On July 10, 2021 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients battling cancer, reported that it has converted all of the $28.0 million aggregate principal of the Company’s 2020 5.00% Convertible Senior Notes due 2048 (the 2020 Notes) in exchange for approximately 8.6 million shares of the Company’s common stock, based on the Company’s existing Mandatory Conversion right (Press release, Verastem, JUL 19, 2021, View Source [SID1234584947]). This transaction, which eliminates substantially all of the Company’s outstanding debt, preserves approximately $31.2 million in cash, including $3.2 million in future interest payments that would have been payable through November 1, 2023.

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Robert Gagnon, Chief Financial Officer of Verastem Oncology, commented: "This conversion of our 2020 Notes eliminates substantially all outstanding debt and provides us with greater financial flexibility, all while reducing future cash needs for interest payments and to repay the notes at maturity. We now enter the second half of 2021 with a stronger balance sheet and believe we are well positioned to execute on our corporate objectives, including the advancement of VS-6766 and defactinib through registration-directed Phase 2 clinical trials in low-grade serous ovarian cancer (LGSOC) and KRAS G12V-mutant non-small cell lung cancer (NSCLC)."

On November 6, 2020, the Company entered into a privately negotiated agreement with an investor who held the Company’s 2018 5.00% Convertible Senior Notes due 2048 (the 2018 Notes), and exchanged approximately $28.0 million aggregate principal amount of the 2018 Notes for approximately $28.0 million aggregate principal amount of newly issued 2020 Notes. Under the terms of the 2020 Notes, Verastem became eligible to exercise its right to cause all outstanding 2020 Notes to be converted automatically because the daily volume weighted average price (VWAP) per share of the Company’s common stock was equal to or exceeded 123.08% of the conversion price on each of at least 20 VWAP trading days during a 30 consecutive VWAP trading day period. The conversion rate for the 2020 Notes was 307.6923 shares of the Company’s common stock per $1,000 principal amount of the 2020 Notes, which is equivalent to a conversion price of approximately $3.25 per share, representing an approximately 153.9% premium to the sale price of $1.28 per share of the Company’s common stock on November 5, 2020.

Verastem Oncology ended the first quarter 2021 with cash, cash equivalents and investments of $127.1 million. With the anticipated proceeds from the sale of COPIKTRA, the Company expects that it will have a cash runway until at least 2024 to deliver on the current programs for VS-6766 and defactinib, including clinical and regulatory milestones and development in LGSOC and KRAS mutant NSCLC.

On July 19, 2021 THERADIAG (ISIN: FR0004197747, Ticker: ALTER), a company specializing in in vitro diagnostics and Theranostics, reported its half-year turnover and its cash level at June 30, 2021, data under audit (Press release, Theradiag, JUL 19, 2021, View Source [SID1234587268]).

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At June 30, 2021, Theradiag achieved a turnover of 5.5 million euros against 4.9 million in the
1 st half of 2020, an increase of 12.5% despite an economic context characterized and health by the persistence in all countries of difficulties in accessing hospital care for patients undergoing immunotherapy.

The Theranostics business continued to grow with growth this semester of + 14.7%, driven in particular by the dynamic sales of the i-Track 10 machine . Marked by strong growth for several semesters, the Theranostics activity represents for the first time the majority of Theradiag’s revenues over these first six months of 2021.

Theranostics activity carried out in the United States in partnership with HalioDX reached 0.5 million euros, in line with the company’s development plan, and grew by 33.6%. In exports, the company maintains a very sustained level of activity with an increase in sales of 27.4% to 1.3 million euros. Penalized by maintaining white planes in hospitals, activity in France slowed slightly, it is set back from 5.2% to 1.0 million euros compared to the 1 st half of 2020.

The In Vitro Diagnosis (IVD) activity posted revenue growth of + 10.4% to reach 2.7 million euros as of June 30, 2021.

