On March 30, 2021 Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, reported financial results for the fourth quarter and year ended December 31, 2020 (Press release, Crinetics Pharmaceuticals, MAR 30, 2021, View Source [SID1234577352]).

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"We are entering 2021 poised to achieve several key milestones that we believe will consolidate our position as a leader in the design and development of novel small molecule drugs for endocrine diseases," said Scott Struthers, Ph.D., Founder and Chief Executive Officer of Crinetics. "Our positive Phase 2 acromegaly data demonstrate the potential of orally administered paltusotine to replace injectable somatostatin receptor ligand (SRL) depots as the standard-of-care. With input from a recently completed FDA meeting, we have designed the paltusotine Phase 3 program to support its approval for all acromegaly patients who require pharmacotherapy, including both untreated patients and those switching from injected standard of care."

Dr. Struthers continued, "Paltusotine’s success and progress serve as a blueprint for our new therapeutic candidates in endocrinology. We plan to follow a similar path with CRN04777 and CRN04894, both of which recently entered Phase 1 proof-of-concept trials in healthy volunteers. Much like paltusotine’s Phase 1 program, we’ve designed these trials to evaluate safety, drug-like pharmacokinetics, and corresponding pharmacodynamic effects on well-validated hormonal biomarkers for their respective indications. We look forward to reporting results from the Phase 1 trials later this year, and to the continued progression of our clinical and preclinical pipelines."

FULL YEAR 2020 AND RECENT HIGHLIGHTS
Advancing paltusotine to a Phase 3 program for acromegaly following the completion of an FDA meeting. In 1Q 2021, Crinetics met with the U.S. Food and Drug Administration (FDA) to discuss its Phase 2 acromegaly data and plans for a Phase 3 program. Based on these interactions and those with other regulators, the Company plans to initiate two Phase 3 studies in 2021. The first of these studies, entitled PATHFNDR-1, is a double-blind, placebo-controlled, nine-month clinical trial evaluating the safety and efficacy of paltusotine in acromegaly patients who are biochemically controlled (IGF-1 ≤ 1.0 × upper limit of normal [ULN]) and who are on stable doses of SRL monotherapy (octreotide LAR or lanreotide depot). The second study, PATHFNDR-2, is a double-blind, placebo-controlled, twelve-week trial in acromegaly patients with elevated IGF-1 levels who are medication naïve or who are not being treated with pharmacotherapy (untreated patients). The primary endpoint for both studies will be the proportion of patients achieving biochemical control comparted to placebo. If successful, Crinetics believes these trials could support registration of paltusotine in the United States and Europe for all acromegaly patients who require pharmacotherapy, including untreated patients and those switching from standard of care. The Company expects to initiate PATHFNDR-1 in 2Q 2021 and PATHFNDR-2 in 2H 2021.
Showcased broad clinical-stage pipeline at ENDO 2021. In March 2021, Crinetics showcased the breadth of its pipeline with presentations on its three clinical programs at the Endocrine Society’s annual ENDO 2021 congress. Posters on the company’s acromegaly program included a summary of the previously announced ACROBAT Edge Phase 2 results, as well as details of a new tablet formulation of paltusotine. Presentations related to the company’s earlier stage clinical programs included a poster with preclinical data supporting the development of CRN04777 as a treatment for congenital hyperinsulinism (congenital HI) and a live oral presentation with preclinical evidence supporting the further evaluation of CRN04894 in Cushing’s disease and congenital adrenal hyperplasia (CAH).
Advanced ACTH antagonist CRN04894 into a Phase 1 study designed to provide clinical proof of concept. In February 2021, Crinetics initiated a Phase 1 study of CRN04894, an investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist being developed for the treatment of diseases associated with excess ACTH such as Cushing’s disease and CAH. In addition to evaluating the safety and tolerability of CRN04894 in healthy volunteers, the placebo-controlled study aims to provide clinical proof-of-concept data by measuring the effect of CRN04894 on the suppression of ACTH-stimulated adrenal secretion of cortisol and related steroids. These endocrine biomarkers are used as key endpoints in patient studies and reflect the ability of CRN04894 to block ACTH-stimulated adrenal function. This Phase 1 trial is expected to provide important information for dose selection and be predictive of efficacy in Cushing’s disease and CAH trials. Crinetics expects to report preliminary safety, pharmacokinetic, and endocrine biomarker data from the single ascending dose portion of the trial in 1H 2021.
Advanced SST5 agonist CRN04777 into a Phase 1 study designed to provide clinical proof of concept. In February 2021, Crinetics initiated a Phase 1 study of CRN04777, an investigational, oral, nonpeptide somatostatin receptor type 5 (SST5) agonist. CRN04777 is being developed as a treatment for congenital HI, a rare genetic disease in which excess insulin secretion causes life-threatening hypoglycemia (low blood glucose). In addition to evaluating the safety and tolerability of CRN04777 in healthy volunteers, the placebo-controlled study aims to provide clinical proof-of-concept data by measuring the ability of CRN04777 to inhibit glucose- and sulfonylurea-induced insulin secretion and observe the corresponding effects on blood glucose levels. These endocrine biomarkers are indicative of the ability of CRN04777 to prevent hypoglycemia and are expected to provide information for dose selection and be predictive of efficacy in patients with hyperinsulinism. Crinetics expects to report preliminary safety and pharmacological effect data from the single ascending dose portion of the trial in mid-2021.
Reported positive topline results for the ACROBAT Phase 2 program of paltusotine in acromegaly patients. In October 2020, Crinetics reported positive top-line data from its Phase 2 program evaluating paltusotine for the treatment of acromegaly. Data showed that levels of insulin-like growth factor 1 (IGF-1), the accepted biomarker of disease control in acromegaly, were maintained in patients switching from standard-of-care injected SRL depots to once-daily oral paltusotine.
Received Rare Pediatric Disease Designation for CRN04777 for the treatment of congenital HI. In September 2020, the FDA granted CRN04777 Rare Pediatric Disease (RPD) Designation for the treatment of congenital HI. Based on this designation, Crinetics may be eligible to receive a priority review voucher (PRV) following approval of CRN04777 if the marketing application submitted for the candidate satisfies certain additional conditions. If issued, a PRV may be redeemed for priority review of a subsequent marketing application for a different product candidate, or the PRV could be sold or transferred to another sponsor.
Received Orphan Drug Designation for paltusotine for the treatment of acromegaly. In July 2020, the FDA granted paltusotine Orphan Drug Designation for the treatment of acromegaly, qualifying Crinetics for certain development incentives such as exemption from FDA prescription drug user fees, financial incentives for qualified clinical development, and seven years of market exclusivity in the U.S. upon FDA approval.
Strengthened company leadership with appointments to clinical team and Board of Directors. Throughout 2020, Crinetics continued to reinforce its in-house expertise in endocrinology, rare disease drug development, and clinical trial management through the appointments of Drs. Alessandra Casagrande, Peter Trainer, and Hjalmar Lagast to the clinical team and the appointment of Dr. Camille L. Bedrosian to the Board of Directors.

