On August 17, 2020 Applied DNA Sciences, Inc. (NASDAQ: APDN) ("Applied DNA" or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing that enables in vitro diagnostics, pre-clinical nucleic acid-based therapeutic drug candidates, supply chain security, anti-counterfeiting and anti-theft technology, reported that it has filed a nonprovisional patent application with the United States Patent and Trademark Office (USPTO) entitled "Methods and Systems of PCR-Based Recombinant Adeno-Associated Virus (AAV) Manufacture" (the "Patent") (Press release, Applied DNA Sciences, AUG 17, 2020, View Source [SID1234563742]). The Patent claims priority to a previously filed provisional patent application filed with the USPTO in August of 2019.

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AAV is utilized to deliver a therapeutic gene of interest to a patient or a patient’s cells to cause the expression of the necessary protein to address a targeted disease. Reflective of its potential as one of the most promising delivery vehicles for genetic medicines, there are approximately 80 active or enrolling clinical trials that utilize AAV. With its new patent application, Applied DNA seeks to leverage its LinearDNA platform to give gene and redirected cell therapy developers the ability to greatly improve the manufacture and quality of their AAV-vectored medicines that have the potential to address many diseases, including COVID-19.

"AAV is generally accepted as the preferred vector for gene therapy, and so, has an enormous breadth as a therapeutic gene delivery system. AAV vectors are manufactured utilizing multiple plasmid DNAs as starting materials, and as the number of gene therapy programs increase, and with improving levels of clinical success and progression of therapies into late-phase clinical studies, the field is being challenged by the need for larger manufacturing scales," said Dr. James A. Hayward, president and CEO of Applied DNA Sciences. "At Applied DNA, we believe we have solved the linear DNA production challenge and can make the DNA sequences at scale for gene therapies. Utilizing our LinearDNA platform to manufacture amplicons, we can deliver gene therapy constructs that potentially lower the risks that come with the use of plasmid-based AAV manufacture. As one of the only companies in the marketplace commercializing a scaled linear DNA manufacturing platform, we believe we are uniquely positioned to deliver linear DNA as an alternative to plasmids, and with this patent filing, we expand our addressable market to including AAVs."

AAV is manufactured by the triple transfection of three plasmid DNA constructs into packaging cell lines to produce recombinant adeno-associated virus. This triple transfection requires large amounts of DNAs that are currently manufactured via plasmids – circular DNA constructs which are propagated in bacteria. The three DNA constructs necessary for successful AAV production are: (i) AAV Rep and Cap; (ii) AAV Helper; and (iii) the therapeutic cargo (transgene) flanked on either side by inverted terminal repeat sequences (ITR). The manufacture of plasmid DNA for the production of AAV, however, presents a number of significant challenges, including scalability, fidelity, mis-incorporation of plasmid-derived DNA sequences, high costs, and long lead times for cGMP production.

Concluded Dr. Hayward, "The ITRs serve as the viral origins of replication and for packaging signals to assemble AAV in the host cell. But the triple transfection of the required plasmids, and in the strict stoichiometries required for AAV assembly, we believe adds enormously to the cost of traditional AAV manufacturing, limiting the availability of many gene therapies. Our success in simplifying the production of the critical plasmid genes for AAV production we believe enable AAV production with minimal or absent plasmids, potentially greatly enhancing production and lowering costs. The use of LinearDNA potentially lowers the risks that come with plasmids, including off-target DNA, contamination by the genes for antimicrobial resistance or other bacterial DNA, endotoxin contamination and the use of antibiotics."

The Patent claims methods for the use of specialized LinearDNATM amplicons, instead of plasmids, to manufacture AAV. The patent also claims methods and systems for the PCR-based manufacturing of AAV transgene constructs flanked on either side by the necessary ITR sequences via the Company’s LinearDNA platform. Due to their complex secondary structures, the ITR sequences necessary for AAV production have historically been very challenging to amplify via PCR. Leveraging the Company’s PCR expertise, the methods and systems claimed in the Patent utilize specialized PCR techniques and primer designs to mitigate the challenges caused by the ITR secondary structures, allowing for the high yield and high-fidelity manufacture of transgene –ITR amplicons.

