On November 3, 2021 The Parker Institute for Cancer Immunotherapy (PICI) and the Cancer Research Institute (CRI) reported the dosing of the first patients in the REVOLUTION trial, a phase I, open label platform study of novel immunotherapy combinations for first-line treatment of metastatic pancreatic cancer (Press release, Cancer Research Institute, NOV 3, 2021, View Source [SID1234594209]).

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"PICI is built on the promise of bringing together the brightest minds to come up with innovative solutions to cancer’s toughest problems, and this trial is a direct result," said Ute Dugan, MD, PhD, PICI’s Chief Medical Officer. "The innovative design also represents a new model of collaborative, end-to-end drug development that allows us to more rapidly advance promising therapeutic combinations from bench to bedside to market, and then to patients."

REVOLUTION uses a platform trial design that allows for more rapid testing of several therapies with more adaptability than a standard clinical trial. In a traditional clinical trial, all elements of the study must be approved prior to beginning. When the study meets its endpoint, researchers must decide what study to do next based on the findings.

In contrast, a platform design allows researchers to interpret the data during the trial and to make changes, such as testing additional treatments, expanding the number of people receiving a therapy that shows promise, or discontinuing a therapy that does not look promising. This allows investigators to follow the science with flexibility and efficiency, avoiding some of the administrative and logistical hurdles involved in starting up individual trials in a safe way and decreasing the likelihood that patients will receive ineffective treatments.

"Platform studies offer a science-informed flexibility that is better able to keep pace with the accelerating advances in clinical cancer immunology, especially those that involve promising drug combinations like those brought together through the Cancer Research Institute’s collaborations with PICI and our academic, industry, and other nonprofit partners," said Jill O’Donnell-Tormey, PhD, CEO and Director of Scientific Affairs at CRI.

REVOLUTION currently consists of two groups of patients. Cohort A will test a combination of standard-of-care chemotherapy, the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab. In addition to providing valuable information on the efficacy of the combination itself, this cohort builds on the findings from PICI’s and CRI’s PRINCE trial, which suggested that the combination of chemotherapy and anti-PD-1 treatment may improve survival compared with chemotherapy alone.

Cohort B will investigate the combination of chemotherapy, ipilimumab and hydroxychloroquine (HCQ). HCQ is a drug that can stop a process called autophagy, which cells use to recycle their own materials to survive, particularly under stress. Previous research has indicated autophagy is a key mechanism by which metastatic pancreatic cancer cells evade the immune system.

The first patients have been dosed in each cohort.

2021-11-03-REVOLUTION_Cohorts_Final_800x400.gif

This trial will also further explore biomarker data generated by the PRINCE study, aiming to better understand which patients stand to benefit from immunotherapy.

"This is an exciting next step in PICI’s and CRI’s commitment to deliver bold, science-driven ideas, and this trial shows how those efforts build on each other as the research progresses," said PICI researcher and CRI Scientific Advisory Council member Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center of the University of Pennsylvania and the study’s overall principal investigator. "REVOLUTION will make use of the same capabilities as PRINCE while adding a framework that can test and advance potentially promising combination therapies more efficiently than standard clinical trials."

REVOLUTION is also designed with the greater field in mind, building off PICI’s and CRI’s shared goals of breaking silos and creating efficiencies through collaboration. PICI has partnered with the Pancreatic Cancer Action Network (PanCAN) and its Precision PromiseSM phase 2/3 platform study in metastatic pancreatic cancer for exactly this purpose. If a cohort of REVOLUTION proves successful, it can be considered for further development under the Precision Promise umbrella. Once again, this accelerates the clinical trial process, ensuring potentially lifesaving therapies make their way to patients as quickly as possible. This partnership also advances CRI’s commitment to discovering and developing immune-based treatments that improve outcomes for all cancer patients, including those who face pancreatic and other hard-to-treat cancers.

In addition to Penn, sites on the trial include the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, the University of California, San Francisco, the University of California, Los Angeles, the University of Texas MD Anderson Cancer Center, and Stanford Medicine.

