On February 24, 2022 OPKO Health, Inc. (NASDAQ: OPK) reported that business highlights and financial results for the three months ended December 31, 2021 (Press release, Opko Health, FEB 24, 2022, View Source [SID1234608980]).

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Business Highlights

Business highlights for the fourth quarter of 2021 and subsequent weeks include the following:

NGENLA (somatrogon) injection granted regulatory approvals in Europe, Japan, Australia and Canada for pediatric growth hormone deficiency. NGENLA is a once-weekly, long-acting recombinant human growth hormone for the long-term treatment of growth hormone deficiency (GHD) in pediatric patients. NGENLA has been approved in the European Union, including Iceland, Norway and Liechtenstein, Japan, Australia and Canada. Under the worldwide agreement with Pfizer Inc., OPKO is eligible to receive a milestone payment after regulatory approvals and pricing determinations are obtained in major markets outside of the U.S. NGENLA became commercially available in Canada to patients with pediatric growth hormone deficiency on February 16, 2022, the product’s first commercial launch.

In the U.S., the Food and Drug Administration (FDA) issued a Complete Response Letter for the Biologics License Application for somatrogon. Pfizer is evaluating the FDA’s comments and intends to work with the Agency to determine an appropriate path forward in the U.S.

RAYALDEE launched in Germany by OPKO’s licensee, Vifor Fresenius Medical Care Renal Pharma (VFMCRP). VFMCRP has initiated the commercial launch of RAYALDEE (extended-release calcifediol) in Germany, the first launch of RAYALDEE outside the U.S. VFMCRP is OPKO’s commercial partner for RAYALDEE in Europe and selected markets outside the U.S. The sales kick-off in Germany began with presentations from several nephrology key opinion leaders. VFMCRP has received marketing authorizations for RAYALDEE in 11 European countries and expects to launch the product in additional markets.

Topline results reported from a Phase 2 clinical trial evaluating RAYALDEE as a treatment for symptomatic COVID-19 outpatients. Topline data indicate that improving vitamin D status with oral RAYALDEE results in earlier resolution of respiratory symptoms associated with mild-to-moderate COVID-19. A preprint manuscript summarizing the topline results is available on medRxiv. This manuscript is currently under review for publication in a peer-reviewed medical journal. We plan to discuss potential next steps with the FDA.

Definitive agreement signed for Sema4 Holdings Corp. (Sema4) to acquire GeneDx, Inc., a leader in genomic testing and analysis. Upon completion of the transaction, OPKO anticipates Sema4 and GeneDx will be one of the largest and most advanced providers of genomic clinical testing in the U.S., with a projected $350 million in pro forma 2022 revenue. Under the terms of the agreement, Sema4 will acquire GeneDx for an upfront payment of $150 million in cash plus 80 million shares of Sema4 common stock, with up to an additional $150 million in revenue-based milestones over the next two years (payable in cash or Sema4 shares at Sema4’s discretion). Based on the closing price of Sema4’s common stock on January 14, 2022, the total upfront consideration is approximately $473 million and the total aggregate consideration including potential milestones is approximately $623 million. As part of the transaction, Sema4 also entered into definitive agreements for a $200 million private placement of Sema4 stock from a syndicate of institutional investors, including Pfizer. The acquisition and the private placement are expected to close in the second quarter of 2022, subject to customary closing conditions including approval by Sema4 stockholders.

BioReference Laboratories (BRL) processed approximately 2.7 million COVID-19 PCR tests in the fourth quarter of 2021 versus 2.2 million in the third quarter of 2021. Demand for COVID-19 PCR tests increased significantly due to the Omicron variant beginning late in the fourth quarter of 2021 and continuing into the first quarter of 2022.

