On April 19, 2021 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 financial results for the fourth quarter and year ended December 31, 2020 (Press release, GT Biopharma, APR 19, 2021, View Source [SID1234578207]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"2020 was a year of robust clinical progress and milestone achievements for GT Biopharma, which allowed us to accomplish a major corporate milestone in listing GT Biopharma on NASDAQ at the beginning of 2021. The emerging data from our GTB-3550 TriKE program in hematological malignancies, MDS and AML, are encouraging in both safety and efficacy profiles. The ongoing data profile has demonstrated significant differences from all other NK cell therapies and NK engager companies, making TriKE a monotherapy, off-the-shelf platform therapeutic. TriKE exerts its therapeutic effect without the need for outside assistance in the form of combination therapies or the addition of supplemental progenitor-derived or autologous/allogenic NK cells. As a result, TriKE therapy cost to patients will be far superior, significantly more economic than progenitor-derived or autologous/allogenic NK cell therapy companies’ offerings. Additionally, the results generated from the GTB-3550 TriKE clinical trial reinforces its versatility, providing a clear rationale to proceed with additional programs in solid tumor and hematologic cancers. As a result, in 2020 we formed a strong GMP manufacturing partnership with Cytovance Biologics to bring our TriKE product candidates forward for evaluation in the clinic," said Anthony J. Cataldo, GT Biopharma’s Chairman and Chief Executive Officer. "In the first quarter of 2021, we have achieved numerous clinical and operational milestones, which included garnering the attention of institutional investors and analyst research coverage as a result of our successful NASDAQ listing and public offering. We transferred all TriKE GMP manufacturing to Cytovance, as we progress our solid tumor TriKE product candidates. Additionally, the interim results from our ongoing Phase I/II clinical trial of GTB-3550 TriKE showed a 63.7% reduction in bone marrow blast (cancer cell killing) levels in patient 9; up from 61% in patient 7 at a lower dose for patients with MDS and AML. We also added the University of Wisconsin-Madison as a second clinical trial site. There will be more trials sites added, as we will soon proceed to the Phase II portion of our ongoing GTB-3550 TriKE clinical trial. We look forward to building on this momentum throughout the year, particularly as we continue to dose escalate our GTB-3550 TriKETM in these incredibly difficult-to-treat relapsed/refractory AML and high-risk MDS patient populations. We thank the patients and their families for their contribution, as we progress this novel, off-the-shelf monotherapy cancer therapeutic that uniquely works without outside supplemental engineered NK cells or the need for any combination drugs."

Corporate Highlights

Strengthened Leadership Team with Key Appointments to Executive Management, Board of Directors, and Scientific and Medical Advisory Board: In November 2020, GT Biopharma announced the appointment of Michael Handelman, CPA as Chief Financial Officer. Mr. Handelman was the former CFO of Iovance Biotherapeutics. Throughout 2020, GT Biopharma announced multiple appointments to its two boards. Bruce J. Wendel was named Vice Chairman and Independent Director of the Board of Directors, and Greg Berk, M.D., Michael Breen and Rajesh Shrotriya, M.D. were appointed as independent directors. Samir Taneja, M.D. and Philip Werthman, M.D., M.M.H. were appointed to the Company’s Scientific and Medical Advisory Board.

Established and Expanded TriKE Partnership with Cytovance Biologics: In October 2020, GT Biopharma announced a partnership agreement with Cytovance Biologics for the exclusive GMP manufacturing of three TriKE product candidates. Under the terms of the agreement, Cytovance will manufacture TriKE product candidates in accordance with its proprietary Keystone bacterial or mammalian expression systems. Subject to certain milestones by Cytovance, GT Biopharma has the option to pay Cytovance up to a total of $6 million. In December 2020, GT Biopharma issued $1 million to Cytovance as a first milestone payment. GT Biopharma’s agreement with Cytovance was further expanded in February 2021 for the manufacturing of all TriKE products.
Subsequent Event:

Closed $28.7 Million Public Offering and Successful Listing onNASDAQ: In February 2021, GT Biopharma announced the successful completion of its NASDAQ up list, in addition to the simultaneous closing of its public offering, in which it raised $28.7 million. Further, the Company retired over $32 million in debt and consolidated its capital structure.
Clinical Highlights