FOURTH QUARTER AND FULL YEAR 2020 FINANCIAL RESULTS
Research and development expenses were $16.8 million and $57.0 million for the three months and full year ended December 31, 2020, respectively, compared to $12.1 million and $41.5 million for the same periods in 2019. The increases were primarily attributable to clinical development and manufacturing activities for paltusotine as well as the company’s preclinical programs.
General and administrative expenses were $5.0 million and $18.0 million for the three months and full year ended December 31, 2020, compared to $3.4 million and $13.5 million for the same periods in 2019. The increases were primarily due to costs to operate as a public company, as well as personnel costs to support the company’s growth.
Net loss for the three months ended December 31, 2020 was $21.6 million, compared to a net loss of $14.5 million for the same period in 2019. For the year ended December 31, 2020, the company’s net loss was $73.8 million compared to a net loss of $50.4 million for the year ended December 31, 2019.
Unrestricted cash, cash equivalents and investments totaled $170.9 million as of December 31, 2020, compared to $186.8 million as of September 30, 2020 and $118.4 million as of December 31, 2019.
As of February 28, 2021, the company had 33,028,876 common shares outstanding.

WEBCAST AND CONFERENCE CALL INFORMATION
Crinetics will hold a live webcast and conference call today, March 30, 2021 at 4:30 p.m. Eastern Time to discuss its 2021 clinical plans and 2020 financial results. To access the webcast, please visit this link to the event. To participate by phone, please dial 877-407-0789 (domestic) or 201-689-8562 (international) and refer to conference ID 13717687. Following the live event, the archived webcast will be available for 90 days.

On March 30, 2021 Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on rare hematologic diseases and cancers, reported financial results for the fourth quarter and full year ended December 31, 2020 (Press release, Forma Therapeutics, MAR 30, 2021, View Source [SID1234577368]). The company also highlighted recent progress and upcoming milestones for its pipeline programs.

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"2020 was a very productive year for Forma, starting with our initial public offering in June and including positive clinical data and progress on our key development programs targeting sickle cell disease, AML and glioma, as well as prostate cancer," said Frank Lee, president and chief executive officer of Forma. "With important events in 2021 for our compounds in development, we look forward to furthering our mission to bring breakthrough therapies to people living with rare hematologic diseases and cancers."

Key Business and Clinical Highlights

PKR Program in Sickle Cell Disease (SCD):

Positive Phase 1 results of FT-4202 presented at scientific conferences. At the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in June 2020, results from a single ascending dose trial demonstrated a favorable tolerability profile and pharmacokinetic/pharmacodynamic (PK/PD) effects in patients with SCD who were administered a 700mg dose of FT-4202. Subsequently, at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in December 2020, data were presented from the ongoing randomized, placebo-controlled Phase 1 multiple ascending dose (MAD) trial. Results from the 300mg MAD1 dose cohort following 14 days of treatment showed an increase in hemoglobin of 1g/dL or greater in 6 of 7 (86%) patients vs. 0% of patients receiving placebo. In addition, markers of hemolysis such as indirect bilirubin, reticulocytes and lactate dehydrogenasewere improved, and measures of oxygen affinity and deformability suggested improvement in RBC health. FT-4202 was generally well-tolerated with no serious adverse events attributed to treatment with the compound.
Positive FT-4202 600 mg multiple ascending dose cohort data support doses being evaluated in Phase 2/3 registrational trial, called the Hibiscus Study. Doubling the dose of FT-4202 to 600 mg daily for 14 days compared to the previous 300 mg cohort was well-tolerated with no dose-limiting toxicities or treatment-related adverse events observed. Improvements in hematologic (hemoglobin and reticulocytes) and hemolytic (bilirubin and LDH) parameters were comparable to that observed with 300 mg dose, with best response typically at the end of the 14-day treatment period. Across 300 mg and 600 mg cohorts, 10 of 14 (71%) patients on FT-4202 for 14 days achieved a hemoglobin increase ≥ 1 g/dL from baseline. The phase 2/3 Hibiscus Study is currently enrolling people living with sickle cell disease (SCD). This adaptive, randomized, placebo-controlled, double-blind, multi-center trial is expected to enroll approximately 344 adults and adolescents with SCD. FT-4202 doses of 200mg and 400mg administered once-daily are being evaluated in the Phase 2 portion of the trial. Primary endpoints in the Phase 3 portion of the trial are hemoglobin response rate at week 24 (increase of > 1 g/dL from baseline), and annualized vaso-occlusive crisis rate during the 52-week blinded treatment period.
CPB/p300 Program in Prostate Cancer:

Preclinical data presented at scientific conference. At the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual meeting in June 2020, a poster was presented with preclinical data for FT-6876, a potent and selective inhibitor of CBP/p300, a known co-activator of the androgen receptor (AR) and a driver of metastatic castration-resistant prostate cancer (mCRPC). The data demonstrated antitumor activity of FT-6876 in AR-dependent breast cancer cell lines and highlight the possible role of CBP/p300 in proliferation and survival of AR-dependent tumors, such as prostate cancer. FT-6876 is a research compound related to FT-7051, although with differing PK/PD properties.
FT-7051 Phase 1 clinical trial initiated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In January 2021, Forma announced that the first patient was dosed in the ongoing Phase 1 trial. The trial is a multicenter, open-label evaluation of the safety and tolerability, preliminary anti-tumor activity (PSA and radiographic responses), and PK/PD of FT-7051 in men with mCRPC who have progressed despite prior therapy with at least one anti-androgen therapy. The trial will include genetic mutation analysis to identify tumors with AR-v7 splice variants, against which there are no approved therapies. This is an adaptive trial design, intended to accelerate the escalation to potentially therapeutic doses and yield important safety information, as well as the identification of biomarkers of clinical benefit such as prostate specific antigen (PSA).
IDH1 Program in AML and Glioma:

Announced positive registrational data for olutasidenib in relapsed/refractory acute myeloid leukemia (R/R AML). In October 2020, Forma announced positive results from the planned interim analysis (IA2) of the Phase 2 registration trial in R/R AML patients with isocitrate dehydrogenase 1 gene mutations (IDH1m). Olutasidenib demonstrated favorable tolerability as a monotherapy and achieved the primary endpoint of a composite complete remission (CR+CRh, or complete remission plus complete remission with partial hematologic recovery) rate of 33.3% (30% CR and 3% CRh). While a median duration of CR/CRh has not been reached, a sensitivity analysis (with a hematopoietic stem cell transplant as the end of a response) indicated a median duration of CR/CRh to be 13.8 months. Safety results were consistent with previously reported Phase 1 clinical trial results. Additional data and analyses indicate that the overall response rate (ORR), comprised CR, CRh, CRi, partial response (PR), and morphologic leukemia-free state (MLFS), was 46% and the median duration of ORR was 11.7 months. The median overall survival (OS) was 10.5 months. For patients with CR/CRh, the median OS has not yet been reached, but the estimated 18-month survival is 87%. The most frequently reported treatment emergent adverse events (≥20%) were nausea (38%), constipation (25%), increased white blood cell count (25%), decreased RBC count (24%), pyrexia (23%), febrile neutropenia (22%), and fatigue (21%). Grade 3/4 adverse events occurring in greater than 10% of patients, regardless of causality, were febrile neutropenia (20%), decreased RBC count (19%), decreased platelet count (16%), and decreased neutrophil count (13%).
An exploratory Phase 1 trial of olutasidenib for glioma showed evidence of disease control. Data presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in June 2020 demonstrated the brain penetrant properties of olutasidenib and preliminary clinical activity, which suggest potential for response and prolonged disease control in the enhanced (grade III/IV) R/R IDH1-mutated glioma. Among 24 evaluable patients treated (4 grade II, 13 grade III, 7 grade IV), one patient had a partial response and 11 patients had stable disease, as determined by investigator response assessment in neuro-oncology, or RANO, criteria. Twenty-two of the patients’ responses were also evaluated by volumetric changes at a central review, where four patients had more than 50% tumor reduction, one patient had 25% to 50% tumor reduction, and an additional seven patients had prolonged stable disease.
Corporate Achievements:

Successful initial public offering in June 2020 and follow-on equity offering in December 2020. On June 23, 2020, the Company completed an initial public offering (IPO) in which the Company issued and sold 15,964,704 shares of its common stock at a public offering price of $20.00 per share. The Company raised approximately $293.3 million in net proceeds after deducting underwriting discounts and commissions and offering expenses. On December 15, 2020, the Company completed an underwritten public offering of 6,095,000 shares of its common stock at a public offering price of $45.25 per share. The Company raised approximately $258.6 million in net proceeds after deducting underwriting discounts and commissions and offering expenses.
Three new board of directors appointments. In July 2020, Wayne A. I. Frederick, M.D., was elected to serve on Forma’s board of directors. Dr. Frederick is the President of Howard University, as well as the Charles R. Drew Professor in Surgery at Howard University’s College of Medicine, and a distinguished researcher and practicing surgeon.

In September 2020, Forma announced the appointment of industry veteran Thomas G. Wiggans to its board of directors. Mr. Wiggans has led successful biopharmaceutical companies from start-up stage into the clinic and later global commercialization and served on the boards of numerous public and private companies.

In January 2021, Forma announced the appointment of Selwyn M. Vickers, M.D., to its board of directors. Dr. Vickers is a world-renowned surgeon, pancreatic cancer researcher and pioneer in health disparities research. He currently serves as senior vice president of medicine and dean of the School of Medicine at The University of Alabama at Birmingham (UAB).
Upcoming Milestones

Phase 1 FT-4202 randomized cohorts successfully completed; open label extension ongoing. Patients with sickle cell disease are now directly enrolling into the 12-week open label extension (OLE) with the 400mg daily dose, which was previously limited to patients who completed the 600mg dose cohort. Initial results from the ongoing 400mg 12-week open label extension are anticipated to be announced at a scientific congress in the second quarter of 2021, and full results expected at a scientific congress in late 2021.
Initial Phase 1 clinical results from FT-7051 in mCRPC anticipated later this year. This adaptive trial is designed to assess multiple doses of FT-7051 with dose escalation dependent upon safety and tolerability. Initial results are anticipated in the second half of 2021, which may include safety/tolerability, PK/PD results and preliminary biomarker data.
NDA being prepared for olutasidenib in R/R AML. Forma is preparing a new drug application (NDA) for submission to the U.S. Food and Drug Administration for refractory/relapsing AML patients with an IDH1 mutation. In addition, a manuscript is being prepared for publication of Phase 1 glioma results.
Possibility of COVID-19 impact remains. The COVID-19 pandemic remains a factor in the successful completion of these milestones. Many clinical trials across the biopharma industry have been impacted by the COVID-19 pandemic, with clinical trial sites implementing new policies in response to COVID-19, resulting in potential delays to enrollment of clinical trials or changes in the ability to access sites participating in clinical trials.
Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $645.6 million as of December 31, 2020, as compared to $173.2 million as of December 31, 2019. Current cash runway is projected through the third quarter of 2024.
Research and Development (R&D) Expenses: R&D expenses were $24.9 million and $93.4 million for the quarter and year ended December 31, 2020, compared to $27.0 million and $111.3 million for the quarter and year ended December 31, 2019. The decline was attributable to a decrease in spending on internal research and development primarily due to restructuring in January 2019, and reductions in spending on olutasidenib and FT-8225, which were partially offset by increases in FT-4202 expenses to conduct the Phase 1 trial, clinical product manufacturing, and preparations for the pivotal Phase 2/3 trial.
General and Administrative (G&A) Expenses: G&A expenses were $7.9 million and $30.8 million for the quarter and year ended December 31, 2020, compared to $6.8 million and $24.4 million for the quarter and year ended December 31, 2019. The increase in general and administrative expense was primarily attributable to a $3.2 million increase in stock compensation expense; $1.2 million increase in insurance related expenses; $1.2 million increase in professional fees; $0.5 million increase in personnel-related costs due to executive and staff hiring, recruiting and an increase in facilities; and IT related expenses of $0.2 million.
Net Income/Loss: Net loss was $28.6 million and $70.4 million for the quarter and year ended December 31, 2020, compared to $24.7 million and $34.8 million for the quarter and year ended December 31, 2019.
Forma will conduct a conference call and webcast on March 30th at 8 a.m. Eastern Standard Time (EST) to discuss 2020 year-end financial results and business update. The call can be accessed by dialing (833) 301-1146 in the U.S., and (914) 987-7386 internationally, with conference ID 5893542.

