On October 27, 2022 XtalPi, Inc., a privately-held solution provider accelerating biopharmaceutical research via its integrated technology platform, reported a research collaboration with Janssen Pharmaceutica NV, one of the Janssen Pharmaceutical Companies of Johnson & Johnson ("Janssen") to deliver chemical matter with validated binding affinities and desirable property profiles (Press release, Janssen Pharmaceutica, OCT 27, 2022, View Source [SID1234622530]). The collaboration was facilitated by Johnson & Johnson Innovation LLC.

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Under the agreement, XtalPi will deliver validated small molecule hits that possess defined properties for a given target nominated by Janssen. XtalPi will deploy its comprehensive, end-to-end platform – Inclusive Digital Drug Discovery & Development (ID4), which includes proprietary cloud-based computations and state-of-the-art wet lab capabilities with the aim to shorten the "Design-Make-Test-Analyze" (DMTA) cycle.

XtalPi has long enjoyed unparalleled success in prediction accuracy of solid-state polymorphism through numerous collaboration projects with pharmaceutical partners but noting that many additional bottlenecks exist in the drug discovery process, the company undertook ambitious plans to expand its capabilities during the last few years. With significant investments in automation, personnel growth in all relevant disciplines of medicinal chemistry, synthetic chemistry, and biology, as well as the deployment of AI to seamlessly improve computational algorithms’ prediction accuracy through rapid validation and refinement against experiments, XtalPi can now offer the full spectrum of research support leading right up to a development candidate.

"I’m excited that we will work together and put our ID4 platform to the test and showcase what it can do," says Dr. Ma Jian, XtalPi’s CEO.

On October 27, 2022 Simcere Pharmaceutical Group (2096.HK), an innovative global pharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s investigational new drug (IND) application for SIM0237, an anti-PD-L1/IL-15 bi-functional fusion protein, for the treatment of adult patients with advanced solid tumors (Press release, Jiangsu Simcere Pharmaceutical Company, OCT 27, 2022, View Source [SID1234622529]). It is the second IND approval Simcere obtained in the US this year. In addition, the IND application of SIM0237 in China was accepted by the National Medical Products Administration on October 10, 2022.

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"There is demonstrated history of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) showcasing strong efficacy in a variety of cancers, but there is a large percentage of oncology patients who are either refractory these therapeutics or develop resistance," said Dr. Bijoyesh Mookerjee, M.D., Chief Medical Officer, Oncology of Simcere. "By developing this compound as a bi-functional fusion protein, that combines an anti-PD-L1 antibody with an IL-15 cytokine, we can direct therapeutic activity to the tumor microenvironment, enabling us to potentially limit toxicity while improving tolerability and enhancing efficacy in patients with metastatic or locally advanced solid tumors."

IL-15 is an immune-activating cytokine that promotes the expansion and activation of NK cells and CD8 + T cells. Previous research has revealed that IL-15 when combined with anti-PD-L1/PD-1 antibodies showed good clinical benefits in patients with advanced malignancies including patients who have either not responded to or have relapsed after immune checkpoint inhibitor treatment. Therefore, bi-functional fusion protein, targeting both IL-15 and PD-1/PD-L1 may have the potential for antitumor efficacy in relapsed/refractory patients after immunotherapy.

About the SIM0237-101 Clinical Trial

SIM0237-101 is a phase 1, first-in-human, open-label, multicenter study to investigate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of SIM0237 in adult participants with advanced solid tumors. The dose escalation phase of the study will evaluate the pharmacokinetics and pharmacodynamics and identify the maximum tolerated dose (MTD) or the recommended dose for expansion (RDE) of SIM0237. The dose expansion phase of the study assess safety, and activity of SIM0237 at the RDE.

About SIM0237

SIM0237 is an anti-PD-L1 monoclonal antibody fused with potency reduced IL-15/IL-15Rα sushi domain developed in-house by utilizing the Simcere’s protein engineering platform. It can block the PD-1/PD-L1 immunosuppressive pathway via binding to PD-L1 and activate the immune system through its IL-15 part, thus playing a synergistic role of relieving immunosuppression and boosting the immune activation to exhibit antitumor effect. The attenuated IL-15 part of SIM0237 prolongs its PK, increases MTD and avoids overstimulation and accompanied anergy of NK and CD8+ T cells. In the meantime, fusion of attenuated IL-15 to full anti-PD-L1 mAb further enhances the half-life of attenuated IL-15 and delivers IL-15 directly to the tumor microenvironment avoiding notorious CRS toxicity induced by systemic IL-15 exposure. Moreover, SIM0237 is able to bridge CD8+ T and NK cells to PD-L1+ APC/tumor cells, which fosters immune synapse formation to further boost the activation of effective cells and promote tumor cell lysis. Preclinical studies showed that SIM0237 is more effective than PD-L1 or IL-15 mono treatment in mouse tumor models, suggesting a high potential for clinical development.

