On May 23, 2022 Oncotelic Therapeutics, Inc. ("Oncotelic", "We" or the "Company") (OTCQB:OTLC) reported financial results for the three months ended March 31, 2022 ("Q1 2022") as compared to the three months ended March 31, 2021 ("Q1 2021"), an update on its product and therapeutic development initiatives and other corporate updates (Press release, Oncotelic, MAY 23, 2022, View Source [SID1234614952]). The financial results were based on the Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 23, 2022.

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Highlights for Q1 2022 and thereafter:

As previously reported, on March 31, 2022, we entered into a joint venture, or JV, with Dragon Overseas Capital Ltd. (Dragon Overseas) and GMP Biotechnology Ltd. (GMP Bio). Dragon Overseas and GMP Bio are affiliated with GMP. The intent is to develop and ultimately market OT-101, individually and in combination with other products, along with our JV partners.

Highlights of the transaction include:

Oncotelic to receive up to $50 million on sale of the RPD voucher following marketing approval of OT-101 for diffuse intrinsic pontine glioma, or DIPG.
Dragon Overseas has agreed to invest cash and other assets with a value of approximately $27.6 million for 55% ownership of the JV.
Oncotelic has licensed OT-101 to the JV for a 45% ownership in the JV.
The JV to be headquartered in Hong Kong.
Initial focus on the further development and commercialization of OT-101, including for DIPG as well as pancreatic cancers and glioblastoma.
The JV is planned to be taken into an IPO at a future point in time.
"With the JV transaction, clinical trial cost and payroll cost related to OT-101 has effectively been transferred to the JV, greatly reducing the operational cost of Oncotelic making up listing a strong possibility," commented Amit Shah, CFO.

"This week, we filed the patent application entitled TGF-beta therapeutics for age disease codifying the treatment of age-related disease such as cancers and infectious diseases as intervention on aging.," said Dr. Trieu, CEO and Chairman "we see a robust future for Oncotelic and the JV as the leaders in this new era of medicine".

When compared between Q1 2022 and Q1 2021, our research and development ("R&D") expenses decreased by approximately $1.0 million. The lower R&D expenses were primarily related to lower clinical trial activity in Q1 2022 as compared to Q1 2021 of approximately $0.9 million and approximately $0.1 million of other operational costs.

When compared between Q1 2022 and Q1 2021, our general and administrative ("G&A") expenses increased by approximately $3.3 million. This was primarily due to the increase of approximately $3.2 million in non-cash stock compensation expense, incurred in connection with issuance of new warrants of approximately $2.9 million and approximately $0.3 million on stock options. Excluding the non-cash stock compensation expense recorded during Q1 2022, our G&A expenses was almost the same as in Q1 2021.

We recorded interest expense, including amortization of debt costs, of approximately $0.3 million for Q1 2022 in connection with debt raised from various convertible notes, including the JH Darbie Financing, as compared to $0.5 million for Q1 2021, due to debt raised from convertible notes in 2021 and the JH Darbie Financing.

During Q1 2022, we recorded a change in the value of the derivative of $0.2 million. We recorded approximately $0.5 million change in value of the derivatives on conversion of the debt to liabilities on the convertible notes issued to our CEO and a bridge investor (collectively, the "Convertible Notes").

During Q1 2022, we recorded a loss on extinguishment of debt of approximately $0.3 million on our JH Darbie Financing, upon granting approximately 33 million warrants to our investors. Correspondingly, we recorded a loss on conversion of debt of $28 thousand million during Q1 2021.

Recent Product Development Highlights

AL-101 CNS Program

AL-101 (intranasal apomorphine) – We had acquired AL-101 in September 2021. AL-101 is our lead fast-to-market 505(b)2 regulatory pathway drug candidate for Parkinson Disease ("PD") and Erectile Dysfunction ("ED"), especially phosphodiesterase 5 ("PDE5") non-responders. Oncotelic also plans to develop AL-101 as a new class of drug against Female Sexual Dysfunction ("FSD"), including Hypoactive Sexual Desire Disorder ("HSDD"). Through targeting the dopamine receptors in the brain AL-101 has multiple central nervous system effects that will be leveraged in its development – mirroring the successes we have had previously with Abraxane and Cynviloq via the 505(b)2 pathway. AL-101 has shown a favorable safety and efficacy profile and is phase 3 ready with six clinical trials completed and over 200 patients (2,200 doses) treated.