In December 2021, BRL announced a collaboration with MVP Health Care (MVP) to offer MVP’s members medically necessary COVID-19 testing, bloodwork and other diagnostic tests in the comfort of their homes. MVP, the first insurer in New York and Vermont to offer this service, is utilizing Scarlet Health, BRL’s seamlessly integrated digital platform that provides specimen collection for laboratory diagnostic services conducted by a Scarlet Health professional in a patient’s home or office.

FDA approved the Premarket Approval Application (PMA) of the 4Kscore Test. This test is approved for use in men aged 45 years and older who have not had a prior prostate biopsy or are biopsy negative and have an age-specific abnormal total prostate specific antigen (PSA) and/or abnormal digital rectal exam. The 4Kscore Test in the intended use population, when used in conjunction with other clinical factors and patient preferences, can contribute to a properly informed decision as to whether or not to proceed with a prostate biopsy. The regulatory approval provides further validation of the 4Kscore Test as an important diagnostic tool and should assist in expanding reimbursement coverage.
Fourth Quarter Financial Results

Consolidated: Consolidated total revenues for the fourth quarter of 2021 were $401.3 million compared with $494.6 million for the comparable period of 2020. Operating loss for the fourth quarter of 2021 was $63.1 million compared with operating income of $49.3 million for the comparable period of 2020. Net loss for the fourth quarter of 2021 was $73.8 million, or $0.11 per share, compared with net income of $32.3 million, or $0.05 per diluted share, for the comparable period of 2020. Operating loss for the fourth quarter of 2021 included non-recurring legal expenses, as well as expenses related to the GeneDx transaction.

Diagnostics: Revenue from services in the fourth quarter of 2021 were to $362.8 million compared to $457.9 million in the prior-year period, primarily due to a decrease in COVID-19 testing volume. Total costs and expenses were $381.4 million in the fourth quarter of 2021 compared to $388.0 million in the fourth quarter of 2020, resulting in an operating loss of $18.6 million compared to operating income of $69.9 million in the 2020 period. The lower operating income is primarily due to a decline in COVID-19 test volume and increased investment in BRL’s base business and digital health activities, principally related to Scarlet. Included in the fourth quarter 2021 results were revenue of $33.1 million and costs and expenses of $43.4 million at GeneDx compared with revenue of $20.3 million and costs and expenses of $36.6 million for the fourth quarter of 2020.

Pharmaceuticals: Revenue from products in the fourth quarter of 2021 increased nearly 15% to $35.3 million compared to $30.8 million in the fourth quarter of 2020, with the increase primarily attributable to the accelerating growth of OPKO’s international pharmaceutical businesses. Revenue from sales of RAYALDEE in the fourth quarter of 2021 was $7.7 million compared to $10.1 million in the prior-year period. Sales of RAYALDEE were negatively impacted by challenges in onboarding new patients due to the COVID-19 pandemic. Revenue from the transfer of intellectual property was $3.3 million in the fourth quarter of 2021 compared to $5.9 million in the 2020 period. Total costs and expenses were $53.3 million in the fourth quarter of 2021 compared to $45.7 million in the prior-year period, reflecting an increase in the cost of product revenue at OPKO’s international operating companies related to higher sales and ongoing expenses for the somatrogon program to support open-label extension studies, as well as the preparation of applications for marketing approvals. Operating loss was $14.8 million in the fourth quarter of 2021 compared to an operating loss of $9.0 million in the fourth quarter of 2020.

Cash and equivalents: Cash, cash equivalents and marketable securities were $134.7 million as of December 31, 2021. In addition, the Company has $64.8 million available under its line of credit with JP Morgan.
CONFERENCE CALL & WEBCAST INFORMATION

OPKO’s senior management will provide a business update, discuss fourth quarter financial results and answer questions during a conference call and live audio webcast today beginning at 4:30 p.m. Eastern time. Participants are requested to pre-register for the conference call using the link here. Upon registering, participants will receive dial-in numbers, an event passcode and a unique registrant ID to gain immediate access to the call and bypass the live operator. Participants may pre-register at any time, including up to and after the start of the call. Alternatively, please dial (888) 869-1189 or (706) 643-5902 and use conference ID 4489338.

