On December 17, 2020 Carina Biotech scientist Dr Veronika Bandara reported data at this week’s Eradicate Cancer Conference on Carina’s latest CAR-T cab off the rank that has demonstrated significant killing of two colorectal cancer cell lines in vitro and complete tumour elimination in a pre-clinical colorectal cancer model (Press release, Carina Biotech, DEC 17, 2020, View Source [SID1234572963]).

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The CAR-T cell was also shown to be highly cytotoxic against two neuroblastoma cell lines.

These cancer-busting CAR-T cells are targeted at LGR5 (leucine-rich repeat-containing G-protein coupled receptor 5) – a cancer stem cell marker that is abundant in solid tumours and particularly highly expressed in colorectal cancer and metastatic colorectal cancer.

Dr Bandara said: "We designed and built six different CAR constructs based on an anti-LGR5 antibody. Four of the constructs showed fantastic cytotoxic activity against the LoVo and LIM1215 colorectal cancer cell lines in vitro. The same constructs were highly cytotoxic against the two neuroblastoma cell lines SHY-5Y-SY and BE-2-ME."

Carina Biotech’s CEO, Dr Deborah Rathjen said: "The data to be presented by Dr Bandara this week is very promising, and suggests that this CAR-T cell is a potential therapeutic for colorectal cancer. The benefit of targeting a cancer stem cell marker is that we can get to the core of some cancers, in this case cancers expressing LGR5. We often see patients, for example with colorectal cancer, go into remission after first-line treatment only for their cancer to return, we think, due to the fact that the cancer stem cells are somehow resistant to traditional anti-cancer therapies."

Dr Bandara said: "The next steps will be to further validate the LGR5 CAR-T cells in multiple pre-clinical animal models and against patient-derived tumour samples. We will also confirm safety of the LGR5 CAR-T cell by testing against normal tissues and by undertaking other safety evaluations. We will also work towards a TGA-approved manufacturing protocol to produce CAR-T cells for first-in-human clinical trials."

This is Carina’s latest CAR-T cell candidate in a growing pipeline, underpinned by its proprietary platform that produces "supercharged" CAR-T cells.

The research is being conducted in conjunction with a $750,000 grant from the Government of South Australia’s Research, Commercialisation and Startup Fund (RSCF). www.innovationandskills.sa.gov.au/rcsf

On December 17, 2020 Applied DNA Sciences, Inc. (NASDAQ: APDN) ("Applied DNA" or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing, reported consolidated financial results for the full fiscal year and quarter ended September 30, 2020 (Press release, Applied DNA Sciences, DEC 17, 2020, View Source [SID1234572983]).

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"Our activities in fiscal 2020 were principally devoted to the establishment of our diagnostic and surveillance testing programs for COVID-19 and to further positioning our proprietary LinearDNA manufacturing platform as what we believe to be a cleaner and higher-performing alternative to traditional vaccine development technologies in an environment moving at pandemic speeds to bring efficacious COVID-19 vaccines to market," said Dr. James A. Hayward, president and CEO, Applied DNA. "With the shutdown in global supply chains severely affecting the performance of our supply chain security business, we redirected resources to our Biotherapeutics and Diagnostics markets: we initiated our own human and veterinary linear DNA COVID-19 vaccine development programs with partner Takis Biotech/EvviVax. While having clear public health goals, these programs also serve to validate our linear DNA manufacturing platform and its manufacturing advantages over plasmid DNA production that underpins current vaccine manufacturing technology; having acquired virus expertise as a result of our vaccine development work, we launched our LineaCOVID-19 Assay Kit (the "COVID-19 test") and related testing services as part of a multi-pronged approach to the pandemic to establish new revenue streams.

"The result of these efforts was the development of a highly sensitive, highly specific, EUA-authorized diagnostic test that, when paired with safeCircle, our pooled surveillance testing platform, is in the marketplace today as a cost-effective, and convenient means to help break the chain of virus transmission. We ended the fiscal year having secured our first customer of size for our kit, established an initial base of recurring revenue for our safeCircle platform, and initiated a clinical path for our lead veterinary vaccine candidate with an end goal of enabling commercial veterinary sales for domestic felines."

