On February 28, 2022 Dynavax Technologies Corporation (Nasdaq: DVAX), a commercial stage biopharmaceutical company developing and commercializing innovative vaccines, reported record 2021 total revenue of $439.4 million for the full year of 2021, marking a significant increase compared to $46.6 million for 2020 (Press release, Dynavax Technologies, FEB 28, 2022, View Source [SID1234609119]).

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"The Company’s strong performance throughout 2021 is a testament to the strategy, hard work and dedication of the Dynavax team. This past year we made tremendous progress across our three strategic focus areas – HEPLISAV-B commercialization, execution of CpG 1018 adjuvant supply for COVID-19 vaccines, and advancement of our clinical pipeline – driving 72% year-over-year growth in HEPLISAV-B sales and $375 million in CpG 1018 adjuvant supply revenue," commented Ryan Spencer, Chief Executive Officer of Dynavax. "With approximately $546 million in cash and investments at year-end, we are able to make thoughtful investments into our pipeline leveraging our proven adjuvant. In 2022, we expect continued growth with HEPLISAV-B and our CpG 1018 adjuvant supply business, generating another profitable year with record total revenue, as well as initial clinical data that we anticipate will support meaningful differentiation to establish our high value pipeline designed to produce best-in-class products targeting large markets."

2021 CORPORATE AND FINANCIAL HIGHLIGHTS

HEPLISAV-B [Hepatitis B Vaccine (Recombinant), Adjuvanted]

•HEPLISAV-B achieved record annual revenue of $61.9 million for 2021, compared to $36.0 million for 2020, despite the disruptions to the healthcare system from the COVID-19 pandemic.
•Market share in the accounts targeted by the field sales team grew to approximately 34%, up from approximately 26% at the end of 2020.
•With a proven clinical profile and strong commercial execution, the Company expects further market share gains and revenue growth in 2022.
•Recent recommendations from the CDC’s Advisory Committee on Immunization Practices (ACIP) advise that all adults aged 19-59 should be vaccinated against Hepatitis-B, creating a significantly expanded market opportunity, which the company estimates to be $800 million in the U.S. by 2027. The Company believes that HEPLISAV-B is well-positioned to secure majority market share.

CpG 1018 Adjuvant Supply for COVID-19 Vaccines

•Dynavax has established a portfolio of global CpG 1018 adjuvant commercial supply agreements leveraging its adjuvant in the development of COVID-19 vaccines across a variety of vaccine platforms.
•CpG 1018 adjuvant revenue for 2021 of $375.2 million, compared to $3.3 million 2020.
•The Company expects 2022 full-year CpG 1018 adjuvant COVID-19 supply revenue to be at least $550 million, based on committed adjuvant orders, with gross margin of approximately 50%.
•CpG 1018 adjuvant supply partner status:
oBiological E (Bio E) received Emergency Use Authorization (EUA) from the Drugs Controller General of India (DCGI) for their subunit COVID-19 vaccine candidate, CORBEVAX adjuvanted with CpG 1018, for adults in

December 2021. In February 2022, Bio E received EUA for adolescents aged 12 to less than 18 years of age by the DCGI.
oClover Biopharmaceuticals reported it is in the process of submitting conditional regulatory approval applications for its protein-based COVID-19 vaccine candidate, SCB-2019 (CpG 1018/Alum) utilizing our CpG 1018 adjuvant, to China’s National Medical Products Administration, the European Medicines Agency (EMA) and the World Health Organization (WHO).
oMedigen Vaccine Biologics Corporation received EUA for MVC-COV1901, its COVID-19 vaccine utilizing our CpG 1018 adjuvant, from the Taiwan Food and Drug Administration in 2021 and from Paraguay’s National Directorate of Health Surveillance (DINAVISA) in February 2022.
oValneva SE reported it is continuing to provide data to the European Medicines Agency (EMA), the UK Medicines and Healthcare products Regulatory Agency, and the National Health Regulatory Authority in Bahrain (NHRA) as part of the rolling submissions process for initial approval of VLA2001.
oCpG 1018 adjuvant supply partners have ongoing clinical trials evaluating the immunogenicity or efficacy of their vaccine candidates for global use, homologous and heterologous boosters, as well as additional indications including pediatrics.