With over 60,000 new patients annually being diagnosed with PD in the United States. Currently there are over 1 million patients in the US and expected to increase to over 1.2 million by 2030. In addition, approximately 10 million suffer from this disease globally. View Source As reported by Pharmaceutical Technology by GlobalData Healthcare on May 26, 2020, KYNMOBI (apomorphine HCI) sublingual film was approved through the 505(b)2 pathway for acute, intermittent treatment of OFF episodes in patients with PD. KYNMOBI dissolves under the tongue. Per GlobalData Healthcare, KYNMOBI is expected to generate $219 million annually. View Source We anticipate AL-101 to be a superior product based on rapid and preferential accumulation in the brain.

ED is the most prevalent male sexual disorder globally. The percentages of men affected by ED are as follows: 14.3-70% of men aged 60 years, 6.7-48% of men aged 70 years, and 38% of men aged 80 years (Geerkens MJM et al. (2019). Eur Urol Focus. pii: S2405-4569(19)30079-3).

FSD is a prevalent problem, afflicting approximately 40% of women and there are few available treatment options. In June 2019, the U.S. Food and Drug Administration approved Vyleesi (bremelanotide) to treat acquired, generalized HSDD in premenopausal women. Currently, this is the only available drug treatment. Vyleesi has essentially replaced the only other drug for HSDD – however, it has a long list of drug-drug interactions, including commonly used antidepressants, such as fluoxetine and sertraline. In addition, it has a black box warning regarding its use with alcohol, a combination that has been associated with hypotension and syncopal episodes. Therefore, there is an urgent need for an effective therapy against FSD and HSDD.

OT-101/PD-1 Oncology Program

The OT-101/PD-1 program is designed to assess the impact of OT-101 across multiple cancer indications, where local tumoral secretion of transforming growth factor-beta ("TGF-β") suppressed the clinical activity of checkpoint inhibitors, CAR-T, and vaccines. Multiple phase 2 trials combination of OT-101, with a PD-1 inhibitor, in collaboration with large pharmaceutical company, and leading KOLs around the world, are being planned and developed. These trials span mesothelioma, glioblastoma, lung, and colorectal cancers where AI driven transcriptome analyses will be used to derive the predictive and prognostic biomarker for TGF-β therapeutics, including OT-101.

TGF- β promotes immune evasion. The different components surrounding a tumor are collectively known as the tumor microenvironment (TME). The TGF-β signaling pathway is activated in the TME and the tumor, leading to alteration in the composition of the TME that favors tumor growth and aggressiveness. A major component of the TME, called Cancer-Associated Fibroblasts. help the tumor grow and escape destruction by the host immune system. As such even if an immune cell is sitting next to the tumor cells, it would not do anything because the tumor is making so much TGF, essentially cloaking the tumors. OT-101 inhibits the making TGF- β protein.

A PD-1 inhibitor, such as pembroluzimab, is not chemotherapy or radiation therapy – it is an immunotherapy and it works with our immune system to help fight cancer. Immunotherapy is spectacularly effective. These agents mobilize the immune system to attack the tumor and achieve cure (not just slowing down of the tumor/remission). However, it will work in only about 10% of patients. The rest have too much TGF- β for PD-1 immunotherapy to be effective. Knocking down TGF with OT-101 should improve the cure rate above the 10%. We are hoping that cure rate can reach 100% in the future.

OT-101/IL-2 Oncology Program

Our OT-101/IL-2 combination trial (the "Trial"), has now successfully completed the safety evaluation of its safety cohort, allowing for further expansion of its clinical program into phase 2 and higher doses.