Continued Dr. Hayward, "Our development efforts in fiscal 2020 have laid the groundwork for multiple inflection points in fiscal 2021. The sales pipelines for our COVID-19 test and safeCircle offerings are building. In particular, safeCircle is experiencing resonance in the marketplace that, together with a recently established ‘return-to-work’ partnership, enables us to target market niches we believe we can exploit profitably, such as local governments, private and enterprise clients, schools, and higher education athletics departments. We anticipate both offerings to scale up their contributions to our top-line over the coming quarters.

"Our own human linear DNA COVID-19 vaccine development program has not progressed as anticipated; however, the preclinical work we have conducted to date serves as the basis for a veterinary COVID-19 vaccine candidate that we believe offers a shorter and less costly regulatory path to commercialization. Domestic cats are a known virus reservoir and can easily transmit the virus to other felines. If all trial endpoints are met, we will apply for conditional licensure from the U.S.D.A., which we project to be in the latter half of the fiscal year. With about 58 million1 domestic cats in the U.S. and a likely first-mover advantage, we believe that a veterinary vaccine could be commercially significant to us if approved. We would then seek to expand the addressable market for our veterinary vaccine to include the farmed mink industry globally that has been ravaged by the virus, resulting in substantial commercial losses.

"As human COVID-19 vaccines obtain regulatory approval, we believe they evidence shortcomings in their manufacture and distribution that we believe are solvable by linear DNA forms of their vaccines. We believe our LinearDNA platform can produce PCR-based linear DNA at large scale enzymatically and likely with an improved safety profile, modify vaccines reliant on plasmids to address mutations in weeks, not months or years, and offer stability in distribution that potentially eliminates the need for expensive cold-chain requirements. This value proposition can benefit not only COVID-19 vaccines but also every nucleic acid-based program under development today. Concurrently, we see an uptick in contract research activity for biotherapeutic applications that we take to reflect the increasing value being placed on linear DNA by drug developers. Today, we are proud to count leading biotechnology and pharmaceutical companies working in the field of nucleic acid-based medicine as contract research customers. As manufacturing and distribution increasingly become key issues in advancing nucleic-acid-based therapeutic development pipelines, we expect that our LinearDNA platform will become increasingly relevant to existing and prospective customers.

"Finally, we await the return of increased demand patterns in our supply chain security market. The need for brand assurance and supply chain integrity remains as evidenced by our new supply agreement for our CertainT platform with Pillar Technologies as it relates to the authenticity of personal protective equipment being consumed by our front-line healthcare workers, and by Nutrition21 who has transitioned its portfolio of IP-protected ingredients to CertainT. We remain cautiously optimistic on the prospects in this business in the new fiscal year," concluded Dr. Hayward.

Fiscal Fourth Quarter 2020 Financial Results:

Revenues decreased 81% for the fourth quarter of fiscal 2020 to $314 thousand, compared with $1.7 million reported in the same period of the prior fiscal year and decreased 27% from $432 thousand for the third quarter of fiscal 2020. The decrease in revenues year over year was due primarily to a decrease in product revenues of approximately $1.1 million, which was primarily from shipments of DNA concentrate to protect the cotton supply chain during the prior fiscal year. The year over year decrease is also due to a decrease of $231 thousand in service revenues. The decrease in revenue quarter over quarter was due to a decrease in service revenue of $183 thousand, primarily related to the textile industry.
Total operating expenses increased to $4.2 million for the fourth fiscal quarter of 2020, compared with $3.2 million in the prior fiscal year’s fourth quarter. This increase is primarily attributable to an approximate $313 thousand increase in payroll. This increase in payroll is primarily attributable to a reversal of voluntary salary reductions and increased staffing at Applied DNA Clinical Laboratories, LLC., as well as an increase in research and development expense of $353 thousand centered on the Company’s LineaCOVID-19 assay kit.
Net loss applicable to common stockholders for the quarter ended September 30, 2020 was $4.1 million, or $0.82 per share, compared with a net loss of $1.5 million, or $1.44 per share, for the quarter ended September 30, 2019
Excluding non-cash expenses, Adjusted EBITDA was negative $3.8 million and negative $1.6 million for the quarters ended September 30, 2020 and 2019, respectively. See below for information regarding non-GAAP measures.
Cash and cash equivalents stood at $7.8 million on September 30, 2020. Subsequent to the fiscal quarter, the Company received two exercises of warrants associated with its November 15, 2019 underwritten public offering (the "2019 Warrants"). The first exercise totaled net proceeds of approximately $1.7 million to the Company that was used to repay all outstanding secured convertible notes of $1.7 million. In accordance with the 2019 Warrants exercise agreement entered into in October 2020, the Company issued approximately 159,000 replacement warrants at an exercise price of $7.52. The second exercise totaled approximately $1.05 million in net proceeds to the Company. Also, in accordance with the 2019 Warrant exercise agreement and the second warrant exercise, the Company issued approximately 100,000 replacement warrants at an exercise price of $6.57 for 50,000 replacement warrants and $6.46 for 50,000 replacement warrants. Approximately 460,000 2019 Warrants are outstanding as of December 10, 2020.
Full Fiscal Year 2020 Financial Results:

Revenues for fiscal 2020 totaled $1.9 million, a decrease of 64% from $5.4 million from the prior fiscal year. The decrease in revenues was due to a decrease in service revenues of $1.9 million, or 60%, and a decrease in product revenues of $1.5 million, or 71%. The decrease in service revenue was primarily attributable to a decrease of $1 million from a cannabis licensing agreement (now terminated), as well as an additional decrease of $613 thousand for a government contract award that ended during the second half of fiscal 2019. The decrease in product revenues relates to a decrease in textiles of $1.35 million for shipments of DNA concentrate to protect the cotton supply chain that occurred during the prior fiscal year. This decrease in textiles revenue is primarily as result of the global shut down related to the COVID-19 pandemic adversely impacting the textile industry.
Operating expenses for the fiscal year ended September 30, 2020 increased slightly by $110 thousand, or 1% as compared to the prior fiscal year.
Net loss applicable to common stockholders for the twelve months ended September 30, 2020 was $13.0 million or $3.32 per share, compared with a net loss of $8.9 million or $9.69 per share for the twelve months ended September 30, 2019.
Excluding non-cash expenses and interest, Adjusted EBITDA for the fiscal year ended September 30, 2020 was a negative $11.6 million as compared to a negative $7.6 million for the prior fiscal year. See below for information regarding non-GAAP measures.
Select Recent Operational Highlights:

COVID-19

LineaCOVID-19 SARS-CoV-2 Diagnostic Assay Kit ("assay kit")

On November 25, 2020, Applied DNA was granted an amendment to its Emergency Use Authorization by the U.S. FDA that expanded the installed base of RT-PCR platforms that can process the assay kit to include the Applied Biosystems 7500 Fast Dx Real-Time PCR System, a system found in the majority of clinical laboratories nationally.
On November 12, 2020, the Company received a blanket purchase order from Stony Brook University Hospital (SBUH) for assay kits and consumables to power SBUH’s newly-launched surveillance testing program that aims to cover testing of 9,000 individuals per week with 1,800 pooled (5 individuals per pool) tests per week. The Company anticipates recurring purchase orders from SBUH to support SBUH’s ongoing surveillance testing needs.
On September 29, 2020, the Company and SBUH signed a one-year Master Service Agreement (MSA) to supply the Company’s COVID-19 assay on an as-needed basis to SBUH. The Company also designed and implemented an automated, high-throughput COVID-19 testing workflow in the SBUH clinical lab that is now being used to enable SBUH’s surveillance testing program. Concurrently, the Company received an initial purchase order under the MSA.
Applied DNA Clinical Labs, LLC (ADCL)

On December 11, 2020, the Company stated that it is experiencing growing demand for its safeCircle pooled COVID-19 surveillance testing program that is being primarily driven by New York State schools moving to comply with the State’s Winter COVID-19 Plan. Applied DNA has secured new agreements with schools and colleges that represent a potential weekly testing population of >5,000 individuals, from which a varying percentage are tested each week. Several contracts are contingent on the schools’ ability to secure funding.
On December 1, 2020, Applied DNA announced that it is providing its pooled surveillance testing program, safeCircle , to the Stony Brook University Seawolves men’s and women’s basketball teams – student-athletes and coaching staff – for the balance of the calendar year.
On November 25, 2020, the Company announced the results of New York State Department of Health’s (DoH) initial inspection report of ADCL that highlighted deficiencies at the clinical lab that were present at the time of the inspection that require remediation prior to the submission of a re-inspection request. The Company expects to complete remediation actions during the first calendar quarter of 2021. The Company’s safeCircle platform and its ability to conduct pooled surveillance testing is not impacted by the DoH’s report.
On November 10, 2020, Applied DNA announced that its assay was selected by SBUH for use in SBUH’s newly launched COVID-19 surveillance testing program that is modeled after the Company’s safeCircle platform, a pooled surveillance testing program. At peak operations, SBUH will test its 9,000-member faculty and staff of SBUH and Renaissance School of Medicine every week that would equate to 1,800 (5 individuals per pooled test) of the Company’s tests per week.
On October 30, 2020, the Company announced that it was boosting its surveillance testing capacity through the expanded use of robotic automation. The Company’s expansion plans support the reception to ADCL’s surveillance testing-as-a-service offering enhanced by ongoing sales and marketing outreach efforts.
On October 12, 2020, announced that it secured COVID-19 surveillance testing contracts that are estimated to generate more than $1.0 million in total annualized revenue beginning October 1, 2020.
Vaccine Candidates

