On December 12, 2019 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported that new data from the global phase III FeDeriCa study conducted by Genentech, a member of the Roche Group, will be presented today at the 2019 San Antonio Breast Cancer Symposium (SABCS) (Press release, Halozyme, DEC 12, 2019, View Source [SID1234552294]).

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The FeDeriCa study investigated a fixed-dose combination (FDC) of pertuzumab (Perjeta) and trastuzumab (Herceptin) for subcutaneous administration using Halozyme’s ENHANZE drug delivery technology in combination with intravenous (IV) chemotherapy.

The FeDeriCa study met its primary endpoint, with subcutaneous administration of the FDC showing non-inferior levels of Perjeta in the blood during a given dosing interval (Ctrough) when compared to IV administration of Perjeta. The geometric mean ratio (GMR; a type of average used when assessing pharmacokinetics) for the primary endpoint was 1.22 (90% CI: 1.14 to 1.31), with the lower limit of the 90% CI of the GMR=1.14≥0.80 (the pre-specified non-inferiority margin).(1)

A secondary endpoint of non-inferior Ctrough of Herceptin was also met, with blood concentrations for people receiving the FDC non-inferior to those receiving IV Herceptin (GMR=1.33 [90% CI: 1.24 to 1.43]; lower limit of 90% CI of GMR=1.24≥0.80). A non-inferiority endpoint was chosen for the study to ensure that people were receiving sufficient dosing with Perjeta and Herceptin as compared to the established IV doses at the same treatment intervals. In addition, rates of total pathological complete response (pCR), a secondary endpoint, were comparable between the treatment arms, with 59.7% of patients receiving the FDC and 59.5% of patients treated with IV Perjeta and Herceptin achieving a total pCR – a difference of 0.15% (95% CI: -8.67 to 8.97). (1)

The safety profile of the FDC in combination with chemotherapy was comparable to that of IV administration of Perjeta plus Herceptin and chemotherapy and no new safety signals were identified, including no meaningful difference in cardiac toxicity. The most common adverse events in both arms were alopecia, nausea, diarrhea and anemia. (1)

"We are excited to see these more detailed results from the primary analysis of the FeDeriCa study presented at this important symposium," said Dr. Helen Torley, President and CEO. "We look forward to our partner beginning regulatory submissions in the near term so that patients suffering from HER2-positive breast cancer may have the option to receive Perjeta and Herceptin in a shorter administration time."

These new data from a primary analysis of the FeDeriCa study will be presented in a spotlight session at 7:00 AM CST today at the 2019 San Antonio Breast Cancer Symposium (SABCS) in Texas, US (Abstract #PD4-07).

Subcutaneous administration of the fixed-dose combination of Perjeta and Herceptin is approximately 8 minutes for the initial loading dose and approximately 5 minutes for each subsequent maintenance dose. Intravenous administration is approximately 150 minutes for the loading dose of Perjeta and Herceptin using standard IV formulations and between 60-150 minutes for subsequent maintenance infusions for the combination. (2,3,4)

About ENHANZE Technology
Halozyme’s proprietary ENHANZE drug-delivery technology is based on its patented recombinant human hyaluronidase enzyme (rHuPH20). rHuPH20 has been shown to remove traditional limitations on the volume of biologics that can be delivered subcutaneously (just under the skin). By using rHuPH20, some biologics and compounds that are administered intravenously may instead be delivered subcutaneously. ENHANZE may also benefit subcutaneous biologics by reducing the need for multiple injections. This delivery has been shown in studies to reduce health care practitioner time required for administration and shorten time for drug administration.

On December 12, 2019 Molecular Partners AG (SIX:MOLN), a clinical-stage biotech company pioneering the use of DARPin therapeutics to treat serious diseases, reported the continued progress of its pipeline of proprietary therapeutic product candidates in oncology, as well as abicipar in ophthalmology (Press release, Molecular Partners, DEC 12, 2019, View Source [SID1234552322]).

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"We are very proud to present the progress of our company over this past year. We continue to see success of our DARPin platform, from its earliest inception, with abicipar, now on the verge of potential FDA approval, to the newest concepts of attacking previously unreachable targets in cancer, and beyond, with the emergence of our peptide-MHC platform. Our pipeline is set up to provide significant value for patients," said Patrick Amstutz, Ph.D., Chief Executive Officer of Molecular Partners. "Today we will hear from both world-class key opinion leaders as well as our own team highlighting our expertise in drug development and clinical execution and how we will continue to succeed into 2020 and beyond."

