On March 14, 2022 DiaMedica Therapeutics Inc. (Nasdaq: DMAC), a clinical-stage biopharmaceutical company focused on developing novel treatments for neurological disorders and kidney diseases, reported a business update and released financial results for the year ended December 31, 2021 (Press release, DiaMedica, MAR 14, 2022, View Source [SID1234610038]). Management will host a conference call Tuesday, March 15, 2022, at 8:00AM Eastern Time / 7:00AM Central Time, to discuss its business update and full year financial results.

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"Our clinical, regulatory, financial and team building achievements in 2021 have laid a solid foundation for success," said Rick Pauls, CEO of DiaMedica. "In 2022, our team is focused on executing on our Phase 2/3 ReMEDy2 trial of DM199 in acute ischemic stroke to reach the blinded interim analysis in 2023."

Pivotal Phase 2/3 ReMEDy Trial of DM199 for Acute Ischemic Stroke Initiated & Building Out Hospital Study Site Network

The Phase 2/3 ReMEDy2 trial is a randomized, double-blind, placebo-controlled Phase 2/3 adaptive trial designed to enroll 350 patients at approximately 75 sites in the United States. Patients enrolled in the study will be treated with either DM199 or placebo within 24 hours of the onset of acute ischemic stroke (AIS) symptoms. The study excludes patients treated with tissue plasminogen activator (tPA) and those with large vessel occlusions. The study population is representative of the approximately 80% of AIS patients who do not have treatment options today, primarily due to the short treatment window of up to 4.5 hours from symptom onset required for administration of tPA.

The ReMEDy2 trial will evaluate the effects of DM199 on both stroke recoveries post AIS, as measured by the well-established modified Rankin Scale (mRS), and the incidence of AIS recurrence at day 90 as two separate, independent, primary endpoints, with each statistically powered for success. Recurrent strokes represent 25% of all ischemic strokes, often occurring in the first few weeks after an initial stroke, and are typically more disabling, costly, and fatal than initial strokes. DiaMedica is actively working to open study sites.

DiaMedica Participates in International Stroke Conference and Received Strong Endorsement From Neurologists

The Company recently exhibited at the American Heart Association’s 2022 International Stroke Conference in New Orleans, LA. DiaMedica presented two abstracts at the conference highlighting the beneficial effects of DM199 on stroke recurrence in the Company’s ReMEDy1 Phase 2 trial as well as the design of the Company’s current pivotal Phase 2/3 ReMEDy2 trial of DM199 in AIS with Scott Kasner, M.D., national principal investigator for the ReMEDy2 trial. DiaMedica also had the opportunity to discuss DM199 and the ReMEDy2 trial with many of the attending neurologists DiaMedica’s Chief Medical Officer, Kirsten Gruis, M.D., commented, "We received encouraging feedback on DM199, its mechanism of improving collateral circulation, its potential benefit for AIS patients and observed safety profile. What is unique about the drug and trial design is that we plan to assess two separate clinically meaningful endpoints, stroke recoveries and prevention of ischemic stroke recurrence, across the same study population giving us potentially two separate endpoints to assess clinical benefit. We are also planning an interim analysis after 40% of patients are enrolled or approximately 140 patients have completed their 90-day follow-up period."

Addition of Chief Medical Officer and Chief Commercial Officer

DiaMedica recently announced the addition of two key senior executives to the leadership team. Dr. Kirsten Gruis, Chief Medical Officer, is a board-certified neurologist with 20 years of experience in both clinical medicine and drug development in large and small biopharmaceutical companies. Dom Cundari, Chief Commercial Officer, has over thirty years of experience launching innovative products and building and managing commercial organizations in multiple therapeutic areas at Genentech, including Activase for AIS.

Last Patient Dosed in REDUX Phase 2 CKD Basket Trial

Enrollment in the Phase 2 REDUX basket trial of DM199 in chronic kidney disease (CKD) has been completed as of December 31, 2021. DM199 continues to be generally safe and well tolerated in CKD patients.