Additional partners on the trial include the 1440 Foundation, Bristol Myers Squibb and PanCAN.

About Pancreatic Cancer
Pancreatic cancer is one of the deadliest types of tumors, and the number of diagnosed cases continues to rise each year. The disease is difficult to catch early, meaning by the time most people are diagnosed, their cancer is advanced and may have already spread. In addition, the tumors usually contain a variety of mutations, meaning one targeted therapy isn’t enough to stop the disease by itself. For patients who are diagnosed after cancer has spread to other parts of the body – a distinction that applies to more than half of all pancreatic patients – the 5-year survival rate is just three percent.

On November 3, 2021 Race Oncology Limited ("Race") reported that it has entered into a collaborative preclinical research program with The University of Newcastle to develop a companion diagnostic to support the use of Zantrene as a precision oncology treatment, targeting the FTO protein (Press release, Race Oncology, NOV 3, 2021, View Source [SID1234594208]). Eminent genomics researcher, Professor Murray Cairns of the University of Newcastle, will lead the project.

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Precision oncology utilises companion diagnostic tests to identify genetic changes in a patient’s cancer that render the cancer sensitive to a particular anti-cancer treatment1. By matching treatment to the cancer’s sensitivities, patients gain better treatment outcomes and avoid unnecessary side effects. Anti-cancer drugs with a companion diagnostic have a significantly increased probability of being approved by regulatory agencies like the US Food and Drug Administration, the European Medicines Agency and Australia’s Therapeutic Goods Administration2.

This project entitled "Genome-wide epitranscriptomic analysis of N6-methyl-adenosine modification at nucleotide resolution using RNA sequencing to identify biomarkers of aberrant tumour RNA methylation" builds on patentable IP developed by Race and will utilise the latest RNA genomics technologies to identify clinically relevant biomarkers of Zantrene sensitivity in human cancer cells and tissue samples.

"Race is extremely pleased to be working with Professor Cairns on this project. He is one of the leading researchers in the RNA genomics field and his background and expertise will maximise our chances of a successful outcome. For companies like Race, having a proprietary companion diagnostic is of increasing importance for our precision oncology clinical programs and will add significant IP protection around Zantrene."

Race Chief Scientific Officer, Dr Daniel Tillett
This work complements the recently announced FTO biomarker collaborative program with the Chaim Sheba Medical Center (ASX announcement: 27 October 2021) by focusing on understanding the m6A methylation status of RNA transcripts at the nucleotide level. This collaboration will provide critical mechanistic data on the effects of FTO inhibition by Zantrene in various cancer types.

"Zantrene’s potency as an FTO inhibitor provides an exciting new opportunity to target cancer by altering its RNA metabolism. I look forward to working with Race to develop a companion diagnostic for the drug’s precision usage in clinical oncology".

Professor Murray Cairns
The work is expected to support current and future clinical trials of Zantrene and provide the scientific basis for developing a clinically validated and Race-proprietary genetic companion diagnostic test for the targeted use of Zantrene in cancer treatment.

This preclinical research program is to start immediately with results to be reported over the coming 12 months.

1. Prasad, V., Fojo, T. & Brada, M. Precision oncology: origins, optimism, and potential. Lancet Oncol 17, e81–e86 (2016).

2. Valla, V. et al. Companion Diagnostics: State of the Art and New Regulations. Biomark Insights 16, (2021).

About Professor Murray Cairns
Professor Cairns is an NHMRC Senior Research Fellow, and Brawn Senior Fellow at the University of Newcastle’s College of Health, Medicine and Wellbeing. He heads the Precision Medicine Laboratory in the school of Biomedical Sciences and Pharmacy, which comprises a team of post-doctoral fellows, research assistants, bioinformaticians and research higher degree students. Professor Cairns has leveraged expertise in bioinformatics and high-throughput sequencing to establish an internationally recognised laboratory specialising in complex trait genomics. He is a leader in genetically informed precision medicine and is developing transformative approaches to address the problem of heterogeneity in the treatment of complex disorders.