To access the live call via webcast, please click on the link OPKO 4Q21 Results Conference Call. Individual investors and investment community professionals who do not plan to ask a question during the call’s Q&A session are encouraged to listen to the call via the webcast.

For those unable to listen to the live conference call, a replay can be accessed for a period of time on OPKO’s website at OPKO 4Q21 Results Conference Call. A telephone replay will be available beginning approximately two hours after the close of the conference call. To access the replay, please dial (855) 859-2056 or (404) 537-3406, and use conference ID 4489338.

On February 24, 2022 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported financial results for the fourth quarter and full year ended December 31, 2021 and highlighted recent corporate accomplishments (Press release, Zentalis Pharmaceuticals, FEB 24, 2022, View Source [SID1234608995]).

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"In 2021, we made significant headway advancing the development of our programs, culminating in an R&D Day in December where we highlighted key updates to our pipeline," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis. "At the R&D Day, we discussed the addition of new capabilities to our Integrated Discovery Engine, reinforced ZN-c3 as the cornerstone of our value proposition and provided evidence supporting ZN-c5 and ZN-d5’s potential as differentiated oncology agents. Additionally, we unveiled a new candidate—a preclinical heterobifunctional degrader targeting BCL-xL—which is expected to enter IND-enabling studies this year. We continue to be guided by our expertise in medicinal chemistry, cancer biology and technology to generate best-in-class treatments and look forward to achieving our upcoming milestones across our portfolio in 2022."

Program Highlights:

In December 2021, Zentalis’ management team, along with three Key Opinion Leaders, held a virtual Research and Development Day. Specific highlights include: the addition of a preclinical BCL-xL heterobifunctional degrader candidate to its pipeline; the initiation of two additional studies with ZN-c3; the preclinical exploration of ZN-c3 into breast cancer, colorectal cancer and immunotherapy combinations; preliminary efficacy data of ZN-d5 in diffuse large B-cell lymphoma and acute myeloid leukemia; and ZN-c5’s differentiated safety and tolerability profile in breast cancer patients.
In November 2021, the FDA granted Fast Track designation to ZN-c3 for the treatment of recurrent or persistent USC. The potentially registrational Phase 2 trial of ZN-c3 in USC is underway, with an initial enrollment and safety update expected in the second half of 2022.
In December 2021, the Company presented a poster at the San Antonio Breast Cancer Symposium, held from December 7-10, 2021. The poster provided an updated interim analysis from the Phase 1/2 trial of its oral SERD, ZN-c5, in combination with palbociclib (marketed as Ibrance by Pfizer) in ER+/HER2- advanced breast cancer.
Fourth Quarter and Full Year 2021 Financial Results

Cash and Marketable Securities Position: As of December 31, 2021, Zentalis had cash, cash equivalents and marketable securities of $339.9 million. The Company believes that its existing cash, cash equivalents and marketable securities as of December 31, 2021 will be sufficient to fund its operating expenses and capital expenditures requirements into the third quarter of 2023.
Research and Development Expenses: Research and development expenses for the year ended December 31, 2021 were $175.6 million, compared to $84.9 million for the year ended December 31, 2020. The increase was primarily due to increases in external research and development expenses related to Zentalis’ lead product candidates, as the Company advanced its clinical pipeline in 2021. In addition, in 2021, Zentalis conducted additional preclinical studies, incurred additional manufacturing costs, and incurred increased costs for study and lab materials.
General and Administrative Expenses: General and administrative expenses for the year ended December 31, 2021 were $40.9 million, compared to $33.9 million during the year ended December 31, 2020. The increase was primarily attributable to an increase of $8.7 million in employee-related costs, of which $4.5 million was driven by non-cash stock-based compensation from incentive grants issued during the period and increased headcount to support its growth.