On August 17, 2020 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported that Jarrod Longcor, chief business officer of Cellectar, presented a poster at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) VIRTUAL MEETING: ADVANCES IN MALIGNANT LYMPHOMA being held August 17-19, 2020 (Press release, Cellectar Biosciences, AUG 17, 2020, View Source [SID1234563740]). The abstract was submitted April 2, 2020.

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The poster, entitled: "CLR 131 Demonstrates 100% Overall Response Rate in Relapsed or Refractory Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom’s Macroglobulinemia (WM): Initial Results from Ongoing Phase 2 trial, CLOVER-1 Study" reviews data from four patients enrolled in the Phase 2a portion of the ongoing Phase 2 CLOVER-1 study of CLR 131. The presentation featured efficacy and safety data highlighting;

-100% overall response rate,
-25% complete response rate,
-75% major response rate (patients achieving partial response or better), and
-Mean duration of response exceeding 17 months (8.4 – 31.7 months); duration of response continues to increase for all patients

The safety profile in these highly pretreated patients with relapsed or refractory LPL/ WM was predictable and adverse events were similar to those observed in previous CLR 131 clinical studies in B-cell malignancies. The predominate treatment emergent adverse event remains cytopenias with all patients recovering. Importantly, no patients experienced adverse events that are frequently associated with treatments prescribed for LPL/WM patients such as atrial fibrillation, peripheral neuropathy, ocular toxicities, bleeding events, liver toxicities, renal toxicities or other "off-target" effects.

"CLR 131’s ability to treat various LPL/WM patients including those who do not respond to or are intolerant of ibrutinib is a potentially important therapeutic advance. The potential for patients to have a long term drug treatment holiday whereby there is no requirement for taking a pill once or twice a day for years is clinically meaningful," said study investigator Sikander Ailawadhi, M.D., Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida.

"The overall product profile and achievement of a complete response as a monotherapy, along with the extended duration of responses in patients that are refractory to at least one prior therapy and have also received multiple lines of treatment is highly encouraging," said Jarrod Longcor. "These patients currently have limited treatment options and CLR 131 may represent an important potentially disease modifying improvement in the LPL/WM treatment paradigm. We plan to initiate our pivotal study and potentially report additional LPL/WM data later this year."

There is currently only one approved drug for the treatment of relapsed or refractory LPL/WM. In May of this year, the U.S. Food and Drug Administration granted Fast Track Designation for CLR 131 in treatment of relapsed or refractory LPL/WM. The company currently continues to enroll patients in the Phase 2b portion of the CLOVER-1 study and plans to initiate a pivotal study in LPL/WM in the fourth quarter of 2020.

About CLOVER 1

The Phase 2 CLOVER-1 study is an open-label study designed to determine the efficacy and safety of CLR 131 in select B-cell malignancies. The CLOVER-1 Phase 2 study completed the Part A dose-exploration portion, conducted in relapsed/refractory (r/r) B-cell malignancies, and is now enrolling in the Part B expansion cohorts evaluating a two cycle dosing regimen that provides approximately 100mCi total body dose of CLR 131 in r/r multiple myeloma (MM) and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM). Patients with LPL/WM must have received at least two prior treatment regimens, unless ineligible to receive standard agents, and have measurable disease, as defined by either a nodal lesion of > 15 mm, an extranodal lesion of > 10 mm, or measurable IgM. Prior external beam radiation therapy was allowed. The median age of the four LPL/WM patients enrolled in the study was 70 (range 54-81) and included 2 females and 2 males who had a median of two prior regimens (range 1-5). CLR 131 was administered intravenously, up to 30 minutes at total body doses (TBD) of <50mCi, ~50 mCi, and ~75mCi.

