On February 27, 2020 MapKure, LLC, a clinical-stage company developing precision medicines for patients with life-threatening diseases, together with BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160) and SpringWorks Therapeutics, Inc. (NASDAQ: SWTX), who are joint owners of MapKure, reported that the first patient has been dosed in Australia in a Phase 1 clinical trial to evaluate BGB-3245, an investigational, next-generation B-RAF inhibitor, in patients with advanced or refractory solid tumors (Press release, MapKure, FEB 27, 2020, View Source [SID1234554894]). The companies also announced that the U.S. Food and Drug Administration (FDA) has allowed the Investigational New Drug (IND) application submitted for BGB-3245 to proceed, which will enable study expansion to U.S. sites.

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B-RAF gene mutations and fusions have been shown to play a key role in the development of certain cancers. BGB-3245 is designed to inhibit both monomeric and dimeric forms of activating B-RAF mutations including V600 and non-V600 mutations, and RAF fusions, and has shown potent preclinical activity against a range of B-RAF gene alterations, including those for which there are no approved targeted therapies and those associated with resistance to currently approved therapies.

"Preclinical data suggest that BGB-3245 could potentially address a range of B-RAF driven tumors, which represent a significant need for patients who currently lack targeted therapeutic options, as well as patients who have developed resistance to first generation B-RAF inhibitors," said Neal Rosen, M.D., Ph.D., the Enid A. Haupt Chair in Medical Oncology at Memorial Sloan-Kettering Cancer Center and Chair of the MapKure Scientific Advisory Board. "If our hypothesis is correct, we believe that BGB-3245 could have meaningful, single agent antitumor activity in B-RAF-altered cancers through its ability to address key primary and resistance gene alterations that are currently unaddressed by approved therapies."

The Phase 1 clinical trial is a first-in-human, open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics (PK) and antitumor activity of BGB-3245 in adult patients with solid tumors, including those harboring specific B-RAF driver mutations and fusions that are likely to respond to a RAF dimer inhibitor, as well as in certain adult patients who have developed resistance to first-generation B-RAF V600 inhibitors. The trial is designed to define the dose and assess the tolerability of BGB-3245 and will capture early antitumor activity signals to allow for potential cohort expansion.

In addition, MapKure has completed the formation of its Scientific Advisory Board (SAB), comprised of renowned leaders in MAPK pathway biology and targeted oncology clinical development. The SAB will continue to collaborate with MapKure’s joint steering committee, consisting of representatives from BeiGene and SpringWorks, to support the advancement of BGB-3245. The composition of the SAB is as follows:

Neal Rosen, M.D., Ph.D., the Enid A. Haupt Chair in Medical Oncology at Memorial Sloan-Kettering Cancer Center. Dr. Rosen is the founding member and Chair of the MapKure SAB.
Antoni Ribas, M.D., Professor of Medicine, Professor of Surgery, and Professor of Molecular and Medical Pharmacology at the University of California Los Angeles.
Kevin Koch, Ph.D., President and CEO of Edgewise Therapeutics; formerly Founder, President, and Chief Scientific Officer of Array BioPharma.
Zhan Yao, Ph.D., Assistant Research Professor, Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center.
Dejan Juric, M.D., Program Director, Investigational Cancer Therapeutics Program and Attending Physician in Medical Oncology, Massachusetts General Hospital.
About the Phase 1 Trial

The Phase 1 trial (NCT04249843) of BGB-3245 is an open-label, dose-escalation trial of BGB-3245 in adult patients with advanced or refractory solid tumors, including those with B-RAF driver mutations and fusions that are likely to respond to a RAF dimer inhibitor. The study will enroll patients who have experienced disease progression during or after at least one prior line of systemic anticancer therapy or for which treatment is not tolerated or acceptable to the participants.

