On July 14, 2022 Repertoire Immune Medicines reported its research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to identify the immune system’s response at various stages of human papillomavirus-positive (HPV+) cancer, including initial oncogenesis and after successful treatment (Press release, Repertoire, JUL 14, 2022, View Source [SID1234616686]).

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The research collaboration aims to identify the antigens present on tumors as well as the T cells and specific T cell receptors (TCRs) that recognize tumor-specific antigens. Using Repertoire’s DECODE platform to map the adaptive immune system’s response can inform the development of novel cell-based therapeutics by confirming the relevant targets for cell-based treatments.

"Understanding the adaptive immune system’s response to cancer allows us to see how it initially responds to diseased cells. When cancer spreads, it is a signal that the immune system can no longer recognize or defend against the cancer," said Anthony Coyle, Ph.D., President, Research and Development, Repertoire Immune Medicines. "The goal of this research collaboration between Memorial Sloan Kettering and Repertoire is to identify the TCR-antigen pairs that are activated when the immune system is successful in fighting HPV+ cancers. This discovery may lead to new cell therapies and give us insight into why some patients respond successfully to currently available treatments, while others have poor or no response to treatment."

Repertoire’s research collaboration with MSK will also seek to identify the TCR repertoire that is engaged and results in successful treatment outcomes with anti-PD-1 treatment and with conventional chemotherapy-radiation treatment. By identifying cancer-specific epitopes and the T cells that recognize these epitopes in successfully treated patients, it may be possible to define the optimal immunogenic profile for a proposed treatment. This map of the immune system’s response could inform treatment considerations for patients with inadequately treated disease.

"Through this collaboration with Repertoire, we hope to identify the TCR-antigen pairs that successfully protect from tumor formation in patients at various stages of their cancer," said Nadeem Riaz, MD, MSc., Director for Precision Radiotherapy at MSK. "By identifying the relevant TCR-antigen pairs, we may be able to improve the specificity of patient treatment, which could lead to improved outcomes."

About the DECODE Platform

The DECODE platform is a powerful discovery engine that characterizes essential elements of the immune synapse. In particular, the platform identifies T cell receptor-antigen pairs in the context of other important features of the immune synapse, such as T cell function and how these antigens are presented by molecules on antigen-presenting cells, known as major human leukocyte antigen, or HLA, molecules. Repertoire intends to utilize these insights into key drivers that govern immune function to design and develop novel immune product candidates.

On July 14, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that the U.S. Food and Drug Administration (FDA) has deferred action on the Biologics License Application (BLA) for tislelizumab as a second-line (2L) treatment for patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) (Press release, BeiGene, JUL 14, 2022, View Source [SID1234616685]). The FDA has been unable to conduct required inspections in China due to COVID-19 related travel restrictions. As a result, the FDA is deferring action on the application until the inspections are complete.

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In the letter, the FDA cited only travel restrictions and the inability to complete inspections as the reason for the deferral. The application remains under review, and the FDA did not provide a new anticipated action date as they continue to monitor the public health situation and travel restrictions. BeiGene and Novartis will continue to work actively with the FDA to support scheduling the required inspections as soon as possible.

"We are working with our partner, Novartis, to facilitate the required inspections and bring tislelizumab to patients with second-line esophageal cancer in the U.S. following regulatory approval," said John V. Oyler, Co-Founder, Chairman and CEO of BeiGene.

In September 2021, the FDA accepted the BLA for tislelizumab in 2L ESCC and provided a Prescription Drug User Fee Act (PDUFA) goal date of July 12, 2022. The evidence base for the BLA submission includes results from RATIONALE 302, a randomized, open-label, multi-regional Phase 3 trial that enrolled 512 patients from Europe, U.S. and Asia and safety data on 1,972 patients who received tislelizumab as a monotherapy from seven clinical trials. The RATIONALE 302 trial demonstrated a 30% reduction in the risk of death (HR=0.70, 95% CI: 0.57-0.85, p=0.0001) and extended median overall survival by 2.3 months compared to chemotherapy in people with unresectable recurrent locally advanced or metastatic ESCC who had received prior systemic therapy. Study results were published in Journal of Clinical Oncology in May 2022.i

About Tislelizumab
Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

The global tislelizumab clinical development program includes more than 9,000 subjects enrolled to-date in more than 35 countries and regions. BeiGene has initiated or completed more than 20 potentially registration-enabling clinical trials, including 17 Phase 3 trials. More information on the clinical trial program for tislelizumab can be found here.

