On December 12, 2022 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported new preclinical data showing its DARPin T-cell engager MP0533 can induce preferential killing of cells expressing two or three tumor-associated antigens (TAAs) compared to cells expressing a single TAA (Press release, Molecular Partners, DEC 12, 2022, View Source [SID1234625238]). The data was disclosed in an oral presentation at the 64th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting in New Orleans.

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MP0533 engages CD3 on T cells while binding up to three tumor-associated antigens (CD33, CD70, and CD123) on AML cells. By modulating the affinity to each TAA, Molecular Partners designed MP0533 to induce T cell-mediated killing preferentially when the cancer cells express two or three of the TAAs. This avidity-driven T cell activation ensures preferential killing of AML cells, that consistently expresses two or three of the target antigens. At the same time, it reduces the damage to healthy cells, which tend to express only one of the target antigens. Such damages have been a recurrent issue with other T-cell engagers in AML.

"Our preclinical data provides a strong base for MP0533’s clinical entry. Its design strategy is to focus the proven power of CD3-mediated T-cell killing onto AML cells and eliminate the systemic toxicity that has been a challenge for CD3 T-cell engagers as a class in this disease. The ability of multi-specific DARPins to exploit the natural differentiation in antigen expression between healthy and cancerous cells supplies a powerful platform for highly targeted immuno-oncology solutions," said Nicolas Leupin, MD, Ph.D., CMO of Molecular Partners. "We look forward to the MP0533 PhI study which, on top of the recent encouraging Phase I data presented at SITC (Free SITC Whitepaper) (Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)) for MP0317 (targeting FAP and CD40, enabling tumor-localized immune activation), illustrates the strength and uniqueness of our DARPin portfolio."

As presented today, MP0533 was able to activate T-cells and destroy AML cells in samples from newly diagnosed and previously treated AML patients with different TAA expressions. Humanized mouse models confirmed MP0533’s ability to activate intra-tumoral T-cells and control tumor growth. The research also showed that MP0533 was able to directly target and kill LSCs while sparing a variety of healthy cells including hematopoietic stem cells. The unique safety profile of MP0533 was further supported by several other parameters including a lower level of cytokine release relative to benchmark mono-targeted T cell engagers, both in vitro in a whole blood assay and in vivo in the humanized mouse AML models.

These results have been disclosed at ASH (Free ASH Whitepaper) 2022 in a podium presentation, which will also be made available on Molecular Partners’ website.

Presentation: "A Multispecific DARPin CD3 Engager Targeting CD33, CD123, and CD70 for the Treatment of AML and MDS Designed to Selectively Target Leukemic Stem Cells"
Session: 604
Timing: December 12, 2022: 5:45PM Central Time
Presenter: Anne Goubier, DVM

A Phase I clinical trial to evaluate safety and dose of MP0533 has been authorized to proceed by Swiss regulatory authorities’ and ethics committees. Patient enrollment is planned to initiate in the near future.

On December 12, 2022 Prothena Corporation plc (NASDAQ:PRTA), a late-stage clinical biotechnology company with a robust pipeline of investigational therapeutics built on protein dysregulation expertise, reported data from the completed phase 3 VITAL study demonstrating that in a post hoc analysis of patients with Mayo Stage IV AL amyloidosis, a statistically significant survival benefit was observed in those treated with birtamimab at 9 months (Press release, Prothena, DEC 12, 2022, View Source [SID1234625236]). The survival benefit of birtamimab in VITAL remained consistent across all key baseline variables in patients with Mayo Stage IV AL amyloidosis. The data were presented in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans, LA.

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Birtamimab is a potential best-in-class amyloid depleter treatment for AL amyloidosis. Based on the totality of the VITAL study data, Prothena has advanced birtamimab into the confirmatory Phase 3 AFFIRM-AL study in patients with Mayo Stage IV AL amyloidosis under a Special Protocol Assessment (SPA) agreement with the U.S. FDA with a primary endpoint of all-cause mortality at p≤0.10. Confirmatory Phase 3 AFFIRM-AL topline data is expected in 2024.