The Trial – A Multi-center, Open label, Phase Ib clinical study to evaluate the safety, tolerance, and efficacy of TASO-001 ("OT-101"), a TGF-β targeting anti-sense oligonucleotide, in combination with recombinant interleukin-2 (Aldesleukin, "IL-2"), in patients with advanced or metastatic solid tumor cancer. ClinicalTrials.gov Identifier: NCT04862767. The Trial is being conducted by Autotelic BIO, a partner of Oncotelic on the OT-101/IL-2 combination.

In the safety cohort treated during the Trial, the standard dosage of 140mg/m2 of OT-101was well tolerated in combination with IL-2, which has allowed for ongoing dose escalation to 190 mg/m2. The 140 mg/m2 dose was shown to be the optimal dose for OT-101 in a prior trial targeting pancreatic cancer, melanoma, and colorectal cancer ("P001"). In the P001 trial, the maximum tolerated dose was not reached even at 330 mg/m2. Therefore, the Company believes that increasing the dose above 140 mg/m2 should further enhance the clinical activity of OT-101.

OT-101 COVID-19 program

On October 18, the data lock of the Study Data and Analysis Data Models (SDTMs & ADaMS Databases) were generated for the Company’s C001 trial for COVID-19. The trial compares OT-101 plus standard of care ("SOC") versus Placebo plus SOC, the SOC which includes dexamethasone (N= 32 pts at 2:1 randomization ratio). Dexamethasone is the only known drug to improve outcome for severe COVID-19. The top line data as previously disclosedare:

Safety endpoints met. OT-101 as a TGF-β inhibitor was safe to administer to COVID-19 patients including severe/critical COVID-19 patients.

Efficacy signals were obtained. End of treatment- Day 7-mortality for the entire study population was 4.5% OT-101 versus 20% Placebo.

Incidence of >96% viral load knockdown on End of Treatment- Day 7- was 89% for OT-101 versus 67% for placebo.

Overall survival improved significantly improved from 4 day for placebo to 14 day OT-101 among critically ill COVID-19 patients.
The data form the basis for us to further develop this as a drug to treat severe respiratory viral infections including flu and COVID. Both tumor cells and the SARS-CovCoV-2 viruses induce TGF-β as part of their immune evasion mechanism. Consequently, inhibiting TGF-β by OT-101 is expected to impact both cancer and COVID. By targeting the host protein, OT-101 is expected to work against multiple respiratory viruses agnostic of the emerging variants, unlike traditional antiviral drugs and vaccines.

Artemisinin COVID-19 Program

We deployed Artemisinin as herbal supplement in India under the name PulmoHealTM together with Chopra Foundation and Heart Care Foundation of India (HCFI) and Parmarth Niketan Ashram to combat COVID during the deadly surge in COVID-19 in summer of 2021 as a humanitarian effort. As we build our patent portfolio around Artemisinin and its analogs for COVID-19 and other respiratory viral infections we are positioning Artemisinin and its analog artesunate as pharmaceutics.

On May 23, 2022 PharmaCyte Biotech, Inc. (NASDAQ: PMCB), a biotechnology company focused on developing cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that it has initiated the first in a series of studies to test the ability of its pancreatic cancer therapy to treat malignant ascites (Press release, PharmaCyte Biotech, MAY 23, 2022, View Source [SID1234614951]). The initiation of this first study was made possible after PharmaCyte’s successful production of a Master Cell Bank as well as the demonstration that the Master Cell Bank is adventitious agent free.

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In PharmaCyte’s initial study, it aims to establish a mouse model of malignant ascites to serve as a basis for further CypCaps plus ifosfamide efficacy studies. This study involves inoculating the peritoneal space of genetically susceptible mice with radiolabelled mouse colon carcinoma cells. Study parameters include survival, clinical signs, body weight, assessment of tumor spread using fluorescence imaging and indexing of total tumor volume.

