On November 12, 2019 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 third quarter ended September 30, 2019 and provided an update on its corporate activities and product pipeline (Press release, Crinetics Pharmaceuticals, NOV 12, 2019, View Source [SID1234550962]).

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"Crinetics has continued to make significant strides in the development of new therapeutics to treat patients suffering from rare endocrine diseases and endocrine-related tumors," said Scott Struthers, Ph.D., Founder and Chief Executive Officer of Crinetics. "Our ACROBAT clinical studies for patients with acromegaly are advancing as is our Phase 1 study for CRN01941 aimed at neuroendocrine tumors. Furthermore, we are excited with the progress we have made to develop novel therapies for patients suffering from Cushing’s disease and hyperinsulinism as we continue to steer these programs towards clinical development."

Third Quarter and Subsequent Highlights

Received final award of SBIR grant from NIH for congenital hyperinsulinism. In July 2019, Crinetics announced that it would receive up to approximately $0.9 million in continued funding under its Small Business Innovation Research (SBIR) grant from the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) of the National Institutes of Health (NIH). The funds are being used to support the ongoing research and development of Crinetics’ nonpeptide somatostatin agonists for congenital hyperinsulinemias (CHI).

Expanded board of directors. In July 2019, Crinetics appointed Stephanie S. Okey, M.S. to its board of directors as an independent board member. Ms. Okey brings extensive leadership and management experience having spent her career in senior commercial roles including, most recently, Head of North America and U.S. General Manager of Rare Diseases at Genzyme.

Third Quarter 2019 Financial Results

Research and development expenses were $11.8 million and $29.4 million for the three and nine months ended September 30, 2019, respectively, compared to $6.9 million and $16.8 million for the same periods in 2018. The increases were primarily attributable to development and manufacturing activities for CRN00808 and CRN01941 as well as the company’s preclinical programs and higher personnel costs.

General and administrative expenses were $3.9 million and $10.1 million for the three and nine months ended September 30, 2019, compared to $1.7 million and $4.1 million for the same periods in 2018. 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 September 30, 2019 was $14.4 million, compared to a net loss of $7.6 million for the same period in 2018. For the nine months ended September 30, 2019, the company’s net loss was $35.9 million compared to a net loss of $18.6 million for the nine months ended September 30, 2018.

Unrestricted cash, cash equivalents and investments totaled $131.7 million as of September 30, 2019, compared to $145.0 million as of June 30, 2019 and $163.9 million as of December 31, 2018. Crinetics expects that its cash, cash equivalents and investments will fund its current operating plan at least through the first half of 2021.

As of October 31, 2019, the company had 24,222,296 common shares outstanding.

On November 12, 2019 Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs (the "Company" or "Regulus"), reported financial results for the third quarter ended September 30, 2019 and provided a summary of recent events (Press release, Regulus, NOV 12, 2019, View Source [SID1234550978]).

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"We recently received the final reports from the chronic toxicity studies in mice and non-human primates and are preparing our submission of our complete response to Food and Drug Administration ("FDA") in our efforts to address the requirements to reinitiate the Multiple Ascending Dose ("MAD") clinical study for RGLS4326," said Jay Hagan, CEO of Regulus. "We look forward to FDA’s feedback and continued productive dialogue."

Third Quarter 2019 Corporate Highlights and Recent Updates

Management Transition to New Chief Financial Officer: In July 2019, the Company appointed Cris Calsada as its new Chief Financial Officer, effective August 30, 2019. Ms. Calsada’s appointment follows the resignation of the Company’s previous Chief Financial Officer, Dan Chevallard, in July 2019.

New Lease Agreement Significantly Reduces Contractual Lease Obligations: In June 2019, the Company entered into an amendment of its lease (the "Lease Amendment") of 24,562 square feet located at 10628 Science Center Drive Suite 100, San Diego, California 92121. Under the terms of the Lease Amendment, the expiration of the lease was accelerated from June 30, 2023 to June 30, 2019, and the lease terminated on July 1, 2019. Concurrently with the Lease Amendment, the Company entered into a new lease agreement for 8,727 square feet located at 10628 Science Center Drive, Suite 225, San Diego, California, 92121, which it uses as its new principal offices and laboratory for research and development. This relocation reduced the Company’s facility size by approximately 65% and reduced its future contractual lease obligations by approximately 78%.