A post hoc analysis of patients with Mayo Stage IV AL amyloidosis showed a statistically significant survival benefit of 74 percent in patients treated with birtamimab versus a survival benefit of 49 percent in patients on placebo at 9 months (HR 0.413, p=0.021). The survival benefit of birtamimab in VITAL remained consistent across all key baseline variables in Mayo Stage IV patients, reinforcing the strength of the survival data in these patients at high risk of early mortality.

"AL amyloidosis is a rare and life-threatening disease without any treatment options that address resident amyloid deposits at the time of diagnosis," said Morie Gertz, MD, Hematologist, Chair emeritus Internal Medicine, Mayo Clinic. "The significant and consistent survival benefits of birtamimab in the VITAL study’s post hoc analysis of patients with Mayo Stage IV AL amyloidosis offers us hope that the removal of amyloid deposits leads to a survival benefit and affirms the potential of birtamimab as a safe, well-tolerated and meaningful therapy. We believe that the VITAL study results set the stage for the AFFIRM-AL trial which we hope will continue to show that birtamimab can help patients with Mayo Stage IV AL amyloidosis, who have the highest risk of early death."

The sensitivity analysis was performed as part of the post hoc analysis of patients with Mayo Stage IV AL amyloidosis. After adjusting for baseline demographic, clinical, and laboratory variables, the adjusted hazard ratios ranged from 0.336 to 0.465, with no upper bounds of the 90% confidence interval crossing 1, indicating a consistent survival benefit with birtamimab at 9 months.

Birtamimab also demonstrated statistically significant improvement over placebo in post hoc analyses of quality of life (assessed with the Short Form-36 version 2 physical component score, SF-36v2 PCS) and cardiac function (assessed with the 6-minute walk test). Patients treated with birtamimab showed a mean difference of 4.65 in the SF-36v2 PCS over placebo at 9 months (p=0.046). Mayo Stage IV patients treated with birtamimab after 9 months demonstrated an increase of 15.22 meters in the 6-minute walk test, whereas patients treated with placebo had a decrease of 21.15 meters (a difference of 36.37; p=0.022).

Birtamimab was generally safe and well tolerated in the overall patient population and in Mayo Stage IV patients. The rates of treatment emergent adverse events (TEAEs) were balanced between treatment arms. The rates of treatment-related TEAEs were similar or lower with birtamimab than in the placebo arm of both the overall population and in Mayo Stage IV patients. Consistent with AL amyloidosis, cardiac disorder was the most common class of fatal TEAEs. There were no fatal TEAEs that were considered treatment related.

Slides from today’s oral presentation at ASH (Free ASH Whitepaper) 2022 will be made available on www.prothena.com under the Investors tab in the Events and Presentations section.

About VITAL Phase 3 Study

VITAL was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of birtamimab plus standard of care versus placebo plus standard of care in newly diagnosed, treatment-naïve patients with AL amyloidosis. The study was terminated early based on a futility analysis. The primary endpoint in the full study population was the composite of time to all-cause mortality and cardiac hospitalization in patients with AL amyloidosis. The primary endpoint in the overall study population favored birtamimab over placebo, but the difference was not statistically significant at the time of early study termination. The primary study population included 260 patients with AL amyloidosis, of which patients who received birtamimab and placebo were evenly split. Approximately one-third of patients in the study had Mayo Stage IV AL amyloidosis (n=77). Patient demographics were generally balanced between the birtamimab and placebo groups in the study population and the Mayo Stage IV sub population.

About Birtamimab

Birtamimab is an investigational monoclonal antibody designed to specifically and selectively target and clear the amyloid that accumulates and causes organ dysfunction and failure in patients with AL amyloidosis. Birtamimab specifically binds to a defined epitope on kappa and lambda AL protein involved in the disease process. Birtamimab is the only investigational therapeutic that has shown a significant survival benefit in patients with Mayo Stage IV AL amyloidosis post-hoc in a placebo-controlled study. Birtamimab has been granted orphan drug designation for AL Amyloidosis by both the U.S. FDA and the European Medicines Agency and has been granted Fast Track designation by the FDA. A SPA was agreed to between Prothena and the FDA for the AFFIRM-AL trial which represents FDA’s agreement that the design and planned analysis for the primary endpoint of time to all-cause mortality adequately address the objectives necessary to support a regulatory submission. Results from the AFFIRM-AL trial are anticipated in 2024. Final marketing approval is predicated upon FDA’s complete review of the entire application.