On November 30, 2020, Applied DNA and its development partner, EvviVax, announced the receipt of regulatory approval from the New York State Department of Agriculture and Markets and the U.S. Department of Agriculture (USDA) to initiate a veterinary clinical trial of its lead LinearDNA COVID-19 vaccine candidate in domestic companion felines. The goal of the trial is to evaluate the vaccine candidate as a strategy for the prevention of SARS-CoV-2, the virus that causes COVID-19, in feline companions of humans that would mitigate the animals as a potential reservoir for infections in humans. Domestic felines are a known COVID-19 reservoir and can transmit the virus to other felines.

The trial allows for immunologic data to be gathered across the clinical trial cohort that may also support the initiation of a near-concurrent challenge trial, which is under development. Achievement of both trials’ primary endpoints we believe would enable the Company and EvviVax to apply for a USDA APHIS conditional license (9 CFR 102.6) for a LinearDNA COVID-19 vaccine candidate for domestic felines.

The Company believes that an efficacious vaccine for domestic felines would be similarly efficacious to mink, another known COVID-19 reservoir. SARS-CoV-2 has severely impacted the farmed mink industry and mink-linked virus mutations now present in humans in at least 7 countries. Applied DNA believes that should its veterinary COVID-19 vaccine candidate gain conditional licensure for the vaccine candidate, it could have significant utility in mitigating the spread of the virus in commercial animal populations and from animal populations to humans.
LineaRx

On November 2, 2020, the Company announced orders for its linear DNA to be evaluated in an RNA vaccine and Adeno-Associated Virus (AAV) production from two new contract research customers, respectively. The Company also announced a follow-on order from a repeat customer for a preclinical CAR T therapy. All orders are expected to ship during the quarter ending December 30, 2020.
On August 17, 2020, Applied DNA filed for a nonprovisional patent application with the United States Patent and Trademark Office (USPTO) entitled "Methods and Systems of PCR-Based Recombinant Adeno-Associated Virus Manufacture" (the "Patent"). The Patent claims priority to a previously filed provisional patent application filed with the USPTO in August of 2019.
Supply Chain Security

On December 7, 2020, the Company announced that Nutrition21 has transitioned to the Company’s CertainT platform to secure its IP-protected portfolio of dietary supplement ingredients. Concurrently, the Company received two follow-on orders for a second year of commercial production, the majority of which is expected to be shipped in the quarter ending December 31, 2020.
On September 21, 2020, Applied DNA entered into a supply agreement for its CertainT platform with Pillar Technologies (Pillar), a subsidiary of ITW (Illinois Tool Works). The Company will supply SigNature molecular tags and SigNify in-field authentication devices to Pillar for use on materials and products treated with Pillar’s patented plasma deposition technology. The supply agreement supports Pillar’s strategy to combat the growing issue of counterfeit PPE entering the healthcare supply chain as the COVID-19 pandemic increases demand and has grown to include other materials and products manufactured by Pillar’s customers.
On August 12, 2020, the Company received a Notice of Allowance for its U.S. Patent Application No. 14/572,552 (US 2016/0168781 A1) entitled "Method and Device for Marking Fibrous Materials." The allowed claims cover methods of DNA-tagging cotton fibers while they travel through the forced air systems found at cotton gins, and later authenticating the DNA-tagged cotton fibers to prove their provenance and/or authenticity all the way to finished goods. The allowed patent application extends the Company’s patent protection for its proprietary DNA Transfer System, a key component of its CertainT platform for cotton
Corporate

On October 8, 2020, Applied DNA announced the repayment of secured convertible notes in an aggregate amount of approximately $1.7 million, representing the outstanding amount of the Notes plus interest through the scheduled maturity of the Notes. The repayment was funded by the exercise of warrants issued as part of the Company’s November 15, 2019 underwritten public offering for total proceeds to Applied DNA of approximately $1.7 million.
Footnote:
1 View Source

Fiscal Fourth Quarter 2020 Conference Call Information

The Company will hold a conference call and webcast to discuss its fiscal fourth quarter-end 2020 results on Thursday, December 17, 2020 at 4:30 PM ET. To participate on the conference call, please follow the instructions below. While every attempt will be made to answer investors’ questions on the Q&A portion of the call, due to the large number of expected participants, not all questions may be answered.