Presented Interim Results for GTB-3550 TriKETM for the Treatment of High-Risk MDS and Refractory/Relapsed AML at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting:

In December 2020, GT Biopharma presented promising proof-of-principle interim results from its lead product candidate, GTB-3550 TriKE, at ASH (Free ASH Whitepaper) in an oral presentation. As of the data cut-off date, six out of seven enrolled patients were evaluable and displayed no signs of clinical immune activation or serious adverse events across all dose cohorts. Data demonstrated that the first patient from the 5 mcg/kg/day cohort achieved stable disease after one course of GTB-3550 TriKE therapy and the first patient from the 25 mcg/kg/day cohort achieved AML blast level decrease from 18% to 12% by morphological analysis after one course of GTB-3550 TriKE therapy. Correlative studies also have shown reproducible NK cell activity across all evaluable patients with NK cell activation increasing during early treatment. Of note, NK cell proliferation started at day 3, is maximal at day 8 and maintained above baseline at days 15 and 22.

Additional clinical data from a patient with HR-MDS were presented, demonstrating that GTB-3550 TriKE safely activated and harnessed native NK cell’s cancer killing ability in a target-directed fashion with no adverse events or dose limiting toxicities. Successful bone marrow blast level reduction from 12% prior to treatment to 4.6% post-treatment was determined by morphological assessment. The patient also achieved stable hematologic parameters, including normal platelet counts throughout therapy.

Expanded Clinical Programs with HER2 TriKETM for the Treatment of Breast and Gastrointestinal Cancers: In December 2020, GT Biopharma announced the initiation of clinical development for TriKETM therapy for the treatment of HER2+, HER3+ and HER2+/HER3+ heterodimer complex breast cancer and gastrointestinal cancers.

Published Results on B7H3-Targeted TriKETM Potential to Enhance NK-Cell Immunotherapy in Solid Tumors: In October 2020, GT Biopharma announced the publication of results conducted by researchers at the University of Minnesota and Massachusetts General Hospital/Harvard Medical School in the journal, Cancers, in an article entitled "NK-Cell-Mediated Targeting of Various Solid Tumors Using B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo." Results indicated that a B7H3-targeted TriKETM has the potential to enhance NK cell immunotherapy in solid tumor settings, particularly where B7H3 is highly expressed on solid tumor surfaces.
Subsequent Events:

Updated Interim Results from GTB-3550 TriKETM Clinical Program for the Treatment of MDS and AML: In March 2021, GT Biopharma announced updated interim results from the Phase I/II Expansion clinical trial of GTB-3550 TriKE for the treatment of high-risk myelodysplastic syndromes (MDS) and refractory/relapsed acute myeloid leukemia (AML) from 9 patients. Results demonstrated up to 63.7% reduction in bone marrow blast levels. All patients treated to date displayed no signs of any grade of cytokine release syndrome (CRS) across all dose cohorts. GTB-3550 TriKE is currently being administered to patients at doses significantly higher than the reported maximum tolerated dose (MTD) for continuous infusion of recombinant human interleukin-15 (IL-15).

GTB-3550 TriKE Interim Results Presented at Innate Killer Summit 2021: In March 2021, Dr. Jeffrey S. Miller, M.D., GT Biopharma’s Consulting Chief Medical Officer and Deputy Director of the Masonic Cancer Center at the University of Minnesota, presented updated interim Phase I/II clinical trial results for GTB-3550 TriKE, being evaluated for the treatment of MDS and AML at the Innate Killer Summit 2021. Dr. Miller’s presentation "NK Cell Therapeutics: Off-the-shelf Strategies to Increase Activity and Specificity" highlighted the clinical power of immune engagement with IL-15 containing TriKEs.

