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MedNess: bite-size biopharma and medtech news

7th July, 2021

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MedNess This Week
HIGHLIGHTS
Onco-I-Analyse
InnoCare’s Orelabrutinib receives Breakthrough Therapy Designation for R/R MCL
On 28th June, InnoCare announced that its BTK inhibitor, orelabrutinib, has been granted breakthrough therapy designation by the US FDA as a treatment option for relapsed/refractory mantle cell lymphoma. The designation is based on results from the Phase 2 study.
Background: Orelabrutinib is a highly potent and selective BTK inhibitor for clinical development in B-cell malignancies and autoimmune diseases. The next-gen BTKi is expected to have better safety profile, higher bioavailability compared to other BTK inhibitors and nearly 100% 24-hour target occupancy. The US FDA has already approved 3 BTK inhibitors for the treatment of R/R MCL, which account for ~3% of all NHL incidence.
Details: The Phase 2 trial is evaluating orelabrutinib in a non-randomized trial for several B-cell malignancies including R/R MCL. In 106 patients, at a median follow-up of 16.4 months, ORR was 87.9% and DCR was 93.9%. CR was reported to be 34.3% and mPFS and mOS were not reached.
The asset demonstrated good safety and tolerability with commonly reported AEs being thrombocytopenia, neutropenia, leukopenia, and hypertension.
Implications: Orelabrutinib is already approved by the China NMPA for R/R CLL, R/R SLL and R/R MCL. In December 2020, it was granted the orphan drug designation by the US FDA for the treatment of MCL. It remains to be seen how orelabrutinib will carve out a place for itself in the treatment regimen of MCL.
Collated by : Shilpa Rawal, PhD
Drug Approvals
U.S. FDA Approves Rylaze™ (asparaginase erwinia chrysanthemi (recombinant)-rywn) for the Treatment of ALL or LBL
"We are excited to bring this important new treatment to patients who are in critical need, and we are grateful to FDA for the approval of Rylaze based on its established safety and efficacy profile. We are pleased Rylaze was approved before the trial is complete and are diligently working to advance additional clinical trial data. We are committed to quickly engaging with FDA to evolve the Rylaze product profile with additional dosing options and an IV route of administration," said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals. "Thank you to our collaborators within the Children's Oncology Group, the clinical trial investigators, patients and their families, and all of the other stakeholders who helped us achieve this significant milestone." 
European Commission Approves KEYTRUDA® + Chemotherapy for Certain Patients With Esophageal Cancer or HER2-Negative GEJ Adenocarcinoma
“We have seen few advances over the last three decades that have improved historically poor survival outcomes for patients with esophageal cancer,” said Professor Antoine Adenis, Department of Medical Oncology, Montpellier Cancer Institute, France. “The European Commission’s approval of KEYTRUDA plus chemotherapy for the treatment of certain patients with esophageal and HER2-negative GEJ cancer provides a new option in the first-line setting that has shown significant improvements in progression-free and overall survival.”
Regulatory News

FDA Granted Fast Track Designation for ALLO-605, the First TurboCAR™ T Cell Therapy, for the Treatment of Relapsed/Refractory Multiple Myeloma
“We are very pleased with the continued momentum of our anti-BCMA portfolio for patients with multiple myeloma and look forward to making allogeneic CAR T therapy a potential option for these patients,” said Rafael Amado, M.D., Executive Vice President of Research and Development and Chief Medical Officer. “With studies now underway for ALLO-715 alone and in combination with a gamma secretase inhibitor, as well as ALLO-605 as our next generation CAR T, we are taking an aggressive three-pronged approach aimed at exploring the unique attributes of AlloCAR T therapies for patients with rapidly progressing disease.”