Clinical Pipeline

•The Company is advancing its clinical pipeline leveraging its CpG 1018 adjuvant to develop improved vaccines in indications with unmet medical need.
•CpG 1018 adjuvant has demonstrated its ability to enhance immune responses with a favorable tolerability profile established through a wide range of clinical trials and real-world commercial use.
•The Company is currently advancing three clinical-stage programs with important milestones in 2022:
oTopline data is expected in the first half of 2022 from the Company’s ongoing Tdap Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity in adults, with adolescent data expected in the second half of 2022.
oIn January 2022, the first patient was dosed in a Phase 1 clinical trial evaluating the safety, tolerability, and immunogenicity in the Company’s investigational shingles vaccine program utilizing CpG 1018 adjuvant. Topline data from the trial is expected by the end of 2022.
oIn collaboration with, and funded by, the U.S. Department of Defense, the Company will conduct a Phase 2 clinical trial for a plague vaccine utilizing CpG 1018 adjuvant with trial initiation anticipated in the second half of 2022.

Board of Directors Additions

•In October, Scott Myers was appointed to the Board of Directors and elected Chairman.
•In December, Elaine Sun was appointed to the Board of Directors.

FOURTH QUARTER AND FULL YEAR 2021 FINANCIAL HIGHLIGHTS

Total Revenues and Product Revenue, Net.

Total revenues for the fourth quarter of 2021 were $195.1 million, compared to $19.6 million for 2020.

•HEPLISAV-B product revenue, net was $17.2 million for the fourth quarter of 2021 compared to $11.5 million for the fourth quarter of 2020.
•CpG 1018 product revenue, net was $177.4 million in the fourth quarter of 2021 compared to $1.6 million in the fourth quarter of 2020.

Total revenues for the full year 2021 were $439.4 million, compared to $46.6 million for the full year 2020.

•HEPLISAV-B product revenue, net increased 72% to $61.9 million for 2021 compared to $36.0 million for the full year 2020.
•CpG 1018 product revenue, net was $375.2 million for 2021 compared to $3.3 million for the full year 2020.
Cost of Sales – Product. Cost of sales – product for the fourth quarter of 2021 increased to $74.0 million, compared to $4.1 million for the fourth quarter of 2020. Full year 2021 cost of sales – product was $173.6 million compared to $11.4 million for the full year of 2020. The increase was primarily due to manufacturing costs for increased volumes of CpG 1018 sold to COVID-19 supply partners, and HEPLISAV-B sales, coupled with approximately $4.8 million in excess capacity charges in connection with an expansion project at the Company’s manufacturing facility in Dusseldorf and $2.6 million write-off of HEPLISAV-B inventory that had been manufactured prior to the beginning of the COVID-19 pandemic and not expected to be sold due to the prolonged impact of the pandemic.

Research and Development Expenses (R&D). R&D expenses for the fourth quarter of 2021 increased to $11.1 million, compared to $9.5 million for the fourth quarter of 2020. Full year 2021 R&D expenses were $32.2 million compared to $28.6 million for the full year 2020. The increase in both periods was primarily driven by higher compensation and personnel costs, including non-cash stock-based compensation, associated with higher headcount and external costs as the Company advances its product candidates with CpG 1018 adjuvant through pre-clinical and clinical collaborations and additional discovery efforts.

Selling, General and Administrative Expenses (SG&A). SG&A expenses for the fourth quarter of 2021 increased to $29.2 million, compared to $17.8 million for the fourth quarter of 2020. Full year 2021 SG&A expenses were $100.2 million compared to $79.3 million for the full year 2020. The increase in both periods was primarily driven by compensation and related personnel costs, including non-cash stock-based compensation, associated with higher headcount as the Company expanded its field sales team to increase HEPLISAV-B market share.

