On March 17, 2020 4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutics, reported an update on the previously reported interim data from an ongoing phase I/II clinical trial, in collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to evaluate 4D pharma’s lead oncology candidate, MRx0518, in combination with MSD’s anti-PD-1 therapy KEYTRUDA (pembrolizumab), in patients with advanced malignancies who have previously responded and whose disease has then progressed on PD-1/PD-L1 inhibitors (Press release, 4d Pharma, MAR 17, 2020, View Source [SID1234555662]).

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The additional data has been presented to delegates of Chardan’s virtual 2nd Annual Microbiome Medicines Summit, on March 16, 2020. The data was presented by Duncan Peyton, CEO and Alex Stevenson, CSO, 4D pharma. The presentation provides additional detail on headline interim results from the phase I/II clinical trial announced on November 6, 2019. The trial is being conducted, and data compiled at MD Anderson, University of Texas, US.

The data is the first global clinical confirmation of a live biotherapeutic product (LBP) initiating a response in cancer patients. The patients in the live biotherapeutic clinical trial had all previously received multiple lines of treatment with little efficacy, exhausting all currently approved treatment options. 4D pharma believes that the data provide evidence that adding the Company’s product, MRx0518, to the checkpoint inhibitor treatment regimen can induce tumour responses in patients who have previously become refractory to these therapies. 4D believes that, if demonstrated in larger studies, the addition of MRx0518 to checkpoint therapy will enable approved checkpoint inhibitors to work more effectively, for a longer duration, and in a wider patient population.

The phase I/II 4D pharma study is an open label trial to evaluate the safety and preliminary efficacy of MRx0518 and KEYTRUDA in patients with renal cell carcinoma (RCC), melanoma, non-small cell lung cancer (NSCLC) and bladder cancer, who have developed resistance to PD-1/PD-L1 inhibitors. Checkpoint therapies, whilst capable of producing durable anti-tumour responses, are not effective in all patients. In addition, those who do respond can develop resistance over time, leading to disease progression. The study has been designed to investigate this effect in patients with advanced metastatic disease.

Clinical observations from the first six patients in part A were presented, including:

Two partial responses (PR) with evidence of tumor shrinkage who remain on study (one patient for over 10 months)
One patient with stable disease (SD), remains on study for over eight months
Evidence of increased tumor-infiltrating lymphocytes (TILs) following treatment
No drug related serious adverse events
Specifically, one stage IV NSCLC patient had received seven lines of therapy over nearly three years with little response. In this patient the combination of MRx0518 + KEYTRUDA achieved an overall 51% reduction in target tumors at last assessment. The patient has now been on drug for 41 weeks.

"The further interim data from the Phase I/II trial provide significant potential for fresh treatment options for oncology patients that have exhausted all other currently approved therapies," said Duncan Peyton, CEO, 4D pharma.

He added: "4D pharma is now delivering the first global clinical evidence of the therapeutic potential of oral live biotherapeutics in cancer. This confirms the significant impact of microbiome immuno-oncology to the pharmaceutical industry in providing additional treatments for patients with underserved needs and little available therapeutic options. This clinical validation of live biotherapeutics to impact diseases external to the gut significantly supports our wider clinical pipeline in other areas such as neurodegeneration and other cancers."

Recruitment for the trial continues to progress as expected, with recruitment for Part A now completed. 4D expects to announce data for all 12 Part A subjects in Q2 and to commence enrolment for Part B, which will expand the study based on the Part A data. It is expected that the study will be expanded to additional international trial locations and sites, initially in the US. 4D pharma also expects to discuss the findings from Part A and avenues for accelerated development with the regulatory agencies.

On March 17, 2020 InnoCare Pharma reported that Beijing priced its Hong Kong IPO at the top end of its proposed range to raise $288 million at a $1 billion valuation, according to insiders (Press release, InnoCare Pharma, MAR 17, 2020, View Source [SID1234555664]). The company develops immunotherapies for cancer and autoimmune diseases. It has three molecules in clinical trials, including its lead product, a BTK inhibitor under NDA review in China for leukemia and lymphoma. The company discovers candidates through its own research and in-licenses products from other biopharmas. Hong Kong has not completed an IPO since January because of the coronavirus outbreak.

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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 Morphic Therapeutic (NASDAQ: MORF), a biopharmaceutical company developing a new generation of oral integrin therapies for the treatment of serious chronic diseases, reported the appointment of Peter G. Linde, M.D., as chief medical officer (Press release, Morphic Therapeutic, MAR 17, 2020, View Source [SID1234555665]). Dr. Linde was previously vice president of medical research at Acceleron Pharma, Inc., where he was responsible for the design and execution of clinical trials with positive outcomes in both pulmonary and hematologic diseases. Dr. Linde will oversee the development of Morphic’s small molecule integrin inhibitors as the company advances its oral integrin inhibitors toward clinical trials.

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"Dr. Linde has an extensive track record of driving clinical advancement across multiple therapeutic areas including inflammatory, pulmonary and hematologic disease. Notably, his experience includes clinical studies in inflammatory bowel disease, the therapeutic target of MORF-057, our lead oral integrin inhibitor anticipated to enter the clinic this year," commented Praveen Tipirneni, M.D., president and chief executive officer of Morphic Therapeutic. "On behalf of everyone at Morphic, I welcome Dr. Linde to the team. We look forward to his leadership in developing the processes, partners and resources to guide MORF-057 and our portfolio of additional product candidates through development."

Dr. Linde brings more than 15 years of experience in pharmaceutical clinical development and research. Most recently he served as vice president of medical research at Acceleron Pharma, Inc., where he led study design and development for clinical trials in pulmonary and hematologic diseases. These studies included the recently successful Phase 2 study of sotatercept in pulmonary arterial hypertension as well as late-stage development work on luspatercept, which in 2019 obtained FDA approval for treatment of transfusion-dependent patients with beta-thalassemia. Prior to this role, Dr. Linde was a project leader in clinical asset development at AbbVie, Inc., where he guided the global development of renal and immunology products. Dr. Linde also served as a senior director of clinical development at FibroGen, Inc., developing trial protocols and leading clinical studies to treat anemia in hemodialysis patients. Dr. Linde began his pharmaceutical career developing new indications for the decompensated heart failure treatment NATRECOR (nesiritide) as a director of clinical research at Johnson & Johnson, Inc.

"Morphic is built on world-class insight into integrin biology, outstanding medicinal chemistry and a growing body of impressive preclinical data. It has also established itself as the leader in the discovery of small molecule drug candidates that specifically target this important receptor class. Oral integrin therapy has the potential to transform treatments for patients suffering from diseases spanning autoimmunity, fibrosis and cancer," said Dr. Linde. "I am very much looking forward to guiding the clinical development of Morphic’s pipeline."

Dr. Linde completed medical school at Stanford University and a residency at the University of Pennsylvania Medical Center in internal medicine. He then went on to complete two fellowships at Massachusetts General Hospital/Harvard Medical School in nephrology and transplantation. Following the completion of his core medical training, Dr. Linde spent approximately 10 years as a practicing clinician, clinical instructor and mentor at several institutions including Allegheny University, Massachusetts General Hospital, Brigham & Women’s Hospital and San Francisco General Hospital. Dr. Linde earned his bachelor’s degrees from the Massachusetts Institute of Technology in both chemical engineering as well as applied biology. He is also an inventor on multiple issued patents relating to stem cell and extracorporeal organ support technologies.

NATRECOR is a registered trademark of Johnson & Johnson.

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.