The live webcast will be available in the "News & Investors" section of Forma’s website www.formatherapeutics.com.

On March 30, 2021 BioNTech SE (Nasdaq: BNTX, "BioNTech" or "the Company"), a next generation immunotherapy company pioneering novel therapies for cancer and infectious diseases, reported financial results for the quarter and full year ended December 31, 2020 (Press release, BioNTech, MAR 30, 2021, View Source [SID1234577327]).

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"2020 was a transformational year for BioNTech with the development and approval of the first mRNA drug in history. As of March 2021, we had delivered more than 200 million doses of our vaccine to more than 65 countries and regions together with our partners, and we are already seeing the first signs of vaccine associated reduction of COVID-19 cases and mortality in multiple countries" said Ugur Sahin, Co-founder and CEO of BioNTech. "We will continue to focus on innovating in the COVID-19 field by advancing new formulations and addressing vaccine variants, as well as initiating new trials in additional sub-populations. At the same time, we are accelerating the development of our cancer immunotherapies. We see a tremendous opportunity to reinvest the proceeds from our COVID-19 vaccine into extending and accelerating the research and development of new vaccines and therapeutics to improve the health of people worldwide by harnessing the full potential of the immune system."

Fourth Quarter 2020 and Subsequent Updates

Infectious disease

COVID-19 vaccine program – BNT162b2
In December 2020, BNT162b2 became the first mRNA vaccine to be approved or authorized for emergency or conditional use. BNT162b2 now has authorization or approval for emergency use or temporary use in more than 65 countries worldwide, including the United States, United Kingdom and European Union.

On November 18, 2020, BioNTech and Pfizer announced that BNT162b2 met the Phase 3 study’s primary efficacy endpoints in the final efficacy analysis. Analysis of the data indicated a vaccine efficacy rate of 95% for the prevention of a COVID-19 disease, measured seven days after the second dose. No serious safety concerns related to the vaccine were observed in the trial, with most solicited adverse events resolving shortly after vaccination. On December 10, 2020, results from the trial were published in the New England Journal of Medicine.
On March 11, 2021, BioNTech and Pfizer announced additional real-world evidence data from the Israel Ministry of Health (MoH) that demonstrated dramatically lower incidence rates of COVID-19 disease in individuals fully vaccinated with our COVID-19 vaccine. The latest data from the MoH show that two weeks after the second vaccine dose, protection is even stronger with a vaccine effectiveness of at about 97% in preventing symptomatic disease, severe/critical disease and death. The analysis also showed a vaccine effectiveness of 94% against asymptomatic SARS-CoV-2 infections. Since this observational analysis was conducted when the variant B.1.1.7 (UK variant) was the dominant strain in Israel, it also provides real-world evidence of the effectiveness of BNT162b2 for prevention of COVID-19 infections, hospitalizations and deaths due to variant B.1.1.7. The data from this observational analysis were published on March 24, 2021, on Lancet’s preprint server.
Clinical development updates

On October 21, 2020, BioNTech and Pfizer announced the start of a Phase 1/2 clinical trial in Japan to evaluate safety, tolerability and immunogenicity of BNT162b2 in healthy adults 20 to 85 years of age.
On November 25, 2020, BioNTech and Fosun Pharma announced the start of a Phase 2 clinical trial of BNT162b2 in China to evaluate the safety and immunogenicity of BNT162b2 in healthy adults.
On February 18, 2021, BioNTech and Pfizer announced that the first participants were dosed in a global Phase 2/3 trial to evaluate the safety, tolerability and immunogenicity of BNT162b2 in preventing COVID-19 in approximately 4,000 healthy pregnant women 18 years of age and older. The study will also assess safety in infants of vaccinated pregnant women and the transfer of potentially protective antibodies to their infants.
On February 18, 2021, BioNTech and Pfizer announced that safety and efficacy data from the global Phase 3 study with subjects 12 to 15 years of age are expected to be submitted to the regulatory authorities in the second quarter of 2021.
On February 25, 2021, BioNTech and Pfizer announced a trial to evaluate the safety and immunogenicity of a third dose of our COVID-19 vaccine on prolonging immunity against COVID-19 and to address potential newly emerging SARS-CoV-2 variants.
In March, 2021, the U.S Food and Drug Administration (FDA) approved an additional amendment to the study protocol of the global Phase 1/2/3 trial for an additional dose of BNT162b2 or its modified version carrying the spike protein sequence of the South African variant (BNT162b2SA) in order to further describe duration of protection, and protection against the emerging variants of concern. An additional dose of either BNT162b2 or BNT162b2SA will be given to approximately 600 Phase 3 participants about five to seven months after their second dose of BNT162b2. A further dose of BNT162b2SA will be given to approximately 30 of those participants who receive BNT162b2SA. Approximately 300 BNT162b2-naïve participants will be enrolled and receive two doses of BNT162b2SA to describe protection against the emerging variants of concern and reference strains. The part of the trial with BNT162b2SA is expected to start in the second quarter of 2021.
In March 2021, first participants were dosed in a Phase 1/2/3 study in healthy children 6 months to under 12 years of age. The Phase 1 dose-finding portion will evaluate the safety, tolerability and immunogenicity of two doses of BNT162b2 separated by 21 days in up to three age groups. Once the preferred dose level of BNT162b2 is identified for each age group, a Phase 2/3 trial to evaluate the safety, tolerability and immunogenicity in each age group will start. In addition, efficacy against confirmed COVID-19 and against asymptomatic infection will be assessed. Approximately 450 participants (300 in the BNT162b2 group and 150 in the placebo group) in each age group are expected to contribute to the immunobridging and persistence of immune response at 6 months after second dose analyses. Participants will be unblinded at the 6-month follow-up visit and participants that received placebo will be offered the opportunity to receive BNT162b2. All of the expected 4,500 participants will contribute to the vaccine effectiveness (VE) analysis for conditional VE and asymptomatic infection.
BioNTech and Pfizer are also planning studies to further evaluate the vaccine in people with compromised immune systems.
BioNTech and Pfizer will start a Phase 3 trial to evaluate the safety, tolerability and immunogenicity of lyophilized BNT162b2 presented in single-dose vials and of frozen liquid BNT162b2 in multidose vials. This trial will also assess the non-inferiority of the lyophilized formulation. The trial will be conducted in healthy adults 18 through 55 years of age and will start in the United States in April. We expect data from this trial in the third quarter of 2021.
Data on SARS-CoV-2 variants

