On September 15, 2020 Ryvu Therapeutics (WSE: RVU), a clinical-stage biopharmaceutical company developing novel small molecule therapies that address emerging targets in oncology, reported today its 2020 H1 financial results and provided a corporate update (Press release, Ryvu Therapeutics, SEP 15, 2020, View Source [SID1234565194]).

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"At Ryvu, we always excelled in moving forward at a rapid pace; however, the first half of 2020 was an exceptionally eventful and intensive period for us. We have managed to achieve a couple of significant clinical milestones such as successful completion of Phase I for SEL24/MEN1703 in acute myeloid leukemia, as well as the receipt of an Orphan Drug Designation for SEL120 for the treatment of AML patients.

"We announced a collaboration with Galapagos focused on the discovery and development of novel small molecule drugs in inflammation. In June, we completed the construction of the R&D Center for Innovative Drugs and subsequently moved into our new laboratories and offices. Soon afterward, we have announced our updated development strategy for 2020-2022, which was followed by the issue of series I shares and raise of over USD 36 million of new capital" – commented Pawel Przewiezlikowski, Chief Executive Officer of Ryvu.

"We have also secured additional non-dilutive grant financing to support the development of our targeted immuno-oncology program. Despite the global pandemic, we participated in numerous scientific and business conferences presenting very good data from our early pipeline projects. What is exceptional is that we managed to do all of this and much more during the ongoing COVID-19 pandemic, including the continuation of SEL120 Phase I study in AML/MDS in the U.S.

"The epidemiological situation required us to adopt numerous preventive measures across our entire organization to keep our scientists safe and, at the same time, assure business continuity. I believe we passed that test with flying colors, and I am proud of the work we have done at Ryvu in these six months" – adds Przewiezlikowski.

Recent Achievements

On February 21, Ryvu signed a grant agreement for the development of targeted oncology therapies based on the synthetic lethality concept. This grant provides Ryvu with almost USD 8.3 million of non-dilutive financing to discover, develop, and select a clinical candidate targeting cancers which had been considered in the past as largely undruggable using rational approaches. The total net value of the project amounts to USD 14 million, and the anticipated project duration is until December 2023.
On March 5, Menarini Group announced the successful completion of Phase I clinical study of SEL24/MEN1703 in Acute Myeloid Leukemia, which entitled Ryvu to receive a USD 1.96 million milestone payment. The full data from the study was be presented as a poster "Results of the dose escalation part of DIAMOND trial (CLI24-001): First-in-human study of SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor, in patients with acute myeloid leukemia" during the Virtual 25th EHA (Free EHA Whitepaper) Congress taking place June 11-21. Throughout the dose escalation part, SEL24/MEN1703 showed an acceptable safety profile up to the recommended dose established at 125 mg/day (14 days ON – 7 days OFF in 21-days cycles). Initial evidence of single agent efficacy was observed with 1 CR and 1 CRi in elderly patients who had exhausted standard therapeutic options. A cohort Expansion study planned in relapsed/refractory AML patients in the United States and Europe, including Poland, will further investigate the single agent activity and the safety profile of SEL24/MEN1703.
On March 27, the U.S. Food and Drug Administration (FDA) granted an orphan drug designation (ODD) to Ryvu’s SEL120 for the treatment of patients with acute myeloid leukemia (AML).
On April 15, Galapagos NV (Euronext &NASDAQ: GLPG) and Ryvu Therapeutics announced a collaboration focused on the discovery and development of novel small molecule drugs in inflammation. Ryvu will contribute its biology and chemistry platform as well as related intellectual property to the program. During the joint research collaboration, Ryvu is responsible for early drug discovery, and Galapagos will be responsible for all further development of the program.
On June 2, Ryvu obtained the occupancy permits for its newly built R&D Center for Innovative Drugs, meaning it has completed the construction of the facility. Subsequently, Ryvu has initiated its move to the new headquarters.
On June 3, NodThera, Ryvu spin-off company, secured GBP 44.5 million (USD 54.5 million) Series B financing. NodThera was founded by Epidarex Capital and Ryvu in 2016 based on world class research on NLRP3 inflammasome conducted at Ryvu (at that time Selvita) in 2012-2016. The Company focused on the development of inflammasome inhibitors has already raised over GBP 80.8 million (over USD 100 million) in three funding series. After the full completion of Series B capital increase, Ryvu owns 4.8% in NodThera.
On June 4, Ryvu signed a grant agreement for the development of targeted immuno-oncology therapy, which provides Ryvu with almost USD 5.6 million of non-dilutive financing to discover, develop and select a clinical candidate targeting cancers which had been considered in the past as largely undruggable using rational approaches. The total net value of the project amounts to over USD 8.9 million, and the anticipated project duration is until December 2023.
On June 15, Ryvu announced its updated development strategy for 2020-2022, which assumes, i.a.: completing Phase I clinical development of SEL120 in AML/MDS by the end of 2022, expanding therapeutic potential for SEL120 in solid tumors and launching a new Phase I study in selected indications in parallel to the ongoing hemato-oncology studies, advancing at least one program into the Phase I of clinical trials from preclinical pipeline.
Important milestones in 2020, before the report date