Interest Expense. Interest expense was $1.7 million in the fourth quarter of 2021 and $11.2 million for the full year 2021, primarily in connection with the convertible senior notes due 2026.

Other income (expense). Other income (expense) includes the change in fair value of warrant liability which is a non-cash adjustment to fair value each reporting period. The change in fair value of warrant liability for the fourth quarter of 2021 resulted in a gain of $19.2 million, compared to a loss of $0.1 million in the fourth quarter of 2020.

Income Tax Expense. Income tax expense was $0.8 million for the full year 2021 and the Company’s effective tax rate was 1.03%. No income tax expense was recorded for the full year 2020. The increase in income tax expense and the effective tax rate are both due to achieving the Company’s first profitable year with GAAP net income of $76.7 million.

Net Income (Loss). GAAP net income was $99.8 million, or $0.80 per share (basic) and 0.55 per share (diluted) in the fourth quarter of 2021, compared to GAAP net loss in the fourth quarter of $15.5 million, or $0.14 per share (basic) and $0.14 per share (diluted) in the fourth quarter of 2020. GAAP net income was $76.7 million, or $0.62 per share (basic) and $0.57 per share (diluted) for the full year 2021, compared to GAAP net loss of $75.2 million, or $0.75 per share (basic) and $0.78 per share (diluted) for the full year 2020.

Cash Flow Statement and Balance Sheet Highlights

•Dynavax ended 2021 with $546 million in cash, cash equivalents and marketable securities, compared to $165 million at the end of 2020.
•Dynavax generated $120.5 million in cash from operations in the fourth quarter of 2021, compared to cash used in operations of $15.7 million in the fourth quarter of 2020. The Company generated $335.5 million in cash from operations for the full year 2021, compared to cash used in operations of $92.3 million for the full year 2020.

2022 Financial Guidance

In 2022, Dynavax anticipates:

•Full year CpG 1018 adjuvant net product revenues of at least $550 million, with associated gross margin of approximately 50%
•Selling, general and administrative expenses to be between approximately $120 – $140 million
•Research and development expenses to be between approximately $55 – $70 million
•Interest expense of approximately $7 million

Conference Call and Webcast Information

Dynavax will hold a conference call today at 4:30 p.m. ET/1:30 p.m. PT. The live audio webcast may be accessed through the "Events & Presentations" page on the "Investors" section of the Company’s website at View Source Alternatively, participants may dial (866) 420-4066 or (409) 217-8237 and refer to conference ID 4678925. A replay of the webcast will be available for 30 days following the live event.

About Hepatitis B

Hepatitis B is a viral disease of the liver that can become chronic and lead to cirrhosis, liver cancer and death. The hepatitis B virus is 50 to 100 times more infectious than HIV,i and transmission is on the rise. There is no cure for hepatitis B, but effective vaccination can prevent the disease.

In adults, hepatitis B is spread through contact with infected blood and through unprotected sex with an infected person. The U.S. Centers for Disease Control (CDC) recommends vaccination for those at high risk for infection due to their jobs, lifestyle, living situations and travel to certain areas.ii Because people with diabetes are particularly vulnerable to infection, the CDC recommends vaccination for adults age 19 to 59 with diabetes as soon as possible after their diagnosis, and for people age 60 and older with diabetes at their physician’s discretion.iii Approximately 26 million U.S. adults have diabetes, and 1.5 million new cases of diabetes are diagnosed each year.iv

About HEPLISAV-B

HEPLISAV-B is an adult hepatitis B vaccine that combines hepatitis B surface antigen with Dynavax’s proprietary Toll-like Receptor (TLR) 9 agonist CpG 1018 to enhance the immune response. Dynavax wholly owns HEPLISAV-B.

Important U.S. Product Information

HEPLISAV-B is indicated for prevention of infection caused by all known subtypes of hepatitis B virus in adults age 18 years and older.

Safety and effectiveness of HEPLISAV-B have not been established in adults on hemodialysis.

For full U.S. Prescribing Information for HEPLISAV-B, click here.

