On September 17, 2020 Synthekine Inc., an engineered cytokine therapeutics company, reported the closing of an $82 million Series A financing (Press release, Synthekine, SEP 17, 2020, View Source [SID1234565316]). The financing was co-led by Canaan Partners, Samsara BioCapital and The Column Group, with participation from other undisclosed investors. Synthekine was founded by K. Christopher Garcia, Ph.D., to leverage discoveries showing that cytokines can be tuned to enhance their therapeutic effects.

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Synthekine combines strengths in immunology, structural insights on cytokines and multiple engineering technologies to create optimized therapeutics against new and validated cytokine targets for the treatment of cancer and autoimmune disorders. Proceeds from this Series A financing will be used to advance Synthekine’s lead therapeutic programs into clinical studies, expand its discovery pipeline and hone its proprietary cytokine engineering platforms. The company currently has two lead programs in IND-enabling development: STK-012, an engineered Interleukin-2 (IL-2) partial agonist for the treatment of cancer, and the combination of STK-009 and SYNCAR-001, an orthogonal IL-2 ligand and a CD-19 CAR-T-cell therapy being studied in combination.

"Cytokines have a fundamental role in the immune system and represent an enormous opportunity for innovative therapeutics. However, most cytokines broadly activate a wide range of cells that can simultaneously stimulate and suppress the immune system, making drug development against these targets challenging," said Debanjan Ray, chief executive officer of Synthekine. "Chris Garcia has shown, for a wide range of therapeutically important cytokines, that cytokine efficacy and toxicity can be decoupled through structure-based protein engineering. These findings mean that many cytokines previously thought to be unsuitable as therapeutics can be transformed into safe and effective drugs. In addition to our highly differentiated IL-2-based programs, we have assembled multiple best-in-class technologies and an accomplished team to develop cytokine therapeutics by engineering them at the molecular level to enhance their activity and selectivity."

Unlocking cytokine therapeutics through unique structural biology insights

Cytokines are small, soluble proteins that are powerful regulators of the immune system and can stimulate a wide range of immune cells, primarily driven by their binding and interaction with cell surface receptors. Most cytokines are pleiotropic, meaning that a given cytokine can exert a range of responses across multiple cell types. Pleiotropy has proven to be a significant obstacle in the development of cytokine therapeutics. Existing cytokine therapeutics, such as aldesleukin (Proleukin) and interferons, demonstrate meaningful efficacy in cancer and other diseases but are limited by significant side effects.

Synthekine has licensed several cytokine programs and platforms from Stanford University. Research conducted in the Garcia lab at Stanford led to insights into the interaction of cytokines and their receptors, allowing researchers to engineer modified cytokines to deliver selective activity to particular cell types of therapeutic interest, giving them the potential for optimized efficacy, a larger therapeutic window and improved safety for patients. This research has been responsible for determining the three-dimensional structures for many different cytokine/receptor complexes, including IL-1, IL-2, IL-4, IL-6, IL-13, IL-15, IL-17, IL-23 and the three different classes of interferons.

A deep preclinical pipeline and proprietary platform

Synthekine is advancing several preclinical programs and innovative platform technologies. These include:

STK-012 – Partial Agonist of IL-2: Designed to selectively agonize T cells that recognize tumor antigens, Synthekine’s lead immuno-oncology IL-2 partial agonist STK-012 has demonstrated single-agent activity in preclinical tumor models. The company anticipates filing an IND in 2021 for this potent immunotherapy.
STK-009 – Orthogonal IL-2 System: Designed to selectively activate CAR-Ts and other adoptive cell therapies (ACTs) in vivo to improve efficacy, persistence and durability of CAR-Ts and other ACTs. Data evaluating STK-009, an orthogonal IL-2 ligand, with SYNCAR-001, an orthogonal IL-2 receptor-modified CD-19 targeted CAR-T, were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting in 2020 and showed the ability to selectively harness the potent anti-tumoral T-cell effector functions of IL-2 and improve the efficacy, durability and manufacturability of CAR-T cell therapy. Synthekine anticipates filing an IND in 2021 for the STK-009/SYNCAR-001 combination.
Synthekine platform: Designed as a combinatorial engineering platform, synthekines are surrogate cytokine agonists that can combine cytokine receptors and drive new signaling activities without reliance on the wild type cytokine. The company is developing synthekines across several families of cytokines receptors.
A collaborative company formation effort and seasoned leadership team

The founding members of Synthekine’s board of directors include Tim Kutzkey, Ph.D., managing partner of The Column Group; Srinivas Akkaraju, Ph.D., founding partner of Samsara BioCapital; and Julie Grant, general partner at Canaan Partners. Synthekine has also appointed biopharma veteran Nils Lonberg as an independent member of its board of directors.

Synthekine’s executive team is led by Debanjan Ray as chief executive officer. Mr. Ray was previously chief financial officer and head of business development at CytomX Therapeutics, where he was responsible for leading financing efforts and securing multiple strategic collaborations with major pharmaceutical companies that generated more than $400 million in upfront payments and up to $4 billion in milestones. The executive team also includes Martin Oft, M.D., as chief development officer, Rob Kastelein, Ph.D., as head of therapeutic discovery and Gregory Yedinak as senior vice president of technical operations.