On July 22, the Extraordinary General Meeting of Ryvu Therapeutics’ Shareholders has decided to issue up to 2,384,245 Series I ordinary bearer shares, with the exclusion of pre-emptive rights. The share issue constituted up to 15 percent of the current Company’s share capital. As a result, Ryvu Therapeutics raised over USD 36 million. Proceeds from the share issue will be allocated primarily to the Company’s R&D programs.
In H1 2020, Ryvu Therapeutics participated and presented at several scientific and investor conferences, including AACR (Free AACR Whitepaper) 2020 Virtual Annual Meeting, Virtual 25th Annual European Hematology Association (EHA) (Free EHA Whitepaper) Congress, Jefferies 2020 Virtual Healthcare Conference, BIO Digital 2020, Solebury Trout Investor Access during JP Morgan 2020, Solebury Trout Virtual Investor Conference, BIO-Europe Spring 2020 and 32nd Annual ROTH Conference.

Ryvu 2020 Half-Year Financial Results

In the first half of 2020, Ryvu Therapeutics noted a 38%* increase in its revenues, up to PLN 24.5 million (USD 6.1 million). Revenues from partnering contracts have increased from PLN 1.9 million (USD 0.5 million ) in H1 2019, up to PLN 14.7 million (USD 3.7 million ) in H1 2020.

Operational costs related in majority to the research and development expenditures amounted in H1 2020 to PLN 36.3 million (USD 9.1 million), as compared to PLN 38.7 million (USD 10.2 million) in the same period last year. Operational loss has decreased and amounted to PLN 11.8 million (USD 3.0 million), compared to PLN 21 million (USD 5.5 million) in H1 2019.

On June 30, 2020, Ryvu Therapeutics held PLN 38.5 million (USD 9.7 million) in cash, cash equivalents, and short-term investments. On September 10, the balance, following the share issue, amounted to PLN 176.9 million (USD 44.4 million).

*Percentage changes in the press release are calculated based on the functional currency [PLN].

On September 15, 2020 Cullinan Oncology, LLC, the German Cancer Research Center and the Eberhard Karls University of Tübingen, Faculty of Medicine (University of Tübingen), Germany, reported the formation of Cullinan Florentine, a company focused on developing a novel FLT3 x CD3 bispecific antibody for the treatment of patients with acute myeloid leukemia (AML) (Press release, Cullinan Oncology, SEP 15, 2020, View Source [SID1234565193]). This antibody has been developed in Tübingen within the German Cancer Consortium (DKTK), whose core center is the German Cancer Research Center (DKFZ) in Heidelberg. Cullinan Florentine has acquired an exclusive license to develop CLN-049 from the University of Tübingen and the DKFZ.

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"We believe the receptor tyrosine kinase FLT3 is among the most attractive targets in AML but is largely untapped as a target for T cell engaging antibodies," stated Jennifer Michaelson, Ph.D., Chief Development Officer, Biologics at Cullinan Oncology. "Given CLN-049’s robust preclinical package and ease of manufacturability, we believe this bispecific antibody has the potential to be a superior treatment option for AML patients. We are looking forward to filing an IND for CLN-049 by year end."