About AL Amyloidosis

AL amyloidosis is a rare, progressive and fatal disease where clonal plasma cells overproduce light chain proteins that misfold, aggregate and deposit as amyloid in vital organs such as the heart. It is estimated that there are 60,000 – 120,000 patients worldwide living with Mayo Stage IV AL amyloidosis. Patients with AL amyloidosis can present with a wide range of general symptoms that are common to other conditions such as fatigue, shortness of breath or edema. Current treatment strategies target plasma cells to reduce production of new amyloid, but do not address the amyloid already deposited in organs. Mortality is driven primarily by cardiac failure. There is an urgent unmet medical need for therapies that improve survival in patients at risk for early mortality due to amyloid deposition.

On December 12, 2022 Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with hematologic malignancies and solid tumors, reported additional positive clinical data from its Phase 1 clinical trial of NX-2127 in two oral sessions by Anthony Mato, M.D., MSCE, former director of the Chronic Lymphocytic (CLL) Program at Memorial Sloan Kettering Cancer Center, and Omar Abdel-Wahab, M.D., Chair of Sloan Kettering Institute (SKI) Molecular Pharmacology Program at Memorial Sloan Kettering Cancer Center (Press release, Nurix Therapeutics, DEC 12, 2022, View Source [SID1234625219]). NX-2127 is a once daily, oral, investigational new drug that combines BTK degradation with immunomodulatory activity. The podium presentations took place at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition which is being held in New Orleans, Louisiana.

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"These early Phase 1 data demonstrate that NX-2127 effectively degrades BTK resulting in clinically meaningful responses independent of prior treatments or BTK mutational status and offering a potential new treatment modality for patients who have otherwise exhausted other approved and emerging treatment options," said Robert J. Brown, M.D., Nurix’s executive vice president of clinical development.

The data presented by Dr. Mato demonstrate that treatment with NX-2127 results in sustained BTK degradation and clinically meaningful responses in heavily pretreated patients with relapsed/refractory CLL independent of prior treatments or BTK mutational status. These presentations included preliminary data from 36 adults with relapsed/refractory B-cell malignancies enrolled in the Phase 1a/b study, including 23 patients with CLL who had undergone and failed a median of five prior therapies including a BTK inhibitor. Approximately 78% of this group had previously received both BTK and BCL2 inhibitors and 35% had been treated with the non-covalent BTK inhibitor pirtobrutinib. Of the CLL patients, 48% had one or more identified BTK resistance mutations prior to treatment with NX-2127. Following treatment with NX-2127 in this heavily pretreated CLL population, sustained BTK degradation and decreased B cell activation were observed regardless of prior treatment and baseline BTK mutation status with an overall response rate (ORR) of 33% (95% CI 12–62%). As of September 21, 2022, the data cut-off date, the median follow up was 5.6 months (0.3 to 15.7 months), and 14 of 23 patients remained on treatment. Importantly, the safety profile of NX-2127 was consistent with prior results from the Phase 1a portion of the trial and reports for BTK-targeted therapies in heavily pretreated patients with B cell malignancies.

"We are excited by the growing body of data generated in our Phase 1a/1b clinical trial of NX-2127 which highlights the significant differentiation and potential advantages of BTK degradation over BTK inhibition, especially in the setting of resistance to existing therapies," said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. "We continue to explore the promise of this first-in-class targeted protein degrader of BTK as we enroll additional CLL patients in the ongoing expansion cohort and continue to enroll patients with non-Hodgkin lymphoma in the dose escalation. We look forward to additional clinical updates in 2023."