Cash position

As of June 30, 2021, Theradiag’s available net cash amounted to € 1.4 million compared to €
3.5 million as of December 31, 2020. This difference results from cash mismatches resolved to date amounting to 0.5 million euros, as well as investments in R&D and international development in line with Theradiag’s strategic plan.

Bertrand de Castelnau, CEO of Theradiag commented:"The 12.5% ​​revenue growth in a delicate health context once again proves that Theradiag’s business model is based on solid fundamentals. In the first half of 2021, the Theranostics activity continued to grow thanks to the deployment of the i-Track solution, the marketing of which had been launched in full containment in 2020. The particularly strong Theranostics dynamic in the United States highlights the success of our partnership with Halio DX in this strategic country. The first semester was also marked by the kick-off of the Humabdiag project with the University of Tours, which will allow us to obtain high quality antibodies which are strategic for the future of the company. For the rest of the 2021 financial year, We are maintaining our investments in innovation and our international deployment efforts, particularly in the United States. "

Pierre Morgon, Chairman of the Board of Directors of Theradiag continues: " This first semester underlines the robustness of the model shaped for years by the Theradiag teams who have demonstrated their performance in times of crisis. World leader in the monitoring of biotherapies, Theradiag has a real technological lead and continues to maintain it thanks to its judicious investment policy. This positive dynamic is supported by an ambitious and clear strategic plan which can only offer a bright future to Theradiag. "

Of the main events of the 1 st half 2021

January 2021: CE marking of the four new i-Tracker test kits from the TRACKER Vedolizumab and Ustekinumab range on the originator molecules and biosimilars
January 2021: Signature of a contract for the supply of quality control reagents with Orgentec
May 2021: Participation in the Humabdiag project, a large-scale research project aimed at bio-production of monoclonal antibodies in Tours
Financial calendar:

Results of the 1 st half of 2021 , Monday, September 20, 2021

On July 19, 2021 Provectus (OTCQB: PVCT) reported that data from an ongoing clinical trial of investigational cancer immunotherapy PV-10 (rose bengal disodium) for the treatment of neuroendocrine tumors (NET) metastatic to the liver (mNET) refractory to somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) (NCT02693067) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, to be held online from September 16-21, 2021 (Press release, Provectus Biopharmaceuticals, JUL 19, 2021, View Source [SID1234584948]).

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The abstract accepted for electronic poster presentation is entitled:

"Phase I study of hepatic intralesional rose bengal disodium (PV10), an autolytic immunotherapy, in metastatic neuroendocrine neoplasms" (#4354).
About PV-10

Intralesional (IL) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB).4 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver. Systemic administration of PV-10 is also undergoing preclinical study as prophylactic and therapeutic treatments for refractory and high-risk adult solid tumor cancers, and as a treatment for relapsed and refractory blood cancers.

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. 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.

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.

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 also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis

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. Provectus2,14, 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

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 (i.e., 16/678,133), which has been allowed.

On July 19, 2021 Celsion Corporation (NASDAQ: CLSN), a clinical-stage company focused on DNA-based immunotherapy and next-generation vaccines, reported that following a pre-planned interim safety review of 55 as treated patients randomized in the Phase I/II OVATION 2 Study with GEN-1 in advanced (Stage III/IV) ovarian cancer, the Data Safety Monitoring Board (DSMB) has unanimously recommended that the OVATION 2 Study continue treating patients with the dose of 100 mg/m2 (Press release, Celsion, JUL 19, 2021, View Source [SID1234584949]). The DSMB also determined that safety is satisfactory with an acceptable risk/benefit, and that patients tolerate up to 17 doses of GEN-1 during a course of treatment that lasts up to six months. No dose-limiting toxicities were reported.

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The OVATION 2 Study combines GEN-1, the Company’s IL-12 gene-mediated immunotherapy, with standard-of-care neoadjuvant chemotherapy (NACT) in patients newly diagnosed with Stage III/IV ovarian cancer. NACT is designed to shrink the cancer as much as possible for optimal surgical removal after three cycles of chemotherapy. Following NACT, patients undergo interval debulking surgery, followed by three additional cycles of chemotherapy to treat any residual tumor.