On March 8, 2021, BioNTech and Pfizer published data in the New England Journal of Medicine from an in vitro study of the neutralizing activity of BNT162b2-elicited serum against the variants first detected in the United Kingdom (B.1.1.7 lineage), Brazil (P.1 lineage) and South Africa (B.1.351 lineage). The findings provide strong support that BNT162b2 will continue to protect against the B.1.1.7 lineage and the P.1 lineage. Sera neutralized all the viruses tested and showed no significant reduction in activity against both B.1.1.7-spike and P.1-spike viruses. While neutralization of the B.1.351-spike virus was lower, it was still robust.
Regulatory updates

On December 2, 2020, BioNTech and Pfizer announced that the Medicines & Healthcare Products Regulatory Agency (MHRA) in the United Kingdom granted a temporary authorization for emergency use for BNT162b2 against COVID-19.
On December 11, 2020, BioNTech and Pfizer announced that the U.S. FDA authorized the emergency use of BNT162b2 in individuals 16 years of age or older. BNT162b2 is authorized in the United States under an Emergency Use Authorization (EUA) while BioNTech and Pfizer gather additional data and prepare to file a planned Biologics License Application (BLA) with the U.S. FDA for full regulatory approval in 2021.
On December 21, 2020, BioNTech and Pfizer announced the European Commission (EC) granted a conditional marketing authorization (CMA) for BNT162b2 in individuals 16 years of age and older. The CMA is valid in all 27 member states of the European Union.
On February 14, 2021, Japan’s Health Ministry approved BNT162b under the exceptional approval scheme in Japan.
On February 25, 2021, the U.S. FDA and on March 26, 2021, the EMA, approved that undiluted frozen vials of BNT162b2 may be transported and stored at conventional temperatures commonly found in pharmaceutical freezers (-25°C to -15°C or -13°F to 5°F) for a period of up to two weeks. Further formulation optimization activities are ongoing.
Commercial Updates
We and our collaboration partners have supplied more than 200 million doses of our COVID-19 vaccine worldwide, as of March 23, 2021.
BioNTech and Pfizer have signed orders of 1.4 billion doses for delivery in 2021. Discussions for additional dose commitments are ongoing.

On February 12, 2021, BioNTech and Pfizer announced that the U.S. government exercised its option for an additional 100 million doses of our COVID-19 vaccine. This agreement brings the total number of doses to be delivered to the United States to 300 million. Consistent with the agreements for the prior 200 million doses, the U.S. government will pay $1.95 billion for the additional 100 million doses.
On February 17, 2021, BioNTech and Pfizer announced an agreement with the EC to supply an additional 200 million doses of our COVID-19 vaccine. The EC has an option for an additional 100 million doses. The total number of doses to be delivered to the European Union by the end of 2021 is now 500 million, with an option for an additional 100 million doses.
Manufacturing
BioNTech and Pfizer expect to increase BNT162b2 manufacturing capacity to up to 2.5 billion doses by the end of 2021. The increase is driven by the optimization of production processes, the recent initiation of production at BioNTech’s Marburg, Germany facility, regulatory approval for six dose vials, and the expansion of our manufacturing and supplier network. Additional measures and discussions with potential partners to further expand the manufacturing capacity and network are ongoing.

In October 2020, BioNTech acquired a GMP manufacturing facility in Marburg, Germany, to accelerate BNT162b2 manufacturing scale-up for commercial supply in 2021.
On March 26, 2021, BioNTech announced that the European Medicines Agency (EMA) approved the manufacturing of our COVID-19 vaccine drug product at the facility in Marburg. The approvals make BioNTech’s Marburg manufacturing site one of the largest mRNA vaccine manufacturing sites worldwide with an annual production capacity of up to one billion doses of our COVID-19 vaccine, once fully operational. Due to optimized operational efficiencies which were initiated last year, BioNTech was able to increase the expected annual manufacturing capacity by 250 million doses. The first batches of vaccines manufactured at the Marburg site are expected to be delivered in the second half of April. BioNTech plans to produce up to 250 million doses of BNT162b2 in the first half of 2021.
Oncology
BioNTech is accelerating the development of its broad oncology pipeline with 13 product candidates in 14 ongoing trials. In 2021, we expect at least four data updates from our oncology pipeline with up to three programs expected to move into randomized Phase 2 trials and six preclinical programs moving into Phase 1 trials. This includes the first-in-human trials started for the lead candidates for both the CARVac (BNT211) and RiboCytokines (BNT151) product candidates.

mRNA programs
FixVac

BNT111 – We expect to start a randomized Phase 2 trial for the treatment of patients with advanced melanoma progressing during or after prior therapy with a PD-1 inhibitor, utilizing a combination of BNT111 and Regeneron and Sanofi’s Libtayo (Cemiplimab) in the first half of 2021 in the United States and the European Union. Our IND for this trial in the United States is active as is a CTA approval in the European Union.
BNT113 – We expect to start a Phase 2 trial evaluating BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy as a first-line treatment in patients with unresectable recurrent or metastatic HPV16+ head and neck squamous cell carcinoma (HNSCC) expressing PD-L1 in the first half of 2021 in the United States and the European Union. BNT113 has not been combined with anti-PD1 before and the Phase 2 trial will start with a run in portion designed to demonstrate the safety of the combination of BNT113 and pembrolizumab. These data are required to address the partial clinical hold on the subsequent randomized part of the Phase 2 trial.
Individualized neoantigen specific immunotherapy (iNeST)

Our iNeST product candidate BNT122 is partnered with Genentech.