A copy of the presentation materials can be accessed on the Events and Presentations section of the Cellectar website once the presentations conclude.

About CLR 131

CLR 131 is a small-molecule Phospholipid Drug Conjugate designed to provide targeted delivery of iodine-131 (radioisotope) directly to cancer cells, while limiting exposure to healthy cells unlike many traditional on-market treatment options. CLR 131 is the company’s lead product candidate and is currently being evaluated in a Phase 2 study in B-cell lymphomas, and a Phase 1 dose-escalating clinical study in pediatric solid tumors and lymphomas. The company recently completed a Phase 1 dose-escalation clinical study in r/r multiple myeloma. The FDA granted CLR 131 Fast Track Designation for both r/r multiple myeloma and r/r diffuse large B-cell lymphoma and Orphan Drug Designation (ODD) for the treatment of multiple myeloma, lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia, neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. CLR 131 was also granted Rare Pediatric Disease Designations for the treatment of neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. Earlier this year, the European Commission granted an ODD for r/r multiple myeloma and most recently, the U.S. Food and Drug Administration granted Fast Track Designation for CLR 131 in lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM) in patients having received two prior treatment regimens or more.

On August 17, 2020 The University of Texas MD Anderson Cancer Center reported that In a Phase II trial led by researchers , the combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, achieved a 51% overall response rate (ORR) in patients with cholangiocarcinoma marked by the BRAF V600E mutation (Press release, MD Anderson, AUG 17, 2020, View Source [SID1234563739]).

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This trial represents the first prospective study for patients with BRAF-mutated cholangiocarcinoma, or bile duct cancer, and suggests this targeted therapy combination could serve as a much-needed treatment option for patients with treatment-resistant advanced disease. The trial results were published today in Lancet Oncology.

"In this study, we saw that the dabrafenib and trametinib combination demonstrates clinical benefit and should be considered as a therapeutic option for these patients ," said lead author Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics. "These findings also reinforce the need for routine testing of BRAF mutations in patients with biliary tract cancers. As we move forward with precision oncology, we’re seeing that alterations present in these rare cancers are actionable and the patients do benefit from targeted therapies."

This study is part of an ongoing Phase II, open-label, multicenter trial testing the efficacy and safety of the combination therapy in patients with a variety of BRAF V600E-mutated rare cancers. The bile duct cohort enrolled 43 patients, all of whom had received at least one prior line of therapy.

Trial participants were 91% Caucasian, 5% Asian (Japanese heritage), 2% Asian (East Asian heritage) and 2% white (Arabic/North African). The median age was 57, with women accounting for 56% and men 44% of participants.

Bile duct cancer is a rare disease diagnosed in about 8,000 people each year in the U.S. Most cases are diagnosed at advanced stages, and thus clinical outcomes are generally poor, with a five-year survival rate below 20%. Standard of care includes surgery, when possible, and chemotherapy.

In patients with advanced disease, median overall survival with chemotherapy treatment is less than one year, so there is a significant unmet need for effective new treatment approaches, explained Subbiah.

Mutations in the BRAF gene are found in 5-7% of those diagnosed with bile duct cancer, and patients with the BRAF V600E mutation are more likely to have poor outcomes. Trials with single-agent therapies targeting BRAF have been effective for treating these patients, but have shown significant toxicities, including secondary malignancies.

However, combining these agents with MEK inhibitors, which act downstream in the same signaling pathway, have proven effective and are FDA-approved for use in other cancer types, including melanoma, lung cancer and anaplastic thyroid cancer. These agents are not currently approved by the FDA to treat cholangiocarcinoma.

In the current trial, the combination therapy achieved an ORR of 51% (22 patients) according to investigator assessments. The median duration of response was 8.7 months, with seven patients seeing an ongoing response beyond 12 months.

Median progression-free survival was 9.1 months and median overall survival was 13.5 months, with 56.4% and 35.8% of patients still alive at 12 months and 24 months, respectively.

