On June 30, 2021 Tweardy reported that it has been studying the signal transducer and activator of transcription 3 (STAT3) gene for 30 years (Press release, Tvardi Therapeutics, JUN 30, 2021, View Source [SID1234584512]). DePinho, who conceived andlaunched MD Anderson’s Cancer Moon Shots Program, successfully founded and raised capital for companies including Aveo Pharmaceuticals Inc. and KaryopharmTherapeutics Inc. Together, they raised $25 million in grants to move molecules targeting STAT3 toward the clinic, followed by $9 million in series A financing at thecompany’s launch in September 2018 to fund early clinical work.

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CEO Imran Alibhai, a long-time biotech investor and University of Texas- and Duke University-educated scientist, was hired to lead the company at the end of 2018. Hewas previously a senior vice president and managing director of Houston-based Dnatrix Inc.

STAT3 is important not only in the tumor itself, but also in the environment around the tumor, Alibhai said. Its activation is observed in about 70% of all cancers and up to95% of hepatocellular carcinomas (the most common type of primary liver cancer), according to research the company presented during a poster session at the 2021American Society of Clinical Oncology meeting.

As an orally bioavailable small molecule, TTI-101 "binds STAT3 and prevents phosphorylation, homodimerization, nuclear translocation, and ultimately, STAT3-mediatedtranscriptional activity," researchers explained.

To date, the drug has been "incredibly well tolerated," Alibhai told BioWorld, distinguishing it from other STAT3 inhibitor programs, such as Otsuka Pharmaceutical Co.Ltd.’s tablet-formulated OPB-31121, which the company quit developing following phase I results that reflected grade 3 adverse events (AEs) including lactic acidosis,diarrhea and vomiting. Another STAT3 gene inhibitor co-developed by Ionis Pharmaceuticals Inc. and Astrazeneca plc, danvatirsen, has also run into drug-related AEs insome patients, though the current status of the I.V.-administered candidate was unclear.
Selective targeting is the "secret sauce" of TTI-101, Alibhai said. "If you perturb STAT3 in general, you could potentially cause issues in all cells. So you have to be veryspecific about how you’re targeting it and only potentially disrupt the nuclear function," he said.

In Tvardi’s ongoing phase I study so far, TTI-101 has not only side-stepped dose-limiting toxicities, but also shown early signs of clinical benefit, Alibhai said. Multipleparticipants in the study also saw durable partial responses. The trial enrolled patients with both unresectable hepatocellular carcinoma and locally advanced, inoperable,metastatic and/or treatment-refractory solid tumors without other therapeutic options.

With dose escalation wrapped up in multiple arms of the study, it’s now moving on to dose-expansion cohorts which pave the way for phase II testing in liver cancer next.While the specific design of the phase II trial hasn’t been disclosed yet, Alibhai said investigators will enroll several cohorts of liver cancer patients which could generatesignals that could transition very quickly into confirmatory trials.

An expedited trial of TTI-101 in fibrosis could follow. So far, Tvardi has preclinical data demonstrating efficacy in liver fibrosis, idiopathic pulmonary fibrosis and sclerosis,Alibhai said. By the end of next year, the company could also move a second-generation STAT3 inhibitor it is developing, TTI-102, to the clinic. The ‘101 and ‘102 programsshare a similar scaffold, but the latter has shown early-on potency three to eight times greater than what has been seen with ‘101.

New investors Slate Path Capital, Palkon Capital, Arrowmark Partners and 683 Capital, led Tvardi’s series B round, with continued funding from existing investors,including Sporos Bioventures. In conjunction with the financing, Jamie McNab, partner at Slate Path Capital, will join Tvardi’s board. The company was Sporos’ firstinvestment. Along the way, it has attracted a number of high-profile scientific advisors, including MD Anderson Department of Immunology Chairman Jim Allison andKeith Flaherty, a professor of medicine at Harvard Medical School who co-founded Loxo Oncology and Scorpion Therapeutics Inc.

"As a physician, I am eager to see the potential of Tvardi’s molecules in diseases of high unmet medical need where STAT3 is a key driver," Flaherty said.

On June 30, 2021 Sirnaomics, Inc., a biopharmaceutical company engaged in the discovery and development of RNAi therapeutics against cancer and fibrotic diseases, reported dose administration for the first patient in a Phase 2b study of the company’s drug candidate, STP705, for the treatment of squamous cell skin cancer in situ (isSCC) (Press release, Sirnaomics, JUN 30, 2021, View Source [SID1234584510]). STP705 is a siRNA (small interfering RNA) therapeutic that takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression.