For those investors unable to attend the live call, a copy of management’s PowerPoint presentation will be available for review under the ‘IR Calendar’ portion of the Company’s Investor Relations web site: View Source

About the LineaTM COVID-19 Assay Kit

The Linea COVID-19 Assay Kit is authorized by FDA EUA for the qualitative detection of nucleic acid from SARS-CoV-2 in respiratory specimens, including anterior nasal swabs, self-collected at a healthcare location or collected by a healthcare worker, and nasopharyngeal and oropharyngeal swabs, mid-turbinate nasal swabs, nasopharyngeal washes/aspirates or nasal aspirates, and bronchoalveolar lavage (BAL) specimens collected by a healthcare worker from individuals who are suspected of COVID-19 by their healthcare provider. The scope of the Linea COVID-19 Assay Kit EUA, as amended, is expressly limited to use consistent with the Instructions for Use by authorized laboratories, certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to perform high complexity tests. The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of in vitro diagnostics for detection and/or diagnosis of COVID-19 is terminated or until the EUA’s prior termination or revocation. The diagnostic kit has not been FDA cleared or approved, and the EUA’s limited authorization is only for the detection of nucleic acid from SARS-CoV-2, not for any other viruses or pathogens.

The Company is offering surveillance testing in compliance with current CDC, FDA, and CMS guidances. The use of saliva and pooled sampling for surveillance testing, which has been internally validated by the Company in compliance with current surveillance testing guidances, is not included in the Company’s EUA authorization for the Linea COVID-19 Assay Kit. (Press release, Applied DNA Sciences, DEC 17, 2020, View Source [SID1234572983])

On December 17, 2020 CNS Pharmaceuticals, Inc. (NASDAQ: CNSP) ("CNS" or the "Company"), a biopharmaceutical company specializing in the development of novel treatments for primary and metastatic cancers of the brain and central nervous system, reported it will host a conference call and live webcast on December 18th, 2020 at 8:30am ET to discuss its Investigational New Drug (IND) approval for its lead product candidate, Berubicin, for the treatment of Glioblastoma Multiforme (GBM), and planned Phase 2 Berubicin clinical trial (Press release, CNS Pharmaceuticals, DEC 17, 2020, View Source [SID1234573006]).

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Details of the webcast are below:

Date:

December 18th, 2020

Time:

8:30 AM ET

Link:

View Source

The dial-in numbers for the conference call are (800) 226-2188 for domestic callers and (602) 563-8462 for international callers. The conference ID is 6455799.

A replay of the call will be available following its completion through December 25th, 2020. To access the replay, dial (855) 859-2056 for domestic callers and (404) 537-3406 for international callers and use the replay conference ID: 6455799.

On December 17, 2020 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) has approved RIABNI (rituximab-arrx), a biosimilar to Rituxan (rituximab), for the treatment of adult patients with Non-Hodgkin’s Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis), and Microscopic Polyangiitis (MPA). RIABNI will be made available in the U.S. in January 2021 (Press release, Amgen, DEC 17, 2020, View Source [SID1234573008]).

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"The approval of RIABNI represents an important milestone across our biosimilar and oncology portfolios," said Murdo Gordon, executive vice president of Global Commercial Operations at Amgen. "Following the proven success of KANJINTI (trastuzumab-anns) and MVASI (bevacizumab-awwb) in the U.S. marketplace, RIABNI reaffirms Amgen’s long-term commitment to providing high quality biosimilars that can potentially offer more affordable, effective treatment options for cancer and other serious diseases and that contribute to the sustainability of healthcare systems."

RIABNI, a CD20-directed cytolytic antibody, was proven to be highly similar to Rituxan based on a totality of evidence, which included comparative analytical, nonclinical and clinical data, with no clinically meaningful differences in safety or effectiveness. The data package was composed of, in part, results from a pharmacokinetic (PK) similarity study and a comparative clinical study.