During its R&D Day in New York, entitled "Novel Therapeutic Designs Applied," the company will provide updates on its clinical and preclinical programs, including:

Abicipar:

Presentation of recently updated two-year results from CEDAR and SEQUOIA demonstrate that vision gains observed after one year with every 8-week and every 12-week dosing were maintained in the second year (presented at AAO 2019).
Abicipar sustained vision gains in year two with quarterly injections compared to monthly ranibizumab.
MP0250:

As stated at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) last week, MP0250 continues to show long-lasting and deepening responses across a variety of patients with multiple myeloma in the relapsed/refractory setting. MP0250 has a novel mechanism of action, designed to target both VEGF and HGF. This design makes MP0250 ideally suited to attack the underlying disease and potentially improve sensitivity, or re-sensitize patients, to existing and emerging treatments.
The company also announced today its intent to evaluate partnering opportunities for MP0250. In conjunction with this endeavor, the company will not start the previously planned clinical trial investigating MP0250 in combination with an IMiD. This is aligned with the company’s corporate strategy to pursue combination data for the most relevant clinical combinations of MP0250, which would be more appropriately determined in collaboration with a partner.
"Given the dynamic landscape of current and emerging treatments for multiple myeloma, along with our strong data recently presented at ASH (Free ASH Whitepaper), we believe that aligning with a partner with an existing hematology franchise will be the best way to accelerate the MP0250 program through the clinic and into the treatment paradigm. In recent discussions with potential collaborators, it is obvious that the time for evaluating this opportunity is now," said Nicolas Leupin, M.D., MBA, Chief Medical Officer of Molecular Partners.

MP0274:

Also discussed today is MP0274, the second-most advanced DARPin drug candidate in the oncology pipeline. It has broad anti-HER activity, inhibiting HER1, HER2 and HER3-mediated downstream signaling via HER2, leading to induction of apoptosis.
The company continues to enroll patients and explore dosing in a phase 1 study.
Current dose levels are presently up to 8mg/kg, and initial data is anticipated in H1 2020.
MP0310 (AMG 506):

MP0310 is a multi-domain DARPin targeting FAP x 4-1BB, designed to activate immune cells specifically in the tumor and not in the rest of the body, potentially delivering greater efficacy with fewer side effects. Preclinical studies of MP0310 have demonstrated immune T-cell activation restricted to solid tumor tissues, and strong CD8 T-cell activation and expansion in vitro and in vivo.
The initial phase 1 study, being conducted by Molecular Partners, was initiated in mid-2019, and dose escalation is underway. Current clinical timelines are on track with initial data expected in H2 2020. In collaboration with Amgen, the clinical program is then expected to expand into additional combination cohorts, to be conducted by Amgen.
Beyond these clinical updates, the company will also detail its growing preclinical pipeline, including the data on FAP x CD40, now designated MP0317, a second multi-specific preclinical DARPin designed for localized activation. In addition to these updates, the company will highlight advances in the DARPin discovery platform, including the advent of peptide-MHC targeting and next-generation T-cell engagers.

In addition to an overview of the Molecular Partners clinical and preclinical pipeline, the R&D Day will feature presentations by the following experts:

Jeremy Wolfe, Practicing Ophthalmology Specialist
Stefan Knop, Department Head Hematology, University of Würzburg, Germany
Jordi Rodon, Associate Professor, Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center
Logistics
The R&D Day for institutional investors, sell-side analysts, investment bankers, and business development professionals will take place at The Yale Club, 50 Vanderbilt Avenue, New York City, from 7:30 am – 10:00 am EST. To RSVP email Seth Lewis at [email protected].
Breakfast starts at 7:30 am EST. The presentations will begin at 8:00 am, followed by a Q&A session.

Audio webcast
The event will be webcast live and will be made available on the company’s website under the Investors section. The replay will be available for 90 days following the presentation.

Financial Calendar
February 6, 2020 Publication of Full-year Results 2019 (unaudited)
April 29, 2020 Annual General Meeting
View Source

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates can engage more than five targets, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapeutics have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology and is advancing a proprietary pipeline of DARPin drug candidates in oncology and immuno-oncology. The most advanced global product candidate in partnership with Allergan is abicipar, a molecule for which phase 3 data have been filed to the respective regulators in both the US and in Europe. Several DARPin molecules for various ophthalmic indications are also in preclinical development. The most advanced DARPin therapeutic candidate wholly owned by Molecular Partners, MP0250, is in phase 2 clinical development for the treatment of hematological tumors. MP0274, the second-most advanced DARPin candidate owned by Molecular Partners, binds to Her2 and inhibits downstream signaling, which leads to induction of apoptosis. MP0274 is currently in phase 1. The company’s lead immuno-oncology product candidate MP0310 is a FAP x 4-1BB multi-DARPin therapeutic candidate designed to locally activate immune cells in the tumor by binding to FAP on tumor stromal cells (localizer) and co-stimulating T cells via 4-1BB (immune modulator). Molecular Partners has closed a collaboration agreement with Amgen for the exclusive clinical development and commercialization of MP0310. The molecule has entered in phase 1 of clinical development in H2 2019. Molecular Partners is also advancing a growing preclinical and research pipeline in immuno-oncology that features its "I/O toolbox" and additional development programs such as novel therapeutic designs to target peptide-MHC complexes. DARPin is a registered trademark owned by Molecular Partners AG.