U.S. accelerated approval voluntarily withdrawn for KEYTRUDA for the treatment of patients with recurrent locally advanced or metastatic PD-L1+ve gastric or GEJ adenocarcinoma
“While there remains an unmet need for heavily pre-treated patients with advanced gastric cancer, we recognize that the treatment landscape has evolved and we respect the FDA’s efforts to continually evaluate accelerated approvals,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “Our research with KEYTRUDA has contributed to recent advances in the treatment of gastric cancer, and we are continuing to advance studies to help more patients with this disease.”
 Click here for more Regulatory News
Trial Results
Yescarta® CAR T-cell Therapy Improved Event-Free Survival by 60% Over Chemotherapy Plus Stem Cell Transplant in 2L R/R Large B-cell Lymphoma
“The top-line results of the randomized ZUMA-7 trial paint the picture of a potential paradigm shift in the treatment of large B-cell lymphoma,” said Frederick L. Locke, MD, ZUMA-7 Lead Principal Investigator and Co-Leader of the Immuno-Oncology Program at Gilead. “The outcomes for patients relapsing after frontline chemotherapy in this study are dramatically improved with rapid referral (to a CAR T center) and a single infusion of axicabtagene ciloleucel as compared to chemotherapy and consolidative autologous transplant, the longstanding second-line standard of care.”
Cabozantinib + Atezolizumab combination Significantly Improved PFS in Ph 3 COSMIC-312 Pivotal Trial in 1L HCC Patients; OS goal may not meet
“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on overall survival versus the comparator arm,” said Michael M. Morrissey, Ph.D., Exelixis’ President and Chief Executive Officer. “As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anti-cancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”
Click here for more Trial Results
Trial/Program Status
Update provided on the Ph 1/2a Trial of Rigosertib-Nivolumab Combination in KRAS+ NSCLC
“The preliminary results from this Phase 1/2a trial are very encouraging and demonstrate the potential of rigosertib to address a critical unmet medical need by overcoming checkpoint inhibitor resistance in KRAS mutated lung adenocarcinoma,” said Mark S. Gelder, M.D., Chief Medical Officer of Onconova. “The observation of preliminary evidence of efficacy in combination with acceptable safety of the doublet in this extremely challenging patient population provides a promising signal. This phase 1 study supports the preclinical observation in melanoma of the up-regulation of crucial cell surface molecules by rigosertib which may synergize with immune checkpoint blockade, as recently published in Molecular Cancer, and strongly supports the continued clinical development of rigosertib-checkpoint inhibitor combination therapy. We look forward to the presentation of preliminary data at the upcoming 3rd Annual RAS Targeted Drug Development Summit taking place September 21-23, 2021, and at a future major medical meeting as the data mature.”
First Patient Treated in Ph 1 Study of DCC-3116 in Patients with Advanced or Metastatic Tumors with a Mutant RAS or RAF Gene
 “Approximately one third of all cancers, including a high percentage of pancreatic, lung, colorectal, and melanoma cancers, are driven by mutations in RAS or RAF genes, representing what we believe to be one of the largest unmet medical needs in oncology,” said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera Pharmaceuticals. “DCC-3116, a first-in-class, highly selective switch-control ULK kinase inhibitor, is designed to suppress autophagy and may offer a novel approach to targeting a broad array of cancers. We look forward to advancing our fourth active clinical development program generated from our switch-control kinase inhibitor platform and further evaluating the role of ULK kinase inhibition and its potential to represent a new treatment paradigm for cancers caused by RAS or RAF mutations.”
Click here for more Trial Statuses
Collated by : Richa Tewari, PhD 
Genes and Therapy
In a breakthrough study, Intellia and Regeneron edit gene inside the human body
On 26th June, Intellia Therapeutics and Regeneron Pharmaceuticals announced positive early data from the first-ever patients to have their DNA edited with an in vivo CRISPR/Cas9 delivered systemically via intravenous infusion. The candidate, NTLA-2001, is being developed as a single-dose treatment for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). NTLA-2001 is designed to inactivate the TTR gene in liver cells to prevent the production of misfolded transthyretin (TTR) protein, which accumulates in tissues throughout the body and causes loss of autonomy and often fatal complications of ATTR amyloidosis. So far, the study has been conducted in a dose-dependent manner in six patients of two cohorts in the UK and New Zealand. To determine the ideal dosage for optimum results, the third cohort is currently enrolling patients.
