On October 14, 2021 Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) reported that Exelixis has exercised its exclusive option under the companies’ July 2019 agreement to in-license XL114 (formerly AUR104), a novel anti-cancer compound that inhibits the CARD11-BCL10-MALT1 (CBM) signaling pathway, which promotes lymphocyte survival and proliferation (Press release, Exelixis, OCT 14, 2021, View Source [SID1234591237]). Exelixis has now assumed responsibility for the future clinical development, commercialization and global manufacturing of XL114. Following the U.S. Food and Drug Administration’s (FDA) recent acceptance of its Investigational New Drug (IND) application, Exelixis will soon initiate a phase 1 clinical trial evaluating XL114 monotherapy in patients with Non-Hodgkin’s lymphoma (NHL). At the American Association of Cancer Research Annual Meeting in April of this year, Aurigene presented preclinical data (Abstract 1266) demonstrating that XL114 exhibited potent anti-proliferative activity in a large panel of cancer cell lines ranging from hematological cancers to solid tumors with excellent selectivity over normal cells. In addition, oral dosing of XL114 resulted in significant dose-dependent tumor growth inhibition in diffuse large B-cell lymphoma (DLBCL) and colon carcinoma models.

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XL114 is the second molecule that Exelixis in-licensed from Aurigene under the companies’ July 2019 collaboration, option and license agreement. Exelixis previously exercised its option to in-license XL102, a potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7), from Aurigene in December 2020 and initiated a phase 1 trial of XL102 as a single agent and in combination with other anti-cancer agents in patients with advanced or metastatic solid tumors in January 2021.

"We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline," said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer, Exelixis. "XL114 has shown potent anti-proliferative activity in lymphoma cell lines that have aberrant activation of the CBM signaling pathway and may have a differentiated profile and potential as a best-in-class molecule that could improve outcomes for patients with Non-Hodgkin’s lymphoma and other hematologic cancers."

XL114 was identified to have anti-proliferative activity in cell lines with constitutive activation of CBM signaling, including activated B-cell-like DLBCL (ABC-DLBCL), mantle cell lymphoma and follicular lymphoma cell lines. Further characterization of XL114 in cell-based assays demonstrated a functional role in B-cell (BCR) signaling pathways. Additionally, XL114 showed dose-dependent tumor growth inhibition in an ABC-DLBCL mouse xenograft tumor model. In preclinical development, XL114 also demonstrated a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. While the precise molecular mechanism underlying XL114’s function in repressing BCR signaling and MALT1 activation has yet to be characterized, the fatty acid-binding protein 5 (FABP5) has been identified as a prominent XL114-binding target.

"XL114 is the second molecule that Exelixis has opted to in-license under our July 2019 agreement, underscoring the significant potential of our approach to the discovery and preclinical development of innovative cancer therapies that target novel mechanisms of action," said Murali Ramachandra, Ph.D., Chief Executive Officer, Aurigene. "Exelixis has a track record of success in the clinical development and commercialization of anti-cancer therapies that provide patients with important new treatment options, and we are pleased that the continued advancement of XL114 will be supported by the company’s extensive clinical, regulatory and commercialization infrastructure."

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to obtain an exclusive license from Aurigene to three preexisting programs, including the compounds now known as XL102 and XL114. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for an additional upfront payment of $2.5 million per program. The collaboration was expanded in 2021 to include three additional early discovery programs. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all nine programs. Exelixis may exercise its option for a program at any time up until the first IND for the program becomes effective. Having exercised options on two programs thus far (XL102 and XL114), if and when Exelixis exercises a future option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. To exercise its option for XL114, Exelixis will make an option exercise payment to Aurigene of $10 million. Once Exelixis exercises its option for a program, Aurigene will be eligible for clinical development, regulatory and sales milestones, as well as royalties on future potential sales of the compound. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

On October 14, 2021 Kriya Therapeutics, Inc., a fully integrated company pioneering novel technologies and therapeutics in gene therapy, reported the appointment of Theresa Heah, M.D., MBA as Chief Medical Officer and President of Kriya’s newly launched ophthalmology division, Kriya Ophthalmology (Press release, Kriya Therapeutics, OCT 14, 2021, View Source [SID1234591253]). Dr Heah will be responsible for advancing Kriya’s current pipeline of ophthalmology gene therapies and continuing to expand Kriya’s ophthalmology portfolio through its in-house R&D and business development engines.

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Kriya Ophthalmology is focused on the discovery and development of transformative gene therapies for ocular diseases with high unmet need. By leveraging Kriya’s computationally enabled vector design, data analytic and manufacturing technologies, Kriya Ophthalmology is uniquely positioned to accelerate the development of best-in-class gene therapies for rare and prevalent ocular diseases. Kriya Ophthalmology is currently advancing therapeutic programs in uveitis, geographic atrophy and additional undisclosed disease areas.