On December 12, 2019 SPL Medical reported that the first patient has been successfully diagnosed with suspected lymph node metastases of prostate cancer with Ferrotran (Ferumoxtran) at the University Hospital Zurich (Press release, SPL Medical, DEC 12, 2019, View Source [SID1234552339]). This follows approval (Sonderbewilligung acc. to Swiss AMBV) by Swissmedic to Universitätsspital Zurich, Institut für Diagnostische und Interventionelle Radiologie, for restricted use of Ferrotran under a compassionate use program. Ferrotran (Ferumoxtran) is a novel contrast agent for use in MRI (magnetic resonance imaging) developed for the detection of lymph node metastases of prostate cancer. It is the first contrast agent for the use in MRI that is able to identify metastases as small as 1.5 mm. The rise of prostate specific antigen (PSA) is often the first symptom of suspected recurrent lymph node metastases. Being able to detect small metastases in prostate cancer early enough should enable a better chance of successful treatment.

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SPL Medical is the manufacturer of Ferrotran and responsible for the worldwide commercialization. The company is about to start a large multicenter trial of Ferrotran that will be conducted in 10 top radiology centers in Germany, Switzerland and the Netherlands, enrolling a total of 180 patients with prostatic cancer.

The development of Ferrotran was initially enabled and accelerated by Prof. Jelle Barentsz of the Radboud university medical center in Nijmegen, the Netherlands. He discovered the unique features of Ferrotran for the early detection of lymph node metastases when he used it as contrast agent for prostate cancer patients. So far, he has diagnosed metastases in more than 1,500 patients using this agent.

"We have built a vast experience with Ferrotran and have started to train radiologists from participating clinical centers to bring them up to speed with the latest use of the product and interpretation of the imaging results," said Prof. Barentsz.

"Ferrotran represents a major opportunity to improve the diagnosis of lymph node metastases from prostate cancer, with patients subsequently having potentially better treatment outcomes and fewer side-effects," stated Dr. Jürgen Feuerstein, Chief Executive Officer of SPL Medical. "The compassionate use program at the University Hospital Zurich provides vital access for prostate cancer patients to this game-changing product. Meanwhile, at SPL Medical, we will continue advancing our clinical development plan to enable potential registration of Ferrotran."

b.e.imaging GmbH, a shareholder of SPL Medical, is the distributor of Ferrotran in Germany, Austria and Switzerland.

About Ferrotran:
Ferrotran belongs to the group of USPIO’s (Ultrasmall Superparamagnetic Particles of Iron Oxide) and is the only contrast agent that can detect lymph node metastases as small as 1.5mm. Standard MRI, CT or PET scan are normally not able to detect metastatic nodes smaller than 7 – 8 mm. Since most prostate cancer patients are dying due to metastases, a precise diagnosis is of utmost importance. The detection of small metastases, combined with a very clear and contrast rich MRI image with the administration of Ferrotran, and excellent visualization of vessels enables an earlier and more precise treatment.

On December 12, 2019 AstraZeneca reported that it has received marketing authorisation from China’s National Medical Products Administration (NMPA) for Imfinzi (durvalumab) for the treatment of patients with unresectable, Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT) (Press release, AstraZeneca, DEC 12, 2019, View Source [SID1234552299]).

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The approval of Imfinzi is based on results from the primary analysis of progression-free survival (PFS) and supported by overall survival (OS) from the Phase III PACIFIC trial, both published in The New England Journal of Medicine. A post-hoc analysis of three-year OS results has since shown that consistent efficacy was maintained for treatment with Imfinzi after additional follow up.1

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: "This approval illustrates our long-standing commitment to improving health outcomes in China, where more than one-third of the world’s lung cancer diagnoses and deaths occur. As the global standard of care in this curative-intent setting, Imfinzi is an important new option for patients in China."

Results demonstrated a statistically significant and clinically meaningful OS and PFS benefit for treatment with Imfinzi vs. placebo after concurrent CRT. Imfinzi reduced the risk of death by 32% (equal to a hazard ratio of 0.68) and prolonged the time patients lived without disease progression or death by more than 11 months (median PFS: 16.8 vs. 5.6 months; hazard ratio of 0.52).

Among patients treated with Imfinzi, the most common adverse reactions (greater than or equal to 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnoea, and rash. Serious adverse reactions occurred in 29% of patients treated with Imfinzi, and 15% of patients discontinued treatment due to adverse reactions.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after CRT in 54 countries and regions, including the US, Japan and across the EU, based on the Phase III PACIFIC trial. The PACIFIC regimen, CRT followed by Imfinzi, is the global standard of care for the treatment of unresectable Stage III NSCLC.