Announced Preclinical Results from ROR1 TriKETM for the Treatment of Prostate Cancer: In March 2021, GT Biopharma announced preclinical in vitro cell assay results demonstrating the ROR1 TriKETM was found to be effective at promoting NK cell killing of prostate cells. Significant NK cell activation and interferon gamma production was also observed as a result of ROR1 TriKETM engagement.
Fourth Quarter and Year End 2020 Financial Results:

Cash Position: As of December 31, 2020, cash, cash equivalents and investments were $5.3 million, compared to $0.3 million as of December 31, 2019. The increase in cash, cash equivalents and investments was primarily due to proceeds from the issuance of convertible notes payable of $12.5 million, offset by cash used in operating activities of $7.3 million.

Research and Development Expenses: Research and development expenses were $233 thousand for the fourth quarter of 2020, compared to $8 thousand for the same period in 2019. Research and development expenses were $485 thousand for the full year 2020, compared to $1.7 million for the full year 2019. The decrease in research and development expenses for the full year 2020 was primarily due to the reduction of consultant and clinical expenses. The Company anticipates clinical costs to increase significantly in 2021.

General Administrative Expenses: General administrative expenses were $2.0 million for the fourth quarter of 2020, compared to $0.9 million for the same period in 2019. General administrative expenses were $6.3 million for the full year 2020, compared to $9.8 million for the full year 2019. The decrease in general administrative expenses for the full year 2020 was primarily attributable to the reduction of stock compensation costs.

Net Income (Loss): Net loss was $14.9 million for the fourth quarter of 2020, compared to a net loss of $1.5 million for the same period in 2019. Net loss was $28.3 million for the full year 2020, resulting in basic and diluted net loss per share of $(6.45). Net loss was $38.6 million for the full year 2019, resulting in basic and diluted net loss per share of $(11.42) before effect of reverse split. Net loss for the full year 2020 was attributable to a loss from operations of $6.8 million and total other expenses of $21.5 million. Net loss for the full year 2019 was primarily attributable to the loss from operations of $16.0 million and total other expenses of $22.6 million.
About GTB-3550 TriKE

GTB-3550 is the Company’s first TriKE product candidate being initially developed for the treatment AML. GTB-3550 is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and anti-CD33 antibodies and a modified form of IL-15. The natural killer (NK) cell stimulating cytokine human IL-15 portion of the molecule provides a self-sustaining signal that activates NK cells and enhances their ability to kill. We intend to study GTB-3550 in CD33 positive leukemias such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and other CD33+ hematopoietic malignancies.

On April 19, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that regulatory submissions based on the Phase 3 ACIS study, which evaluated the combination of ERLEADA (apalutamide) and ZYTIGA (abiraterone acetate) plus prednisone in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC), will not be pursued (Press release, Johnson & Johnson, APR 19, 2021, View Source [SID1234578279]). As presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary (ASCO GU) Cancers Symposium in February 2021, the ACIS study met its primary endpoint of radiographic progression-free survival (rPFS); however, combination treatment did not show significant benefit over the active control ZYTIGA plus prednisone in key secondary endpoints, including overall survival (OS).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"Safety results from ACIS were consistent with prior studies of ERLEADA and ZYTIGA plus prednisone, with no new safety signals observed. The study also generated valuable scientific outcomes and insights in subgroups of patients with luminal type in PAM50 test and tumors with average or high androgen receptor activity (molecular signatures of hormone sensitivity), which warrant further investigation," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "These data will be important in informing future programs in our pipeline, as we look to build upon our leadership and commitment in bringing transformational therapies to patients diagnosed with prostate cancer."

About the ACIS Study
ACIS was a Phase 3 randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of ERLEADA and ZYTIGA plus prednisone compared to placebo and ZYTIGA plus prednisone in 982 patients with chemotherapy-naïve mCRPC who received ADT. The primary endpoint of the study was rPFS. Secondary endpoints of the study included OS, time to chronic opioid use, time to initiation of cytotoxic chemotherapy, and time to pain progression.