Important U.S. Safety Information (ISI)

Do not administer HEPLISAV-B to individuals with a history of severe allergic reaction (e.g., anaphylaxis) after a previous dose of any hepatitis B vaccine or to any component of HEPLISAV-B, including yeast. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of HEPLISAV-B. Immunocompromised persons, including individuals receiving immunosuppressant therapy, may have a diminished

immune response to HEPLISAV-B. Hepatitis B has a long incubation period. HEPLISAV-B may not prevent hepatitis B infection in individuals who have an unrecognized hepatitis B infection at the time of vaccine administration. The most common patient reported adverse reactions reported within 7 days of vaccination were injection site pain (23% to 39%), fatigue (11% to 17%) and headache (8% to 17%).

Important EU/EEA Product Information

HEPLISAV B is indicated for active immunization against hepatitis B virus infection (HBV) caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

The use of HEPLISAV B should be in accordance with official recommendations.

It can be expected that hepatitis D will also be prevented by immunization with HEPLISAV B as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

For full EU/EEA. Prescribing Information for HEPLISAV-B, click here.

Important EU/EEA Safety information

Do not receive HEPLISAV B if you have had a sudden life-threatening, allergic reaction after receiving HEPLISAV B in the past, or if you are allergic to any of components of this vaccine, including yeast. Signs of an allergic reaction may include itchy skin, rash, shortness of breath and swelling of the face or tongue.

Appropriate medical treatment and supervision should be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

The administration of HEPLISAV B should be postponed in subjects suffering from acute severe febrile illness.

Immunocompromised persons may have a diminished immune response to HEPLISAV B.

Because of the long incubation period of hepatitis B, it is possible for unrecognized HBV infection to be present at the time of immunization. HEPLISAV B may not prevent HBV infection in such cases.

There are very limited data on the immune response to HEPLISAV B in individuals who did not mount a protective immune response to another hepatitis B vaccine.

As a precautionary measure, it is preferable to avoid the use of HEPLISAV B during pregnancy. Vaccination during pregnancy should only be performed if the risk-benefit ratio at the individual level outweighs possible risks for the fetus.

The most common patient-reported side effects reported within 7 days of vaccination were pain, swelling or redness at the injection site, feeling tired, headache, muscle aches, feeling unwell and fever.

About CpG 1018 Adjuvant

Dynavax developed CpG 1018 adjuvant to provide an increased vaccine immune response with improved tolerability profile, which has been demonstrated in HEPLISAV-B and two COVID-19 vaccines that have received Emergency Use Authorization. CpG 1018 adjuvant provides a well- developed technology and a significant safety database, potentially accelerating the development and large-scale manufacturing of novel or improved vaccines.

On February 28, 2022 MaaT Pharma (EURONEXT: MAAT – the "Company"), a French clinical-stage biotech and a pioneer in the development of microbiome-based ecosystem therapies dedicated to improving survival outcomes for patients with cancer reported its cash position as of December 31, 2021, and its full-year 2021 revenues (Press release, MaaT Pharma, FEB 28, 2022, View Source [SID1234609135]).

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"2021 has been an eventful year for MaaT Pharma. Promising results from our Phase 2 and from the Early Access Program for MaaT013, our lead candidate ready to enter a Phase 3 study, marked our clinical development. We also reached a new milestone in our history in 2021 with the success of our IPO on the Euronext, which allowed us to raise EUR 35.7 million. We are in a solid financial position and are moving forward in our development with value-creating clinical milestones expected in the upcoming months for MaaT013 and our second drug candidate, MaaT033, as well as scaling up our manufacturing capacities," stated Hervé Affagard, CEO and co-founder of MaaT Pharma.

Cash position1
As of December 31, 2021, total cash and cash equivalents were EUR 43.3 million, as compared to EUR 19.9 million as of December 31, 2020. The increase in cash flow is due to the capital raise of EUR 35.7 million following the Company’s IPO on Euronext on November 8, 2021. The Company believes it has sufficient cash to cover needs of the development programs presented during the IPO up until the end of the third quarter of 2023.