BeiGene Oncology
BeiGene is committed to advancing best- and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D and medical affairs team of approximately 2,900 colleagues dedicated to advancing more than 100 clinical trials that have involved more than 16,000 subjects. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the U.S., China, the European Union, Great Britain, Canada, Australia, and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody, tislelizumab, as well as the PARP inhibitor, pamiparib, in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen, Bristol Myers Squibb, EUSA Pharma and Bio-Thera. We also plan to address greater areas of unmet need globally through our other collaborations including with Mirati Therapeutics, Seagen, and Zymeworks.

In January 2021, BeiGene and Novartis announced a collaboration granting Novartis rights to co-develop, manufacture, and commercialize BeiGene’s anti-PD1 antibody, tislelizumab, in North America, Europe, and Japan. Building upon this productive collaboration, BeiGene and Novartis announced an option, collaboration, and license agreement in December 2021 for BeiGene’s TIGIT inhibitor, ociperlimab, that is in Phase 3 development. Novartis and BeiGene also entered into a strategic commercial agreement through which BeiGene will promote five approved Novartis Oncology products across designated regions of China.

On July 14, 2022 Veracyte, Inc. (Nasdaq: VCYT) reported that it will release financial results for the second quarter of 2022 after the close of market on Tuesday, August 2, 2022 (Press release, Veracyte, JUL 14, 2022, View Source [SID1234616684]). Company management will host a conference call and webcast to discuss financial results and provide a general business update at 4:30 p.m. Eastern Time on the same day.

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The conference call will be webcast live from the company’s website and will be available via the following link: View Source A webcast replay will be available following the conclusion of the live broadcast and will be accessible on the company’s website at View Source

The conference call dial-ins can be accessed by registering at: https://register.vevent.com/register/BI2d52800c01ef45e7b962619638558741

On July 14, 2022 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel products for serious rare and ultra-rare genetic diseases, reported the sale of 30% of the company’s royalty interest from Kyowa Kirin Co., Ltd on the future sales of Crysvita (burosumab) in the United States (U.S.) and Canada to OMERS, one of Canada’s largest defined benefit pension plans, for $500 million (Press release, Ultragenyx Pharmaceutical, JUL 14, 2022, View Source [SID1234616683]). OMERS’ right to receive royalty payments is based on net sales of the product beginning in April 2023 and total payments are capped at 1.45 times the purchase price.

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"In North America, Crysvita has generated more than $1.3 billion net sales in the first four years on the market making it one of the most successful launches in the rare disease field. This non-dilutive financing bolsters Ultragenyx’s balance sheet, funds the ongoing commercialization of multiple approved medicines and the advancement of our diverse clinical pipeline," said Mardi Dier, Chief Financial Officer of Ultragenyx. "We are pleased to partner with OMERS on this transaction who, like us, recognizes the ongoing and future value of Crysvita, the tremendous success of the launch and the significance for patients who will continue to benefit from this important medicine."

"Ultragenyx has successfully launched Crysvita, meaningfully improving the lives of thousands of pediatric and adult patients with two rare diseases. We are proud to invest in a product that has made a difference for so many and that aligns with the investment strategy at OMERS," said Rob Missere, Managing Director and Head of Life Sciences, OMERS Capital Markets. "This deal furthers our mandate of delivering steady, long-term returns to our more than 541,000 members."