BNT122 has been given the international non-proprietary name (INN) "autogene cevumeran".
An open-label Phase 1a/1b trial evaluating the safety, tolerability, immune response and pharmacokinetics of autogene cevumeran as a single agent and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors (basket trial) is ongoing.
A Phase 2 open-label trial evaluating the efficacy and safety of autogene cevumeran in combination with pembrolizumab versus pembrolizumab alone in patients with previously untreated advanced melanoma is ongoing.
Given challenging accrual timelines in the context of the SARS-CoV-2 pandemic and the evolving landscape of treatment options in non-small cell lung cancer (NSCLC), BioNTech and Genentech decided to discontinue the previously planned Phase 2 trial in patients with high-risk resected early stage NSCLC. Genentech and BioNTech are evaluating further options for treating early disease cancer patients with autogene cevumeran.
One of these early disease development options is adjuvant treatment of colorectal cancer. First patient dosing in a randomized Phase 2 trial in circulating tumor DNA positive, surgically resected Stage 2 (high risk)/Stage 3 colorectal cancer is expected in the first half of 2021.
RiboCytokines

BNT151 is a nucleoside-modified mRNA encoding for an IL-2 variant, a key cytokine in T cell immunity supporting the differentiation, proliferation, survival and effector functions of T cells. BNT151 is designed to stimulate anti-tumoral T cells without extensively triggering immunosuppressive regulatory T cells. In February 2021, the first patient was dosed in a first-in-human, open-label, multicenter Phase 1/2a trial. The trial evaluates dose escalation, safety, pharmacokinetics and pharmacodynamics of BNT151 with expansion cohorts in multiple solid tumor indications, including HNSCC, hepatocellular carcinoma (HCC), renal cell cancer (RCC), NSCLC, and triple-negative breast cancer (TNBC). The monotherapy dose escalation will enroll patients with tumors that are metastatic or unresectable with no available standard therapy likely to confer clinical benefit. In the combined treatment dose escalation, patients with different solid tumors will be enrolled and treated with BNT151 and the respective standard of care.
BNT152+153 – In February, the U.S. FDA approved the IND for a Phase 1 trial for BNT152+153. We plan to start a Phase 1 trial for BNT152 (encoding IL-7) plus BNT153 (encoding IL-2) in multiple solid tumors in the first half of 2021.
RiboMabs

BNT141 – In February, the U.S. FDA approved the IND for a Phase 1 first-in-human clinical trial for BNT141. We expect to start the trial in the second half of 2021.
BNT142 – We expect to start a Phase 1 clinical trial for BNT142 in the second half of 2021.
Antibodies
Next-generation checkpoint immunomodulators

BNT311 and BNT312 are partnered with Genmab.

BNT311/GEN1046 – Data from a first-in-human Phase 1/2a trial of BNT311 (PD-L1x4-1BB) in 61 heavily pretreated patients with advanced solid tumors was presented at the SITC (Free SITC Whitepaper) conference in November 2020. We expect a data update from this trial in the second half of 2021.
BNT312/GEN1042 – We expect first data disclosure from the Phase 1/2a trial of BNT312 in solid tumors in the second half of 2021.
Cell therapies
CAR-T cell immunotherapy

BNT211, BioNTech’s most advanced CAR-T product candidate, targets the tumor-specific antigen CLDN6 and was developed in combination with a CAR-T cell Amplifying RNA Vaccine (CARVac) that encodes the CAR target for in vivo expansion upon CAR-T administration. CARVac is based on RNA-LPX technology known from FixVac and selectively delivers the RNA-encoded CAR target to antigen presenting cells, leading to CAR target expression on the cell surface.

BNT211 – In February 2021, the first patient was dosed in a first-in-human Phase 1/2a open-label, multi-center dose escalation and dose expansion basket trial of BNT211 with or without a CLDN6 CARVac in patients with CLDN6-positive relapsed or refractory advanced solid tumors including but not limited to ovarian and testicular cancers. The combination with CLDN6 CARVac is expected to improve expansion and persistence of CLDN6 CAR-T. The primary outcome measure of the trial will be safety, with secondary efficacy outcome measures to include objective response rate, disease control rate and duration of response. We expect a data update for this trial in the second half of 2021.
Neoantigen-targeting T cell therapy

BNT221 (NEO-PTC-01) – Dosing of the first patient in a Phase 1 dose escalation trial for the treatment of metastatic melanoma in patients who are refractory or unresponsive to checkpoint inhibitors is expected in the first half of 2021. The primary objectives of the trial will be to evaluate the safety and feasibility of administering BNT221, in addition to an evaluation of immunogenicity and clinical efficacy.
Small molecule immunomodulators
Toll-like receptor binding agonist

BNT411 – A Phase 1/2a dose-escalation trial of BNT411 as a monotherapy in patients with solid tumors, and in combination with atezolizumab, carboplatin and etoposide in patients with chemotherapy-naïve extensive-stage small cell lung cancer (ES-SCLC) remains ongoing. We expect a data update from this trial in the second half of 2021.
Full Year 2020 Financial Results
Revenues: Total revenues were estimated to be €345.4 million for the three months ended December 31, 2020, compared to €28.0 million for the three months ended December 31, 2019. For the year ended December 31, 2020, total revenues were estimated to be €482.3 million, compared to €108.6 million for the comparative prior year period. Total revenues increased due to recognizing revenues for the first time under our two new collaboration agreements to develop a COVID-19 vaccine and ultimately led to the recognition of COVID-19 vaccine commercial revenues. Under the Pfizer collaboration, territories have been allocated to BioNTech and Pfizer based on marketing and distribution rights. Our commercial revenues comprise an estimated amount of €188.5 million1 share of gross profit from COVID-19 vaccine sales in the collaboration partner’s territory, which represents a net figure. In addition, €61.4 million sales to our collaboration partner of products manufactured by us and €20.6 million direct COVID-19 vaccine sales to customers in our territory Germany have been recognized.