The randomized, double-blind, comparative clinical study evaluated the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability and immunogenicity of RIABNI compared to Rituxan in subjects with grade 1, 2, or 3a follicular B-cell NHL and low tumor burden. There were 256 patients enrolled and randomized (1:1) to receive 375 mg/m2 intravenous infusion of either RIABNI or Rituxan, once weekly for 4 weeks followed by dosing at weeks 12 and 20. The primary endpoint, an assessment of overall response rate (ORR) by week 28, was within the prespecified margin for RIABNI compared to Rituxan, showing clinical equivalence. PK, PD, safety and immunogenicity of RIABNI were similar to Rituxan.

The Wholesale Acquisition Cost (WAC or "list price") of RIABNI in the U.S. will be 23.7% lower than the reference product, Rituxan. RIABNI is being made available at a WAC of $716.80 per 100 mg and $3,584.00 per 500 mg single-dose vial, 23.7% less than the WAC for Rituxan, 15.2% less than the WAC for Truxima (biosimilar to Rituxan) and matching the WAC for Ruxience (biosimilar to Rituxan). At launch, RIABNI will be priced 16.7% below the current Rituxan Average Selling Price (ASP). RIABNI will be available from both wholesalers and specialty distributors.

Amgen has a total of 10 biosimilars in its portfolio, five of which have been approved in the U.S., and three that are approved in the European Union (EU).

About RIABNI (rituximab-arrx) in the U.S.
RIABNI is a biosimilar to Rituxan, an anti-CD20 monoclonal antibody. The active ingredient of RIABNI is a monoclonal antibody that has the same amino acid sequence as Rituxan. RIABNI also has the same strength as Rituxan, and the dosage form and route of administration are identical to the IV formulation of Rituxan.

RIABNI is currently not yet available commercially. This is not an offer for sale. The following information is derived from the approved label in the U.S.

In the U.S., RIABNI is approved for:

Non-Hodgkin’s Lymphoma (NHL)
RIABNI (rituximab-arrx) is indicated for the treatment of adult patients with:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
Chronic Lymphocytic Leukemia (CLL)
RIABNI, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)
RIABNI, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA).

Important Safety Information

BOXED WARNINGS: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Infusion-Related Reactions: Rituximab product administration can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RIABNITM infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions.
Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products. Discontinue RIABNITM in patients who experience a severe mucocutaneous reaction. The safety of readministration of RIABNITM to patients with severe mucocutaneous reactions has not been determined.
Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RIABNITM. Discontinue RIABNITM and concomitant medications in the event of HBV reactivation.
Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products. Discontinue RIABNITM and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Infusion-Related reactions (IRR)

Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes.
Rituximab-product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.
Premedicate patients with an antihistamine and acetaminophen prior to dosing. For patients with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA), methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RIABNITM. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.
Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3).
Severe Mucocutaneous Reactions

Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.
The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue RIABNITM in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined.
Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases, increase in bilirubin levels, liver failure, and death can occur.
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RIABNITM. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RIABNITM treatment.
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RIABNITM therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.
In patients who develop reactivation of HBV while on RIABNITM, immediately discontinue RIABNITM and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming rituximab product treatment in patients who develop HBV reactivation. Resumption of RIABNITM treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.
Progressive Multifocal Leukoencephalopathy (PML)

JC virus infection resulting in multifocal leukoencephalopathy (PML) and death can occur in rituximab-product -treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab.
Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue RIABNITM and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
Tumor Lysis Syndrome

Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12−24 hours after the first infusion of RIABNITM in patients with non-Hodgkin’s lymphoma (NHL). A high number of circulating malignant cells (≥25,000/mm3), or high tumor burden, confers a greater risk of TLS.
Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.
Infections

Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure).
New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue RIABNITM for serious infections and institute appropriate anti-infective therapy.
RIABNITM is not recommended for use in patients with severe, active infections.
Cardiovascular Adverse Reactions

Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RIABNITM for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.
Renal Toxicity

Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RIABNITM is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RIABNITM in patients with a rising serum creatinine or oliguria.
Bowel Obstruction and Perforation

Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1−77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.
Immunization