The trial is designed in two parts: the Phase 1a portion will consist of a dose-escalation and dose-finding component to establish the maximum tolerated dose and/or the recommended Phase 2 dose and to evaluate the pharmacokinetics of BGB-3245 in patients with MAPK pathway aberrations. The Phase 1b portion will consist of one or more expansion cohorts to further evaluate the pharmacokinetics, safety, and tolerability of BGB-3245 at the recommended Phase 2 dose and to assess the preliminary antitumor activity of the compound in patients with select tumor types and B-RAF status (B-RAF point mutations and gene fusions).

About BGB-3245

BGB-3245 is an investigational, oral, selective small molecule inhibitor of monomer and dimer forms of activating B-RAF mutations including V600 B-RAF mutations, non-V600 B-RAF mutations, and RAF fusions. These mutations and fusions have been identified in a number of solid tumors to be drivers of cancer growth, including in non-small cell lung cancer, colorectal cancer, thyroid cancer, and brain tumors. Preclinical data have demonstrated that BGB-3245 has activity in patient-derived xenografts driven by B-RAF fusions and non-V600 mutations for which approved B-RAF inhibitors are ineffective. In addition, BGB-3245’s preclinical activity in cancer models driven by V600 B-RAF mutations has suggested that it could provide an additional therapeutic option for patients with the potential to reduce dimer-driven resistance.

In addition to its intended use as a monotherapy in several genetically defined solid tumor types, BGB-3245 also has the potential to be used in rational combination therapies in the future.

On February 27, 2020 Nurix Therapeutics, Inc., a company developing targeted protein modulation drugs, reported that CEO Arthur Sands will present at the Cowen & Co. 40th Annual Health Care Conference on Wednesday, March 4, 2020, 3:30 PM ET in Boston, MA (Press release, Nurix Therapeutics, FEB 27, 2020, View Source [SID1234554893]).

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A live webcast of the presentation can be accessed on the News section of Nurix’s website at View Source An archived replay will be available for 30 days following the presentation.

On February 27, 2020 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported that it will host a live conference call and webcast at 8:30 a.m. ET on Thursday, March 5, 2020 to report its fourth quarter and full year 2019 financial results and provide a corporate update (Press release, Syros Pharmaceuticals, FEB 27, 2020, View Source [SID1234554892]).

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To access the live conference call, please dial 866-595-4538 (domestic) or 636-812-6496 (international), and refer to conference ID 2764269. A webcast of the call will also be available on the Investors & Media section of the Syros website at www.syros.com. An archived replay of the webcast will be available for approximately 30 days following the presentation.

On February 27, 2020 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel products for rare and ultra-rare diseases, and Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), a global specialty pharmaceutical company creating innovative medical solutions using the latest biotechnology, reported that the U.S. Food and Drug Administration (FDA) has accepted for review the supplemental Biologics License Application (sBLA) for Crysvita (burosumab) for the treatment of FGF23-related hypophosphatemia associated with phosphaturic mesenchymal tumors (tumor-induced osteomalacia; TIO) that cannot be curatively resected or localized (Press release, Kyowa Hakko Kirin, FEB 27, 2020, View Source [SID1234554891]). The FDA has assigned priority review designation with a Prescription Drug User Fee Act (PDUFA) target date of June 18, 2020.

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"We appreciate the FDA’s collaboration in evaluating the data, and as a result, we are another step closer to bringing the first treatment to patients with this devastating disease in the setting of an unresectable tumor," said Camille L. Bedrosian, M.D., Chief Medical Officer of Ultragenyx. "We look forward to continuing to work closely with the FDA with the goal of bringing Crysvita to patients with TIO as quickly as possible."

"The discovery and submission of Crysvita has meant a great deal to patients and families that previously had no other treatment options," said Tomohiro Sudo, Head of Global Product Management Office of Kyowa Kirin. " "If approved, we believe Crysvita may also become a meaningful treatment option for many patients with TIO in the U.S."

The sBLA package includes data from two single-arm Phase 2 studies, a 144-week study in 14 adult patients conducted by Ultragenyx in the U.S. and an 88-week study in 13 adult patients conducted by Kyowa Kirin in Japan and South Korea.