Program Updates

RGLS4326 for Autosomal Dominant Polycystic Kidney Disease ("ADPKD"): RGLS4326, a novel oligonucleotide designed to inhibit miR-17, is in Phase 1 clinical development for the treatment of ADPKD and currently on a partial clinical hold. In January 2019, the Company submitted a comprehensive data package for RGLS4326 to FDA that included the results from the planned 13-week interim analysis of the repeat mouse chronic toxicity study, as well as results from additional investigations, analytical testing, additional data from the previously terminated mouse chronic toxicity study, data from the completed Phase I single ascending dose ("SAD") study and data from the first cohort of the Phase I MAD study, to support its plan to resume the Phase I MAD study. After review of the requested submission,

FDA notified the Company in July 2019 of additional nonclinical data requirements and placed the IND on a partial clinical hold, formalizing the specific requirements to initiate the MAD study and further proceed into chronic dosing in ADPKD patients. The additional data requirements have been outlined in two parts. In order to resume the MAD study, FDA has requested the final reports from the chronic toxicity studies in both mice and non-human primates and satisfactory related analyses to ensure subjects can be safely dosed. Additional information and analyses from new nonclinical studies, planned to be generated over the next several quarters, are required for chronic dosing and will be submitted at a later date. The Company recently received the final reports from the chronic toxicity studies in mice and non-human primates and is preparing to submit a complete response to the partial clinical hold in order to be able to resume the MAD study, pending agreement with FDA. Regulus anticipates a response from FDA before the end of the year. Regulus is allowed to proceed with additional SAD clinical studies as part of the process to gather additional supporting information to guide the future development of the program.

In September 2019, the Company announced that Nature Communications published an article entitled, "Discovery and preclinical evaluation of anti-miR-17 for the treatment of polycystic kidney disease." The article highlights preclinical research that identifies RGLS4326, a first-in-class anti-miR-17 oligonucleotide, as a potential disease-modifying treatment for ADPKD. In addition, a poster highlighting this work was presented at the Oligonucleotide Therapeutics Society (OTS) Annual Meeting held October 13-16, 2019 in Munich, Germany.

Third Quarter 2019 Financial Results

Cash Position: As of September 30, 2019, Regulus had $14.6 million in cash and cash equivalents.

Revenue: Revenue was less than $0.1 million and $6.8 million for the three and nine months ended September 30, 2019, respectively, compared to less than $0.1 million and $0.1 million for the three and nine months ended September 30, 2018. The increase for the nine months ended September 30, 2019 was attributable to revenue recognition of the upfront payments received under the 2018 Sanofi Amendment related to the transfer of RG-012.

Research and Development (R&D) Expenses: R&D expenses were $2.4 million and $10.3 million for the three and nine months ended September 30, 2019, compared to $6.9 million and $28.7 million for the same periods in 2018. The decreases were driven by decreases in external development expenses, primarily attributable to the voluntary pause of the RGLS4326 Phase 1 MAD clinical study in the third quarter of 2018 and commencement of the transfer of the RG-012 program to Sanofi in the fourth quarter of 2018. Additionally, the decreases were driven by reductions in personnel and internal expenses, primarily attributable to a reduction in costs subsequent to our corporate restructuring in the third quarter of 2018.

General and Administrative (G&A) Expenses: G&A expenses were $2.6 million and $9.0 million for the three and nine months ended September 30, 2019, compared to $3.0 million and $10.1 million for the same periods in 2018. These amounts reflect personnel-related and ongoing general business operating costs. The decreases were driven by a reduction in costs subsequent to our corporate restructuring in the third quarter of 2018.

Net Loss: Net loss was $5.4 million, or $0.26 per share (basic and diluted), and $13.7 million, or $0.86 per share (basic and diluted), for the three and nine months ended September 30, 2019, respectively, compared to $10.3 million, or $1.18 per share (basic and diluted), and $40.1 million, or $4.62 per share (basic and diluted), for the same periods in 2018. Historical and current period net loss per share values have been retroactively adjusted to reflect our October 2018 reverse stock split.

About Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD, caused by the mutations in the PKD1 or PKD2 genes, is among the most common human monogenic disorders and a leading cause of end-stage renal disease. The disease is characterized by the development of multiple fluid filled cysts primarily in the kidneys, and to a lesser extent in the liver and other organs. Excessive kidney cyst cell proliferation, a central pathological feature, ultimately leads to end-stage renal disease in approximately 50% of ADPKD patients by age 60.

About RGLS4326

RGLS4326 is a novel oligonucleotide designed to inhibit miR-17 and designed to preferentially target the kidney. Preclinical studies with RGLS4326 have demonstrated direct regulation of PKD1 and PKD2 in human ADPKD cyst cells, a reduction in kidney cyst formation, improved kidney weight/body weight ratio, decreased cyst cell proliferation, and preserved kidney function in mouse models of ADPKD. The RGLS4326 IND is currently on a partial clinical hold by the U.S. Food and Drug Administration.

On November 12, 2019 Exelixis, Inc. (NASDAQ:EXEL) reported that its partner Ipsen Biopharmaceuticals Canada Inc. received Health Canada approval of CABOMETYX (cabozantinib) tablets for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Press release, Exelixis, NOV 12, 2019, View Source [SID1234550996]).

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"Liver cancer is the fourth leading cause of cancer-related death globally, and there is an urgent need for more treatment options for patients living with this aggressive disease," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "The Health Canada approval of CABOMETYX brings a much-needed new therapy to Canadian patients with liver cancer and we look forward to our continued collaboration with Ipsen in our efforts to make our medicines available to patients around the world."

The Health Canada approval was based on results from the CELESTIAL phase 3 pivotal trial of CABOMETYX for patients with advanced HCC who received prior treatment with sorafenib. CABOMETYX demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo.