The OVATION 2 Study is designed with an 80% confidence interval for an observed Progression Free Survival (PFS) Hazard Ratio of 0.75, which would mean an approximate 33% improvement in risk for cancer progression when comparing the treatment arm (NACT + GEN-1) with the control arm (NACT only). GEN-1 is an immunotherapy that produces safe and durable local levels of IL-12, a pluripotent cytokine associated with the stimulation of innate and adaptive immune response against cancer. The GEN-1 nanoparticle comprises a DNA plasmid encoding IL-12 gene and a synthetic polymer facilitating plasmid delivery vector. Cell transfection is followed by persistent, local secretion of the IL-12 protein at therapeutic levels.

The Company also announced that more than 50% of the projected 110 patients have been enrolled in the OVATION 2 Study. Interim clinical data from the first 36 patients who have undergone interval debulking surgery are as follows:

Of the 36 patients who have undergone interval debulking surgery in the OVATION 2 Study:
20 patients were treated with GEN-1 at a dose of 100 mg/m² plus NACT, with 16 out of 20 patients (80%) having a complete tumor resection (R0), which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed; and
16 patients were treated with NACT only, with 9 out of 16 patients (56%) having R0 resections.

When combining these results with the surgical resection rates observed in the Company’s prior Phase Ib dose-escalation trial (the OVATION 1 Study), a population of patients with inclusion criteria identical to the OVATION 2 Study, the data reflect the strong dose-dependent efficacy of adding GEN-1 to NACT:
% Patients with R0 Resections
0, 36, 47 mg/m² of GEN-1 plus NACT n=22 50 %
61, 79, 100 mg/m² of GEN-1 plus NACT n=28 82 %

The objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the 16 patients treated with NACT only were comparable, as expected, to the 20 patients treated with GEN-1 at a dose of 100 mg/m² plus NACT, with both groups demonstrating an approximate 80% ORR.
"These findings show a consistent dose-dependent clinical response in both surgical outcome and tumor response, which is further supported by translational data of the tumor microenvironment," noted Nicholas Borys, M.D., Celsion’s executive vice president and chief medical officer. "Continuing our clinical research program at the 100 mg/m2 dose in patients with advanced-stage ovarian cancer holds promise and is strongly encouraged by our study investigators and medical advisors."

"We thank the DSMB members for their work and advice," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "We are encouraged by the current rate of patient recruitment and expect to complete enrollment around the end of this year. FDA Fast Track and Orphan Drug Designations for GEN-1 in advanced ovarian cancer are important for our future commercialization efforts. In addition, under the Biologics Price Competition and Innovation Act of 2009, sponsors of new, licensed biological products like GEN-1 that are approved through a Biologics License Application receive 12 years of market exclusivity. The FDA cannot license any 351(k) application for a biosimilar or interchangeable product that relies on the previously approved product as a reference for biosimilarity during this 12-year period."

In February 2021, the Company announced that GEN-1 received FDA Fast Track Designation in advanced ovarian cancer. Celsion plans to request FDA Breakthrough Therapy Designation for GEN-1 based on the encouraging clinical data announced today.

About GEN-1 Immunotherapy

GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy or a combination therapy in patients with advanced peritoneally metastasized primary or recurrent ovarian cancer, and recently completed a Phase Ib dose-escalation trial (OVATION 1 Study) of GEN-1 in combination with carboplatin and paclitaxel in patients with newly diagnosed ovarian cancer.

On July 19, 2021 Eluminex Biosciences (Suzhou) Limited (Eluminex), an ophthalmology-focused biotechnology company headquartered in Suzhou, China with a US-subsidiary office in San Francisco Bay Area, California, reported that it has exclusively licensed global rights for the development and commercialization of an investigational biosynthetic cornea derived from recombinant human collagen Type III intended to treat patients with corneal blindness, from FibroGen, Inc. (FibroGen; NASDAQ: FGEN) (Press release, FibroGen, JUL 19, 2021, View Source [SID1234586988]).