Crysvita is approved by the U.S. FDA for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients six months of age and older, and by Health Canada and Brazil’s National Health Surveillance Agency (ANVISA) for the treatment of XLH in adult and pediatric patients one year of age and older. In Japan, it is approved by the Ministry of Health, Labor and Welfare (MHLW) for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. In Europe, Crysvita has received European conditional marketing authorization for the treatment of XLH with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons, and an application for the expanded use in adults with XLH is currently under review by the European Medicines Agency.

See below for Important Safety Information for Crysvita in X-linked hypophosphatemia.

About Tumor-Induced Osteomalacia (TIO)
TIO is caused by typically benign tumors that produce excess levels of fibroblast growth factor 23 (FGF23), causing phosphate wasting in the urine that leads to severe hypophosphatemia, osteomalacia, muscle weakness, fatigue, bone pain and fractures. The symptoms rapidly resolve if the causal tumors or lesion can be resected; however, there are cases in which resection is not feasible or recurrence of the tumor occurs after resection. In patients for whom the tumor or lesion is inoperable, the current treatment consists of oral phosphate and/or vitamin D replacement. Efficacy of this management is often limited, as it does not treat the underlying disease and its benefits must be balanced with monitoring for potential risks such as nephrocalcinosis, hypercalciuria and hyperparathyroidism. An estimated 500-1,000 people in the United States have TIO, and approximately half of all cases are inoperable.

About Crysvita
Crysvita (burosumab-twza) is a recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Kirin, against the phosphaturic hormone FGF23. FGF23 is a hormone that reduces serum levels of phosphorus and active vitamin D by regulating phosphate excretion and active vitamin D production by the kidney. Phosphate wasting in TIO and other hypophosphatemic conditions, including XLH, is caused by excessive levels and activity of FGF23. Crysvita is designed to bind to and thereby inhibit the biological activity of FGF23. By blocking excess FGF23 in patients with TIO and XLH, Crysvita is intended to increase phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.

Kyowa Kirin and Ultragenyx have been collaborating in the development and commercialization of Crysvita globally based on the collaboration and license agreement between the parties.

INDICATION (IN THE U.S.)

Crysvita is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.

IMPORTANT SAFETY INFORMATION Crysvita should not be taken if:

• An oral phosphate supplement and/or a specific form of vitamin D supplement are taken (such as calcitriol, paricalcitol, doxercalciferol, calcifediol).

• Phosphorus levels from a blood sample are within or above the normal range for age.

• Kidney problems are present. What is the most important information to know about Crysvita?

• Some patients developed allergic reactions (rash and hives) while taking Crysvita. Doctors will monitor for symptoms of an allergic reaction while Crysvita is taken.

• High levels of phosphorus in the blood have been reported in some patients taking Crysvita. This may be related to a risk of high calcium levels in the kidneys. Doctors will collect samples to monitor levels.

• Administration of Crysvita may result in reactions at the injection site, such as hives, reddening of the skin, rash, swelling, bruising, pain, severe itching of the skin, and collection of blood outside of a blood vessel (hematoma). What are the possible side effects of Crysvita?

• The most common adverse reactions that were seen in children with XLH are: o Fever o Injection site reaction o Cough o Vomiting o Pain in arms and legs o Headache o Tooth infection o Dental cavities o Diarrhea o Decreased vitamin D levels o Toothache o Constipation o Muscle pain o Rash o Dizziness o Nausea

• The most common adverse reactions that were seen in adults with XLH are: o Back pain o Headache o Tooth infection o Restless leg syndrome o Decreased vitamin D levels o Dizziness o Muscle spasms o Constipation o Phosphorus levels increased in the blood

• Narrowing of the spaces within the spine is common in adults with XLH and pressure on the spinal cord has been reported in adults taking Crysvita. It is not known if taking Crysvita worsens the narrowing of the spaces within the spine or the pressure on the spinal cord. Before taking Crysvita, doctors should be informed about all medications (including supplements) and medical conditions, including if:

• One is taking oral phosphate and/or active vitamin D (such as calcitriol, paricalcitol, doxercalciferol, calcifediol).