About PACIFIC

The PACIFIC trial was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (i.e. regardless of PD-L1 status) with unresectable, Stage III (locally advanced) NSCLC whose disease had not progressed following concurrent platinum-based CRT.

The trial was conducted at 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate, and duration of response.

About Stage III NSCLC

Stage III (locally advanced) NSCLC is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.2 Stage III disease is different from Stage IV disease, when the cancer has spread throughout the body (metastasised), as the majority of Stage III patients are currently treated with curative intent.2,3

Stage III NSCLC represents approximately one-third of NSCLC incidence and in 2015 was estimated to affect nearly 200,000 patients in the following eight key countries: China, France, Germany, Italy, Japan, Spain, UK, US.4,5 The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.6 Prior to approval of Imfinzi in this setting, no new treatments beyond CRT had been available to patients for decades.7-10

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in 11 countries, including the US.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.

About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and ongoing Phase III trials ADAURA, LAURA, and FLAURA2 as well as the Phase II combination trials SAVANNAH and ORCHARD.11-13

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a targetable genetic mutation which represents approximately three-quarters of all patients with lung cancer.14 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON, PEARL, and CASPIAN) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy.

About AstraZeneca’s approach to Immuno-Oncology (IO)

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca believes that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On December 12, 2019 Provectus (OTCQB: PVCT) reported that data from the Company’s ongoing Phase 1 study of lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with standard of care immune checkpoint blockade for the treatment of uveal melanoma metastatic to the liver (NCT00986661, a single-center expansion cohort) were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology (I-O) Congress 2019, held from December 11-14, 2019 in Geneva, Switzerland (Press release, Provectus Pharmaceuticals, DEC 12, 2019, View Source [SID1234552323]). PV-10 is administered percutaneously when targeting primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer, metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

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Provectus’ ongoing, multi-center, open-label, Phase 1 basket study is evaluating the safety, tolerability, and preliminary efficacy of PV-10 in patients with solid tumors metastatic to the liver. mUM patients are being enrolled into a single-center study cohort at MD Anderson Cancer Center (MDACC) in Houston, Texas. Up to three hepatic tumors can be injected per treatment cycle. Response assessments are performed at Day 28, and then every three months. Patients with multiple injectable visceral hepatic tumors may receive additional PV-10 after Day 28. Eligible mUM patients may also receive standard of care checkpoint blockade during and after treatment with PV-10. This mUM clinical trial work has been led by Sapna Patel, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine at MDACC.

Preliminary Metastatic Uveal Melanoma Results from the Presentation at ESMO (Free ESMO Whitepaper) I-O Congress 2019:

Baseline characteristics (N=13): 46% men; median age of 61 years; 46% elevated LDH.
Disease characteristics: 100% Stage IV M1a-b; 38% of patients were refractory to one or more prior lines of treatment, with 31% having received prior immunotherapy.
Treatment summary: 7 patients received 1 cycle of PV-10; 6 patients received 2 cycles; 26 tumors were injected with PV-10.
Combination therapy: 9 patients received concomitant standard of care checkpoint blockade (i.e., maintenance anti-PD-1, anti-PD-1 subsequent to PV-10 treatment, or anti-CTLA-4+anti-PD-1 subsequent to PV-10 treatment).
Safety: 3 cases of Grade 3/4 transaminitis that resolved to Grade 1 or better within 72 hours; additional Grade 1 PV-10 related events seen in 1 patient each included pink stool, pink urine, photosensitivity, injection site pain, and hyperbilirubinemia; Additional adverse events, such as nausea, headache, myalgias, blurry vision, decreased white blood cells, and fatigue, were attributed to concomitant checkpoint blockade.
Preliminary injected target lesion efficacy (n=22): 32% partial response (PR); 32% overall response rate (ORR); 50% stable disease (SD); 82% disease control rate (DCR).
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "These preliminary safety and efficacy data of PV-10 combination therapy for the treatment of uveal melanoma metastatic to the liver, an immunologically cold and low tumor mutation burden tumor type, indicate that the triplet cancer therapy of PV-10, an anti-CTLA-4 agent, and an anti-PD-1 agent may have a role in an emerging standard of care. Upon assessing survival benefit with this new treatment approach, the next step in PV-10’s drug development program for this cancer indication would be a registration-directed clinical trial."

A copy of the ESMO (Free ESMO Whitepaper) I-O Congress 2019 poster presentation is available on Provectus’ website at View Source

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 (e.g., the ‘stomach’ of the cell, the cell’s ‘trash bin’), 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 functioning7. 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 this 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 the Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (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 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 one currently being investigated that plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, temporally-distinct, 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 (RB) disodium (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.