Revenues in 20211
MaaT Pharma reported revenues of EUR 1.0 million for the year ended December 31, 2021, which includes compensation from the Temporary Authorization for Use program (ATUn), known as compassionate access program since July 1, 2021, and approved by the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM). In 2021, new patients, mostly suffering from graft-versus-host disease, were granted early access treatment with MaaT013. To date in 2022, requests for the early access program are following as similar trend to that observed in 2021.

Upcoming financial communication and investor conference participation
March 3, 2022 (10:00am CET) – Ordinary and Extraordinary Shareholders’ General Meeting (regarding resolutions relative to the implementation of a Liquidity Contract, the Annual General meeting will take place at a later date).
April 15, 2022 – Annual results 2021
April 20 and 21, 2022 – 14th Kempen Life Sciences Conference, Amsterdam
June 29 and 30, 2022 – 9th Portzamparc Annual conference, Paris

On February 28, 2022 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported that its Chief Executive Officer, Nancy Simonian, M.D., will participate in a panel discussion and present a corporate overview at two upcoming virtual investor conferences in March (Press release, Syros Pharmaceuticals, FEB 28, 2022, View Source [SID1234609152]). Management will also be available for one-on-one meetings. Details are as follows:

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Cowen 42nd Annual Healthcare Conference
Date: Monday, March 7
Panel Title: Novel Oncology Targets
Panel Time: 12:50 p.m. ET

Oppenheimer 32nd Annual Healthcare Conference
Date: Wednesday, March 16
Presentation Time: 3:20 p.m. ET

To access the webcasts and subsequent archived recording of each event, please visit the Investors & Media section of the Syros website at www.syros.com. An archived replay of each webcast will be available for approximately 30 days following each presentation.

On February 28, 2022 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, reported that the U.S. Food and Drug Administration (FDA) has approved its first product, CARVYKTI (ciltacabtagene autoleucel; cilta-cel), for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) who have received four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody (Press release, Legend Biotech, FEB 28, 2022, View Source [SID1234609171]). Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel in December 2017.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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CARVYKTI is a chimeric antigen receptor T-cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting single domain antibodies and given as a one-time infusion with a recommended dose range of 0.5 to 1.0 x 106 CAR-positive viable T cells per kg of body weight. In the pivotal CARTITUDE-1 study, deep and durable responses were seen in patients with RRMM (n=97), with a high overall response rate (ORR) of 98 percent (95 percent confidence interval [CI]: 92.7-99.7) including 78 percent of the patients achieving stringent complete response (sCR, 95 percent CI: 68.8-86.1).1 At a median of 18 months follow-up, the median duration of response (DOR) was 21.8 months (95 percent CI 21.8-not estimable).1

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.1 The Safety Information for CARVYKTI includes a Boxed Warning regarding Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged and/or recurrent cytopenia.1 Warnings and Precautions include prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies and effects on ability to drive and use machines.1 The most common adverse reactions (≥20 percent) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.1

"Multiple myeloma remains an incurable disease with heavily pretreated patients facing poor prognoses with limited treatment options," said Ying Huang, PhD, CEO and CFO of Legend Biotech. "Today’s approval of CARVYKTI is a pivotal moment for Legend Biotech because it is our first-ever marketing approval, but what really excites us is the drug’s potential to become an impactful therapy option for patients in need of long, treatment-free intervals. This is the first of many cell therapies we plan to bring to patients as we continue advancing our pipeline across disease states."

Multiple myeloma affects a type of white blood cell called plasma cells, which are found in the bone marrow.2 The majority of patients relapse after undergoing initial treatment and face poor prognoses after treatment with three major drug classes, including immunomodulatory agent, a proteasome inhibitor and anti-CD38 monoclonal antibody.3,4,5

"The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse with fewer patients achieving a deep response as they progress through later lines of therapy," said Dr. Sundar Jagannath, MBBS, Professor of Medicine, Hematology and Medical Oncology at Mount Sinai, and principal study investigator. "This is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population. Today’s approval of CARVYKTI helps address a great unmet need for these patients."