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The randomized, double-blind, placebo-controlled Phase 2b study is evaluating the safety and efficacy of intralesional injection of STP705 in up to 100 adult patients with isSCC. This portion of the trial will further evaluate the two most efficacious dosing regimens of 30 ug and 60 ug. The primary endpoint of this trial is the proportion of participants with histological clearance of treated isSCC lesion at the end of treatment. Histological clearance will be defined as the absence of detectable evidence of isSCC tumor cell nests as determined by central pathology review.

"For many patients with isSCC, surgery is still considered the only viable treatment option, so with our first patient dosed in this Phase 2b study, we’ll be able to observe the efficacy of STP705, which has to the potential to be a non-surgical, non-invasive alternative," said Michael Molyneaux M.D., Chief Medical Officer. "Our interim readout later this year will guide our clinical development for this indication."

"After a high rate of patients achieved histological clearance in the Phase 2a study of STP705 for isSCC, we’re looking forward to seeing the results of our Phase 2b study as we begin patient dosing," said Patrick Lu, Ph.D., founder, President and CEO of Sirnaomics. "The anticipated clinical readout in the second half of 2021 will provide more insights into the potential of STP705 for the treatment of non-melanoma skin cancer and the impact of RNAi therapeutics in oncology."

Additional information about this clinical trial is available at clinicaltrials.gov using the identifier: NCT04844983.

About Non-melanoma Skin Cancer and Squamous Cell Carcinoma In Situ
Skin cancer is the most common type of all cancers diagnosed each year in the United States. It is estimated that nearly half of cancers diagnosed every year will be skin cancers. Over the past decade, the incidence of skin cancers has increased dramatically. According to the JAMA Dermatology paper (Rogers, et. al. JAMA Dermatol. 2015151(10):1081-1086), an estimated 3.3 million people in the US suffer from non-melanoma skin cancer (NMSC) along with 5.43 million people that are currently living with cancer lesions.

Squamous cell carcinoma in situ, also called Bowen disease, is the earliest form of squamous cell skin cancer (SCC). Along with basal cell carcinoma, SCC is one of two major subtypes of NMSC. The key driver for development of SCC is ultraviolet rays from the sun. It is believed that development of SCC is linked closely to genomic perturbations, genetic mutations, and altered expression of key molecules (e.g., overexpression of TGF-β1 and COX-2) that impacts squamous cell lineage commitment and terminal differentiation.

Surgery is the currently the most common treatment option for the treatment of NMSC. The various forms of surgical modalities carry significant cutaneous adverse events, risk of scar, infection and bleeding. Surgery can also have a significant recurrence rate. As a result, there is a high unmet need for an FDA approved local injection therapy that is safe and effective.

About STP705
Sirnaomics’ product candidate, STP705, is a siRNA (small interfering RNA) therapeutic that takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. The product candidate has received multiple IND approvals from both the US FDA and Chinese NMPA, including treatments of cholangiocarcinoma, nonmelanoma skin cancer and hypertrophic scar. STP705 has also received Orphan Drug Designation for treatment of cholangiocarcinoma and primary sclerosing cholangitis. A Phase 2a study of STP705 for treatment of squamous cell skin cancer (isSCC) in adult patients demonstrated positive efficacy and safety results, with 76% of all patients (19/25) achieving complete histologically clearance and the two optimal dosing ranges achieving 90% histological clearance of tumor cell in the lesion. No significant or serious adverse events, including no significant cutaneous skin reactions, were reported in the study, and the company was able to define a clear therapeutic window in advance of later stage studies.

On June 30, 2021 SELLAS Life Sciences Group, Inc. (NASDAQ: SLS) ("SELLAS" or the "Company"), a late-stage clinical biopharmaceutical company focused on developing novel cancer immunotherapies for a broad range of indications, reported promising updated clinical data and initial immunobiological data from its Phase 1/2 clinical trial with its lead asset, galinpepimut-S (GPS), the Company’s Wilms Tumor-1 (WT1)-targeting peptide immunotherapeutic, in combination with the checkpoint inhibitor pembrolizumab (Keytruda) (Press release, Sellas Life Sciences, JUN 30, 2021, View Source [SID1234584509]).