Professor Cairns has attracted more than $14 million in funding to support his research programs, which have led to publications in the highest-ranking journals in the field, including Nature, Science, Cell, Nature Biotechnology, Nature Genetics, Nature Reviews Genetics, Nature Neuroscience and Molecular Psychiatry. Collectively, these publications have received more than 14,000 citations. His high-impact collaborative studies highlight an international reputation for research in complex disease genomics, posttranscriptional gene regulation, systems biology, and precision medicine.

On November 3, 2021 Micronoma, the first cancer detection biotech company to diagnose cancer at an early stage with microbiome-driven liquid biopsy technology, reported that added the Health Tech Challengers award in the diagnostics category to the list of accolades it has earned for its groundbreaking work this year (Press release, Micronoma, NOV 3, 2021, View Source [SID1234594207]). Health Tech Challengers identifies and brings together top global digital health tech startups that are innovators in one of six tracks fostering the digital health revolution. The award marks the fourth Micronoma has achieved this year.

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Micronoma Wins Fourth Innovation Award This Year

"It has been a wonderful year of recognition for our team, and the awards are important for bringing awareness and distinction to breakthrough technology like Micronoma’s Oncobiota liquid biopsy for true early-stage detection of cancer," said Sandrine Montgomery-Miller, CEO of Micronoma. "As we are preparing to make our innovations available to clinicians and their patients next year, it is invigorating to be recognized by distinguished experts who see the promise our work offers."

Other recognition Micronoma has received this year include:

-September 2021: Selection from among hundreds of companies as a finalist in the New Life Sciences Diagnostic category for the UCSF Health Award. The UCSF Health Awards honors outstanding health technologies and innovations dramatically transforming healthcare.

-July 2021: Winning the Bio-IT World Innovative Practices Award Grand Prize. This elite awards program highlights outstanding examples of how technology innovations and strategic initiatives can advance life sciences research, from basic biomedical research to drug development and beyond.

-February 2021: Winning the Unicorn Battle Silicon Valley, billed as the "World’s Largest Startup Pitch Contest" by geography and number of entries. This event recognizes startup companies that have accomplished impressive innovations.

The diagnostic implications of Micronoma’s work to use microbiome markers in liquid and tissue biopsies for early-stage cancer diagnosis are extensive. These distinctions show Micronoma is uniquely leading the way toward preventing unnecessary suffering caused by later-stage diagnoses and potentially enabling earlier, personalized, and less-invasive treatments.

On November 3, 2021 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) reported financial results for the three and nine months ended September 30, 2021 and recent business achievements (Press release, Ionis Pharmaceuticals, NOV 3, 2021, View Source [SID1234594206]).

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"Among recent business highlights, we further expanded our broad late-stage pipeline to seven Phase 3 programs now that the olezarsen Phase 3 CORE study in patients with severe hypertriglyceridemia is underway. We were encouraged that while tofersen did not achieve the primary endpoint in the Phase 3 VALOR study, trends favoring tofersen were seen across multiple secondary and exploratory measures of disease progression in patients with SOD1-ALS. We also expanded our LICA platform capabilities by licensing technology from Bicycle Therapeutics," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "We are looking forward to multiple near-term catalysts, beginning with the presentation of donidalorsen Phase 2 data in patients with hereditary angioedema at the ACAAI Annual Meeting this weekend. We anticipate initiating the donidalorsen Phase 3 study before year-end. We also expect multiple catalysts in 2022, including results from the eplontersen Phase 3 study in patients with TTR polyneuropathy mid-year 2022. Furthermore, at our virtual investor day on December 9th, we look forward to outlining commercial preparations for our lead programs ahead of our first potential launch with eplontersen in patients with TTR polyneuropathy in 2023. Based on our anticipated near- and mid-term catalysts, we remain on track to have 12 or more products on the market in 2026."