Under the terms of the Collaboration Agreement with Ipsen, Exelixis will receive a milestone payment of $2 million for the Health Canada approval.

CABOMETYX is also approved in Canada for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor targeted therapy and for the first-line treatment of adults with intermediate or poor risk advanced RCC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior treatment with sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial. The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

In October 2017, Exelixis announced that the independent data monitoring committee for the CELESTIAL study recommended that the trial be stopped for efficacy following review at the second planned interim analysis, with cabozantinib providing a statistically significant and clinically meaningful improvement in OS compared with placebo in patients with previously treated advanced HCC. The data, originally presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Gastrointestinal Cancers Symposium (ASCO-GI) in January 2018, was published in The New England Journal of Medicine in July 2018.1

About HCC

Liver cancer is a leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.2The Canadian Cancer Society estimates that 3,000 Canadians will be diagnosed with liver cancer in 2019.3 In the U.S., the incidence of liver cancer has more than tripled since 1980.4 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2019.4 HCC is the fastest-rising cause of cancer-related death in the U.S.5 Without treatment, patients with advanced HCC usually survive less than 6 months.6

About the Exelixis and Ipsen Collaboration

In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. Under the terms of the Collaboration Agreement with Ipsen, Exelixis is entitled to receive a tiered royalty of 22 percent to 26 percent of annual net sales.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma and for the treatment of patients with HCC who have been previously treated with sorafenib. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. 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.

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. 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: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed 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 event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred 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.
Proteinuria: Proteinuria occurred 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 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding 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 commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
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.
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. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On November 12, 2019 Boston Scientific Corporation (NYSE: BSX) (the "Company") reported a public offering of €900.0 million aggregate principal amount of 0.625% Senior Notes due 2027 (the "Notes") (Press release, Boston Scientific, NOV 12, 2019, View Source [SID1234551012]). The Company has applied to list the Notes on the New York Stock Exchange.

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In addition, the Company completed its previously announced cash tender offer (the "Tender Offer") for up to $1.0 billion aggregate principal amount of certain outstanding senior notes, pursuant to which it accepted $206,429,000, $566,455,000, and $227,117,000 of tendered principal amounts of its 4.125% Senior Notes due 2023, 4.000% Senior Notes due 2028 and 3.850% Senior Notes due 2025, respectively on the early settlement date.

The Company used the net proceeds from the offering to (i) fund the Tender Offer and (ii) pay accrued and unpaid interest, premiums, fees and expenses in connection with the Tender Offer.

On November 12, 2019 Merck , a leading company in the scientific and technological sector, reported that it has signed a license agreement that provides Evotec SE with access to Merck’s base CRISPR intellectual property (Press release, Merck & Co, NOV 12, 2019, View Source [SID1234551027]). Evotec, an international biotech company based in Hamburg (Germany), will use Merck’s genome CRISPR technology to create modified cell lines for Evotec’s commercial and internal research purposes.

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Merck’s CRISPR license to Evotec is the impetus for important drug testing and discovery, which will accelerate research and lead to new therapy development
Merck’s CRISPR license to Evotec is the impetus for important drug testing and discovery, which will accelerate research and lead to new therapy development

"This CRISPR license will be an engine for important drug tests and discoveries that promise to accelerate research and generate the development of new treatments," said Udit Batra , a member of the Merck Board of Directors and CEO of Life Science. "Merck has been at the forefront of innovation in genome modification for 15 years and continues to work with the sector and the academic environment to solve complex problems through our patented CRISPR technology, in an ethical and responsible manner."

Evotec plans to use Merck’s CRISPR intellectual property portfolio to develop very precise tests to determine the biology and toxicity of possible drugs during the drug development cycle.

"Evotec is proud to be able to continue its solid collaboration with Merck by licensing its revolutionary CRISPR technology," said Craig Johnstone , director of Operations for Evotec. "Our vision and passion for innovation includes the use of CRISPR technology to test and improve the effectiveness of the new drugs we develop, in order to alleviate the suffering of patients with diseases with insufficient attention from around the world."

This new license reinforces previous collaborations between Merck and Evotec. In November 2016, the companies signed a series of agreements through which Evotec would provide selection services thanks to Merck’s set of genetic reagents, including CRISPR and ARNhc banks. The combination of access to Merck genome modification banks with Evotec’s selection knowledge offers a faster way to explore and identify new pharmacological targets.

Merck has 20 CRISPR patents worldwide in terms of methods and composition, including the fundamental technology of CRISPR Cas9 for genetic integration into mammalian cells.

Merck supports genome editing research paying close attention to ethical and legal norms. The company has created an external and independent Bioethics Advisory Body in order to offer research orientations in which the company participates, such as the work in which genome editing is studied or used. Merck has also defined a clear operational position that takes into account scientific and social problems to inform promising therapeutic approaches for use in research and applications.

All Merck press releases are distributed by email at the same time they are published on the Merck website. To register, modify your selection or unsubscribe from this service, visit www.merckgroup.com/subscribe .