Cowen acted as exclusive financial advisor to Ultragenyx on the transaction. Gibson Dunn LLP acted as legal advisor to Ultragenyx. Davies Ward Phillips & Vineberg LLP and Latham & Watkins LLP acted as legal advisors to OMERS.

About Crysvita

Crysvita (burosumab) 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.

In North America, Crysvita is approved by the U.S. Food and Drug Administration (FDA) and by Health Canada for the treatment of X-linked hypophosphatemia (XLH) and FGF23-related hypophosphatemia in tumor induced osteomalacia (TIO).

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.

U.S. INDICATION
Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23)-blocking antibody indicated for the treatment of:

X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.
FGF23-related hypophosphatemia in tumor-induced osteomalacia (TIO) associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older.
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

With oral phosphate and/or active vitamin D analogs (e.g., calcitriol, paricalcitol, doxercalciferol, calcifediol).
When serum phosphorus is within or above the normal range for age.
In patients with severe renal impairment or end stage renal disease.
WARNINGS AND PRECAUTIONS

Hypersensitivity

Discontinue Crysvita if serious hypersensitivity reactions occur and initiate appropriate medical treatment.
Hyperphosphatemia and Risk of Nephrocalcinosis

For patients already taking Crysvita, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.
Patients with TIO who undergo treatment of the underlying tumor should have dosing interrupted and adjusted to prevent hyperphosphatemia.
Injection Site Reactions

Discontinue Crysvita if severe injection site reactions occur and administer appropriate medical treatment.
ADVERSE REACTIONS
Pediatric XLH Patients

Adverse reactions reported in 10% or more of Crysvita-treated pediatric XLH patients across all studies are: pyrexia, injection site reaction, cough, vomiting, pain in extremity, headache, tooth abscess, dental caries, diarrhea, vitamin D decreased, toothache, constipation, myalgia, rash, dizziness, and nausea.
Post-marketing experience reported in pediatric XLH patients receiving Crysvita – blood phosphorus increased.
Adult XLH Patients

Adverse reactions reported in more than 5% of Crysvita-treated adult XLH patients and in at least 2 patients more than placebo in one study are: back pain, headache, tooth infection, restless legs syndrome, vitamin D decreased, dizziness, constipation, muscle spasms, and blood phosphorus increased.
Spinal stenosis is prevalent in adults with XLH, and spinal cord compression has been reported. It is unknown if Crysvita therapy exacerbates spinal stenosis or spinal cord compression.
Adult TIO Patients

Adverse reactions reported in more than 10% of Crysvita-treated adult TIO patients in two studies are: tooth abscess, muscle spasms, dizziness, constipation, injection site reaction, rash, and headache.
USE IN SPECIFIC POPULATIONS

There are no available data on Crysvita use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Serum phosphorus levels should be monitored throughout pregnancy. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line at 1-888-756-8657.
There is no information regarding the presence of Crysvita in human milk or the effects of Crysvita on milk production or the breastfed infant.

On July 14, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported it entered into a clinical trial collaboration with Pharmacyclics, an AbbVie company, that includes supply of ibrutinib for its Phase 3 clinical trial (Press release, Oncternal Therapeutics, JUL 14, 2022, View Source [SID1234616682]).

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"This agreement represents a significant milestone for Oncternal as we advance towards the planned initiation of our registrational study ZILO-301 in the third quarter of 2022," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "Ibrutinib was the first Bruton’s tyrosine kinase (BTK) inhibitor in the market and its approval changed the treatment paradigm for patients suffering from certain hematological malignancies. We are pleased that this collaboration will support the development of an innovative combination of zilovertamab and ibrutinib that we believe may address important unmet needs of patients with MCL."

Under the terms of the collaboration, the supply of ibrutinib will support the company’s global registrational Phase 3 clinical trial of zilovertamab for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL), ZILO-301. The agreement also includes the supply of ibrutinib for Study ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the initial four months of ibrutinib monotherapy from Study ZILO-301.

About Zilovertamab (formerly Cirmtuzumab)
Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or marginal zone lymphoma (MZL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.