The presentation by Dr. Abdel-Wahab highlighted critical scientific findings underlying the emergence of new BTK inhibitor resistance mutations that lack BTK’s enzymatic function but still drive tumor growth. These so-call "kinase deficient" and "kinase dead" mutations underscore the importance of BTK’s scaffolding function, which is uniquely addressable by the BTK degrader modality. In the presentation, five different clinically emergent BTK resistance mutations were analyzed and categorized as kinase proficient, kinase deficient, or kinase dead, each conferring a different spectrum of resistance to available therapies. NX-2127 was found to be broadly active against all these mutations. These findings translated into clinically meaningful BTK degradation in the Phase clinical 1 trial and clinical activity independent of baseline BTK mutations.

Webcast details

The live KOL webcast event, which will begin at 8:30 pm CT (9:30 pm ET) on Monday, December 12, 2022, and the subsequent replay, will be available in the Investors section of the Nurix website under Events and Presentations.

About the Phase 1, Study of NX-2127

The multicenter Phase 1 study is designed to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary clinical activity of orally administered NX-2127 in adult patients with relapsed or refractory B-cell malignancies. The study is being conducted in two parts. The Phase 1a element is a dose-escalation study in which cohorts of patients will receive ascending oral doses of NX-2127 once daily to determine the maximum tolerated dose (MTD) and/or the optimal Phase 1b dose based on safety and tolerability. The second portion of the study, Phase 1b, is a dose expansion phase in which cohorts of patients with specific cancers will receive NX-2127 to further evaluate the safety and clinical activity of the recommended dose. The study is expected to enroll eligible patients with the following cancers: chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL), who have required and received prior systemic therapies. Additional information on the clinical trial can be accessed at ClinicalTrials.gov (NCT04830137).

About NX-2127

NX-2127 is a novel bifunctional molecule that degrades Bruton’s tyrosine kinase (BTK) and cereblon neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). NX-2127 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies.

On December 12, 2022 Agilent Technologies Inc. (NYSE: A) reported that the U.S. Food and Drug Administration (FDA) has approved Agilent Resolution ctDx FIRST as a companion diagnostic (CDx) to identify advanced non-small cell lung cancer (NSCLC) patients with KRAS G12C mutations who may benefit from treatment with KRAZATITM (adagrasib) (Press release, Agilent Technologies, DEC 12, 2022, View Source [SID1234625190]).

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This is the first liquid biopsy NGS assay approved by the FDA as a CDx for the newly approved KRAZATI in advanced NSCLC and was developed in collaboration with Mirati Therapeutics. ctDx FIRST has also been approved by the FDA for tumor profiling of the epidermal growth factor receptor (EGFR) gene for use by qualified health care professionals in accordance with professional guidelines in oncology patients with NSCLC.

As a professional service*, the ctDX FIRST test report includes broad genomic profiling on 109 genes across four types of alterations: single nucleotide variants (SNVs), insertions and deletions (indels), copy number amplifications (CNAs), and fusions.

Lung cancer is one of the most prevalent cancers among men and women in the U.S. and is the leading cause of cancer mortality, comprising 25% of all cancer-related deaths.1 Most patients with NSCLC are diagnosed at later disease stages due to undetected early symptoms.2 Approximately 14% of NSCLC patients harbor a KRAS G12C mutation, and approximately 32% of NSCLC patients have a mutation within their EGFR gene, making this new test an attractive solution to inform treatment decisions for these patients. 3,4 ctDx FIRST provides NSCLC patients and their oncologists with a new minimally invasive blood test to help clarify precision treatment options.

The ctDx FIRST assay uses novel propriety technology to detect genomic alterations in circulating tumor DNA (ctDNA) from plasma. This minimally invasive approach is preferred by 90% of cancer patients compared to more invasive tissue biopsy tests.5 In addition, liquid biopsy overcomes some limitations encountered with tissue-based methods providing a notably faster turn-around time to potentially accelerate treatment decisions.6

"Expanding access to accurate and fast genomic profiling is an essential step to unlocking important medicines for patients in desperate need," said Kenna Anderes, Mirati’s Vice President of Translational Medicine and Companion Diagnostics. "We appreciate the opportunity to partner with companies like Agilent who are committed to creating more opportunities for ‘decision medicine’ for people living with cancer."

"We are thrilled to partner with Agilent as they work to create greater access to efficient, effective and minimally-invasive tests to support clinicians with information that is critical to their patient care," said Alan Sandler, M.D., Mirati’s Chief Medical Officer. "At Mirati, we are focused on creating meaningful impacts on the lives of people with cancer. Tests like ctDx FIRST are important to realizing our commitment to patients."