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"We are extremely excited to bring this novel technology initially to the China market to help meet a large unmet medical need for an alternative to human donor cornea tissue," commented Dr. Jinzhong ("JZ") Zhang, Chairman and CEO of Eluminex. "Over 100,000 cases of corneal blindness occur each year in China due to scarring from traumatic injury or infection that could be treated with a surgically implanted bioengineered cornea. Typical treatments in China include human donor corneal transplantation or use of corneal tissue harvested from genetically modified pigs. There is a significant shortage of human donor tissue and porcine corneas have issues with a lack of optical clarity and durability, however, and both methods require the need for additional immunosuppressive medications to prevent graft rejection. The biosynthetic cornea, that is optically clear, offers an alternative using human Type III collagen, a key structural protein that is found in normal human corneas and therefore does not require immunosuppressive medications."

Under the terms of the agreement, Eluminex will make an $8 million upfront payment to FibroGen. In addition, FibroGen may receive up to a total of $64 million in future manufacturing, clinical, regulatory, and commercial milestone payments for the biosynthetic cornea program, as well as $36 million in commercial milestones for the first recombinant collagen III product that is not the biosynthetic cornea. FibroGen will also be eligible to receive royalties based upon worldwide net sales.

Eluminex also announced that Edward Holland, M.D., has joined the company’s Scientific Advisory Board (SAB). Charles Semba, M.D. and Chief Medical Officer of Eluminex commented, "We are excited to introduce Dr. Edward Holland, Professor of Ophthalmology at the University of Cincinnati and Director of the Cornea Service at the Cincinnati Eye Institute and past Chairman of the Eye Bank Association of America, as the newest member of our SAB. He is an internationally recognized expert in corneal allograft surgery and ocular surface disease. Additionally, over the past three decades, he has taught and lectured in China regarding corneal transplant techniques and will provide us critical insights into our biosynthetic cornea program."

"The possibility for an abundant global supply of a biosynthetic human corneal tissue substitute has real potential to transform the lives of the hundreds of thousands of patients around the world in regions where corneal donations are scarce and who otherwise are unlikely to receive a sight-saving corneal transplant," said Dr. Holland.

"We are pleased to enter into this agreement with Eluminex and license this technology to a seasoned ophthalmology team," said Enrique Conterno, CEO of FibroGen. "This transaction enables FibroGen to focus on development of next generation biopharmaceutical therapies in our core areas of cancer, autoimmune and fibrotic diseases, and anemia."

About the Eluminex Biosynthetic Cornea Program
The Eluminex biosynthetic cornea (EB-301) is a clinical stage corneal stromal substitute that will be initially developed for the China market. EB-301 is regulated as a Class III medical device and is anticipated to enter a clinical market authorization registration study in China in 2H 2022 to confirm its safety and effectiveness. The corneal device has been implanted in 10 patients in Europe with 4 years of follow-up and has demonstrated excellent biocompatibility, maintenance of optical clarity, and significantly improved visual acuity without immunosuppression. (Fagerholm et al, Biomaterials, 35 (2014): 2420-2427).

About Corneal Blindness in China
According to the World Health Organization, corneal diseases are one of the leading causes of blindness globally. Approximately 180,000 sight-restoring corneal transplantations are performed worldwide in which nearly a quarter are conducted in the United States. China is the largest most populous developing country in the world and corneal diseases are the second leading cause of blindness with an estimated 2-3 million patients with corneal blindness in at least one eye. However, due to the scarcity of donor corneas, only approximately 5000 to 9000 corneal transplants are conducted in China each year. Corneal porcine xenografts have been available in China since 2015 but technical issues remain with the lack of optical clarity and secondary immunologic complications (eg, graft dissolution and graft rejection). An unmet need exists for a suitable corneal stromal tissue replacement as an alternative to the shortage of donated human cornea and an alternative to porcine xenografts.