As a personalized medicine, CARVYKTI’s administration requires extensive training, preparation, and certification to ensure a seamless experience for patients. Through a phased approach, Legend and Janssen will activate a limited network of certified treatment centers as they work to scale production capacity and increase the availability of CARVYKTI throughout the U.S. in 2022 and beyond, ensuring that the CARVYKTI treatment can be provided to oncologists and their patients in a reliable and timely manner.

About CARVYKTI (Ciltacabtagene autoleucel; cilta-cel)

CARVYKTI is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.1

In December 2017, Legend Biotech Corporation entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. to develop and commercialize cilta-cel.

In April 2021, Legend announced the submission of a Marketing Authorisation Application to the European Medicines Agency seeking approval of cilta-cel for the treatment of patients with relapsed and/or refractory multiple myeloma. In addition to U.S. Breakthrough Therapy Designation granted in December 2019, cilta-cel received a Breakthrough Therapy Designation in China in August 2020. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, and from the European Commission in February 2020.

About the CARTITUDE-1 Study
CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, single arm, multi-center trial evaluating cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma, who previously received at least three prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody. Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.1

The longer-term efficacy and safety profile of cilta-cel is being assessed in the ongoing CARTITUDE-1 study, with two-year follow-up results recently presented at ASH (Free ASH Whitepaper) 2021.6

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.2 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.7 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.8 Although treatment may result in remission, unfortunately, patients will most likely relapse.3 Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody, have poor prognoses and few treatment options available.4,5

CARVYKTI Important Safety Information

INDICATIONS AND USAGE
CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.
Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.
CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.
WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade)1 occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1-12 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at www.CARVYKTIrems.com or 1-844-672-0067.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion, and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS
The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information including Boxed Warning for CARVYKTI.

On February 28, 2022 Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company developing next-generation products to address the growing needs in oncology, reported an update regarding the Company’s negotiations with China Grand Pharmaceutical and Healthcare Holdings Limited (China Grand) (Press release, Clarity Pharmaceuticals, FEB 28, 2022, View Source [SID1234609197]).

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As noted in the Company’s Prospectus, Clarity and China Grand agreed to enter exclusive discussions for the grant of a licence to permit China Grand to develop, manufacture and commercialise one or more of the Company’s products in the Greater China territory. In connection with those discussions, and in consideration for exclusivity, the Company and China Grand entered into an Option Deed on 1 July 2021, with an expiration date on the earlier of a number of events including a period of six months from the date of the Company listing on the ASX.

Under the Deed, the Company issued 25,543,912 options to China Grand to acquire shares at an exercise price of A$1.75. Those options lapsed and were cancelled at 5pm on 25 February 2022 (Expiry Date), being six months from Clarity’s listing date, and the exclusivity period for the licencing negotiations also expired at that time. Clarity continues to progress strategic discussions in relation to its pipeline and technology globally and is now clear to negotiate the Greater China territory on a non-exclusive basis.

Clarity’s Executive Chairman, Dr Alan Taylor, commented, "We consider China Grand to be a quality pharmaceutical group who could be a potential future partner. We welcome the interest they have shown in our entire platform, products and technology as well as the opportunity to discuss collaborative opportunities in the Greater China territory. The Clarity Board of Directors is committed to ensuring that any collaborative agreement provides maximum value for Clarity shareholders and reflects the long-term potential returns to all parties.

"Clarity has rapidly expanded its clinical program and manufacturing and supply capabilities in the past 12 months, clearly differentiating itself as an effective and sustainable player in the radiopharmaceutical market, a market that is undergoing rapid growth. The Company is currently recruiting in four clinical trials in the US and Australia with plans to open a number of additional trials across all our products over the next 12 months. This provides a broad range of strategic partnering opportunities globally, which we continue to explore.

"With our continued clinical momentum in a range of products in rare and large indications, it is an exciting time for the Company as we look to create substantial value for shareholders while we progress towards our ultimate goal of better treating children and adults with cancer."

This announcement has been authorised for release by the Executive Chairman.