On June 7, 2021 Novartis flexed its clinical muscles over the weekend, reported that results from multiple studies across various indications, including different types of cancer and kidney disease (Press release, Novartis, JUN 7, 2021, View Source [SID1234583935]).

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Some of the oncology data were presented at the virtual 2021 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting, including data from the ongoing Phase II GEOMETRY mono-1 study assessing Tabrecta in patients with EGFR wild-type, ALK-negative rearrangement, metastatic NSCLC harboring mutations that lead to MET exon-14 skipping.

The ASCO (Free ASCO Whitepaper) presentation includes new data from a treatment-naïve expansion cohort (7) and previously-treated cohort (6) and mature data from previously reported cohorts. Novartis said the latest data demonstrates Tabrecta’s effectiveness as a treatment option for patients with this particular form of lung cancer.

Data showed that Tabrecta, which was approved by the U.S. Food and Drug Administration last year, showed significant improvements in overall survival for this cancer type. The study revealed that Tabrecta provided 20.8 months of OS for treatment-naïve patients and 13.6 months for previously-treated patients.

Jeff Legos, Head of Oncology Drug Development for Novartis Oncology, touted the data as additional proof for the use of Tabrecta in this patient population.

"The introduction of Tabrecta a year ago dramatically changed the treatment landscape for patients with METex14 NSCLC. Now we have further evidence that Tabrecta… has the potential to help people live longer," Legos said in a statement.

In addition to OS, Novartis noted the median duration of response was 12.6 months among treatment-naïve patients in one of the cohorts. In two cohorts of previously treated patients, the DOR was 9.7 months and 8.4 months. The overall response rate was much higher in treatment naïve patients, 67.9% and 65.6% across two cohorts. For previously treated patients, ORR was 40.6% and 51.6% across two cohorts.

Esophageal Cancer

Also presented at ASCO (Free ASCO Whitepaper) was data from the pivotal Phase III RATIONALE 302 study that showed the company’s checkpoint inhibitor tislelizumab improved overall survival in patients with unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who had received prior systemic therapy. In the study, tislelizumab, an investigational anti-PD-1 immune checkpoint inhibitor, was assessed against chemotherapy.

The study showed tislelizumab extended median OS by 2.3 months compared to chemotherapy with a 30% reduction in the risk of death. In PD-L1 positive patients, tislelizumab extended median OS by 3.5 months with a 46% reduction in the risk of death.

Legos expressed his excitement about the Phase III study. He said data shows tislelizumab has the potential to help patients with esophageal squamous cell carcinoma live longer. Legos said data from the study would be shared with regulatory agencies.

Chemotherapy did best tislelizumab when it came to progression-free survival. Treatment with tislelizumab demonstrated median progression-free survival of 1.6 months compared to 2.1 months for chemotherapy. Tislelizumab showed a higher and more durable anti-tumor activity than chemotherapy, 20.3% vs. 9.8%, and a greater median duration of response, 7.1 months compared to 4 months.

Prostate Cancer

Data from the Phase III VISION study showed Lu-PSMA-617, a targeted radioligand therapy, plus best standard of care (SOC), demonstrated significant improvement in overall survival in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Lu-PSMA-617 plus SOC was evaluated against SOC alone.

Novartis said the OS difference between the Lu-PSMA-617 combination and SOC was statistically significant, with an estimated 38% reduction in risk of death in the 177Lu-PSMA-617 arm. Data from the Phase III VISION study was presented at ASCO (Free ASCO Whitepaper) over the weekend.

Patients who received Lu-PSMA-617 also demonstrated a statistically significant 60% risk reduction for radiographic progression-free survival or death, compared to the best standard of care only arm.

John Tsai, Head of Global Drug Development and Chief Medical Officer for Novartis, said the VISION study is the first to demonstrate the potential of a radioligand therapy in advanced prostate cancer. Novartis is planning to assess Lu-PSMA-617 in earlier line treatment settings for metastatic prostate cancer. The company will investigate the radioligand therapy in the mCRPC pre-taxane setting (PSMAfore) and the metastatic hormone-sensitive setting (PSMAddition).