On February 24, 2022 GT Biopharma, Inc. (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary natural killer (NK) cell engager, TriKE protein biologic technology platform, reported that GT Biopharma will be participating in the following upcoming medical conferences (Press release, GT Biopharma, FEB 24, 2022, View Source [SID1234609014]):

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Abstract and poster presentation details are as follows:

ESMO Targeted Anticancer Therapies Congress (TAT) (March 7-8, 2022)

Title:

Driving NK cell immunotherapy against NSCLC, in the context of hypoxia, using Tri-specific Killer Engager (TriKE)

Abstract Number:

250

Session:

Immunotherapy

Presentation Type:

Poster

Session Date and Time:

March 7, 9:20AM (CET) (On-demand e-poster display)

Location:

Virtual

Poster Board Number:

17P

48th Annual European Society for Blood and Marrow Transplantation (EBMT) (March 19-23, 2022)

Title:

A Tri-specific Killer Engager (TriKE) against B7-H3 enhances NK cell mediated killing of multiple myeloma

Abstract Number:

AS-EBMT-2022-00508

Session:

New Drugs- and Cell-Based Immune Therapies

Presentation Type:

Poster

Session Date and Time:

March 19, 2022, 9:50 AM (CET)

Location:

Prague Congress Center, Czech Republic

Poster Board Number:

P153

American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (April 8-13, 2022)

Title:

GTB-5550 (cam16-IL15-camB7H3) Tri-specific Killer Engager (TriKE) drives natural killer cell activation and antibody dependent cellular cytotoxicity against head and neck squamous cell carcinomas

Abstract Number:

Abstract control number 3334, permanent abstract number 3435

Session:

Clinical Research Excluding Trials, Combination Immunotherapies / Therapeutic Antibodies

Presentation Type:

Poster

Session Date and Time:

April 12, 2022 1:30 PM – 5:00 PM

Location:

Ernest N. Memorial Convention Center, Exhibit Halls D-H, Poster Section 32, New Orleans

Poster Board Number:

16

On February 24, 2022 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism pioneering therapies for genetically defined diseases, reported business highlights and financial results for the fourth quarter and year ended Dec. 31, 2021 (Press release, Agios Pharmaceuticals, FEB 24, 2022, View Source [SID1234608948]).

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"With last week’s FDA approval of PYRUKYND for the treatment of hemolytic anemia in adults with PK deficiency, we have delivered the first therapy for a rare, debilitating, lifelong disease – and we have set the stage for Agios’ next chapter as a leader in the genetically defined disease space," said Jackie Fouse, Ph.D., chief executive officer at Agios. "We have made incredible progress over the past year, following our transformational decision to divest our oncology business and accelerate and expand our genetically defined disease portfolio. We are poised to expand our impact to thalassemia, sickle cell disease, myelodysplastic syndrome and beyond, and I am optimistic about the future we are building together with patient communities, our clinical and research collaborators and our dedicated Agios team."

Fourth Quarter 2021 & Recent Highlights

Received approval from the U.S. Food and Drug Administration (FDA) for PYRUKYND, the first therapy for the treatment of hemolytic anemia in adults with PK deficiency and Agios’ first genetically defined disease medicine.
Dosed first patients in all three pivotal trials of PYRUKYND in thalassemia and sickle cell disease.
Hosted investor day on Nov. 17 to share updates on the company’s research and development pipeline, including progress on the PKM2, BCAT2 and PAH programs, and provide insights into the commercial launch strategy.
Presented the following key data at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition:
Long-term efficacy data of PYRUKYND in adults with PK deficiency who participated in the Phase 3 ACTIVATE and ACTIVATE-T trials
Long-term efficacy and safety data of PYRUKYND in adults with thalassemia who do not receive regular transfusions
Efficacy, safety and translational data of PYRUKYND in sickle cell disease from ongoing collaborator-led studies
Phase 1 healthy volunteer study data of AG-946, the company’s novel PK activator
Anticipated 2022 Key Milestones & Priorities