The planned series of studies will build on previous data obtained by Prof. Matthias Löhr of the Karolinska Institute in Stockholm, Sweden, and his colleagues that showed PharmaCyte’s treatment for pancreatic cancer can slow the production and accumulation of malignant ascites. Heidelberg Pharma Research, a leading German biotechnology company focused on cancer therapies, will conduct the study.

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "The expansion of our oncology program is continuing with the pursuit of a treatment for malignant ascites. This patient population is dealing with advanced cancer, and malignant ascites only compounds the problems these patients must endure at a very difficult time. The establishment of a reliable malignant ascites animal model is a critical step on the path to create a first-ever treatment for malignant ascites and represents our desire to address unmet medical needs and the patient’s quality of life."

Ascitic fluid is normally produced in the peritoneum, a sheet of tissue that covers the organs in the abdomen; however, the presence of cancer can cause the peritoneum to produce too much ascitic fluid when cancer cells irritate the peritoneum, which causes the abdomen to swell as fluid accumulates. This is known as malignant ascites. It is more likely to develop in patients who have ovarian, uterine, cervical, colorectal, stomach, pancreatic, breast and liver cancers. In most patients, development of malignant ascites is a sign of advanced disease and poor prognosis.

Malignant ascites can result in impairment to the quality of life of a cancer patient. In addition to abdominal distention, pain and difficulty breathing, it may also cause nausea, vomiting, early satiety, lower extremity edema, weight gain and reduced mobility. These symptoms can interfere with a patient’s ability to eat, to walk and to perform daily activities. They also reduce a patient’s ability to withstand anti-cancer therapies, potentially reducing survival.

As a supportive or palliative measure, malignant ascites can be drained by paracentesis, percutaneously implanted catheters, peritoneal ports or peritoneovenous shunts. These treatments are invasive, can be painful and are expensive. PharmaCyte expects its treatment to offer cancer patients a therapy that slows down or eliminates the production and accumulation of malignant ascites fluid. There is currently no such treatment on the market.

To learn more about PharmaCyte’s pancreatic cancer treatment and how it works inside the body to treat locally advanced inoperable pancreatic cancer, we encourage you to watch the company’s documentary video complete with medical animations at: View Source

On May 23, 2022 OncoSec Medical Incorporated (NASDAQ: ONCS) (the "Company" or "OncoSec") reported that it is the recipient of the 2022 Vanguard Award presented by the Triple Negative Breast Cancer (TNBC) Foundation (Press release, OncoSec Medical, MAY 23, 2022, View Source [SID1234614949]). OncoSec’s Head of Patient Advocacy, Kimberly Irvine, will accept the award on behalf of the Company at the Foundation’s gala titled, "No One Fights Alone," on May 25, 2022.

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"On behalf of OncoSec, I want to thank the TNBC Foundation for this distinguished honor and recognition," said Kimberly Irvine, Head of Patient Advocacy. "Our efforts aiming to provide much needed therapies to patients with metastatic TNBC (mTNBC) is one key pillar of our mission to help patients with cancer who don’t respond to currently available treatments. As a two-time breast cancer survivor, myself, I understand the unmet need. We look forward to continuing our research and working with the TNBC patient community to learn about their experiences and how we can better meet their needs."

Hayley Dinerman, Executive Director at TNBC Foundation, added, "Triple negative breast cancer accounts for up to 15% of breast cancers in the U.S., but many patients have never heard of TNBC. As the leading advocacy group for the TNBC community, it’s our goal to educate and support patients battling this disease, and to recognize academic, pharmaceutical and biotech industry partners who work to improve patient outcomes. The TNBC Foundation is thrilled to recognize OncoSec as the 2022 Vanguard Award recipient for its unrelenting dedication to cancer research and to patients struggling with TNBC. We are excited to see new developments from the company as it progresses its TNBC program."

The Triple Negative Breast Cancer Foundation’s Vanguard Award for Excellence in Oncology Research was previously awarded to Immunomedics (acquired by Gilead Sciences, Inc.) in 2019, Eisai Co., Ltd. in 2018, and Hackensack University Medical Center in 2017.