Third Quarter 2021 Financial Results

Third quarter results reflect Ionis’ focus on its strategic objectives
$133 million in total revenues
$185 million of operating expenses on a non-GAAP basis(1) and $219 million on a GAAP basis
Net loss of $48 million on a non-GAAP basis(1) and $82 million on a GAAP basis
Well capitalized with cash and investments of $2 billion as of September 30, 2021
"Since our last quarterly update, we further advanced our strategic objectives through investments in our expanding Phase 3 pipeline and technology. We also advanced our commercial readiness initiatives in anticipation of multiple product launches potentially beginning as early as 2023," said Elizabeth L. Hougen, chief financial officer of Ionis. "We remain on track to achieve our 2021 financial guidance driven by increased R&D revenue in the fourth quarter as several of our partner programs advance. We also project increased expenses in the fourth quarter as we continue to invest for growth. Importantly, with $2 billion in cash, we remain well-capitalized with the resources we need to achieve our strategic objectives."

(1)

All non-GAAP amounts referred to in this press release exclude non-cash compensation expense related to equity awards and expenses related to the Akcea Merger and restructured commercial operations and the related tax effects. Please refer to the section below titled "Financial Impacts of Akcea Merger and Restructured Commercial Operations" for a summary of the costs specific to these transactions. Additionally, please refer to the detailed reconciliation of non-GAAP and GAAP measures, which is provided later in this press release.

Third Quarter 2021 Marketed Products Highlights

SPINRAZA: the global market leader for the treatment of spinal muscular atrophy (SMA) patients of all ages
$444 million in worldwide sales in the third quarter
More than 11,000 patients worldwide on therapy at the end of the third quarter across commercial, expanded access and clinical trial settings
Biogen plans to initiate the Phase 3b ASCEND study evaluating the potential benefit of an investigational higher dose of nusinersen in children, teens and adults with later-onset SMA previously treated with Evrysdi (risdiplam)
TEGSEDI and WAYLIVRA: important medicines approved for the treatment of patients with severe rare diseases
TEGSEDI achieved innovative drug pricing in Brazil reflecting the significant unmet medical need and prevalence of TTR polyneuropathy in Brazil
WAYLIVRA was approved in Brazil as the first and only treatment for patients with familial chylomicronemia syndrome
Third Quarter 2021 and Recent Events

Advancing Ionis’ leading cardiovascular and metabolic disease pipeline
Initiated the Phase 3 CORE study of olezarsen (IONIS-APOCIII-LRx) in patients with severe hypertriglyceridemia (sHTG)
Reached 50 percent enrollment in the Phase 3 Lp(a) HORIZON outcome study of pelacarsen for patients with established cardiovascular disease and elevated Lp(a), resulting in a $25 million payment from Novartis
Achieved full enrollment in the Bayer Phase 2b RE-THINc ESRD study of fesomersen (IONIS-FXI-LRx), with data expected in the first half of 2022
Achieved proof-of-mechanism, a strong indication of proof-of-concept and good safety and tolerability in a Phase 2 study and a preliminary assessment from an open-label extension study of cimdelirsen (IONIS-GHR-LRx) in acromegaly patients uncontrolled on standard of care therapy, supporting continued development. Data from the ongoing open-label extension study and monotherapy study are expected in 2022. The results from the Phase 2 study of cimdelirsen are posted to Ionis’ website and may be accessed here
Addressing substantial unmet medical need with Ionis’ broad neurological disease pipeline
The Biogen Phase 3 VALOR study of tofersen in patients with SOD1-ALS did not meet the primary endpoint of change from baseline to week 28 in the ALS Functional Rating Scale-Revised (ALSFRS-R); however, signs of reduced disease progression across multiple secondary and exploratory endpoints were observed
Achieved full enrollment in the Phase 3 NEURO-TTRansform study of eplontersen in patients with TTR polyneuropathy, with data expected in mid-2022
Reported data from the Biogen Phase 1/2 study of IONIS-MAPTRx in patients with Alzheimer’s disease, demonstrating durable, time and dose-dependent reductions in CSF tau protein; IONIS-MAPTRx was generally well tolerated
Investing in expanding the reach of Ionis’ technology
Entered a license agreement with Bicycle Therapeutics for exclusive rights to Bicycle’s peptide technology targeting transferrin receptor 1 to expand the capabilities of Ionis’ LICA technology
Entered a license agreement with Flamingo Therapeutics for the development and commercialization of programs from Ionis’ oncology pipeline
2021 Pipeline Milestones(2)