Cost of Sales: Cost of sales were estimated to be €41.0 million for the three months ended December 31, 2020, compared to €4.4 million for the three months ended December 31, 2019. For the year ended December 31, 2020, cost of sales were estimated to be €59.3 million, compared to €17.4 million for the comparative prior year period. €35.6 million estimated cost of sales were recognized for the first time with respect to our COVID-19 vaccine sales and include Pfizer’s share of gross profits earned by BioNTech. Cost of sales do not include costs relating to production of pre-launch products since those are expensed as research and development expenses in the period incurred.

Research and Development Expenses: Research and development expenses were €257.0 million for the three months ended December 31, 2020, compared to €65.4 million for the three months ended December 31, 2019. For the year ended December 31, 2020, research and development expenses were €645.0 million, compared to €226.5 million for the comparative prior year period. The increase was mainly due to an increase in research and development expenses for our BNT162 program. Research and development expenses include our share of expenses under the terms of the Pfizer collaboration agreement. Development costs are shared equally between Pfizer and us. The increase was further driven by an increase in expenses for purchased laboratory supplies as well as an increase in headcount leading to higher wages, benefits and social security expenses. In addition, from May 6, 2020, the date of acquisition of our new U.S.-based subsidiary, BioNTech US Inc., contributed to our research and development expenses.

General and Administrative Expenses: General and administrative expenses were €36.1 million for the three months ended December 31, 2020, compared to €11.1 million for the three months ended December 31, 2019. For the year ended December 31, 2020, general and administrative expenses were €94.0 million, compared to €45.5 million for the comparative prior year period. The increase was mainly due to higher expenses for professional services, an increase in headcount leading to higher wages, benefits and social security expenses and higher insurance premiums. In addition, from May 6, 2020, the date of acquisition of our new U.S.-based subsidiary, BioNTech US Inc., contributed to our general and administrative expenses.

Income Taxes: Following the authorization and approval of our COVID-19 vaccine for emergency or temporary use or having been granted conditional marketing authorization, the recognition of deferred tax assets was reevaluated. As of December 31, 2020, net deferred tax assets with respect to the accumulated tax losses and temporary differences of the German tax group were recognized with €161.0 million income tax effect.

Net Profit / Loss: Net profit was €366.9 million for the three months ended December 31, 2020, compared to €58.2 million net loss for the three months ended December 31, 2019. For the year ended December 31, 2020, net profit was €15.2 million, compared to €179.2 million net loss for the comparative prior year period.
Cash Position: Cash and cash equivalents as of December 31, 2020 were €1.2 billion.

Shares Outstanding: Shares outstanding as of December 31, 2020 were 241,521,065.

COVID-19 vaccine order book update:

Estimated COVID-19 vaccine revenues to BioNTech upon delivery of currently signed supply contracts (~1.4 billion doses): ~€9.8 billion.

Estimate reflects:

Expected revenues from direct COVID-19 vaccine sales to customers in our territories
Expected revenues from sales to our collaboration partners
Expected sales milestone payments from our collaboration partners
Expected revenues related to our share of gross profit from COVID-19 vaccine sales in the collaboration partners’ territories
Additional revenues related to further supply contracts for deliveries in 2021 expected.

Full year 2021 manufacturing capacity target raised from 2.0 to 2.5 billion doses to be able to address increased demand.
2021 financial outlook: BioNTech is providing the following outlook for the full year 2021 of selected financial metrics based on the current base case projections:

Planned Full Year 2021 Expenses and Capex2
R&D expenses €750 million – €850 million

Ramp-up of R&D investment in 2H 2021 and beyond planned to broaden and accelerate pipeline development.
SG&A expenses Up to €200 million
Capital expenditures €175 million – €225 million
Estimated Full Year 2021 Tax Assumptions
German tax group corporate tax rate ~31%
German tax group accumulated tax loss carryforwards as of December 31, 2020 ~€450million3
Full financial statements can be found in the 20F filing as published on the SEC website under View Source

1 Estimated figures based on preliminary data shared between Pfizer and BioNTech as fully described in our Annual Report on Form 20-F. Changes in our share of the collaboration partner’s gross profit will be recognized prospectively.
2 Ranges reflect current base case projections.

3 €457.9 million corporate income tax losses and €450.9 million trade tax losses related to the German tax group.

On March 30, 2021 Bellicum Pharmaceuticals, Inc. (Nasdaq: BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers, reported financial results for the fourth quarter and full year 2020 and provided an operational update (Press release, Bellicum Pharmaceuticals, MAR 30, 2021, View Source [SID1234577353]).

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"In 2020, we refined our focus on our next generation CAR-T cell therapies," said Rick Fair, President and Chief Executive Officer. "We are excited to have resumed our trial of BPX-601 with a focus on prostate cancer and initiated the BPX-603 trial in HER2+ solid tumors, and we look forward to providing updates on both programs as the year progresses."

Program Highlights and Current Updates

BPX-601 GoCAR-T

In January, Bellicum announced the U.S. Food and Drug Administration (FDA) had lifted the clinical hold on patient enrollment and dosing in an ongoing Phase 1/2 dose-escalation clinical trial evaluating BPX-601 and rimiducid in patients with previously treated metastatic pancreatic or prostate cancer. Bellicum has worked with clinical investigators to resume screening for patient enrollment without modification to the current study protocol.