The Company expects that the final data will be consistent with the interim data from REDUX which was presented at the American Society of Nephrology’s annual Kidney Week meeting in November 2021. Noting that the overall and individual sample sizes are small, the IgA Nephropathy (IgAN) cohort demonstrated a statistically significant geometric mean reduction of 34% in albuminuria in participants with moderate to severe baseline albuminuria. The trial also demonstrated early signals of potential disease modification with the APRIL and IgA1 biomarkers decreasing 35% and 22%, respectively, in all participants, regardless of baseline albuminuria. The hypertensive African American cohort, demonstrated a clinically meaningful geometric mean reduction of over 50% in the patients with moderate to severe baseline albuminuria and large reductions in systolic/diastolic blood pressure levels of -19/-13 mmHg at the 2 µg/kg dose level.

CKD represents an attractive development opportunity for DM199 and the Company is evaluating next steps for this program.

Financial Results

Research and development (R&D) expenses increased slightly to $8.8 million for the year ended December 31, 2021, up from $8.2 million in the prior year. This increase was primarily due to a combination of costs incurred for the Company’s pivotal Phase 2/3 ReMEDy2 trial and increased personnel costs associated with adding staff to support R&D operations. This increase was partially offset by decreased costs incurred for the Company’s earlier ReMEDy1 Phase 2 acute ischemic stroke trial, which completed during 2020, and decreased costs for the REDUX trial, as the number of enrollments in the REDUX trial declined throughout 2021 as the study neared completion.

General and administrative (G&A) expenses were $4.9 million and $4.5 million for the years ended December 31, 2021 and 2020, respectively. This increase was due to a number of factors, including increased costs associated with professional services, the payment to Catalent of a milestone obligation under a technology license agreement with Catalent, increased directors and officers liability insurance costs and increased personnel costs to support the Company’s expanding clinical programs. These increases were partially offset by reduced non-cash, share-based compensation costs.

Balance Sheet and Cash Flow

As of December 31, 2021, DiaMedica had cash, cash equivalents and marketable securities of $45.1 million, working capital of $43.9 million and shareholders’ equity of $44.0 million, compared to $27.5 million in cash, cash equivalents and marketable securities, $25.9 million in working capital and shareholders’ equity of $26.0 million as of December 31, 2020. The increases in combined cash, cash equivalents and marketable securities and in working capital are due primarily to the net proceeds from the Company’s September 2021 private placement, partially offset by cash used in operating activities during 2021.

Net cash used in operating activities for the year ended December 31, 2021 was $12.3 million compared to $9.2 million for the year ended December 31, 2020. This increase relates primarily to the increase in the net loss, partially offset by non-cash share-based compensation and the effects of the changes in operating assets and liabilities.

Conference Call and Webcast Information

DiaMedica Management will host a conference call and webcast to discuss its business update and 2021 financial results on Tuesday, March 15, 2021, at 8:00 AM Eastern Time / 7:00 AM Central Time:

Interested parties may access the conference call by dialing in or listening to the simultaneous webcast. Listeners should log on to the website or dial in 15 minutes prior to the call. The webcast will remain available for play back on DiaMedica’s website, under investor relations – events and presentations, following the earnings call and for 12 months thereafter. A telephonic replay of the conference call will be available until March 22, 2022, by dialing (800) 770-2030 (US Toll Free) and entering the replay passcode: 4814247.

About DM199

DM199 is a recombinant (synthetic) form of human tissue kallikrein-1 (KLK1). KLK1 is a serine protease (protein) that plays an important role in the regulation of diverse physiological processes including blood flow, inflammation, fibrosis, oxidative stress and neurogenesis via a molecular mechanism that increases production of nitric oxide and prostaglandin. KLK1 deficiency may play a role in multiple vascular and fibrotic diseases such as stroke, chronic kidney disease, retinopathy, vascular dementia, and resistant hypertension where current treatment options are limited or ineffective. DiaMedica is the first company to have developed a recombinant form of the KLK1 protein. The KLK1 protein, produced from porcine pancreas and human urine, has been used to treat patients in Japan, China and South Korea for decades. DM199 is currently being studied in patients with acute ischemic stroke and patients with chronic kidney disease. In September 2021, the FDA granted Fast Track Designation to DM199 for the treatment of acute ischemic stroke.