The safety of immunization with live viral vaccines following rituximab product therapy has not been studied, and vaccination with live virus vaccines is not recommended before or during treatment.
For patients treated with RIABNITM, physicians should review the patient’s vaccination status and patients should, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating RIABNITM; administer non-live vaccines at least 4 weeks prior to a course of RIABNITM.
Embryo-Fetal Toxicity

Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception with RIABNITM and for at least 12 months after the last dose.
Concomitant Use with Other Biologic Agents and Disease Modifying Antirheumatic Drugs (DMARDs) in GPA and MPA

Limited data are available on the safety of the use of biologic agents or DMARDs. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products.
Adverse Reactions

The most common Grade 3 or 4 adverse reactions in clinical trials of NHL and chronic lymphocytic leukemia (CLL) were infusion-related reactions, neutropenia, leukopenia, anemia, thrombocytopenia, and infections. Additionally, lymphopenia and lung disorder were seen in NHL trials; and febrile neutropenia, pancytopenia, hypotension, and hepatitis B were seen in CLL trials.
The most common adverse reactions (incidence ≥25%) in clinical trials of NHL and CLL were infusion-related reactions. Additionally, fever, lymphopenia, chills, infection, and asthenia were seen in NHL trials; and neutropenia was seen in CLL trials.
Nursing Mothers

There are no data on the presence of rituximab products in human milk, the effect on the breastfed child, or the effect on milk production. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RIABNITM and for at least 6 months after the last dose.
Clinical Trials Experience in GPA and MPA

Adverse reactions reported in ≥15% of rituximab-treated patients were infections, nausea, diarrhea, headache, muscle spasms, anemia, and peripheral edema (other important adverse reactions include infusion-related reactions).
Induction Treatment of Patients with Active GPA/MPA (GPA/MPA Study 1)
Infusion-Related Reactions

In GPA/MPA Study 1, 12% vs 11% (rituximab-treated vs cyclophosphamide-treated, respectively) of patients experienced at least one infusion-related reaction. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the rituximab group, the proportion of patients experiencing an infusion reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were premedicated with antihistamine and acetaminophen before each rituximab infusion and were on background oral corticosteroids, which may have mitigated or masked an infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion-related reactions.
Infections

In GPA/MPA Study 1, 62% vs 47% (rituximab-treated vs cyclophosphamide-treated, respectively) of patients experienced an infection by Month 6. The most common infections in the rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% vs 10% (rituximab-treated vs cyclophosphamide-treated, respectively), with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.
Hypogammaglobulinemia

Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with rituximab in GPA/MPA Study 1. At 6 months, in the rituximab group, 27%, 58%, and 51% of patients with normal immunoglobulin levels at baseline had low IgA, IgG, and IgM levels, respectively, compared to 25%, 50%, and 46% in the cyclophosphamide group.
Immunogenicity

A total of 23/99 (23%) rituximab-treated adult patients with GPA or MPA tested positive for anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximab-treated adult patients is unclear.
Treatment of Patients with GPA/MPA Who Have Achieved Disease Control with Induction Treatment (GPA/MPA Study 2)

In GPA/MPA Study 2, the safety profile was consistent with the known safety profile of rituximab in immunologic indications.
Infusion-Related Reactions (IRR)

In GPA/MPA Study 2, 7/57 (12%) patients in the non-US-licensed approved rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). One patient had two serious IRRs; two IRRs led to a dose modification; and no IRRs were severe, fatal, or led to withdrawal from the study.
Infections

In GPA/MPA Study 2, 30/57 (53%) patients in the non-US-licensed approved rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all-grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis.
Attention Healthcare Provider: Provide Medication Guide to patient prior to RIABNITM infusion and advise patients to read guide.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Amgen at 1-800-772-6436.

Please see the full Prescribing Information, including BOXED WARNINGS and Medication Guide, for additional Important Safety Information.

About Amgen Biosimilars
Amgen is committed to building upon Amgen’s experience in the development and manufacturing of innovative human therapeutics to expand Amgen’s reach to patients with serious illnesses. Biosimilars will help to maintain Amgen’s commitment to connect patients with vital medicines, and Amgen is well positioned to leverage its nearly four decades of experience in biotechnology to create high-quality biosimilars and reliably supply them to patients worldwide.