Synthekine’s scientific advisory board is led by its founder, K. Christopher Garcia, Ph.D., professor of molecular and cellular physiology and structural biology at Stanford University School of Medicine, a Howard Hughes Medical Institute (HHMI) investigator and a member of both the National Academy of Sciences and the National Academy of Medicine.

On September 17, 2020 DAVITA INC. (NYSE: DVA) ("DaVita") a health care provider focused on transforming care delivery to improve quality of life for patients globally and one of the largest providers of kidney care services in the United States, reported the final results of its modified "Dutch auction" tender offer for up to $1.0 billion of its common stock at a price per share not less than $77.00 and not more than $88.00, which expired at 12:00 midnight, New York City time, at the end of the day on September 14, 2020 (Press release, DaVita, SEP 17, 2020, View Source [SID1234565332]).

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Based on the final count by the depositary for the tender offer, a total of 7,981,679 shares of DaVita’s common stock were validly tendered and not validly withdrawn at or below the price of $88.00 per share. DaVita accepted all of these shares for purchase at a purchase price of $88.00 per share, for a total cost of $702,387,752, excluding fees and expenses related to the tender offer. The total of 7,981,679 shares accepted for payment represents approximately 6.5% of DaVita’s total outstanding common stock as of September 16, 2020. The depositary for the tender offer will promptly pay for the shares accepted for purchase pursuant to the tender offer. Payment for shares purchased will be made in cash, without interest, but subject to applicable withholding taxes.

DaVita will finance the share purchases in the tender offer with cash on hand.

The dealer manager for the tender offer was BofA Securities, Inc. Georgeson LLC served as the information agent for the tender offer and Computershare served as the depositary for the tender offer.

On September 17, 2020 Selvita, one of the largest preclinical contract research organizations in Europe, reported that it will present at the 20th Annual Biotech in Europe Forum For Global Partnering & Investment. Instead of hosting an in-person format, the conference will be delivered as a fully digital event that will take place on the 21-24 September (Press release, Selvita, SEP 17, 2020, View Source;utm_medium=rss&utm_campaign=selvita-to-present-at-the-20th-annual-biotech-in-europe-forum-for-global-partnering-investment [SID1234565420]). The main program is being spread throughout four days and will feature high-level speeches and panel discussions. This event draws together public companies with leading investors, analysts, money managers, and pharma licensing executives.

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Edyta Jaworska, Member of the Management Board, Integrated Drug Discovery, is scheduled to present during the panel: Exciting Opportunities in Krakow, Poland – Life Science is Growing Here. The meeting will take place on the 23rd of September at around 4:00 PM CET and will last approximately 30 minutes. The virtual panel will include discussion, a brief presentation by each speaker as well as the Q&A session from the audience.

On September 17, 2020 ADC Therapeutics SA (NYSE: ADCT), a late clinical-stage oncology-focused biotechnology company pioneering the development and commercialization of highly potent and targeted antibody drug conjugates (ADCs) for patients with hematological malignancies and solid tumors, reported the presentation of an on-demand e-poster titled "First-in-Human Study of Camidanlumab Tesirine (ADCT-301, Cami), an anti-CD25 Targeted Therapy in Patients with Advanced Solid Tumors: Pharmacokinetics (PK) and Biomarker Evaluation" (abstract #1030P) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 (Press release, ADC Therapeutics, SEP 17, 2020, View Source [SID1234565280]).

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The ongoing, multicenter, open-label Phase 1b clinical trial of camidanlumab tesirine (Cami, formerly ADCT-301) is enrolling patients with selected locally advanced or metastatic solid tumors. The primary objective of the trial is to characterize the safety and tolerability of Cami and identify recommended dose(s) and schedule(s) for future studies.

"The early PK and biomarker data from our ongoing first-in-human trial of Cami as a single agent in solid tumors support the continued evaluation of its immune-mediated anti-tumor activity through the depletion of CD25-positive regulatory T cells in the tumor microenvironment," said Jay Feingold, MD, PhD, Senior Vice President and Chief Medical Officer of ADC Therapeutics. "What we have observed thus far in the Phase 1b trial, as well as in a preclinical study that was recently published in the Journal for ImmunoTherapy of Cancer, also indicates that the exploration of Cami in combination with other immuno-modulating therapies is warranted. We look forward to advancing Cami as a novel immuno-oncology approach for the treatment of solid tumors while we also continue to evaluate Cami in our pivotal Phase 2 trial in patients with relapsed or refractory Hodgkin lymphoma."

Preliminary Data from Phase 1b Trial of Cami in Advanced Solid Tumors at ESMO (Free ESMO Whitepaper)

As of July 31, 2020, 41 patients were enrolled and treated every three weeks at doses of: 20 (n=3), 30 (n=5), 45 (n=5), 60 (n=5), 80 (n=8), 100 (n=7), 125 (n=6), and 150 µg/kg (n=2). The two most common tumor types were colorectal and pancreatic (both n=14).

