses for the quarter and year ended December 31, 2019 were $42.0 million and $129.3 compared to $28.9 million and $95.7 million for the quarter and year ended December 31, 2018. The increase in research and development expenses was primarily attributable to increases in personnel-related expenses, including stock-based compensation expense driven by increased headcount and the commencement of the 2019 Employee Stock Purchase Plan (the "2019 ESPP"), clinical trial material purchases and external research and development expenses associated with the advancement of NGM’s growing pipeline and aldafermin program expenses for ongoing Phase 2b clinical trials.

General and administrative expenses for the quarter and year ended December 31, 2019 were $6.4 million and $23.6 million compared to $5.1 million and $17.3 million for the quarter and year ended December 31, 2018. The increase in general and administrative expenses was primarily attributable to increases in personnel-related expenses, including stock-based compensation expense driven by increased headcount and the commencement of the 2019 ESPP, insurance expenses, legal expenses associated with maintaining our intellectual property rights and other professional service expenses required to support NGM’s operations as a public company.

Cash, cash equivalents and short-term marketable securities were $344.5 million as of December 31, 2019, compared to $206.6 million as of December 31, 2018. The increase of $137.9 million was primarily attributable to net cash proceeds of $173.7 million from the Company’s IPO and concurrent private placement, related party revenue from Merck, partially offset by cash used in operations during the period.