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."

On October 27, 2022 Pulse Biosciences, Inc. (Nasdaq: PLSE), a novel bioelectric medicine company commercializing the CellFX System powered by Nano-Pulse Stimulation (NPS) technology, reported it will report financial results for the third quarter of 2022 after market close on Thursday, November 10, 2022 (Press release, Pulse Biosciences, OCT 27, 2022, View Source [SID1234622525]). Company management will host a corresponding conference call beginning at 1:30pm PT / 4:30pm ET.

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Investors interested in listening to the conference call may do so by dialing 1-877-704-4453 for domestic callers or 1-201-389-0920 for international callers. A live and recorded webcast of the event will be available at View Source

On October 27, 2022 Clovis Oncology, Inc. (NASDAQ: CLVS) reported the presentation of data from the TRITON3 Phase 3 trial in men with metastatic castration-resistant prostate cancer with BRCA or ATM mutations (Press release, Clovis Oncology, OCT 27, 2022, View Source [SID1234622524]). The presentation titled, "TRITON3: A Phase 3 Study of Rucaparib vs. Physician’s Choice of Therapy in mCRPC Associated with Homologous Recombination Deficiency (HRD)" is being presented by Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and co-principal investigator of the TRITON3 trial during the session titled, "Novel Clinical Trial Updates" at the 29th Annual Prostate Cancer Foundation (PCF) Scientific Retreat.

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The presentation is available at View Source

"We believe that the positive results from TRITON3 further demonstrate the important role that Rubraca may play as a treatment option for men with metastatic castration-resistant prostate cancer associated with homologous recombination deficiency. This is the first and only PARP inhibitor that has demonstrated superior radiographic PFS compared to a control arm containing docetaxel chemotherapy, which is today the standard of care for these patients," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We look forward to submitting additional data for presentation during a medical meeting in 2023."

Earlier this month, the Company reported top-line data from the TRITON3 (NCT02975934) study evaluating Rubraca monotherapy versus chemotherapy or second-line second-generation androgen pathway inhibitor in patients with chemotherapy-naive mCRPC with mutations in BRCA or ATM achieved the primary endpoint of improved radiographic progression-free survival (rPFS) by independent radiology review (IRR).

About the TRITON3 Clinical Trial

TRITON3 (NCT02975934) is a Phase 3, multicenter, open-label, randomized trial of Rubraca in patients with chemotherapy-naïve mCRPC. Patients with a mutation in BRCA or ATM were randomized to Rubraca or the control group, which consisted of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. The primary objective was efficacy, as analyzed by independent radiology review (IRR) of radiographic progression-free survival (rPFS) in patients with mutations in BRCA1, BRCA2 or ATM. TRITON3 was designed as a Phase 3 trial to confirm and expand the efficacy data from TRITON2 in an earlier treatment setting against a relevant control arm.

About Prostate Cancer

The American Cancer Society estimates that approximately 268,000 men in the US will be diagnosed with prostate cancer in 2022, and the GLOBOCAN Cancer Fact Sheets estimated that approximately 473,000 men in Europe were diagnosed with prostate cancer in 2020. Castrate-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castrate-resistant prostate cancer (mCRPC) is an incurable disease, usually associated with poor prognosis.i Approximately 43,000 men in the US were expected to be diagnosed with mCRPC in 2020.ii According to the National Cancer Institute, the five-year survival rate for mCRPC is approximately 30%. BRCA1, BRCA2 or ATM mutations have been detected in approximately 19% of patients with mCRPC according to articles published in JCO Precision Oncology in 2017 and in Clinical Cancer Research in 2021. These molecular markers may be used to select patients for treatment with a PARP inhibitor.iii

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca is an unlicensed medical product outside of the US and Europe.

Rubraca US FDA Approved Indications

Ovarian Cancer

Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Prostate Cancer

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) have occurred in patients treated with Rubraca and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28-day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common adverse reactions in TRITON2 (≥ 20%; Grade 1-4) were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.

On October 27, 2022 Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, reported new data from two studies demonstrating the potential of DecisionDx-Melanoma and DecisionDx-UM to accurately stratify risk of death from melanoma (cutaneous melanoma (CM) and uveal melanoma (UM), respectively) in a group of real-world, unselected and prospectively tested patients (Press release, Castle Biosciences, OCT 27, 2022, View Source [SID1234622523]). The studies are part of the Company’s ongoing collaboration with the National Cancer Institute (NCI) to link DecisionDx-Melanoma and DecisionDx-UM clinical testing data with data from the Surveillance, Epidemiology and End Results (SEER) Program’s registries on CM and UM cases, respectively. The data were shared in poster presentations at the 19th International Congress of the Society for Melanoma Research (SMR) in Edinburgh, United Kingdom.

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"Castle is committed to providing innovative and clinically actionable tests that can guide more informed and more personalized treatment decisions," said Derek Maetzold, president and chief executive officer of Castle Biosciences. "We believe our DecisionDx family of GEP tests has clinical value, and the studies that we have done in collaboration with the NCI’s SEER Program provide a unique opportunity to demonstrate their performance, specifically DecisionDx-Melanoma and DecisionDx-UM, in real-world patients with known survival outcomes."