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Conducted under a Clinical Trial Collaboration and Supply Agreement with Merck & Co., Inc., Kenilworth, N.J. USA (known as MSD outside of the United States and Canada), the study is investigating the combination of GPS and pembrolizumab in treating patients diagnosed with second- or third-line WT1(+) relapsed or refractory platinum-resistant, advanced metastatic ovarian cancer. The WT1 antigen is one of the most widely expressed cancer antigens in multiple malignancies and has been ranked by the National Cancer Institute as the top priority among cancer antigens for immunotherapy.

The study details are as follows:

Eleven patients (median age: 63 years) who received at least three GPS doses, the last of which was combined with pembrolizumab, were evaluated for clinical responses and three of those patients were also evaluated for immune responses.
66.7 percent of evaluable patients were refractory to or had failed their second-line therapies, and 33.3 percent failed third-line therapy or later.
All enrolled patients (100 percent) were resistant to the standard of care platinum-based therapy. Expected overall survival for patients receiving standard of care platinum-based therapy is nine to 12 months.
Median overall survival among the patients in this trial is not yet known as all patients are still alive at the time of the analysis, which period of time exceeds nine months.
Disease Control Rate
An ad hoc analysis of clinical outcomes in the cohort of 11 patients shows a disease control rate (DCR), the sum of overall response rate and rate of stable disease, of 63.6 percent, with a median follow-up of 15.4 weeks. In December 2020, the Company reported initial data showing a DCR of 87.5 percent in eight patients, with a median follow-up of 9.4 weeks. In this very difficult treatment-resistant patient population, at the time of the follow-up analysis, median progression-free survival (PFS) was 11.8 weeks. The landmark PFS rate by log-rank analysis at six months (26 weeks) was 33 percent.

Analysis of the updated data, using a validated immunohistochemistry assay during the eligibility screening period, shows that the rate of WT1 ovarian tumor positivity in this patient population remained high at approximately 63.6 percent. As of the time of this analysis, all patients are alive, and five patients (45.5 percent) are continuing to receive investigational therapy. Enrollment for this study is ongoing, with a target of approximately 20 total evaluable patients.

The safety profile of the GPS-pembrolizumab combination was similar to that seen with pembrolizumab alone, with the addition of only low-grade, temporary local reactions at the GPS injection site, consistent with previously performed clinical studies with GPS.

Immunobiological Data
CD8+ and CD4+ T-lymphocytes were isolated from peripheral blood mononuclear cells from three patients from whom samples had been collected both at baseline and at the time of the sixth GPS dose (i.e., 18 weeks after starting investigational therapy). The T-cells were assayed ex-vivo for immune responses against the pool of the four peptides that comprise GPS using the validated assay intracellular cytokine staining with fluorescence-activated single cell sorting (ICS-FACS) (Scorpion Biological Services, San Antonio, Texas), with appropriate positive and negative controls.

A total of five cytokine "channels" were used for the analysis (i.e., interferon-g, TNF-a, interleukin-2, CD107a and MIP-1b). The peptide re-challenge incubation period was seven days. At the 18-week time point versus pre-vaccination baseline, the assay demonstrated a relative increase in WT1-specific T-lymphocyte frequencies in peripheral blood averaging +242 percent (range: +104 to +385 percent across five cytokines) for CD8+ and +80.5 percent (range: +1 to +174 percent) for CD4+. There was also evidence of polyfunctional T-cell activation (increases in secretion of >2 cytokines) in two out of three patients (66 percent).

"Considering the overall poor prognosis in this particular clinical setting and based on the observed median PFS, overall survival and DCR in this study, combining GPS with the PD1 inhibitor pembrolizumab appears to be clinically promising as compared to bevacizumab-free salvage chemotherapy regimens and without the toxicity burden associated with the latter," said Angelos Stergiou, M.D., Sc.D. h.c., President and CEO, SELLAS. "Patients treated with GPS plus pembrolizumab also appear to maintain a considerable degree of stable disease, as evidenced by the median DCR of 63.6 percent – all evaluable patients are alive. Continuing to review the clinical data will help us determine the fundamental value of the combination approach to fighting this disease. The initial trends are promising, and further maturity of the data and studying additional patients will allow us to draw more definitive conclusions regarding the clinical benefit. We expect to perform another set of similar ad hoc clinical and immunobiological analyses over the next six months as the study progresses."