About Metastatic Castration-Resistant Prostate Cancer
Metastatic castration-resistant prostate cancer characterizes cancer that no longer responds to ADT and has spread to other parts of the body. The most common metastatic sites are bones, followed by lymph nodes, lungs, and liver.[1] Prostate cancer is the second most common type of cancer in men worldwide. More than one million men around the world are diagnosed with prostate cancer each year.[2]

About ERLEADA (apalutamide)
ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).[3] ERLEADA received U.S. Food and Drug Administration (FDA) approval for nmCRPC on February 14, 2018 and was approved for mCSPC on September 17, 2019. To date, more than 25,000 patients worldwide have been treated with ERLEADA. ERLEADA is taken orally, once daily, with or without food.3 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide (ERLEADA) with continued androgen deprivation therapy**† as a Category 1 Preferred treatment option for patients with non-metastatic (M0) castration-resistant prostate cancer and a PSADT ≤10 months.[4] The NCCN Clinical Practice Guidelines also include apalutamide (ERLEADA) with androgen deprivation**† as a Category 1 Preferred treatment option for patients with metastatic (M1) castration-naive prostate cancer.‡4 The American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) recommend clinicians offer apalutamide (ERLEADA) with continued androgen deprivation therapy (ADT) as one of the treatment options for patients with nmCRPC at high risk for developing metastatic disease (Standard; Evidence Level Grade A)***.[5] ERLEADA is being further studied in two ongoing Phase 3 clinical trials.
For more information about ERLEADA, visit www.ERLEADA.com.

*© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed December 11, 2020. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.
**Orchiectomy, LHRH agonist, or LHRH antagonist
†Use of an LHRH agonist plus a first-generation antiandrogen is an option for patients receiving ADT alone, but is not an option for patients receiving apalutamide.
‡The term "castration-naive" is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castration-naive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.
***Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.
***Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

About ZYTIGA (abiraterone acetate)
ZYTIGA (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with mCRPC, approved by the U.S. FDA on April 28, 2011 and by the European Commission on September 7, 2011. Additionally, ZYTIGA was approved for the treatment of high-risk mCSPC by the European Commission on November 20, 2017 and by the U.S. FDA on February 8, 2018.[6] Since its first approval in the U.S. in 2011, ZYTIGA has been approved in combination with prednisone or prednisolone, in more than 100 countries. More than 500,000 patients worldwide have been prescribed ZYTIGA.

ERLEADA IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS

Cerebrovascular and Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.

Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA with increased frequency in the elderly. Evaluate patients for fall risk.

Seizure — In 2 randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA have not been established in females. Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS
Adverse Reactions — The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea and fracture.
Laboratory Abnormalities — All Grades (Grade 3-4)

Hematology — In the TITAN study: white blood cell decreased ERLEADA 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)
Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA 17% (3%), placebo 12% (2%). In the SPARTAN study: hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)
Rash — In 2 randomized studies, rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA treatment (6%) vs placebo (0.5%).

The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA.

Hypothyroidism — In 2 randomized studies, hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS
Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.

Please see the full Prescribing Information for ERLEADA.

ZYTIGA IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess – ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment.

Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. In post marketing experience, QT prolongation, and torsades de pointes have been observed in patients who develop hypokalemia while taking ZYTIGA. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)].

Adrenocortical Insufficiency – Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency if prednisone is stopped or withdrawn, if the prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. Perform appropriate tests, if clinically indicated, to confirm adrenocortical insufficiency. Increased dosages of corticosteroids may be used before, during, and after stressful situations [see Warnings and Precautions (5.1)].

Hepatotoxicity – In post marketing experience, there have been ZYTIGA-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure, and deaths. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.4)].

Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride – ZYTIGA plus prednisone/prednisolone is not recommended for use in combination with radium Ra 223 dichloride outside of clinical trials. Increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received ZYTIGA plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with ZYTIGA plus prednisone/prednisolone [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity – The safety and efficacy of ZYTIGA have not been established in females. Based on animal reproductive studies and mechanism of action, ZYTIGA can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with ZYTIGA and for 3 weeks after the last dose of ZYTIGA [see Use in Specific Populations (8.1, 8.3)]. ZYTIGA should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].

ADVERSE REACTIONS
Adverse Reactions – The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory tract infection, cough, and headache.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

Drug Interactions – Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA.

Use in Specific Populations –

Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception.
Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C).