• One is pregnant, thinks she may be pregnant, or plans to become pregnant. There is not enough experience to know if Crysvita may harm an unborn baby. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line at 1-888-756-8657.

• One is breastfeeding or plans to breastfeed. There is not enough experience to know if Crysvita passes into breast milk. Women should talk with their doctors about the best way to feed their babies while taking Crysvita. While taking Crysvita, doctors should be informed if one experiences:

• An allergic reaction such as rash or hives

• A rash, swelling, bruising or other reaction at the injection site

• New or worsening restless leg syndrome

These are not all the possible side effects of Crysvita. Doctors should be contacted for medical advice about side effects.

Side effects may be reported to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

Side effects may also be reported to Kyowa Kirin, Inc. at 1-888-756-8657.

Please see full Prescribing Information for additional Important Safety Information.

On February 27, 2020 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento"), reported that Dr. Henry Ji, Chairman and CEO, will present at the 9th Annual LEERINK Partners Global Healthcare Conference (Lotte New York Palace Hotel, New York) on Thursday Feb 27 at 11:00-11:25 AM (Presentation Room Adams) (Press release, Sorrento Therapeutics, FEB 27, 2020, View Source [SID1234554870]).

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Key updates:

Both RTX Phase 1b Cancer Pain and Phase 1b Osteoarthritis (OA) Knee Pain studies have completed initial enrollment with preliminary positive results: no dose limiting toxicities observed and significant efficacy signal confirmed.
Allogeneic "Off-the-Shelf" Dimeric Antigen Receptor-T (DAR-T) cell therapy products targeting hematologic cancer targets (BCMA, CD38, CD20, CD123) and solid tumor targets (GD2, CEA, EGFR, and many others) have been successfully produced.
Proprietary DAR construct for coronavirus targeting, including COVID-19, has been successfully generated; COVID-19 targeting DAR-T cells and DAR-NK cells will be produced next in Sorrento’s cGMP facilities (San Diego) as part of the IND-enabling package necessary to promptly initiate human clinical studies.
DAR-T specific developments:

Sorrento’s proprietary DAR structure offers potential advantages over the conventional CAR (chimeric antigen receptor) structure by:

increasing specificity and functionality of the DAR-T cells as compared to CAR-T cells due to higher inherent stability of the Fab fragment used in the DAR
potentially reducing the clinical dose due to increased functional activity (preclinical data)
In addition to the proprietary DAR structure, Sorrento’s proprietary non-viral knockout-knockin (KOKI) manufacturing approach offers several potential benefits over virus-based transduction currently used for CAR-T therapies:

site-specific integration of transgenes into pre-selected loci in the T cell genome
enhanced clonal expansion of the DAR-T cells
streamlined method for transgene construct production without the need for laborious and time-consuming virus production, release and validation processes, resulting in a shorter research and development timelines for IND-enabling activities.
Combining those approaches, the allogeneic DAR-T products could potentially have the following major advantages over current autologous CAR-T therapy technologies:

off-the-shelf availability allowing for immediate patient access to allogeneic cell therapies (by using healthy donor cells instead of modifying a patients’ own cells)
significantly improved cost of goods (by making much greater patient-doses in each manufacturing run)
easier execution of global trials and international market access due to established shipping logistics and distribution processes (drug like product)
Beyond targeting cancer related indications, which is the primary focus of Sorrento’s immuno-oncology business, Sorrento believes it can apply its KOKI DAR-T platform against pandemic infectious pathogens, including but not limited to coronaviruses, HBV, HIV, malaria, measles and fungi.

The potential spread of the COVID-19 coronavirus from Wuhan, China is only one example of how quickly a local infection can become a pandemic. Sorrento’s agile KOKI DAR-T and DAR-NK cell therapy platforms, coupled with in-house cGMP manufacturing facilities, should allow for emergency adoptive T cell and innate NK cell therapies being produced rapidly for clinical testing.

COVID_DAR_001 has been added to the Sorrento development pipeline and allocated internal priority both to demonstrate the maturity, agility and development readiness of the proprietary platform and to address an emergency and potentially critical patient need in the upcoming months.