Agios expects to execute on the following key milestones and priorities in 2022:

Pyruvate Kinase (PK) Deficiency

Receive European Medicines Agency (EMA) regulatory decision for PYRUKYND in adults with PK deficiency by year-end.
Initiate Phase 3 ACTIVATE-kids and ACTIVATE-kidsT studies of PYRUKYND in not regularly transfused and regularly transfused pediatric patients with PK deficiency, respectively, in mid-2022.
Thalassemia

Enroll a meaningful portion of patients in the Phase 3 ENERGIZE and ENERGIZE-T studies of PYRUKYND in not regularly transfused and regularly transfused adults with thalassemia, respectively, by year-end.
Sickle Cell Disease

Complete enrollment in the Phase 2 portion of the RISE UP study of PYRUKYND in sickle cell disease by year-end.
Initiate the sickle cell disease cohort of the Phase 1 study of novel PK activator AG-946 in the first half of 2022.
Expansion and Acceleration of PK Activation Portfolio

Initiate Phase 2a study of AG-946 in adults with low- to intermediate-risk myelodysplastic syndrome (MDS) by year-end.
Continue to publish clinical and translational data supporting the utility of PK activators across key disease areas and elucidating the burden of disease for PK deficiency, thalassemia and sickle cell disease.
Fourth Quarter and Full Year 2021 Financial Results

The financial results discussion compares Agios’ continuing operations. All periods have been adjusted to exclude discontinued operations related to the divested oncology business.

Research and Development (R&D) Expenses: R&D expenses for continuing operations were $73.3 million for the fourth quarter of 2021 compared to $59.4 million for the fourth quarter of 2020, and $257 million for the year ended Dec. 31, 2021 compared to $220.8 million for the year ended Dec. 31, 2020. This year-over-year increase was largely driven by start-up costs for PYRUKYND pivotal studies, including ENERGIZE, ENERGIZE-T and RISE UP, offset by closeouts of ACTIVATE and ACTIVATE-T studies; regulatory filings for PYRUKYND in the U.S. and EU; and increased workforce spend across R&D.

Selling, General and Administrative (SG&A) Expenses: SG&A expenses for continuing operations were $31.5 million for the fourth quarter of 2021 compared to $25.9 million for the fourth quarter of 2020, and $121.4 million for the year ended Dec. 31, 2021 compared to $115.1 million for the year ended Dec. 31, 2020. This year-over-year increase was driven primarily by PYRUKYND launch preparations and disease education, including field sales build, training and marketing.

Non-Operating Income: Non-operating income included approximately $2.6 million from TIBSOVO (ivosidenib) royalties for the fourth quarter of 2021, and $6.6 million for the year ended Dec. 31, 2021.

Net Loss: Net loss was $98.6 million for the fourth quarter of 2021 compared to a net loss of $84.5 million for the fourth quarter of 2020, and $356.5 million for the year ended Dec. 31, 2021 compared to $329.3 million for the year ended Dec. 31, 2020.

Cash Position and Guidance: Cash, cash equivalents and marketable securities as of Dec. 31, 2021, were $1.3 billion compared to $670.5 million as of Dec. 31, 2020. The company expects that its cash, cash equivalents and marketable securities will enable the company to execute its operating plan through major catalysts and to cash-flow positivity without the need to raise additional equity.