On October 27, 2022 Cytovia Therapeutics, Inc., a biopharmaceutical company empowering natural killer (NK) cells to fight cancer through stem cell engineering and multispecific antibodies, reported that it will be presenting new preclinical data for its CD38-targeted Flex-NK cell engager antibodies at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s 64th Annual Meeting (ASH 2022) taking place in New Orleans, LA, and virtually December 10-13th, 2022 (Press release, Cytovia Therapeutics, OCT 27, 2022, View Source [SID1234622528]).

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Details about the ASH (Free ASH Whitepaper) poster presentation are as follows:

Title: Biological Characterization and Differential Gene Expression Analysis of CYT-338 NK Cell Engager (NKE) Against Multiple Myeloma (MM) Tumors
Abstract Number: 3142
Session Name: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II
Date and Time: Sunday, December 11th, 2022 (6-8PM CST)
Location: Ernest N. Morial Convention Center, Hall D, New Orleans, LA
Abstracts available online: November 3, 2022, 9:00 a.m. Eastern time

About Multiple Myeloma
Multiple Myeloma is a currently incurable cancer, affecting a type of white blood cell known as plasma cells. It leads to an accumulation of tumor cells in the bone marrow, rapidly outnumbering healthy blood cells. Instead of producing beneficial antibodies, cancerous cells release abnormal proteins causing several complications. According to the World Cancer Research Fund, Multiple Myeloma is the 3rd most common blood cancer, with 176,404 new cases worldwide in 2020 including more than 50,000 cases in Europe, 35,318 in the US, and 31,890 in Eastern Asia. There have been more than 117,000 deaths worldwide in 2020 with a median overall survival of less than 12 month in patients refractory to standard of care.
Initial treatment comprises of a combination of different biological and targeted chemotherapies, and bone marrow transplants for eligible patients. Immunotherapy with monoclonal antibodies against CD38 such as daratumumab and isatuximab are the most rapidly growing treatment option. Antibody-drug conjugates and Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA and T-Cell Engager Bispecific Antibodies have recently been approved for Multiple Myeloma but high cost, limited product supply and the need for strict safety monitoring may limit their use.

On October 27, 2022 Totus Medicines, a drug discovery company with the mission to make any protein druggable through its breakthrough chemical biology platform, reported that the poster presentation for TOS-358 at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA 2022) held in Barcelona Oct 26-28, 2022 (Press release, Totus Medicines, OCT 27, 2022, View Source [SID1234622527]). The poster exhibits data from the clinical development candidate TOS-358, the first highly selective covalent molecule targeting PI3Kα, which is the most mutated oncogene in cancer. Totus Medicines is set to start clinical trials of TOS-358 in early 2023.

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Presentation Title: Preclinical characterization of TOS-358, a potent and selective covalent inhibitor of wild-type and mutant PI3Kα with superior anticancer activity
Session title: New Drugs
Session type: Poster Session
Catalog number: 107
Presentation number: PB097

TOS-358 is a highly selective covalent inhibitor of PI3Kα. TOS-358 demonstrates clear superiority compared to non-covalent molecules by achieving deep and durable inhibition of PI3K-AKT signaling. In various preclinical disease models, including over 30 patient derived xenograft (PDX) models, TOS-358 led to dramatically superior efficacy compared with non-covalent compounds targeting PI3Kα such as alpelisib and GDC-0077. This stems from TOS-358’s unique ability to robustly and durably inhibit the PI3K/AKT pathway in cells prone to pathway feedback and re-activation. Based on well-established mechanistic understandings of PI3Kα and in vivo TOS-358 data across multiple preclinical species, TOS-358 has an excellent therapeutic window with minimal glucose effects in the clinic. Totus plans to present this data at a future scientific conference.

TOS-358 highlights the company’s ability to identify highly specific and potent molecules against previously poorly drugged or undrugged targets.

On October 27, 2022 Terex Corporation (NYSE: TEX) reported its results for the third quarter 2022 (Press release, Zhejiang Terex Pharmaceutical, OCT 27, 2022, View Source [SID1234622526]).

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CEO Commentary
"We are pleased with our strong financial performance in the quarter as a result of continued progress on our strategy and the relentless focus of our team members to deliver our products and solutions to customers and dealers," said Terex Chairman and Chief Executive Officer John L. Garrison, Jr. "We grew sales 21% when adjusting for FX rates and ended the quarter with total backlog of $3.9 billion, an increase of 33% year-over-year and a clear indication of the strength of demand from our customers."