To learn more about the Vanguard Award and the TNBC Foundation visit, tnbcfoundation.org.

About TAVO
OncoSec’s gene therapy technology combines TAVO (tavokinogene telseplasmid), a DNA plasmid-based interleukin-12 (IL-12), with an intra-tumoral electroporation gene delivery platform to achieve endogenous IL-12 production in the tumor microenvironment that enables the immune system to target and attack tumors throughout the body. TAVO has demonstrated a local and systemic anti-tumor response in several clinical trials, including the pivotal Phase 2b trial KEYNOTE-695 for metastatic melanoma and the KEYNOTE-890 Phase 2 trial in triple negative breast cancer (TNBC). TAVO has received both Orphan Drug and Fast-Track Designation by the U.S. Food & Drug Administration for the treatment of metastatic melanoma.

On May 23, 2022 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported it has submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for N-803, a first-in-class IL-15 superagonist, plus Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease (Press release, ImmunityBio, MAY 23, 2022, View Source [SID1234614948]). The BLA is supported by the results of ImmunityBio’s studies in bladder cancer including the pivotal QUILT 3032 study (NCT03022825), where 71% of patients who had failed on previous therapies showed an over 50% increase in both response and median duration compared to the FDA-approved alternatives Valrubicin and Pembrolizumab, a systemic checkpoint inhibitor therapy for this indication.1

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The FDA previously granted N-803 Breakthrough Therapy and Fast Track designations when used in combination with Bacillus Calmette-Guerin (BCG) for the treatment of BCG-unresponsive NMIBC CIS. If approved by the FDA, N-803 plus BCG would be the first new immunotherapy for this indication in 23 years that can be delivered directly to the bladder (intravesically) to induce natural killer cells and T cells, providing a new treatment option for patients with this form of bladder cancer. The results of the pivotal Phase 2/3 clinical trial demonstrated the therapeutic combination gives patients a greater chance to avoid removal of the bladder itself—a surgical procedure referred to as radical cystectomy. This surgery is one of the last remaining options for many patients that do not respond to other therapies, but is costly to the healthcare system and comes with a high risk of mortality and complications that affect patient quality of life.

"This immunotherapy represents a potential new option for bladder cancer patients who fail to respond to BCG, the current standard of care. The results of the study of N-803 plus BCG indicate that this combination provides a durable response with a reduced need for a cystectomy," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. "We believe that the durable responses seen in this study provide further support for our hypothesis that by orchestrating natural killer cells, T cells and memory T cells, long-term durable remissions can be achieved in patients suffering from cancer. The results from the QUILT series of ongoing trials across multiple tumor types, including pancreatic, lung and other solid tumors, could lead to a paradigm shift in cancer therapy that ImmunityBio is developing. We are hopeful that this combination immunotherapy of BCG acting as a prime and N-803 as the boost to the immune system will not only provide a new path for these patients, but also help us continue to broaden our understanding of how we might apply this novel mechanism of action to other difficult-to-treat diseases."

The BLA submission for BCG-unresponsive NMIBC is based on data from 171 subjects from Phase I and 2 trials in bladder cancer and on 84 subjects treated in ImmunityBio’s Pivotal Phase 2/3 QUILT 3032 study of the combination of N-803 and BCG. The combination had a well-tolerated profile and the full results of this study will be presented at an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting to be held June 3-7 in Chicago.

ImmunityBio’s IL-15 superagonist N-803 (Anktiva)

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated for adult patients in two clinical NMIBC trials. QUILT 2005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT 3032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC CIS and Papillary Disease.

Mechanism of Action & Contribution of N-803 and BCG for Bladder Cancer

Trained immunity is a recently discovered immune system response triggered by BCG. Natural Killer (NK) and T cells are activated by BCG resulting in bladder cancer cell death. When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration of immunological response. N-803, an IL-15 superagonist which proliferates NK and T cells, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG. ImmunityBio believes this mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, contributes to the high complete response rate and prolonged 24-month durable complete response reported in this trial.