Kidney Disease

In kidney disease, Phase II data showed the investigational asset iptacopan reduced protein in the urine (proteinuria), which is a surrogate marker correlating with progression in kidney failure. It also showed promise in stabilizing kidney function in patients with IgA nephropathy (IgAN), Novartis said. Iptacopan is a first-in-class, oral, targeted factor B inhibitor that targets the alternative complement pathway, a key driver of complement-driven renal diseases.

In the Phase II IgAN study presented at the ERA-EDTA Congress, iptacopan met its primary endpoint by demonstrating a statistically significant dose-response effect on reduction in proteinuria compared to placebo after 90 days. A 200mg dose of iptacopan twice per day achieved a 23% reduction in proteinuria.

Iptacopan also demonstrated a trend towards stabilizing kidney function. Additionally, iptacopan showed a favorable safety and tolerability profile, the company said.

"Complement-driven renal diseases, such as IgAN, are devastating and mostly affect young adults, imposing a high disease burden. These new data in IgAN add to the growing body of evidence around the potential of iptacopan to target a key driver in these rare renal diseases," Tsai said in a statement.

Iptacopan is also in development for the blood disorder paroxysmal nocturnal hemoglobinuria.

On June 7, 2021 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that the company has entered into a clinical trial collaboration agreement with Seagen Inc. to evaluate nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, in combination with SEA-BCMA, Seagen’s investigational monoclonal antibody targeting B-cell maturation agent (BCMA), in patients with relapsed or refractory multiple myeloma (Press release, SpringWorks Therapeutics, JUN 7, 2021, View Source [SID1234583795]).

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Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of myeloma cells. In preclinical models, nirogacestat has been shown to increase levels of membrane-bound BCMA and reduce levels of soluble BCMA, thereby enhancing the activity of BCMA-targeted therapies.

"We continue to make significant progress advancing nirogacestat as a potential best-in-class cornerstone of BCMA combination therapy for patients with multiple myeloma and are delighted to work with Seagen to study nirogacestat in combination with SEA-BCMA, our first collaboration with a monoclonal antibody targeting BCMA," said Saqib Islam, Chief Executive Officer of SpringWorks. "Our goal is to meaningfully improve clinical outcomes for patients with multiple myeloma and we look forward to generating clinical data using nirogacestat in combination with BCMA-directed therapies across modalities."

Under the terms of the agreement, Seagen will sponsor and conduct the Phase 1 study to evaluate the safety, tolerability and preliminary efficacy of the combination, and will assume all costs associated with the study, other than expenses related to the manufacturing of nirogacestat and certain expenses related to intellectual property rights. Seagen and SpringWorks will also form a joint development committee to manage the clinical study, which is expected to commence in the second half of 2021.

In addition to its ongoing clinical collaborations with BCMA-directed therapies, SpringWorks is conducting a global Phase 3, double-blind, randomized, placebo-controlled clinical trial (the DeFi Trial) to evaluate nirogacestat as a monotherapy in adults with progressing desmoid tumors.

About Nirogacestat
Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.

In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has six collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, two bispecific antibodies and a monoclonal antibody. In addition, SpringWorks and Fred Hutchinson Cancer Research Center have entered into a sponsored research agreement to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA directed therapies using a variety of preclinical and patient-derived multiple myeloma models developed by researchers at Fred Hutch.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.

On June 7, 2021 Thermo Fisher Scientific, the world leader in serving science, and Newomics, a commercial-stage biotechnology company, reported that they are collaborating to develop a novel native liquid chromatography-mass spectrometry (LC−MS) platform to support various LC−MS applications (Press release, Lifescience Newswire, JUN 7, 2021, View Source [SID1234583793]). This agreement utilizes Newomics’ experience in creating innovative and integrative platforms and solutions for precision medicine and Thermo Fisher’s cutting-edge LC-MS systems to improve the throughput and robustness of microflow LC-MS in proteomics and biopharmaceutical applications.

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The agreement will bring together Thermo Fisher’s new-generation LC-MS systems, providing high-performance, innovative technology, and the Newomics Microflow-nanospray Electrospray Ionization (MnESI) source, to achieve high-sensitivity and high-throughput LC-MS analysis of bioorganic complexes, while maintaining their native state. The platform can tolerate a wide range of LC flow rates and high salt concentrations, which are critical for accommodating different native LC methods. The MnESI-MS platform provides a highly sensitive and reproducible analysis of nanospray applications, such as targeted peptide quantitation, and intact native and denatured protein analysis.