On March 14, 2022 ARCA biopharma, Inc. (Nasdaq: ABIO), a biopharmaceutical company applying a precision medicine approach to developing genetically targeted therapies for cardiovascular diseases, reported 2021 financial results and provided a corporate update (Press release, Arca biopharma, MAR 14, 2022, View Source [SID1234610037]).

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Dr. Michael Bristow, ARCA’s President and Chief Executive Officer, commented, "We have completed blinded data collection from the Phase 2b clinical trial evaluating rNAPc2 as a potential treatment for patients hospitalized with COVID-19 and look forward to unblinding and subsequently reporting results of the study in the last week of this month. We believe rNAPc2 has the potential to be effective in addressing the impact of COVID-19 from multiple pathways due to its combination of anticoagulant, anti-inflammatory and antiviral properties. We look forward to sharing the data with the FDA at an end of Phase 2 meeting."

Pipeline Update

rNAPc2 (AB201) – a small recombinant protein being developed as a potential treatment for COVID-19 and potentially other viral diseases.

Topline data from Phase 2b ASPEN-COVID-19 clinical trial evaluating rNAPc2 as a potential treatment for patients hospitalized with COVID-19 anticipated in the last week of March 2022.
Gencaro (bucindolol hydrochloride) – a pharmacologically unique beta-blocker and mild vasodilator being developed as a potential genetically-targeted treatment for atrial fibrillation (AF) in patients with heart failure (HF).

In January 2022, ARCA announced that the paper entitled "Dose Limiting, Adverse Event Associated Bradycardia with β-blocker Treatment of Atrial Fibrillation in the GENETIC-AF Trial" (William Abraham, et al) was published in Heart Rhythm O2, a publication of the Hearth Rhythm Society. The paper details an analysis that examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF Phase 2b clinical trial. In the genetically defined population of GENETIC-AF (all ADRB1 Arg389Arg genotype), the prevalence of clinically important bradycardia was lower for Gencaro compared to metoprolol.
The Company continues to evaluate the feasibility and potential timing for initiation of PRECISION-AF relative to the COVID-19 pandemic and the ability to recruit patients for a cardiovascular clinical trial.
Full Year 2021 Summary Financial Results

Cash and cash equivalents were $53.4 million as of December 31, 2021, compared to $49.1 million as of December 31, 2020. ARCA believes that its current cash and cash equivalents, will be sufficient to fund its operations through the middle of 2023.

Research and development (R&D) expenses were $13.8 million for the year ended December 31, 2021, compared to $5.0 million for 2020. The $8.8 million increase in R&D expenses in 2021 as compared to 2020 was primarily related to the conduct of the rNAPc2 clinical trial. R&D expenses in 2022 are expected to be consistent with 2021.

General and administrative (G&A) expenses were $5.5 million for the year ended December 31, 2021, compared to $4.8 million for 2020, an increase of approximately $0.7 million. The increase in expenses during 2021 was comprised primarily of increased personnel and insurance costs, offset by lower legal costs in 2021, as compared to 2020. G&A expenses in 2022 are expected to be consistent with those in 2021 as the Company maintains administrative activities to support our ongoing operations.

Total operating expenses for the year ended December 31, 2021 were $19.3 million compared to $9.8 million in 2020.

Net loss for the year ended December 31, 2021 was $19.3 million, or $1.39 per basic and diluted share, compared to $9.7 million, or $2.07 per basic and diluted share in 2020.