DecisionDx-Melanoma | Poster #: P- 036

Improving patient selection for adjuvant therapy: Considerations for the role of the 31-gene expression profile test

Pembrolizumab (KEYTRUDA) received expanded FDA approval as an adjuvant therapy for patients with stage IIB-IIC melanoma in late Dec. 2021 but is associated with a high adverse-event rate, suggesting that the benefit-to-risk ratio for patient selection could be improved by identifying patients who would have high survival rates without therapy. The study evaluated the risk stratification performance of DecisionDx-Melanoma in a group of real-world, unselected and prospectively tested patients with stage I-III CM in the SEER registry (n=4,687), including stage IIB-IIC patients who could potentially benefit from better selection for adjuvant therapy.

In the study, DecisionDx-Melanoma was a statistically significant and independent predictor of melanoma-specific survival (MSS), consistent with previously published retrospective and prospective studies. Patients with stage IIB or IIC melanoma and a low-risk (Class 1A) DecisionDx-Melanoma test result had higher three-year MSS than patients with a high-risk (Class 2B) result (Class 1A: 100% vs. Class 2B: 88.3%, p=0.04); similar results were observed for patients with stage III CM (Class 1A: 96.1% vs. Class 2B; 79.6%, p=0.03). Additionally, DecisionDx-Melanoma was a statistically significant and independent predictor of MSS across all stages of disease, with a hazard ratio of 7.00 for the Class 2B result. Overall, the study data show that DecisionDx-Melanoma can identify patients with a low risk of death from CM who could potentially forego unnecessary adjuvant therapies, thereby reducing healthcare costs and adjuvant therapy-related adverse events; conversely, the test can identify patients who are at a much higher likelihood of progressing, potentially enabling more aggressive decisions regarding the use of adjuvant therapy.

The poster may be viewed here.

DecisionDx-UM | Poster #: P- 035

A collaborative outcome study in uveal melanoma with the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program Registries (NCI SEER): Performance of the 15-gene expression profile test in clinically tested uveal melanoma patients

The study evaluated the risk-stratification performance of DecisionDx-UM in a real-world, unselected, clinically tested cohort of patients with UM (n=615). On behalf of the SEER registries, a third-party honest broker conducted a linkage of all patients with UM from 16 NCI SEER registries to those clinically tested with DecisionDx-UM. The study included all linked cases diagnosed in 2018 with survival outcome information and a DecisionDx-UM test result. Patients with stage IV disease (evidence of distant metastasis) at initial presentation were excluded from the analysis.

In the study, DecisionDx-UM accurately stratified patient risk of death from UM. Patients with a low-risk (Class 1A) DecisionDx-UM test result had higher 18-month overall survival (OS) and 18-month MSS than patients with a high-risk (Class 2) test result (OS=97.1% vs. 86.2%, P=0.02; MSS= 98.9% vs. 92.7%; P=0.02). Additionally, patients with a high-risk DecisionDx-UM test result had a ten-fold higher risk of death from UM than patients with a low-risk test result (hazard ratio=10.06, p=0.033). Overall, the study data confirm the accurate risk-stratification performance of DecisionDx-UM shown in previously published studies, which is important for guiding management decisions regarding the frequency of follow-up and metastatic surveillance imaging, as well as participation in clinical trials.

The poster may be viewed here.

About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile risk stratification test. It is designed to inform two clinical questions in the management of cutaneous melanoma: a patient’s individual risk of sentinel lymph node (SLN) positivity and a patient’s personal risk of melanoma recurrence and/or metastasis. By integrating tumor biology with clinical and pathologic factors using a validated proprietary algorithm, DecisionDx-Melanoma is designed to provide a comprehensive and clinically actionable result to guide risk-aligned patient care. DecisionDx-Melanoma has been shown to be associated with improved patient survival and has been studied in more than 9,000 patient samples. DecisionDx-Melanoma’s clinical value is supported by more than 35 peer-reviewed and published studies, providing confidence in disease management plans that incorporate the test’s results. Through June 30, 2022, DecisionDx-Melanoma has been ordered 105,239 times for patients diagnosed with cutaneous melanoma. More information about the test and disease can be found at www.CastleTestInfo.com.

About DecisionDx-UM

DecisionDx-UM is Castle Biosciences’ 15-gene expression profile (GEP) test that uses an individual patient’s tumor biology to predict individual risk of metastasis in patients with uveal melanoma. DecisionDx-UM is the standard of care in the management of newly diagnosed uveal melanoma in the majority of ocular oncology practices in the United States. Since 2009, the American Joint Committee on Cancer (AJCC; v7 and v8) Staging Manual for UM has specifically identified the GEP test as a prognostic factor that is recommended for collection as a part of clinical care. Further, the National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma include the DecisionDx-UM test result as a prognostic method for determining risk of metastasis and recommended differential surveillance regimens based on a Class 1A, 1B, and 2 result. DecisionDx-UM is the only prognostic test for uveal melanoma that has been validated in prospective, multi-center studies, and it has been shown to be a superior predictor of metastasis compared to other prognostic factors, such as chromosome 3 status, mutational status, AJCC stage and cell type. It is estimated that nearly 8 in 10 patients diagnosed with uveal melanoma in the U.S. receive the DecisionDx-UM test as part of their diagnostic workup. More information about the test and disease can be found at www.CastleTestInfo.com.