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. AML remains one of the most challenging blood cancers, with high unmet medical need due to low median survival rates in patients. FLT3 is expressed on leukemic cells from the majority of AML patients, including prominent expression on leukemic progenitor cells.

FLT3 is a commercially validated target in AML, yet unlike small molecule inhibitors targeting FLT3, a T cell engaging antibody like CLN-049, which binds to the extracellular domain of FLT3, is agnostic to mutations in the intracellular signaling domain, opening up a broader patient population and avoiding resistance mechanisms. FLT3 has potential advantages over the more commonly selected target antigens for T cell engagers, such as CD33 and CD123, given the low-level expression of FLT3 on normal myeloid cells and hematopoietic stem cells. CLN-049 is therefore predicted to have an improved safety profile.

"We’ve long held the belief that FLT3 is among the most attractive targets in AML," stated Helmut Salih, DKFZ/DKTK Professor and physician at Tübingen University Hospital, and Gundram Jung, Professor at Tübingen University, the originators of the molecule. "And we look forward to advancing CLN-049 into clinical testing with the help of the Cullinan team given their deep domain expertise in the bispecific field."

On September 15, 2020 AVEO Oncology (Nasdaq: AVEO) reported that final overall survival (OS) results from its Phase 3 TIVO-3 study were published in the journal European Urology (Press release, AVEO, SEP 15, 2020, View Source [SID1234565192]). TIVO-3 is the Company’s pivotal Phase 3 trial comparing tivozanib, AVEO’s next-generation vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI) drug candidate, to sorafenib in third and fourth line renal cell carcinoma (RCC) . The article, titled "Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma," is available online first via this link.

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"TIVO-3 represents the first positive superiority study in the growing population of patients who have relapsed or become refractory to multiple lines of therapy, including checkpoint inhibitors," said Sumanta (Monty) Pal, MD, Associate Clinical Professor, Department of Medical Oncology and Therapeutics Research, and Co-director, Kidney Cancer Program, at City of Hope Comprehensive Cancer Center, and lead author. "TIVO-3 data suggest a favorable safety and efficacy profile relative to sorafenib as demonstrated by superior anti-tumor progression free survival and overall response activity vs. another VEGFR TKI, coupled with fewer dose reductions, interruptions and discontinuations. The OS hazard ratio (HR) is consistent with previous Phase 3 studies comparing two VEGF-directed agents. I believe that tivozanib has the potential to offer patients a meaningful new treatment option in a setting currently lacking an evidence-based standard of care."

"For RCC patients who have relapsed or are refractory to multiple lines of therapy, the lack of well controlled clinical data to guide treatment decisions in this advanced relapsed/refractory population poses challenges for patients and treating physicians," said Michael Bailey, president and chief executive officer of AVEO. "We expect that Tivozanib’s TIVO-3 data has the potential to guide important treatment decisions in this setting and ultimately improve outcomes and patient experience. We look forward to working with the U.S. Food and Drug Administration (FDA) as they continue to review our New Drug Application (NDA) submission."

In June 2020, AVEO announced that the FDA accepted for filing its NDA seeking approval for tivozanib as a treatment for relapsed or refractory RCC. The FDA has assigned the application standard review and a Prescription Drug User Fee Act target action date of March 31, 2021. The FDA also indicated that they do not currently plan on convening an Oncologic Drug Advisory Committee (ODAC) to discuss the application. The NDA submission is based on the TIVO-3 study and is also supported by three additional trials in RCC and includes safety data from over 1,000 clinical trial subjects and several years of commercial availability in Europe.

Results in Detail

Patients enrolled in the TIVO-3 trial (n=350) were randomized and stratified by prior regimen and IMDC prognostic score. Prior treatment regimens included prior checkpoint inhibitor and VEGF TKI therapies (n=91), two prior VEGF TKI therapies (n=159) and prior VEGF TKI and other therapies (n=100). As previously announced, the TIVO-3 trial met the primary endpoint of progression free survival (PFS), with a median PFS of 5.6 months in the tivozanib arm vs. 3.9 months in the sorafenib arm (HR=0.73; p=0.02), and the secondary endpoint of overall response rate (ORR) (18% vs. 8%; p=0.02).