All patients experienced at least one adverse event, with the most common being fever, nausea, vomiting, diarrhea and fatigue. Twenty-four patients (56%) experienced a Grade 3 or 4 adverse event, the most common of which was an increase in gamma-glutamyltransferase, an enzyme found in the liver and bile ducts. According to the authors, these side effects were consistent with those seen previously from this combination in other cancer types.

"The trajectory of cholangiocarcinoma is changing rapidly," said co-author Milind Javle, M.D., professor of Gastrointestinal Medical Oncology. "Targeted therapy has made meaningful inroads, and this study is an excellent example of that. This is an important development for patients with cholangiocarcinoma and BRAF V600E mutations, who often have limited treatment options."

This research was supported by GlaxoSmithKline and Novartis. Co-authors from MD Anderson include Milind Javle, M.D., of Gastrointestinal Medical Oncology. A full list of co-authors and disclosures can be found with the full paper here.

On August 17, 2020 G1 Therapeutics, Inc. (Nasdaq: GTHX), a clinical-stage oncology company, reported that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for trilaciclib for small cell lung cancer (SCLC) patients being treated with chemotherapy and granted Priority Review with a Prescription Drug User Fee Act (PDUFA) action date of February 15, 2021 (Press release, G1 Therapeutics, AUG 17, 2020, View Source [SID1234563738]). Trilaciclib is a first-in-class investigational therapy designed to preserve bone marrow and immune system function during chemotherapy and improve patient outcomes.

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"There are currently no available therapies to protect patients from chemotherapy-induced toxicities before they occur," said Raj Malik, M.D., Chief Medical Officer and Senior Vice President, R&D. "If approved, trilaciclib would be the first proactively administered myelopreservation therapy that is intended to make chemotherapy safer and reduce the need for rescue interventions, such as growth factor administrations and blood transfusions."

The FDA grants Priority Review to applications for potential therapies that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. The trilaciclib NDA was supported by compelling myelopreservation data from three randomized, double-blind, placebo-controlled clinical trials in which trilaciclib was administered prior to chemotherapy treatment in patients with SCLC. Trilaciclib has been granted Breakthrough Therapy Designation by the FDA. In the NDA acceptance letter, the FDA also stated that it is currently not planning to hold an advisory committee meeting to discuss this application.

"While undergoing chemotherapy, many patients experience significant myelosuppression, become fatigued and susceptible to infection, and often require transfusions and growth factor administrations," said Jared Weiss, M.D., Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC. "Preventing bone marrow damage proactively is an opportunity to improve the quality of life of patients receiving chemotherapy for small cell lung cancer and reduce costly rescue interventions."

Myelosuppression is the result of damage to bone marrow stem cells and is one of the most common side effects of chemotherapy. Myelosuppression can lead to serious conditions such as anemia, neutropenia or thrombocytopenia, which have broad ranging clinical, patient experience and economic impacts on ongoing cancer treatment and overall outcomes. In clinical trials, trilaciclib significantly reduced chemotherapy-induced myelosuppression, and patients receiving trilaciclib experienced fewer dose delays/reductions, infections, hospitalizations, and need for rescue therapies compared to patients receiving chemotherapy alone.

Expanded Access Program
G1 is making trilaciclib available to SCLC patients in the U.S., who are unable to enter clinical trials and for whom there are no appropriate alternative treatments while the trilaciclib NDA is under regulatory review, pursuant to FDA’s expanded access program (EAP). To facilitate needed access through the EAP, G1 is collaborating with Bionical Emas, a global specialist clinical research organization (CRO). For more information about the EAP access to trilaciclib, email [email protected].

"Complications from myelosuppression have been a long-standing challenge when treating patients with SCLC," said Dr. Malik. "Establishing an expanded access program provides qualified patients in serious need with access to trilaciclib while the NDA is under review."