"Gene therapy has the potential to deliver transformative clinical benefits to address severe ocular diseases for which there are currently few effective treatment options," said Shankar Ramaswamy, M.D., Co-Founder and Chief Executive Officer of Kriya Therapeutics. "The launch of Kriya Ophthalmology, and the appointment of Theresa to lead our specialized division focused exclusively on diseases of the eye, reflects our commitment to delivering better products to patients suffering from a range of rare and prevalent ocular diseases. We believe that Kriya’s advanced technology platforms, combined with Theresa’s leadership and track record in ophthalmology, uniquely position this division to become one of the industry leaders in the development of gene therapies for ocular diseases."

"We are thrilled to welcome Theresa to lead Kriya Ophthalmology," said Ilise Lombardo, M.D., Chief Medical Officer of Kriya Therapeutics. "Her success in developing and launching treatments for ocular diseases will help Kriya play a pivotal role in the advancement of novel gene therapies that address a range of severe ocular conditions."

Dr. Heah is an accomplished executive with more than 20 years of R&D, regulatory strategy and clinical development experience. She previously served as Chief Medical Officer and Executive Vice President of Operations for AsclepiX Therapeutics where she led the company’s Series A financing and advancement of its pipeline products into the clinic. Prior to joining AsclepiX Therapeutics, Dr. Heah served as Chief Medical Officer at Applied Genetic Technologies Corporation (AGTC), where she worked to develop gene therapies in ophthalmology and rare diseases. She has also held several leadership positions with increasing responsibility in early-stage private companies (Fovea Pharmaceuticals), publicly traded companies (Aerie Pharmaceuticals, Allergan) and big pharmaceutical companies (Bayer Healthcare, Sanofi).

Dr. Heah has led multiple successful global regulatory submissions and commercialization of products including Ozurdex, EYLEA, Rhopressa and Rocklatan. While at Bayer, she launched EYLEA successfully into its eventual status as a blockbuster drug. She earned her M.D. from Guy’s, King’s and St. Thomas’ School of Medicine, King’s College, University of London, and her Executive Master’s in Business Administration from the European School of Management & Technology (ESMT), Berlin.

"My career has been dedicated to patients and the development of transformative and meaningful therapies aimed at improving their quality of life," said Dr. Heah. "Many still suffer from serious eye diseases for which there are no viable treatments. There is immense untapped potential in gene therapy, and it will be our mission to uncover and advance novel medicines for the betterment of underserved patient communities."

On October 14, 2021 BeiGene reported that inked a deal with Celgene Logistics Sarl, which is now a subsidiary of Bristol Myers Squibb (Press release, BeiGene, OCT 14, 2021, View Source [SID1234591391]). The deal was a license and supply agreement giving BeiGene exclusive right to distribute and market Abraxane, Revlimid and Vidaza in China, excepting Hong Kong, Macau and Taiwan. Then, in March 2020, the Chinese National Medical Products Administration (NMPA) suspended importation, sales and use of Abraxane in China under the deal. BMS then initiated a recall of Abraxane in China. The entire suspension and recall were related to inspection findings at Bristol Myers Squibb-Celgene’s contract manufacturing plant in the U.S.

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On October 6, 2021, Bristol Myers Squibb and Celgene terminated the original deal related to Abraxane and gave BeiGene 180 days of notice that it was withdrawing Abraxane from the deal. The Notice stated:

"Indeed, as you are aware, due to the National Medical Products Association decision to suspend the importation, sale, or use of Abraxane in China on March 25, 2020, Celgene has been unable to manufacture Abraxane for China and, thus, has been unable to manufacture Abraxane on a global basis…"

The notice went on to say that after the NMPA suspended manufacturing at the facility in Illinois, the company shifted production to a facility in Phoenix, Arizona. In July 2021, there was a failure in media fill testing at that facility. After a root cause investigation and corrective actions, there was still rejection of additional vials. Celgene is working on the issue, but currently all manufacturing of Abraxane at the Phoenix facility has halted, and they have notified the U.S. Food and Drug Administration.

The Illinois site was run by contract drug manufacturing (CDMO) company Fresenius Kabi and the Phoenix site is owned by BMS.

BeiGene indicates they believe the "reasons stated in the Notice do not provide a valid basis for terminating the Agreement with respect to Abraxane, and that the Notice is a tactical maneuver on the part of BMS-Celgene to reduce its damages in the on-going arbitration proceedings described above. The Company intends to contest the purported termination vigorously."

On a little less threatening note, BeiGene also said that BMS and Celgene had not told them how long the manufacturing delays in Phoenix would last, but "would be happy to work with BMS-Celgene to help get the Phoenix manufacturing facility or another facility qualified to restore the supply of Abraxane for patients in China as soon as possible."

Abraxane is approved for use in advanced non-small cell lung cancer with carboplatin, in advanced pancreatic cancer with gemcitabine, and for advanced breast cancer.