For the secondary endpoint of OS, the OS HR, which assesses the overall relative risk of death, was 0.97 (95% CI: 0.75-1.24; p=0.82), favoring tivozanib and improving from the previously reported interim HR of 0.99. Median OS, representing a single point in time in the OS curve, was 16.4 months for tivozanib (95% CI: 13.4-22.2) and 19.2 months for sorafenib (95% CI: 15.0-24.2). These OS HR results are similar to those of prior VEGFR TKI vs. VEGFR TKI studies in RCC.1-4

Tivozanib was found to be generally well-tolerated, with grade 3 or higher adverse events (AEs) consistent with those observed in previous tivozanib trials. The most common AE in patients receiving tivozanib was hypertension (38% vs. 25% for sorafenib, of treated patients), an AE known to reflect effective VEGF pathway inhibition. Infrequent but severe AEs reported in greater number in the tivozanib arm were thrombotic events (5% vs. 4% for sorafenib, of treated patients) similar to those observed in previous tivozanib studies. Dose reductions and interruptions due to AEs were significantly lower for tivozanib vs. sorafenib, despite nearly double the average number of cycles initiated for the tivozanib arm (11.9 months vs. 6.7 months for sorafenib), and treatment related AEs leading to permanent discontinuation were 8% for tivozanib vs. 15% for sorafenib.

About Tivozanib (FOTIVDA)

Tivozanib is an oral, once-daily, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved as FOTIVDA for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union and other countries in the EUSA territory. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.5,6 Tivozanib is being studied in the TIVO-3 trial, which is supporting a regulatory submission of tivozanib in the U.S. seeking marketing approval as a treatment for relapsed or refractory RCC. Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models7 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC.8 Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers. Tivozanib is also being studied by partner Kyowa Kirin in non-oncology indications.

On September 15, 2020 BostonGene Corporation, a biomedical software company committed to defining optimal precision medicine-based therapies for cancer patients, reported a scientific collaboration with Brigham and Women’s Hospital, a world-class academic medical center and a major teaching hospital of Harvard Medical School based in Boston, Massachusetts (Press release, BostonGene, SEP 15, 2020, View Source [SID1234565190]).

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In this collaboration, BostonGene provides the analysis of whole transcriptome sequencing (RNA seq) data sets generated from tumor and blood samples from patients with recurrent glioblastoma (GBM) treated with an oncolytic virus as part of a Phase I clinical trial. As part of the effort, BostonGene correlation analysis aims to identify novel biomarkers of response to therapy. The collaboration will further demonstrate the powerful advantages of transcriptomic data analysis for prediction of the response to novel therapies for malignant brain tumors.

"We are very excited to enter into this collaboration with BostonGene in our efforts to fully understand the molecular underpinnings of responses to novel engineered viruses-based therapies," said Ennio Antonio Chiocca, MD, PhD, Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery at Brigham and Women’s Hospital. "This collaboration is another step in allowing us to make better individual treatment decisions for patients with GBM."

"We’re honored to collaborate with Brigham and Women’s Hospital to demonstrate the clinical utility of BostonGene’s analytical tools that have been designed to improve diagnosis and treatment decisions for cancer patients," said Andrew Feinberg, President & CEO at BostonGene. "We firmly believe that advanced computational analytics will better equip physicians as they identify personalized treatment plans."

On September 15, 2020 Tyme Technologies, Inc. (NASDAQ: TYME), an emerging biotechnology company developing cancer metabolism-based therapies (CMBTsTM), reported that the final results of its SM-88 Phase II Prostate Cancer study designed to evaluate the safety, tolerability and efficacy of SM-88 in patients with non-metastatic biochemical recurrent prostate cancer, was published on September 13th, 2020 in the peer-reviewed journal Investigational New Drugs (Press release, TYME, SEP 15, 2020, View Source [SID1234565184]). The article, titled "Phase II Trial of SM-88, a Cancer Metabolism Based Therapy, in Non-Metastatic Biochemical Recurrent Prostate Cancer," is available online at View Source

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The study demonstrated that SM-88 had promising efficacy and safety outcomes for prostate cancer patients while sparing testosterone. The study also demonstrated a reduction of CTCs, an important prognostic indicator, that may prove to be a better surrogate for patient outcomes than PSA, particularly for SM-88.