"Based on this early data, it is encouraging to see the induction of WT1-specific T-cell immune responses with the administration of GPS in combination with pembrolizumab with a validated complex ex-vivo immune response assay on peripheral blood from patients with platinum-refractory metastatic ovarian cancer who had undergone numerous prior therapies," added Jeffrey S. Weber, M.D., Ph.D.; Deputy Director of the Perlmutter Cancer Center at New York University (NYU)-Langone Health; Co-Director of its Melanoma Research Program Center; and Chair of SELLAS’ Scientific Advisory Board. "Expansion of these results with data from additional patients, as well as at time points longer than 18 weeks (when such patient samples become available for testing), will be key in getting a more comprehensive picture of the combination immunotherapy’s biological effect."

About Ovarian Cancer
Ovarian cancer is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women in the United States. Over 22,000 cases are diagnosed annually, and there are an estimated 15,500 deaths per year. The majority of patients have widespread disease at presentation. The five-year survival for the advanced-stage disease remains less than 30 percent. Combining GPS with the checkpoint inhibitor pembrolizumab, which beneficially and profoundly alters the tumor microenvironment (TME), is hypothesized to increase the proportion of patients who develop an immune response against their cancer and potentially improve their clinical outcome over pembrolizumab monotherapy, without the burden of additional toxicities in macroscopically measurable malignancies.

On June 30, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that it will hold its second-quarter 2021 sales and earnings conference call with institutional investors and analysts at 8:00 a.m. EDT on Thursday, July 29 (Press release, Merck & Co, JUN 30, 2021, View Source [SID1234584508]). During the call, company executives will provide an overview of Merck’s performance for the quarter.

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Investors, journalists and the general public may access a live audio webcast of the call on Merck’s website at View Source A replay of the webcast, along with the sales and earnings news release and supplemental financial disclosures and slides highlighting the results, will be available at www.merck.com.

Institutional investors and analysts can participate in the call by dialing (833) 353-0277 or (469) 886-1947 and using ID code number 5951886. Members of the media are invited to monitor the call by dialing (833) 353-0277 or (469) 886-1947 and using ID code number 5951886. Journalists who wish to ask questions are requested to contact a member of Merck’s Media Relations team at the conclusion of the call.

On June 30, 2021 Genomic Testing Cooperative, a first-in-class diagnostic company based on a cooperative business model (Co-Op) using the most recent advances in NGS technology, reported a collaboration with Elevation Oncology to enhance identification of patients with any solid tumor harboring an NRG1 fusion who may be eligible for enrollment in the Phase 2 CRESTONE study (Press release, Genomic Testing Cooperative, JUN 30, 2021, View Source [SID1234584507]).

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GTC’s business is based on a cooperation model and has partnerships with multiple Co-Op members, all offering identical menus as GTC. This identification of patients with tumors harboring an NRG1 fusion is extended to all Co-Op members laboratories including Anthology Diagnostics in Edison, NJ and Key Genomics Laboratory at the John Theurer Cancer Center. Patients identified at these sites may be eligible for referral into the CRESTONE study.

"Our goal is to provide comprehensive actionable molecular profiling so patients and their treating physicians can personalize therapy and select the proper treatment that has the potential of improving outcome," stated Dr. Maher Albitar, GTC Chief Executive Officer and Chief Medical Officer "The Co-Op model allows us to enable all members of the Co-Op to update their offering and make testing for NRG1 fusion available to their patients."

"We believe that comprehensive biomarker testing of DNA and RNA is critical to give each patient their best chance of getting matched with a precision medicine," said Shawn Leland, PharmD, RPh, Founder and Chief Executive Officer of Elevation Oncology. "We are pleased to add Genomic Testing Cooperative to our growing community of collaborators, who share our vision of profiling every patient’s tumor to identify genomic driver alterations that may be actionable."

The Solid Tumor Profile Plus offered by GTC combines the analysis of DNA with RNA to provide comprehensive evaluation of cancer that includes detection of single nucleotide variation, copy number variation, expression and fusion. This includes testing of abnormalities in 434 DNA genes and 1408 RNA genes.

Under the terms of the agreement, GTC will help Elevation Oncology identify patients with advanced solid tumors that harbor an NRG1 fusion for participation in Elevation Oncology’s CRESTONE trial. Eligible patients will be referred to active clinical trial sites in Elevation Oncology’s Phase 2 CRESTONE trial of seribantumab in adult patients with recurrent, locally advanced or metastatic solid tumors that harbor an NRG1 fusion.

Patients and physicians can learn more about the CRESTONE study at www.nrg1fusion.com or on www.ClinicalTrials.gov under the NCT number NCT04383210.