In the third quarter of 2021, the Company continued to advance its late-stage pipeline, including reaching 50 percent enrollment in the Phase 3 Lp(a) HORIZON study of pelacarsen for which it earned a $25 million milestone payment from Novartis. As its partnered programs advance, the Company expects R&D revenue to increase in the fourth quarter of 2021 compared with the third quarter of 2021.

In the second quarter of 2021, the Company successfully completed the transition of its TEGSEDI operations in North America to Sobi. As a result, the Company’s commercial revenue from product sales shifted to distribution fees based on net sales generated by Sobi. In the third quarter of 2021, the Company earned a $4 million milestone payment from PTC Therapeutics when WAYLIVRA was approved in Brazil.

Financial Impacts of Akcea Merger and Restructured Commercial Operations

In October 2020, Ionis completed a merger transaction with Akcea such that following the completion of the merger Akcea became a wholly owned subsidiary of Ionis. Additionally, in December 2020 and April 2021, Ionis restructured its European operations and its North American TEGSEDI operations, respectively, as a result of entering into distribution agreements with Sobi. For the three and nine months ended September 30, 2021, the Company incurred $3 million and $24 million of costs in conjunction with the Akcea merger and restructuring of the Company’s commercial operations, respectively. The Company excluded these costs from its non-GAAP amounts for those periods. Please refer to the detailed reconciliation of non-GAAP and GAAP measures that is provided later in this press release.

Operating Expenses

Ionis’ operating expenses for the three and nine months ended September 30, 2021 increased compared with the same periods last year driven by an increase in R&D expenses, partially offset by a decrease in SG&A expenses. Higher R&D expenses were primarily driven by the Company’s investments in advancing its late-stage wholly owned pipeline, including advancing the Phase 3 program for eplontersen and start-up costs associated with the Phase 3 study for a second indication for olezarsen. Additionally, the Company recognized $35 million in R&D expense in the third quarter of 2021 for licensing Bicycle’s technology. Lower SG&A expenses primarily reflect operating efficiencies achieved from integrating Akcea and restructuring the Company’s commercial operations. The Company projects its operating expenses to increase in the fourth quarter as it continues to invest for growth.

Net Loss Attributable to Ionis Common Stockholders

Net loss attributable to Ionis’ common stockholders for the three and nine months ended September 30, 2021 increased compared with the same periods in the prior year for the reasons discussed above.

Balance Sheet

As of September 30, 2021, Ionis had cash, cash equivalents and short-term investments of $2.0 billion, compared with $1.9 billion as of December 31, 2020. The Company intends to utilize $62 million of its cash to pay the remaining principal balance of its 1 percent convertible notes at maturity in November 2021.

The Company revised its 2020 amounts to reflect the simplified convertible instruments guidance the Company adopted retrospectively on January 1, 2021.

Webcast

Ionis will conduct a webcast today at 11:30 a.m. Eastern time to discuss this announcement and related activities. Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address.

On November 3, 2021 Genmab A/S (Nasdaq: GMAB) reported that its CEO, Jan van de Winkel, Ph.D., will take part in a fireside chat at the Jefferies Virtual London Healthcare Conference on November 18, 2021 (Press release, Genmab, NOV 3, 2021, View Source [SID1234594205]). A webcast of the event will be available on Genmab’s website from November 18, 2021, 9:00 AM CET at View Source

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