On April 19, 2021 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer and infectious diseases, reported that the U.S. Food and Drug Administration (US FDA) has requested additional information regarding its Chimeric Antigen Receptor-T cell therapy (CAR-T) being developed in partnership with Moffitt Cancer Center (MCC) (Press release, Anixa Biosciences, APR 19, 2021, View Source [SID1234578176]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

The study under the Investigational New Drug (IND) application has been placed on clinical hold pending submission of additional information requested by the FDA. Within the next 30 days, it is expected that the FDA will provide a letter to MCC with detailed and specific information requested. MCC will assemble and submit information addressing the request as soon as possible thereafter. Successive to the submission, the FDA will continue its review of the IND.

This technology is an autologous cell therapy that requires the manufacture of a unique drug product for each individual patient. The therapeutic product is comprised of engineered T-cells that target the follicle stimulating hormone receptor (FSHR). FSHR is found at immunological levels exclusively on the granulosa cells of the ovaries. Since the target is a hormone receptor, this technology is also known as CER-T (Chimeric Endocrine Receptor T-cell) therapy, a new type of CAR-T.

Dr. Amit Kumar, President and CEO of Anixa Biosciences, stated, "We are eagerly awaiting guidance from the FDA with details about the specific information requested to clear the IND, enabling initiation of clinical trials."

On April 19, 2021 XBiotech (NASDAQ: XBIT) reported that the FDA has granted permission to commence clinical trials with its novel drug candidate for treating patients with pancreatic cancer (Press release, XBiotech, APR 19, 2021, View Source [SID1234578192]). From 1992 to 2018 the death rate from pancreatic cancer steadily increased in the USA. It is now predicted that pancreatic cancer will claim 48,220 lives and be the 3rd leading cause of cancer death in the USA in 2021 (National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Pancreatic cancer is typically identified at an advanced stage and treatment often includes surgery and aggressive chemotherapy. A current approved treatment involves combination chemotherapy including ONIVYDE and 5-fluorouracil, drugs that have significant toxicities and provide only modest response rates. XBiotech’s new drug candidate (XB2001) specifically targets a process potentially involved in the growth and spread of malignant tumors; and the drug also blocks inflammation associated with tissue injury, which may reduce toxicity associated with the chemotherapy and allow these drugs to be better tolerated and more effective.

The Phase I/II clinical study will evaluate XBiotech’s new drug candidate when added to the ONIVYDE/5-FU combination therapy. The clinical study is chaired by Dr. Shubham Pant, a leading researcher and oncologist at MD Anderson Cancer Center; and will involve at least 15 other top cancer centers around the United States. The Phase 1 portion of the study will examine increasing doses of XBiotech’s new drug and assess tolerability of the combination at escalating doses. Once a safe dose has been determined, the phase 2 portion will begin, enrolling 60 patients, which will be randomized to receive treatment with ONIVYDE/5-FU or ONIVYDE/5-FU combined with XB2001. Clinical endpoints in the study are safety, overall survival, objective response rate, progression free survival, time to treatment failure, clinical benefit response, number of severe adverse advents, as well as biological measures of experimental drug activity.

Dr. Razelle Kurzrock, M.D., Murray Professor of Medicine, Clinical Science Director, Center for Personalized Cancer Therapy, University of California, San Diego commented, "We need more effective treatments for pancreatic cancer and I believe IL-1a, the target of XB2001, represents an important novel target in oncology. This novel drug approach may both antagonize the biology of the tumor and mitigate chemotherapy-related toxicities—offering hope for improved outcomes in cancer, including tumors of the pancreas."

John Simard, Chairman and CEO of XBiotech, stated, "The launch of our new drug into this challenging area of oncology speaks to our strong conviction to the mechanism of this drug and the substantial unmet medical need for patients suffering from pancreatic cancer."

Several classes of therapeutics are undergoing development for pancreatic cancer, such as new cytotoxic chemotherapy, so called PKIs and immunotherapies. However, each of these treatments approaches are expected to provide, at best, modest improvements in survival and are not expected to replace existing current cytotoxic agents. Thus, significant opportunity exists for new drugs that could synergize with existing cytotoxic agents to reduce treatment and disease-related morbidity, and improve treatment outcomes. XBiotech believes its new drug is strongly positioned for this opportunity.