"Commercializing the ctDx FIRST test enables us to support clinicians to positively impact the lives of patients with advanced NSCLC," said Sam Raha, Agilent’s President of the Diagnostics and Genomics Group. "Agilent values opportunities to partner with Mirati and other pharmaceutical companies in developing clinically relevant NGS-based diagnostics that enhance confidence in targeted cancer therapy."

To learn more about the test and order visit http://www.agilent.com/genomics/ctDxFIRST

* CLIA validated, not FDA approved

On December 12, 2022 AvenCell Therapeutics, Inc. reported updated safety and efficacy data from its lead CD-123-directed Universal CAR T Cell Candidate ("UniCAR") (Press release, AvenCell Therapeutics, DEC 12, 2022, View Source [SID1234625187]). These data, based on AvenCell’s Universal Targeting platform, were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans, Louisiana.

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The oral presentation (#979) included updated data from the first-in-human phase I dose escalation study of AVC-101 in patients with relapsed/refractory acute myeloid leukemia (r/r AML) designed to assess safety and tolerability and identify an MTD. Secondary and exploratory objectives include efficacy, biological activity, and PK.

As of October 13, 2022, of 16 patients treated with AVC-101, five patients (31%) achieved complete response with incomplete count recovery (CRi) or MRD negative conversion and the overall response rate was 56% (n=9). Of evaluable patients with minimal residual disease (MRD+; n=2), both converted to MRD negative status after the treatment.

"The AVC-101 [UniCAR CD123] program shows extremely promising results in the most challenging AML patients who have exhausted all options," said Prof. Dr. med. Martin Wermke, head of Early Clinical Trial Unit at University Hospital Carl Gustav Carus in Dresden, Germany. "This study shows preliminary evidence of clinical efficacy including multiple CRs in the dose escalation stage, manageable toxicity, and proof of principle that the switchable technology can be turned on and off to manage toxicities thereby enabling targets too challenging for traditional CAR Ts. We are hopeful for additional trials of this platform to build on this encouraging data."

The presentation reports results from 16 heavily pre-treated R/R AML patients with a median of six prior lines of therapies (min-max: 2-9 lines), with nine patients having received a prior allogeneic hematopoietic stem cell transplantation. Median age of patients was 64.5 (range 18-80), with four patients over the age of 70.

"We are excited to be at ASH (Free ASH Whitepaper) for the first time as AvenCell and to showcase the Universal Targeting platform, which has the potential to address some of the most difficult efficacy and safety challenges with cell therapies seen to date," said Andrew Schiermeier, Ph.D., chief executive officer, AvenCell Therapeutics. "The data presented by Dr. Gerhard Ehninger is indicative of the promise of the platform to treat a multitude of difficult cancer targets, where the ability to precisely and reliably control CAR T cell activity in vivo after administration is critical."

About AVC-101

AVC-101 is an investigational CD-123-directed cell therapy targeting acute myeloid leukemia, that utilizes AvenCell’s proprietary Universal Targeting platform, a regulatable CAR T cell technology that can turn CAR T cells "OFF" and "ON" by means of a separately infused Targeting Module. With AVC-101, AvenCell is aiming to create a solution to address the heterogeneity and aggressive nature of acute myeloid leukemia. CD123 is a target in acute myeloid leukemia, but its on-target off-tumor toxicity makes a conventional CD-123-directed CAR very challenging.

AvenCell’s proprietary Universal Targeting Platform is part of a new paradigm in cell therapy through one-time engraftment of Universal CAR T Cells, which can then be controlled in vivo with the separate administration of Targeting Modules that direct the Universal CAR T cells to cancer cells for activation and killing. The platform’s ability to control CAR T activity after infusion via repeatable, titratable, and switchable Targeting Module infusion provides extensive flexibility to address such issues as avoiding T cell exhaustion, antigen escape, and reacting rapidly to any potential adverse events.

AVC-101 is not approved for any indication in any geography and has not been demonstrated safe or effective for any use.