Bellicum plans to present a Phase 1 data update on BPX-601 and rimiducid in patients with metastatic castration-resistant prostate cancer in the first quarter of 2022.
BPX-603 GoCAR-T

In December, Bellicum announced the enrollment and apheresis of the first patient in the Phase 1/2 clinical trial for BPX-603 in patients with solid tumors that express human epidermal growth factor 2 (HER2), including breast, endometrial, ovarian, gastric, and colorectal cancers. BPX-603 is the company’s first dual-switch GoCAR-T product candidate, which incorporates Bellicum’s iMC activation and CaspaCIDe safety switch technologies. The company expects to provide initial Phase 1 data from this trial in the second half of 2021.
CaspaCIDe

In February, Bellicum announced the first reported use of the CaspaCIDe safety switch to mitigate CAR-T cell toxicity. The report, published as an ahead-of-print publication in the digital edition of Blood, a journal published by The American Society of Hematology (ASH) (Free ASH Whitepaper), was a case from an investigator-sponsored trial (IST) at the University of North Carolina Lineberger Comprehensive Cancer Center of autologous CAR-T cells expressing CD19 and CaspaCIDe. In this patient, grade 3-4 immune effector cell-associated neurotoxicity syndrome (ICANS) refractory to standard therapies was treated with rimiducid to activate CaspaCIDe. Within twelve hours of rimiducid administration, ICANS grade improved from 3 to 1 and was fully resolved after four days.
Corporate Updates

In November, Bellicum completed an underwritten offering of 1,040,000 shares of common stock, pre-funded warrants to purchase 3,109,378 shares of common stock and accompanying warrants to purchase 4,149,378 shares of common stock. Gross proceeds to Bellicum were approximately $25.0 million, before deducting underwriting discounts and commissions and other offering expenses payable by Bellicum and excluding any proceeds that may be received upon exercise of the warrants.

In October, Bellicum implemented a restructuring program to focus on the clinical development of BPX-601 and BPX-603, reduce headcount, pause the BCMA GoCAR-NK program, and discontinue discovery research and new product development.

In October, Bellicum repaid in full all outstanding indebtedness and terminated all commitments and obligations under its loan agreement with Oxford Finance, for a payment of $27.4 million.
Fourth Quarter 2020 Financial Results

R&D Expenses: Research and development expenses were $8.7 million and $39.1 million for the fourth quarter and year ended December 31, 2020, respectively, compared to $13.3 million and $64.5 million during the comparable periods in 2019. The reduction in expenses in the fourth quarter resulted primarily from reduced expenses related to reduced rivo-cel related activities, reduced expenses resulting from Bellicum’s sale of its manufacturing facility and the corporate restructuring implemented during the fourth quarter of 2020, partially offset by an increase in expenses related to the GoCAR programs.

G&A Expenses: General and administrative expenses were $3.4 million and $15.5 million for the fourth quarter and year ended December 31, 2020, respectively, compared to $5.7 million and $30.0 million during the comparable periods in 2019. The reduction in expenses during the fourth quarter relative to the comparable period in 2019 was primarily due to the reduction in rivo-cel related commercialization activities as well as the effects of the corporate restructuring that reduced employee-related charges.

Loss from Operations: Bellicum reported a loss from operations of $13.0 million and $51.7 million for the fourth quarter and year ended December 31, 2020, respectively, compared to a loss from operations of $13.9 million and $87.4 million for the comparable periods in 2019.

Net Income/Loss: Bellicum reported net income of $18.8 million and a net loss $7.7 million for the fourth quarter and year ended December 31, 2020, respectively, compared to a net loss of $29.0 million and $112.5 million for the comparable periods in 2019. The results included a non-cash gain of $31.9 million and $46.1 million related to the change in fair value of the warrant and private placement option liability for the fourth quarter and year ended December 31, 2020, respectively.

Shares Outstanding: As of March 22, 2021, Bellicum had 8,318,273 shares of common stock and 452,000 shares of preferred stock outstanding. Each share of preferred stock can be converted into 10 shares of common stock. In the November 2020 financing, the company issued 1,040,000 shares of common stock and pre-funded warrants to purchase 3,109,378 shares of common stock.

Cash Position and Guidance: Bellicum reported cash and cash equivalents and restricted cash totaling $37.0 million as of December 31, 2020, compared to $93.8 million as of December 31, 2019. Based on current operating plans, Bellicum expects that current cash resources will be sufficient to meet operating requirements into the second quarter of 2022.

Conference Call and Webcast
Bellicum’s management will host a webcast and conference call today at 5 p.m. ET / 2 p.m. PT, March 30, 2021, to discuss the financial results for the fourth quarter 2020 and provide a corporate update. The live call may be accessed by dialing (877) 407-3103 for domestic callers and (201) 493-6791 for international callers. A live webcast of the call will be available from the Investors and Media section of the company’s website at www.bellicum.com and a replay will be available shortly after the live event.

On March 30, 2021 Exelixis, Inc. (Nasdaq: EXEL) reported that COSMIC-313, the phase 3 pivotal trial evaluating the combination of cabozantinib (CABOMETYX), nivolumab (OPDIVO) and ipilimumab (YERVOY) versus the combination of nivolumab and ipilimumab in patients with previously untreated advanced intermediate- or poor-risk renal cell carcinoma (RCC), has completed enrollment (Press release, Exelixis, MAR 30, 2021, https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-enrollment-completion-phase-3-cosmic-313 [SID1234577369]). The primary endpoint of the trial is progression-free survival, and additional endpoints include overall survival and objective response rate.

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"Following the promising final results of a phase 1b trial evaluating this triplet combination in advanced genitourinary tumors, this milestone in the phase 3 pivotal trial brings us a step closer to understanding whether cabozantinib in combination with nivolumab and ipilimumab may improve outcomes for patients with previously untreated advanced kidney cancer," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "We look forward to sharing initial results from the event-driven analysis of COSMIC-313 when available and to learning more about the potential of cabozantinib in combination with immunotherapies."

COSMIC-313 is a multicenter, randomized, double-blind, controlled phase 3 pivotal trial that enrolled approximately 840 patients at 180 sites globally. Patients were randomized 1:1 to receive cabozantinib plus nivolumab and ipilimumab or matching placebo plus nivolumab and ipilimumab. The design of COSMIC-313 was informed by the results of the CheckMate -214 trial that supported regulatory approval of nivolumab in combination with ipilimumab for the first-line treatment of patients with intermediate- and poor-risk RCC, and by results from the phase 1b study of cabozantinib in combination with nivolumab with or without ipilimumab in patients with relapsed or refractory metastatic genitourinary cancers, including RCC. Final results from that phase 1b trial were presented during the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary Cancers Symposium.

Bristol Myers Squibb is providing nivolumab and ipilimumab for use in this trial.

More information about this trial is available at ClinicalTrials.gov.

About RCC
The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. 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 United States 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 United States.

CABOMETYX is not indicated for use in combination with nivolumab and ipilimumab in previously untreated advanced renal cell carcinoma.

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 and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. 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 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% 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.

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 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 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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.

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 is observed. 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.

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, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

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.