On March 14, 2022 Akoya Biosciences, Inc. (Nasdaq: AKYA) ("Akoya"), The Spatial Biology Company, reported its financial results for the fourth quarter and full year ending December 31, 2021 (Press release, Akoya Biosciences, MAR 14, 2022, View Source [SID1234610036]).

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"Our strong finish to 2021 demonstrates the continued and accelerating adoption of our leading spatial biology solutions and is a result of sound execution of our financial and strategic plans," said Brian McKelligon, Chief Executive Officer, Akoya Biosciences. "We set another record in quarterly revenue, grew our installed base to nearly 700 instruments worldwide, and have approximately 500 publications on Akoya platforms to date. Highlighting our strong quarter was the commercial launch of the PhenoCycler-Fusion System and additional near-term menu offerings across protein and RNA, delivering the fastest, single-cell, multi-omic spatial biology solution in the market."

Fourth Quarter 2021 Financial Highlights

Total revenue was $16.2 million in the fourth quarter of 2021, compared to $12.9 million in the prior year period; an increase of 26%.
Product revenue was $12.9 million in the fourth quarter of 2021, compared to $10.5 million in the prior year period; an increase of 23%.
Services and other revenue totaled $3.2 million in the fourth quarter of 2021, compared to $2.4 million in the prior year period; an increase of 33%.
Gross profit was $10.2 million in the fourth quarter of 2021, compared to $7.9 million in the prior year period; an increase of 29%; and gross profit margin was 63.3% in the fourth quarter of 2021, compared to 61.3% in the prior year period.
46 instruments were sold in the fourth quarter of 2021; 21 PhenoCyclers, 25 PhenoImagers (which includes Fusion, HT, and earlier PhenoImager workflow instruments such as the Mantra and Vectra).
Instrument installed base of 697 as of December 31, 2021; 182 PhenoCyclers, 515 PhenoImagers.
Full Year 2021 Financial Highlights

Total revenue was $54.9 million for the FY 2021, compared to $42.4 million in the prior year; an increase of 29.5%.
Product revenue was $44.5 million for the FY 2021, compared to $33.4 million in the prior year; an increase of 33%.
Services and other revenue totaled $10.4 million for the FY 2021, compared to $9.0 million in the prior year; an increase of 16%.
Gross profit was $34.2 million for the FY 2021, compared to $25.9 million in the prior year; an increase of 32%; and gross profit margin was 62.3% for FY 2021, compared to 61.0% in the prior year.
147 instruments were sold for the FY 2021; 70 PhenoCyclers, 77 PhenoImagers.

Fourth Quarter 2021 Business Highlights

There were 278 publications in 2021 featuring Akoya’s platforms, as compared with 109 publications in 2020.
Akoya’s inaugural ‘Spatial Day’ held on December 15, 2021 featured a preview of our new integrated suite of solutions, including the PhenoCycler-Fusion System, novel spatial transcriptomics chemistry and universal protein chemistry, and additionally brought together academic, clinical, and industry leaders who highlighted how Akoya’s spatial phenotyping platforms are uniquely equipped to address key questions across discovery, translational, and clinical research.
Announced full commercial launch of the PhenoCycler-Fusion System, the fastest single-cell, multi-omic, spatial biology solution.
Announced a groundbreaking collaboration with PathAI to combine spatial biology with AI-powered tools to facilitate discovery of novel predictive biomarkers.
Announced a strategic partnership with Bio-Techne to deliver an automated spatial multiomics workflow using the RNAScope technology to enable comprehensive spatial phenotyping of RNA and protein biomarkers on the PhenoCycler-Fusion System.
Announced the securing of CLIA lab certification, a milestone for applying spatial biology technologies to accelerate precision cancer therapies.
Appointment of Marilee Moy as Chief People Officer, who brings more than 30 years of HR leadership experience at high-performing life sciences and technology companies and will be instrumental in defining and executing Akoya’s human resource strategy as the company enters a new phase of global growth.
$113.1 million of cash and cash equivalents as of December 31, 2021, well capitalized to deliver on our existing strategic plan.
2022 Outlook

The company, based on its current plans and initiatives, expects a full year 2022 revenue guidance range of $69-71 million.