Preliminary findings indicate that treatment with Cami is associated with clinically relevant modulation of immune cells, both in the circulation and in tumor tissue, with mild to moderate inter-patient variability in tumor tissue. Increases in soluble CD25 and cytokines in serum post-dosing followed a similar pattern to increases in CD4-positive and CD8-positive T cells, suggesting an increase in activated lymphocytes. Changes in lymphocyte subpopulations in the blood resulted in a dose-related increase in the effector T cell (Teff) to regulatory T cell (Treg) ratio.

The e-poster became available on the ESMO (Free ESMO Whitepaper) Congress platform today and will be available until 20:00 CEST / 2 p.m. EDT on Monday, September 21, 2020. Thereafter, the e-poster will be available on ADC Therapeutics’ website, www.adctherapeutics.com.

For more information about the company’s Phase 1b clinical trial of Cami in solid tumors, visit www.clinicaltrials.gov (identifier NCT03621982).

About Camidanlumab Tesirine (Cami)

Camidanlumab tesirine (Cami, formerly ADCT-301) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine. Once bound to a CD25-expressing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead killing the cell. This applies to CD25-expressing tumor cells, and also to CD25-expressing Tregs. The intra-tumoral release of its PBD warhead may also cause bystander killing of neighboring tumor cells and PBDs have also been shown to induce immunogenic cell death. All of these properties of Cami may enhance immune-mediated anti-tumor activity. Cami is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL), as well as in a Phase 1a/1b clinical trial in patients with relapsed or refractory HL and non-Hodgkin lymphoma and a Phase 1b clinical trial in solid tumors.

On September 17, 2020 Provectus (OTCQB: PVCT) reported that 2-year landmark survival, response, and safety data from the Company’s Phase 1b/2 study of small molecule autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus’ proprietary rose bengal disodium (RBD), in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced cutaneous melanoma in patients naïve to immune checkpoint blockade (CB) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, held online from September 19-21, 2020 (Press release, Provectus Biopharmaceuticals, SEP 17, 2020, View Source [SID1234565298]).

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Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death and induce tumor-specific reactivity in circulating T cells.1-3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with CB.4

ESMO 2020 Presentation Summary Data of this CB-Naïve Cohort:

2-year Survival Analysis
62% overall survival (OS) (55% for KEYTRUDAa alone)
Median OS not reached (median OS not reached for KEYTRUDAa alone)
65% disease-specific survival (DSS); median DSS for all patients not reached; 23.5-month median DSS for Stage IV M1c patients
Safety
Consistent with the established patterns for single-agent use of each drug; principally grades 1 and 2 injection site reactions for PV-10; principally grades 1 to 3 immune-mediated reactions for KEYTRUDA
Synergy of approved and investigational first-line cutaneous melanoma combination therapies: Schmidt et al. (JAMA Netw Open 2020b) have proposed a Bliss independent activity model to analyze observed combination therapy overall response rates (ORRs) and a Z score to measure the difference between observed and calculated ORRs. The higher the Z score, the greater the contribution of the combination therapy. Provectus calculated a Z score of 25% for the PV-10+KEYTRUDA combination. Other first-line (i.e., CB-naïve) advanced cutaneous melanoma combination therapy Z scores include:b

15.5% for OPDIVO+YERVOY, 23.4% for KEYTRUDA+YERVOY,
-0.8% for KEYTRUDA+epacadostat (IDO-1), 30% OPDIVO+epacadostat,
13.5% for KEYTRUDA+IMLYGIC (oncolytic virus), and
13% for OPDIVO+bempegaldesleukin (interleukin-2)c.
Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "These two-year survival landmark data support the clinical value of PV-10 in combination with immune checkpoint blockade in a predominantly Stage IV melanoma patient population, including those with extensive visceral disease. These data illustrate a stable, non-overlapping safety profile over time; highlight substantial, efficient, upfront tumor destruction by PV-10 directly against injected disease burden; and appear to be the result of a strong, PV-10-induced, tumor-specific, functional T cell response.2 Taken together,PV-10’s clinical and mechanistic attributes may better leverage the strengths of checkpoint blockade for the durable treatment benefit of melanoma patients."

A copy of the poster presentation is available on Provectus’ website at View Source

About the Phase 1b/2 Combination Therapy Trial (NCT02557321)

The Phase 1b portion of the study completed enrollment of 23 patients with metastatic cutaneous melanoma in April 2018 at clinical sites in the U.S.; of these patients, 21 were naïve to checkpoint inhibition treatment. Patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of up to 12 weeks, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial was safety and tolerability. Overall response rate and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. The Company manufactures cGMP RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers. By targeting tumor cell lysosomes, RBD treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1-3 Adaptive immunity can be enhanced by combining CB with RBD.4 IL PV-10 is undergoing clinical study for relapsed and refractory adult solid tumor cancers, such skin and liver cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Tumor Cell Lysosomes as the Seminal Cancer 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.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD 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 of the process, with 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 in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate 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. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

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

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 cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council 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 RBD and CB (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; US patent application numbers include 20200138942.