"Oral SM-88 has demonstrated potential efficacy and a well-tolerated safety profile that may represent a new treatment option for more than 450,000 prostate cancer patients in the U.S. alone seeking a non-cytotoxic, non-hormonal therapy," said Giuseppe Del Priore, M.D., M.P.H., Chief Medical Officer at TYME. "We are encouraged by the clinical results of our unique proprietary approach using cancer metabolism-based therapies that we believe attack the cancer cells from within, interrupting the cancer metabolic processes."

From September 2016 to April 2019, twenty-three evaluable patients with non-metastatic pancreatic cancer with rising PSA levels, detectable circulating tumor cells and no radiographically detectable metastases were assessed in a Phase II trial. All patients received 230 mgs twice per day of SM-88 orally. Patients also received oral doses of methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg) once per day. Most patients had previously received androgen-deprivation therapy (ADT) after radiation therapy or surgery, but ADT treatment changes were not permitted during the trial.

From the initial diagnoses of PSA rise, 100% of patients (23/23) remained free of metastatic progression (MFS) and 87% of patients (20/23) have maintained radiographic progression-free survival (rPFS) with a median duration of therapy of 6.5 months since starting SM-88 treatment. All patients who have maintained meaningful reductions in circulating tumor cells (CTCs) on SM-88 were 100% free of any radiographic progression.

At baseline, the median PSA for patients with radiographic progression was 13.4 compared to 5.6 for patients with no radiographic progression (p=0.02). Among evaluable patients, PSA stabilized in 83% of patients (19/23). Importantly, 52% of evaluable patients (12/23) experienced an improvement in median PSA doubling time (DT), a positive prognostic indicator. In all patients who completed three cycles of therapy, the median DT improved nearly 34.4% from 6.1 to 8.2 months (n=20). After 12 weeks, or three cycles of therapy, 78.2% of patients (18/23) demonstrated a decrease in CTC from baseline, with a median decrease of 65.3%.

Patients without local progression (20/23) had slightly higher testosterone levels at baseline and throughout treatment on SM-88 as compared to those who experienced local radiographic progression (3/23). According to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, patients generally reported stable cognitive and sexual function domain measures, with no detectable worsening in any domain. Patient weight, EKG QTc, glucose and hematocrit and other measures, which are often side effects of ADT, did not appear affected while receiving SM-88.

The SM-88 therapy was well tolerated in all patients. There were no treatment-related serious adverse events. No adverse events resulted in dose delay, discontinuation, or reduction. The majority of Grade 1 AEs possibly or probably related to the SM-88 investigational therapy were gastrointestinal in nature.

The Phase II prostate cancer trial results are from an investigational study. SM-88 is not approved for the treatment of patients with any disease condition.

About Advanced Prostate Cancer

Prostate cancer is the most common malignancy in men, accounting for approximately 31,620 deaths in the United States in 2019.1 Approximately 15% of men with prostate cancer present with metastatic disease, and 20% to 30% of men with localized disease treated with definitive local therapy subsequently develop metastatic disease. While the vast majority of patients with metastatic disease demonstrate a transient response to androgen deprivation, eventually all patients develop hormone refractory prostate cancer (HRPC) and virtually all prostate cancer deaths are due to the development of metastatic HRPC.2 While chemotherapy regimens have shown a modest survival advantage in HRPC patients, median survival remains approximately 19 months,3,4 and not all patients are candidates for chemotherapy. Novel agents and new approaches such as oral cancer metabolic-based therapies are needed.

About SM-88

SM-88 is an oral investigational modified proprietary tyrosine derivative that is believed to interrupt the metabolic processes of cancer cells by breaking down the cells’ key defenses and leading to cell death through oxidative stress and exposure to the body’s natural immune system. Clinical trial data have shown that SM-88 has demonstrated encouraging tumor responses across 15 different cancers, including pancreatic, lung, breast, prostate and sarcoma cancers with minimal serious grade 3 or higher adverse events. SM-88 is an investigational therapy that is not approved for any indication in any disease. Learn more.