On May 23, 2022 Seagen Inc. (Nasdaq:SGEN) reported positive topline results from the pivotal phase 2 MOUNTAINEER clinical trial investigating TUKYSA (tucatinib) in combination with trastuzumab in patients with previously treated HER2-positive metastatic colorectal cancer (mCRC) (Press release, Seagen, MAY 23, 2022, View Source [SID1234614946]). Data from this trial will form the basis of a planned supplemental New Drug Application to the U.S. Food and Drug Administration (FDA) under the FDA’s Accelerated Approval Program. Merck, known as MSD outside the U.S. and Canada, is commercializing TUKYSA in regions outside of the U.S., Canada and Europe and plans to discuss these results with health authorities as it continues to accelerate the filing of TUKYSA in its territory.

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Results showed a 38.1% confirmed objective response rate (cORR) [95% Confidence Interval (CI): 27.7, 49.3] per blinded independent central review (BICR). The median duration of response (DoR) per BICR was 12.4 months [95% CI: 8.5, 20.5]. The combination of tucatinib and trastuzumab was generally well-tolerated, and the most common (greater than or equal to 20%) treatment-emergent adverse events were diarrhea, fatigue, nausea and infusion-related reaction, which were primarily low-grade.

Please see Important Safety Information at the end of this press release for further safety information regarding tucatinib.

"People with HER2-positive previously treated metastatic colorectal cancer have a significant unmet need for new therapies. We are excited by the potential for this tucatinib combination to help patients based on the excellent anti-tumor activity with durable responses and a tolerable safety profile," said Roger Dansey, M.D., interim CEO and Chief Medical Officer, Seagen. "Based on the strength of these data, we are planning to engage in regulatory discussions with the FDA with the intent to submit a supplemental New Drug Application for TUKYSA."

Full data from the MOUNTAINEER trial will be presented by John H. Strickler, M.D., Duke University Medical Center, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer in Barcelona, Spain from June 29 through July 2, 2022.

About MOUNTAINEER

MOUNTAINEER is a U.S. and European multicenter, open-label, phase 2 clinical trial of tucatinib in combination with trastuzumab or as a single agent in 117 patients with HER2-positive metastatic or unresectable colorectal cancer following previous standard-of-care therapies. The primary endpoint of the trial is confirmed objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria per blinded independent central review in patients receiving the combination of tucatinib and trastuzumab. Duration of response, progression-free survival, overall survival and safety and tolerability of the combination regimen are secondary objectives.

About Colorectal Cancer

Colorectal cancer is the third leading cause of cancer-related deaths in the U.S. and is anticipated to lead to about 52,580 deaths in 2022.1 Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the advanced stage.2 Human epidermal growth factor receptor 2 (HER2) is overexpressed in 3-5% of patients with metastatic colorectal cancer.3,4 There are currently no FDA-approved therapies that specifically target HER2 in colorectal cancer.

About TUKYSA (tucatinib)

TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.

TUKYSA is approved in 36 countries. It was approved by the U.S. FDA in April 2020 and by the European Medicines Agency and the UK Medicines and Healthcare Products Regulatory Agency in February 2021. Merck, known as MSD outside the U.S. and Canada, has exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.

U.S. Indication and Important Safety Information

TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Warnings and Precautions

Diarrhea – TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Hepatotoxicity – TUKYSA can cause severe hepatotoxicity. In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase >5 × ULN, 6% had an AST increase >5 × ULN, and 1.5% had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Embryo-Fetal Toxicity – TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for at least 1 week after the last dose.
Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions led to treatment discontinuation in 6% of patients who received TUKYSA; those occurring in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; those occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Lab Abnormalities

In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were: decreased phosphate, increased ALT, decreased potassium, and increased AST. The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

Drug Interactions

Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicity.
Use in Specific Populations

Lactation: Advise women not to breastfeed while taking TUKYSA and for at least 1 week after the last dose.
Renal Impairment: Use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (CLcr < 30 mL/min), because capecitabine is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.