Trilaciclib in Small Cell Lung Cancer
Trilaciclib is a first-in-class investigational therapy designed to improve outcomes for people with cancer treated with chemotherapy. In 2019, trilaciclib received FDA Breakthrough Therapy Designation, and, in June 2020, G1 submitted the NDA based on myelopreservation data from three randomized, double-blind, placebo-controlled clinical trials in which trilaciclib was administered prior to chemotherapy in patients with small cell lung cancer (SCLC). In August 2020, G1 received FDA Priority Review with the Prescription Drug User Fee Act (PDUFA) date of February 15, 2021.

In June 2020, G1 announced a co-promotion agreement with Boehringer Ingelheim for trilaciclib in small cell lung cancer in the U.S. and Puerto Rico. If approved, G1 will lead marketing, market access and medical engagement initiatives for trilaciclib. The Boehringer Ingelheim oncology commercial team, well-established in lung cancer, will lead sales force engagement initiatives. G1 will book revenue and retain development and commercialization rights to trilaciclib and pay Boehringer Ingelheim a promotional fee based on net sales. The three-year agreement does not extend to additional indications that G1 is evaluating for trilaciclib. Press release details of the G1/ Boehringer Ingelheim agreement can be found here.

Evaluating Trilaciclib in Other Cancers
In a randomized trial of women with metastatic triple-negative breast cancer, preliminary data showed that trilaciclib improved overall survival when administered in combination with chemotherapy compared with chemotherapy alone. The company plans to present final overall survival data from this trial in the fourth quarter of 2020. Trilaciclib is being evaluated in neoadjuvant breast cancer as part of the I-SPY 2 TRIAL, and the company expects to initiate a Phase 3 trial in patients treated with chemotherapy for colorectal cancer in the fourth quarter of 2020.

On August 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 that it has commenced a modified "Dutch auction" tender offer for shares of its common stock for an aggregate purchase price of up to $1.0 billion at a price per share of not less than $77.00 and not more than $88.00 (Press release, DaVita, AUG 17, 2020, View Source [SID1234563733]). The tender offer will expire at 12:00 midnight, New York City time, at the end of the day on September 14, 2020, unless extended by DaVita or otherwise terminated. Tenders of shares must be made on or prior to the expiration of the tender offer and may be withdrawn at any time prior to the expiration of the tender offer, in each case, in accordance with the procedures described in the tender offer materials.

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A modified "Dutch auction" tender offer allows shareholders to indicate how many shares and at what price within DaVita’s specified range they wish to tender. Based on the number of shares tendered and the prices specified by the tendering shareholders, DaVita will determine the lowest price per share within the specified range that will enable DaVita to purchase shares having an aggregate purchase price of up to $1.0 billion. DaVita also reserves the right, in the event that more than $1.0 billion of its shares are tendered in the tender offer at or below the purchase price, to purchase at its option up to an additional number of outstanding shares of common stock not to exceed 2% of the total number of its shares of common stock (exclusive of any shares of common stock held by or for DaVita’s account or by or for the account of any of DaVita’s subsidiaries) without amending or extending the tender offer. All shares purchased by DaVita in the tender offer will be purchased at the same price. Shareholders whose shares are purchased in the tender offer will be paid the determined purchase price in cash, less any applicable withholding taxes and without interest, promptly after the expiration of the tender offer.

DaVita expects to finance the share purchases in the tender offer with cash on hand, and to the extent necessary, borrowings under its currently undrawn $1.0 billion revolving line of credit under its senior secured credit facilities. The tender offer is not conditioned upon the receipt of financing or any minimum number of shares being tendered, but it is subject to certain other conditions. The tender offer documents contain tendering instructions and a complete explanation of the tender offer’s terms and conditions.

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

Neither DaVita, its directors, the dealer manager, the information agent, nor the depositary makes any recommendation as to whether to tender shares or as to the price at which to tender them.

Additional Information Regarding the Planned Tender Offer