Webcast and Conference Call Details

Akoya will host a conference call today, March 14, 2022, at 5:00 p.m. Eastern Time to discuss its fourth quarter and full year 2021 financial results. The dial-in numbers are (833) 562-0146 for domestic callers or (661) 567-1226 for international callers, followed by Conference ID: 5291099. A live webcast of the conference call will be available on the "Investors" section of the Company’s website at View Source The webcast will be archived on the website following the completion of the call for three months.

On March 14, 2022 Emergent BioSolutions Inc. (NYSE: EBS) reported that members of the company’s executive management team will participate in the following investor conferences (Press release, Emergent BioSolutions, MAR 14, 2022, View Source [SID1234610035]):

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KeyBanc Life Sciences & MedTech Investor Forum
March 22, 2022
Company fireside chat scheduled for 1:30 pm eastern
View Source
BofA Securities 2022 Healthcare Conference
May 10, 2022
Presentation scheduled for 12:00 pm eastern
Goldman Sachs 7th Annual Leveraged Finance and Credit Conference
May 11 to 13, 2022
Presentation date and time will be updated on the Emergent website as the information becomes available.
For conferences where a presentation is planned, the company’s webcast presentation may include a discussion of the company’s recent business developments as well as its financial results and guidance. The webcasts will be available both live, if possible, and by replay, and will be accessible from the Emergent website.

On March 14, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported results from the final analysis of the second primary endpoint of overall survival (OS) from the phase 3 COSMIC-312 trial, which evaluated cabozantinib (CABOMETYX) in combination with atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma (HCC) (Press release, Exelixis, MAR 14, 2022, View Source [SID1234610034]). The final analysis showed neither improvement nor detriment in OS for cabozantinib in combination with atezolizumab versus sorafenib. Based on this outcome for OS and the rapidly evolving treatment landscape for previously untreated advanced HCC, Exelixis does not intend to submit a supplemental New Drug Application to the U.S. Food and Drug Administration (FDA). Full results will be presented at a future medical meeting.

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"Exelixis has a longstanding commitment to patients with liver cancer, exemplified by the 2019 approval of CABOMETYX for previously treated advanced liver cancer, and we remain steadfast in our journey to further therapies for this and other difficult-to-treat cancers," said Vicki L. Goodman, M.D., Executive Vice President, Product Development and Medical Affairs, and Chief Medical Officer, Exelixis. "We are grateful to the investigators and patients who participated in the COSMIC-312 trial and contributed greatly to this research."

About COSMIC-312

COSMIC-312 is a global, multicenter, randomized, controlled phase 3 trial that enrolled 837 patients at 281 study centers globally. Patients were randomized approximately 2:1:1 to one of three arms: cabozantinib (40 mg) in combination with atezolizumab (n=432), sorafenib (n=217) or cabozantinib (60 mg; n=188). Data from the analysis of the primary endpoint of progression-free survival was previously reported. Exelixis is sponsoring COSMIC-312, and Ipsen is co-funding the trial. Genentech, a member of the Roche Group, is providing atezolizumab for use in this trial. More information about COSMIC-312 is available at ClinicalTrials.gov.

About HCC

More than 900,000 new cases of liver cancer are diagnosed worldwide each year, and it is a leading cause of cancer death, accounting for more than 800,000 deaths annually.1 HCC is a leading cause of cancer-related death, expected to cause 1 million global deaths annually by 2030.2 Without treatment, patients with advanced HCC usually survive less than 6 months. 3 Median survival for patients with symptomatic advanced HCC who are treated with systemic therapies is just 1 to 1.5 years.4 Research has shown that gastrointestinal varices – which are associated with a higher risk of death from bleeding – occur in about 60-75% of patients with advanced HCC, the presence of which can impact the therapies available to these patients. 5,6

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with HCC who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX is not indicated as a treatment for previously untreated advanced HCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.