Cytotoxic chemotherapy agents result in systemic toxicity—which is considered a trade-off for potential anti-tumor activity. Toxicity is of acute importance clinically, but consequences of inflammatory responses induced by cytotoxic agents may also have a more profound impact, promoting tumor growth and compromising the efficacy and durability of the therapy itself. Cytotoxic agents upregulate inflammatory pathways, including activation of leukocytes, vascular endothelium and stromal cells of the tumor microenvironment. IL-1a may be a key player in the tumor and treatment related inflammatory pathway.

XBiotech’s new drug XB2001 is a naturally occurring antibody that potently neutralizes IL-1⍺ and is thus a safe and promising approach to block inflammation that occurs with advanced malignancies and chemotherapy. Unchecked, IL-1⍺ can stimulate angiogenesis, enhancing blood and nutrient supply to the tumor; IL-1⍺ may also act to recruit unwanted leukocytes (such as myeloid suppressor cells) into the tumor, that can suppress the ability of the body’s immune system to fight off the tumor; and systemically, IL-1⍺ can mediate metabolic dysfunction, and cause fatigue, anorexia, and anxiety. IL-1⍺ is thus a central player in paraneoplastic inflammation and XBiotech’s new drug therapy holds promise for treating a wide array of cancers.

About True Human Therapeutic Antibodies

XBiotech’s True Human antibodies are derived without modification from individuals who possess natural immunity to certain diseases. With discovery and clinical programs across multiple disease areas, XBiotech’s True Human antibodies have the potential to harness the body’s natural immunity to fight disease with increased safety, efficacy and tolerability.

On April 19, 2021 Lotus Pharmaceutical Co., Ltd. ("Lotus" or "the Company", Taiwan TWSE ticker: 1795), an Alvogen company, reported the issuance of new shares through private placement to be acquired by Innobic (Asia) (Press release, Lotus Pharmaceutical , APR 19, 2021, View Source [SID1234578208]). The move is aimed at further strengthening the company’s market access in the ASEAN region. Innobic (Asia) is a wholly owned subsidiary of PTT Public Company Limited ("PTT", SET ticker: PTT), the largest publicly listed conglomerate in Thailand. PTT, whose majority owner is the Ministry of Finance in Thailand, is the nation’s only company listed in the Fortune Global 500.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Under the agreement, Innobic (Asia), PTT’s Pharmaceutical and Life Science arm, commits to an investment of approximately US$50 million, to subscribe 17,517,348 new shares via private placement at the price of NT$80.7 per share.

Through this strategic alliance, Lotus and Innobic (Asia) will jointly explore opportunities in the South East Asia pharmaceutical markets, including but not limited to Thailand, Vietnam, Philippines, Malaysia and other ASEAN countries. The partnership combines Lotus’ strong pipeline, wide portfolio, R&D and Business Development capabilities, combined with extensive industry knowledge and high Good Manufacturing Practices (GMP) standards, with Innobic and PTT’s solid market access, local knowledge, creditability, potential commercial network and business relationship.

Robert Wessman, Chairman of Lotus Pharmaceuticals, commented: "This partnership is an important milestone in realizing our vision to establish Lotus as a global leader in generic oral oncology products. Lotus has secured partnerships with many of the leading pharmaceutical companies around the world to market and commercialize our products. The addition of Innobic (Asia) as a shareholder, will further support the long-term growth of Lotus in Asia and its mission to become a global leader in oral oncology."

Dr. Buranin Rattanasombat, Senior Executive Vice President PTT group and Chairman of Innobic (Asia), commented: "PTT Group has continuously expanded our business value-chain to satisfy the changing demands of a diversified and broader customer base. With the rising concern on the importance of healthcare eco-system, it has become a part of our Innobic (Asia)’s strategy to promote innovative medicines in Thailand and South East Asia to improve patient’s access to more affordable medicines with quality. Today’s venture marks yet another successful milestone towards this goal. We are delighted to be partner with Lotus who we trust as leader in the industry."