On December 17, 2020 Stand Up To Cancer (SU2C) reported that unveiled a collaborative initiative aimed at improving colorectal cancer screening, early detection and prevention across the United States (Press release, Exact Sciences, DEC 17, 2020, View Source [SID1234573009]). The transformative $10 million grant from Exact Sciences, a provider of cancer screening and diagnostic tests, will fund a colorectal cancer ‘Dream Team’ of researchers, as well as a comprehensive public awareness campaign to increase screenings.

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The new Dream Team will be awarded in early 2021 and will identify communities near anchor institutions that serve minority and medically underserved communities, pinpoint the unique local needs of those areas and turn participating at-risk communities into "Stand Up To Cancer Zones" with high rates of colorectal cancer screening. The Dream Team will provide free colorectal cancer testing in the identified zones and will study samples collected via approved tests for colorectal cancer, including colonoscopy, CT colonography, flexible sigmoidoscopy, and at-home stool tests that analyze fecal DNA and/or blood. The research will aim to develop better approaches to colorectal cancer interception.

Fellowships for early-career investigators committed to studying health equity and disparities in colorectal cancer will also be funded. Public awareness campaigns will focus on medically underserved communities to increase awareness of the importance of colorectal cancer screening and early detection, and the availability of multiple effective screening options, such as traditional colonoscopy as well as options used at home.

"This funding allows us to bring together institutions, clinicians and communities to address the challenges we face in colorectal cancer screening," said Nobel laureate Phillip A. Sharp, PhD, chair of Stand Up To Cancer’s Scientific Advisory Committee and an Institute professor at the David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology. "Due to the COVID-19 pandemic, it’s more important than ever to make sure people are informed about both the benefits of colorectal cancer screening and their options."

"We’re excited to work with Stand Up To Cancer on this bold new initiative," said Kevin Conroy, chairman and CEO of Exact Sciences. "We want to change the way people think about colorectal cancer screening. This collaboration will move cutting-edge research and education efforts forward so we can help more people."

This year, nearly 148,000 Americans will receive a new diagnosis of colon or rectal cancer.i Colorectal cancer is treatable in 90% of cases when detected early,ii yet 1 in 3 adults over age 50 are not up-to-date on recommended colorectal cancer screening.iii The COVID-19 pandemic has further compounded the problem with screening rates dropping significantly due to stay-at-home orders. For example, the total number of colonoscopies and biopsies performed declined by nearly 90% by mid-April 2020 compared to April 2019.iv Concurrently, new cases of colorectal cancer are occurring at a growing rate among young and middle-aged adults in the US, with the number of cases of colorectal cancer in people under 50 expected to almost double by 2030.v The disease disproportionately impacts people of color; Black people have the highest rates of colorectal cancer of any racial or ethnic group in the US.vi In October 2020, the US Preventive Services Task Force released a draft recommendation to lower the colorectal cancer screening age from 50 to 45,vii but educating the public about the benefits of screening, as well as screening options, remains vital.

"We want people to understand that this disease is highly preventable and that a simple test can save lives," said Sung Poblete, PhD, RN, CEO of Stand Up To Cancer. "When it comes to screening for colorectal cancer, the best test is the test that gets done. People will always benefit from simple and accessible healthcare options, and at-home preventive care is particularly vital to keeping people healthy during the pandemic. Together with Exact Sciences, we’re going to make this message mainstream and our hope is that other collaborators, such as healthcare providers, community leaders and advocacy groups, will join us in taking a stand against colorectal cancer."

Research has shown that colorectal cancer screening rates are the lowest in Hispanic communities, with 59% of Hispanics getting screened, compared to 66% of Black people and 69% of white people getting screened.viii Black and Hispanic people are typically diagnosed at a later stage in the disease when it is more difficult to treat. These disparities could be driven by financial barriers, lack of insurance, existing health inequities and insufficient information about colorectal cancer and colorectal cancer screening options.

SU2C, along with Exact Sciences, plans to engage with other collaborators to help reach the underserved communities, foster scientific research and guide public participation. The multi-pronged approach intends to ensure that colorectal cancer remains a disease that is treatable and survivable through widespread screening and early detection.

SU2C announced a Health Equity Initiative in January 2020. The initiative requires all future teams seeking Stand Up To Cancer funding to address recruitment and retention of patients from different ethnic and racial groups and underserved communities to improve diverse participation in cancer clinical trials. The initiative also includes collaborations with advocacy groups and industry and corporate supporters to move research and public awareness efforts forward. The new grant from Exact Sciences is the next critical step in SU2C’s movement to ensure cancer research, screening and treatment benefit everyone.