Conference Call Information
Agios will host a conference call and live webcast with slides today at 8:00 a.m. ET to discuss fourth quarter and year end 2021 financial results and recent business activities. To participate in the conference call, please dial 1-877-377-7098 (domestic) or 1-631-291-4547 (international) and refer to conference ID 9873227. The live webcast can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

On February 24, 2022 Genmab A/S (Nasdaq: GMAB) and Seagen Inc. (Nasdaq: SGEN) reported that it will present preliminary data from the innovaTV 207 global, open-label, multicenter phase 2 trial of tisotumab vedotin (TIVDAK) as a monotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN) who experienced disease progression on or after a first-line platinum-containing regimen and a checkpoint inhibitor (Press release, Genmab, FEB 24, 2022, View Source [SID1234608965]). Early results showed tisotumab vedotin demonstrated a manageable safety profile and promising preliminary antitumor activity in this patient population with the primary endpoint of confirmed objective response rate (ORR) per investigator, achieved by 16 percent of patients (95% CI: 5.5 to 33.7). Findings will be presented as part of a plenary session at the American Society for Radiation Oncology (ASTRO) 2022 Multidisciplinary Head and Neck Cancers Symposium on February 25.

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"There is a significant unmet need for additional treatment options for patients diagnosed with squamous cell carcinoma of the head and neck that has progressed despite the use of chemotherapy," said David S. Hong, M.D., deputy chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and lead investigator of the innovaTV 207 clinical trial. "These preliminary data provide important insight into the safety of tisotumab vedotin in this tumor type and demonstrate the value of exploring this potential use further in the innovaTV 207 trial."

The SCCHN cohort of the innovaTV 207 trial enrolled 31 patients with a median age of 65 (range 47 to 78) years whose disease progressed on or after systemic therapy. Patients received 2 milligrams (mg)/kilogram (kg) tisotumab vedotin (maximum dose: 200 mg per infusion) intravenously on day one of each 21-day cycle. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS) per investigator and overall survival (OS). DCR per investigator was 58.1 percent (95% CI: 39.1 to 75.5), median PFS was 4.2 months (95% CI: 2.7 to 4.8), median follow-up was 10.0 months (95% CI: 8.5 to 13.1) and median OS was 9.4 months (95% CI: 8.1 to 11.8). Adverse events were consistent with the known safety profile of tisotumab vedotin: twenty-one (67.7%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and incidence of treatment-related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post-procedural hemorrhage [n=1]).

See TIVDAK U.S. Important Safety Information, including Boxed Warning, below.

"We recognize the high medical need for additional treatment options for patients with head and neck cancers," said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab. "These initial data results are encouraging and underscore the importance of our ongoing clinical trial program that will assess the potential utility of tisotumab vedotin in various cancers."

For more information about the ongoing phase 2 innovaTV 207 clinical trial of tisotumab vedotin, please visit www.clinicaltrials.gov (Identifier: NCT03485209).

"The presentation of these preliminary data represents another step forward in our work to advance the tisotumab vedotin development program," said Roger Dansey, M.D., Chief Medical Officer, Seagen. "In partnership with Genmab, we will continue to recruit additional patients for trials to further investigate tisotumab vedotin in patients with squamous cell carcinoma of the head and neck, including its potential use as a combination therapy."

About the innovaTV 207 Trial
The phase 2 innovaTV 207 clinical trial evaluates the activity, safety, and tolerability of tisotumab vedotin in selected solid tumors with high tissue factor (TF) expression. The trial is a global, multicenter, open label basket trial which will enroll an estimated 532 adult patients with relapsed, locally-advanced or metastatic disease in separate tumor-specific cohorts. The primary endpoint of the trial is confirmed ORR per investigator, defined as the proportion of patients who achieve a confirmed complete or partial response. Key secondary endpoints include confirmed and unconfirmed ORR, DCR, duration of response, PFS, OS, safety and tolerability. For more information about the phase 2 innovaTV 207 clinical trial of tisotumab vedotin, please visit www.clinicaltrials.gov (Identifier: NCT03485209).

About Tisotumab Vedotin
Tisotumab vedotin-tftv (TIVDAK) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin (TIVDAK) in patients with previously treated recurrent or metastatic cervical cancer. TIVDAK is the first and only approved ADC for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Indication
TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

BOXED WARNING: OCULAR TOXICITY
TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions
Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8 % of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions
In the innovaTV 204 clinical trial (n=101), serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.