"We remain focused on executing our multi-year growth plan and continue to invest in new technologies and products across our businesses. In our Materials Processing segment we expanded the capabilities of our growing environmental business with the recent acquisition of ZenRobotics, allowing us to deploy robot technologies that pick, sort and recycle waste material. In addition, our Genie team continued to execute their product electrification plans with the introduction of a new lithium-ion battery option for the line of GS E-Drive slab scissor lifts. We are proud of our execution this quarter despite continued global supply chain disruptions, significant inflationary pressures and foreign exchange rate volatility. Following the strong performance in the third quarter, we are raising our full year EPS outlook to a range of $4.00 to $4.20. Our globally recognized brands, industry-leading and innovative new products, backlog, and strong balance sheet position us well to successfully navigate the near-term macro challenges and deliver long-term value."

Third Quarter Operational and Financial Highlights

Net sales of $1.1 billion in the third quarter of 2022 increased 12.7%, compared to $1.0 billion in the third quarter of 2021. The increase was primarily due to improved price realization necessary to mitigate rising costs across all segments and healthy demand for our products which was partially offset by a 7.9% negative impact from changes in foreign exchange rates.
Income from operations of $120.8 million, or 10.8% of net sales in the third quarter of 2022, improved from $74.2 million, or 7.5% of net sales, in the prior year. The year-over-year increase of $46.6 million was driven by price realization, favorable mix and incremental margin achieved on higher sales volume, which more than offset cost increases and the negative impact of foreign exchange rates during the quarter. Price / cost dynamics improved sequentially, increasing operating margins by 120 bps from the second quarter of 2022.
Income from continuing operations in the third quarter of 2022 was $81.8 million, or $1.20 per share, up 79.1% compared to $47.5 million, or $0.67 per share, in the third quarter of 2021.
Return on invested capital of 19.0% significantly exceeded our cost of capital as we continued to invest in the business and return cash to shareholders through dividends and share repurchases.
Business Segment Review

Materials Processing

Net sales were $457.9 million for the third quarter of 2022, up 9.4% or $39.2 million year-over-year, primarily due to price realization necessary to mitigate rising costs and healthy demand for our products across multiple businesses. Excluding the impact of foreign exchange rates of approximately $43 million, net sales increased 19.6% year-over-year.
Income from operations increased to $66.8 million for the third quarter of 2022, or 14.6% of net sales, compared to $57.1 million, or 13.6% of net sales, in the prior year. The $9.7 million increase was driven by price realization, favorable mix and incremental margin on higher sales volume and partially offset by significant inflationary pressures and the negative effects of foreign exchange rate changes.
Aerial Work Platforms

Net sales were $662.6 million for the third quarter of 2022, up 15.7% or $90.1 million year-over-year. Excluding the impact of foreign exchange rates of approximately $35 million, net sales increased 21.9% year-over-year. The increase was primarily due to price realization necessary to mitigate rising costs and higher demand driven by fleet replacement and end-market growth for aerial work platforms. Utility product growth was strong in North America.
Income from operations increased to $63.5 million for the third quarter of 2022, or 9.6% of net sales, compared to $34.9 million, or 6.1% of net sales in the prior year. The $28.6 million increase was driven by price realization, favorable mix and incremental margin on higher sales volume and was partially offset by increased costs, as well as the negative effects of foreign exchange rate changes.
Income from operations increased 81.9% year-over-year and margins were up sequentially from the second quarter of 2022 by 190 basis points. This sequential improvement was the result of strong execution on strict cost management and pricing actions to mitigate inflationary cost pressures.
Disciplined Capital Allocation

As of September 30, 2022, the Company had liquidity (cash and availability under our revolving line of credit) of $658.0 million.
Working capital of $895.7 million was 20.0% of trailing three month annualized net sales and reflects higher inventory levels as a result of supply chain disruptions.
For the year-to-date period, Terex deployed $128.9 million for capital expenditures and growth investments.
Year-to-date, Terex has executed $92.0 million in share repurchases and paid $26.8 million in dividends.
CFO Commentary
Julie Beck, Senior Vice President and Chief Financial Officer, said "We are proud that our strong balance sheet has allowed us to return approximately $120 million of cash to shareholders year-to-date. Our teams continue to execute on our multi-year growth plan, driving sales and expanding margins through disciplined pricing and expense management. As a result, we are raising our full year sales, margin and EPS guidance ranges."