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.

On October 14, 2021 Tizona Therapeutics, Inc., a privately held, clinical-stage company developing first-in-class cancer immunotherapies, reported that its lead investigational therapy, TTX-080, a novel antibody targeting HLA-G, has advanced to Phase 1b (Press release, Tizona Therapeutics, OCT 14, 2021, View Source [SID1234591254]). This phase includes expansion tumor arms to evaluate the safety and efficacy of TTX-080 as monotherapy and combination regimens in patients with advanced malignancies.

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The Phase 1b is a dose expansion study designed to assess TTX-080 as monotherapy and in combination with either pembrolizumab or cetuximab in patients with advanced refractory or resistant solid tumor malignancies, including head and neck squamous cell carcinoma, non-small cell lung cancer, colorectal cancer, and triple negative breast cancer. In addition to evaluating the anti-tumor activity of TTX-080, the study will continue to evaluate the safety, pharmacokinetics, and immunogenicity of TTX-080. Exploratory pharmacodynamic and biomarker analyses will also be conducted.

"The initiation of the Phase 1 dose expansion study is an important milestone for the TTX-080 clinical development program," said Christine O’Brien, Chief Executive Officer, Tizona. "As a novel checkpoint inhibitor, the TTX-080 program offers an opportunity to apply new understandings of immune regulation within the tumor microenvironment in solid tumor indications where patient outcomes remain a major unmet medical need."

The Phase 1b expansion study follows the Phase 1a study, an open label, multicenter, dose escalation clinical trial designed to assess the safety and tolerability of TTX-080 as monotherapy. The Phase 1a stage of the study, which has completed enrollment, determined a recommended Phase 2 dose of TTX-080 when administered as a single agent.

About TTX-080

TTX-080 is a potential first-in-class medicine that targets HLA-G, a novel and emerging immune checkpoint expressed across multiple tumor types. By blocking the interaction of HLA-G with its receptors, TTX-080 prevents the suppression of both innate and adaptive immune activity and has the potential to enhance anti-tumor responses. Tizona is currently enrolling patients in a Phase 1b clinical trial (NCT04485013) evaluating TTX-080 both as a monotherapy and in combination with other agents in patients with advanced cancers.

On October 14, 2021 Telix Pharmaceuticals reported that radiation therapy is regaining a foothold in oncology (Press release, Telix Pharmaceuticals, OCT 14, 2021, View Source [SID1234591392]). This isn’t the therapy your parents remember, though. Modern radiation therapy is tightly targeted to dramatically reduce toxicity and side effects and often can be administered on an outpatient basis.

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"There’s a lot of innovation in this field," Bernard Lambert, Ph.D., president and chief operating officer for Telix Pharmaceuticals (U.S.) told BioSpace. Telix’s own program is a case in point. The company has molecularly-targeted radiation (MTR) products under development or under review by the regulatory authorities for imaging and therapy. Telix has programs from preclinical to Phase III underway, as well as one imaging agent in final review at the U.S. Food and Drug Administration.

"MTR molecules are a concept of precision and personalized medicine," Lambert said. "Rather than flooding the body with radiation and killing healthy cells in addition to tumors, we can selectively target the tumor (and tumor supportive cells) and deliver the radioisotope directly to it, saving healthy cells and, therefore, reduce the side effects."

At a basic level, Telix attaches a radioactive isotope to a small molecule or antibody that targets the surface antigen on cancer cells. Once in the body, these molecules home-in on the cancer cell and deliver their radioactive payload, killing only the cancer cell. The decay rate varies from an hour or two to several days.

What really sets Telix apart from its competitors in this space, Lambert said, is that "we are covering a different stage of clinical development. Many (other companies) are in preclinical development. Telix, in contrast, is a pioneer in the industry. Our portfolio ranges from commercial to preclinical products in several indications, but mainly in oncology." Notably, the same MTR platform can be used therapeutically to treat multiple indications by changing the delivery molecule. The platform also can deliver lower-energy radioisotopes for imaging, which can be used to determine treatment effectiveness or to stage cancer treatments.

Currently, the company is prioritizing prostate, kidney, brain and bone-marrow cancers, and just dosed its first patient in a Phase II triple-negative breast cancer trial studying TLX250-CDx (89Zr-DFO-girentuximab) in France. "That particular trial targets an antigen, carbonic anhydrase IX (CA9), that is overexpressed in patients with renal cell carcinoma," he said, as well as lung and oesophageal cancers.

The breast cancer study, led by Caroline Rousseau at the Institut de Cancérologie de l’Ouest (ICO) in St. Herblain, France, evaluates how CA9 imaging and positron emission tomography can be used to diagnose triple-negative breast cancer (a particularly aggressive form of cancer with high unmet need) and to stage treatments. It is the second in a series of studies evaluating CA9 as a target for cancers beyond renal cell carcinoma.

Other programs targeting CA9 are in a Phase II therapeutic study for renal cell carcinoma and a Phase III imaging study for that indication. A separate study is underway in bladder cancer.

The side effects of MTR products vary depending on the molecule Telix uses, but Lambert said, "our safety profile is quite better than with chemotherapy, although like any of the drugs, it has some side effects, such as headaches, vomiting and pain at the injection point. They’re manageable."

"Historically, radiation therapy was used at the end of the patient journey to extend the patient’s life when everything else had failed. Yet, research is showing it works well as a front-line treatment," Lambert said. "It can’t be used for every tumor type, but it does address a lot of unmet needs and contribute to patients’ quality of life." The challenge is convincing physicians that it can be used effectively as an early-stage treatment.

There’s another challenge, too: Delivering products with very short half-lives to patients throughout the U.S. and Europe. "We need a high level of coordination with our manufacturers in the U.S. and Europe," Lambert pointed out. To manage the logistical hurdles, Telix is working with Cardinal Health and other radiopharmacy networks to ensure the products are near radiologic imaging centers. It is also establishing manufacturing sites in the U.S. and Europe.

In terms of upcoming milestones, Lambert said he is anticipating what he hopes will be FDA approval for TLX591-CDx, Telix’s prostate imaging product, and then submitting TLX250-CDx, its kidney cancer imaging product, for review. "We have a therapeutic program that’s active for prostate and kidney cancers, too," he said. Telix also is planning to meet with the FDA to bring its glioblastoma product to Phase II/III trials that he anticipates will occur in 2022.