The other drugs are Revlimid, which with dexamethasone is used to treat multiple myeloma, and Vidaza, a chemotherapy used to treat myelodysplastic syndrome (MDS). They do not appear to be part of the dispute.

At least one analyst, Andrew Berens, with SVB Leerink, suggests that the real issue is competition between BMS’s checkpoint inhibitor Opdivo and BeiGene and Novartis’s tislelizumab. Berns projected BeiGene would rake in $100 million in Abraxane sales in China next year once the marketing hold is resolved. Berns is taking that figure out of the equation, but believes that the BeiGene-BMS deal isn’t as important as it used to be, particularly now that BeiGene and Amgen have a strategic collaboration that initiated in January 2020.

That deal is to accelerate Amgen’s oncology presence in China. Amgen also has a 20.5% stake in BeiGene, which it paid $2.8 billion in cash for. Under that deal, BeiGene is commercializing Amgen’s XGEVA (denosumab), Kyprolis (carfilzomib) and Blincyto (blinatumomab) in China. Two of the drugs will revert to Amgen, one after five years and one after seven. After the commercialization period, BeiGene will keep the rights to one of the drugs and be eligible for royalties on sales in China for another five years on the drugs returned to Amgen. XGEVA was launched in China in September 2019.

The two companies are also collaborating on 20 drugs from Amgen’s oncology pipeline in China and globally.

Another hit against Abraxane occurred in August 2021. Roche had an accelerated approval for its Tecentriq (atezolizumab) in combination with Abraxane for adults with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) whose tumors express PD-L1. After consulting with the FDA, Roche withdrew the accelerated approval. It only affected the mTNBC indication in the U.S. for that indication. It was granted accelerated approval in March 2019, the first immunotherapy to be approved for that setting. It was based on progression-free survival (PFS) in the Phase III IMpassion 130 study, but continued approval was

On October 14, 2021 Apmonia Therapeutics’ lead candidate TAX2 (AP-01) in ovarian cancer therapy, and shows how selective antagonization of TSP-1:CD47 axis is a new powerful way of activating anti-tumor immunity (Press release, Apmonia Therapeutics, OCT 14, 2021, View Source [SID1234591413]).

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We believe our innovative technology to be a safer and effective approach with the potential to treat multiple indications of solid tumors.

On October 14, 2021 Exelixis, Inc. (Nasdaq: EXEL) and STORM Therapeutics (STORM) reported that they have entered into an exclusive collaboration and license agreement under which the parties will discover and advance novel drug leads intended for the treatment of cancer (Press release, Exelixis, OCT 14, 2021, View Source [SID1234591238]). The collaboration will focus initially on ADAR1, advancing early work by STORM applying its proprietary RNA epigenetic platform, as well as explore an additional undisclosed target.

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Under the terms of the agreement, Exelixis will pay STORM an upfront fee of $17 million in exchange for licensing two of STORM’s discovery programs targeting RNA modifying enzymes, including ADAR1, as well as provide funding for discovery research activities conducted or managed by STORM. Exelixis will be solely responsible for global development, manufacturing and commercialization activities of any resulting molecules. STORM will be eligible for development, regulatory and commercialization milestones, as well as tiered royalties on the annual net sales of any compounds that are successfully commercialized under the collaboration.

"ADAR1 holds tremendous promise as a novel target for cancer. However, discovery efforts to identify ADAR1 inhibitors have remained a challenge, notably the development of rigorous, relevant assays to support small molecule drug discovery," said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer, Exelixis. "STORM has extensive expertise in RNA-modifying enzymes and has successfully developed advanced mass spectrometry-based high-throughput screening assays and implemented a suite of technologies to enable the discovery of ADAR1 inhibitors. We believe this collaboration has the potential to expand our portfolio of differentiated small molecule therapies in the field of oncology and deliver a first-in-class ADAR1 inhibitor."

"STORM has established industry-leading expertise and know-how through ground-breaking research on the discovery of small molecule therapies targeting RNA-modifying enzymes. This collaboration with Exelixis validates the significant value of our technology platform and expanding pipeline," said Keith Blundy, Director and Chief Executive Officer, STORM Therapeutics. "Exelixis has a proven history of success in the discovery, development and commercialization of innovative small molecule cancer therapies to provide patients with clinically meaningful treatment options. Access to Exelixis’ development expertise and funding will enable more rapid advancement of our ADAR1 discovery program, as well as other target activities under the collaboration."

ADAR1 edits double-stranded RNA (dsRNA) molecules, reducing their ability to activate innate immunity. Depletion or inhibition of ADAR1 can activate the innate immune response in tumor cells, which can trigger tumor cell death. Notably, up to 30% of tumor cells in The Cancer Genome Atlas have high interferon-stimulated gene signatures and may be dependent on ADAR1, suggesting that ADAR1-targeted therapies could have potential in a wide variety of solid tumors as a single agent therapy. In addition, ADAR1 inhibition may also sensitize tumors to immune checkpoint inhibition and overcome mechanisms of resistance to this class of therapies.