"Native MS is a powerful technique for studying the structure of intact proteins, large protein complexes, and protein-protein, protein-ligand interactions; however, the analysis of large native protein complexes and their mixtures in a high-throughput manner is challenging," said Andreas Huhmer, senior director of omics marketing, Thermo Fisher Scientific. "Our workflow with Newomics provides a hands-free approach to improve throughput for native MS analysis of large bioorganic complexes, providing the sensitivity of nanospray and the ability to maintain the native state of protein complexes during the MS analysis."

Dr. Daojing Wang, founder and CEO of Newomics, said, "Newomics is very excited to be launching our second co-marketing agreement with Thermo Fisher Scientific. When coupled with Thermo Fisher’s industry-leading mass spectrometers, Newomics’ new MnESI source offers an unmatched balance of sensitivity, robustness and reproducibility for small-volume, high-throughput analysis of biomolecules, such as therapeutic antibodies and RNAs for drug discovery and clinical research. The plug-and-play MnESI source works by rapidly delivering small amounts of samples to the award-winning Newomics M3 multinozzle emitters. The M3 emitter was the focus of Newomics’ first co-marketing agreement with Thermo Fisher in 2019, and once again, we’ll be working closely with their team to fulfill customer needs and address any challenges in mass spectrometry workflows."

To find out more about Thermo Fisher Scientific’s next-generation LC-MS systems, please browse our complete portfolio here.

Thermo Fisher Scientific will showcase its newest products, software solutions and collaborations in a company-hosted virtual event, "Innovation Summit: Shaping the Future of LC-MS in Life Science Together," from June 8-10, 2021. Register here to learn more.

On June 7, 2021 Elevation Oncology reported that it has filed to raise $100 million in an IPO (Press release, Elevation Oncology, JUN 7, 2021, View Source [SID1234583792]). The money will support development of an anti-HER3 antibody that failed multiple trials at Merrimack Pharmaceuticals before being picked up by Elevation and repositioned as a treatment for solid tumors harboring an NRG1 fusion.

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The antibody, seribantumab, failed multiple midphase trials, causing Sanofi to return the rights to the drug and ultimately leading to Merrimack offloading it to Elevation in 2019. Elevation picked up the molecule after identifying HER3 inhibition as an approach for tumors driven by an NRG1 fusion. In preclinical tests, HER3 inhibition led to reductions of growth for NRG1 fusion-driven tumors.

"We believe that direct inhibition of the NRG1 activation of HER3 with a monoclonal antibody approach may drive improved responses for these patients given its direct role in sustaining proliferation and survival of tumors harboring an NRG1 fusion," Elevation wrote in its IPO paperwork.

Elevation raised almost $100 million across series A and B rounds from investors including Aisling Capital, venBio Partners and Cormorant Asset Management, giving it the means to start a phase 2 clinical trial. Now, the biotech is seeking public investment for further development of seribantumab.

If successful, Elevation believes the phase 2 may support a filing for FDA approval. The 55-subject pivotal cohort of the study is enrolling patients with a centrally confirmed NRG1 fusion who haven’t been previously treated with an EGFR-, HER2- or HER3-directed therapy. The primary endpoint is the overall response rate.

Elevation sees other ERBB or HER3 inhibitors in development at companies including Merus, Rain Therapeutics, Hummingbird Bioscience, GamaMabs Pharma and AVEO Oncology as the key rivals to seribantumab. Other companies such as Daiichi Sankyo, GlaxoSmithKline and Boehringer Ingelheim are working on similar drugs, but Elevation is unsure whether they are targeting NRG1 fusion tumors.

On June 7, 2021 Ambrx, a San Diego clinical-stage biotech with operations in Shanghai, reported that it has filed for a US IPO that is expected to raise $100 million (Press release, Ambrx, JUN 7, 2021, View Source [SID1234583791]). Founded in 2003, Ambrx develops antibody-drug conjugates and bispecifics for unmet oncology needs. It builds engineered precision biologics by incorporating synthetic amino acids (SAAs) into proteins within living cells, a technology that offers better efficacy and safety, according to the company. Its lead drug, an ADC candidate, is being tested in a China Phase II/III trial for HER2-positive metastatic breast cancer led by a China partner, NovoCodex Biopharma.

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