Researchers at the International Space Station (ISS) National Lab carried out the first transformation of live cells (Saccharomyces cerevisiae) and CRISPR/Cas9 genome editing in microgravity. This is a significant expansion of the molecular biology toolkit onboard the ISS. The study is aimed to understand the specific DNA repair mechanisms of choice in microgravity in the body of astronauts as they face increased risk of DNA damage due to the ionizing radiation that permeates space. The study carried out crucial molecular biology experiments with adapted protocols that work in microgravity. This study lays a foundation of hope and scientific quest for similar and expansive experiments for future explorations in space.
Click here for more on Genes and Therapy
MedNess HealthIT
Coding pattern in cells to be deciphered by ML algorithm
Every single cell in our body shows unique and dynamic pattern of gene expression within its life cycle. It takes several molecular methodologies, and therefore time, to identify the most active genes expressed by a cell at one point. Transcription factors (TF) are the doers to determine which genes are activated or repressed. Understanding the expression pattern of the TFs can aid basic research to medical intervention, at different levels.
University of Illinois Chicago has developed an algorithm through machine learning by “combining new gene expression profile data gathered from single cell RNA sequencing with existing biological data on transcription factor target genes”. They have named the program BITFAM, standing for Bayesian Inference Transcription Factor Activity Model. The aim is to run multiple computer-based simulations and utilize predictive analysis to identify the best fit of TFs to be present in the cell. According to Shang Gao, first author of the study, "Our approach not only identifies meaningful transcription factor activities but also provides valuable insights into underlying transcription factor regulatory mechanisms". The researchers have made the program publicly available to aid the work of thousands of colleagues worldwide. Jalees Rehman, UIC professor in the department of medicine and the department of pharmacology and regenerative medicine at the College of Medicine stated the power of the model through a widely applicable example: “For example, we would like to understand if there is transcription factor activity that distinguished a healthy immune cell response from an unhealthy one, as in the case of conditions such as COVID-19, heart disease or Alzheimer's disease where there is often an imbalance between healthy and unhealthy immune responses."
Neurodegenerative disease now gets a new indicator
Early demographic and social determinants of health (SDH) data, gathered by The Institute for Translational Research at The University of North Texas Health Science Center at Fort Worth may hold the key to unravel the biology of Alzheimer’s disease. The demographic data originated in a 2017 study named Health and Aging Brain among Latino Elders (HABLE), conducted by Sid O’ Bryant, PhD. According to him, the data is uniquely positioned to shed lights on this disease. "We will for the first time be able to examine the biology of Alzheimer's among Mexican Americans as well as non-Hispanic whites all within the context of sociocultural, environmental and behavioral factors", said O’Bryant in a press release.
So far, demographic data of Mexican Americans is severely underrepresented in Alzheimer’s research with a lack of understanding on biomarkers, whereas 65 percent of Hispanic people in the US are of Mexican decent. The data from the study suggests that Hispanic people may see the largest increase in Alzheimer’s disease related to dementias by 2060. “Early findings suggest that beta amyloid protein -- one of the biomarkers of Alzheimer's -- is less common among Mexican Americans yet Mexican Americans seem to have a younger onset of cognitive loss,” according to the press release by University of North Texas Health Science Center. The study included 1,000 Mexican Americans and 1,000 non-Latino White people over age 50, giving them reoccurring and comprehensive interviews, function exams, clinical laboratory tests, brain MRIs, and PET scans. Differences over time in the development of biomarkers between Mexican Americans and non-Latino Whites was revealed through PET scans.
Collated by: Debarati Banik
MedNess Reviews

Grails Publishes Promising Study on The Accuracy of its Galleri Cancer Diagnostic Test
Earlier this month, Grail launched its prescription Galleri diagnostic in the U.S. The test is designed to spot as many as 50 different cancers and uncover their original organ sites from a blood sample.

In the recent publication in the cancer journal Annals of Oncology using data gathered from the company’s Circulating Cell-free Genome Atlas study, researchers found the test could detect cancer before symptoms developed while offering an overall false-positive rate of 0.5%. However, the test’s performance varied based on cancer type and how far the cancer had progressed when it came to correctly identifying tumors from samples.

The test is based and analyzing small pieces of DNA released by tumors into the bloodstream, with some cancers shedding more genetic material than others. For example, esophageal, liver and pancreatic tumors, diseases that also have limited screening methods were easier for the test to find than cancers of the breast, bowels, cervix and prostate. The tests sensitivity also increased with cancer’s malignancy across all tumor types.

Across all cancer types and all four stages, Grail’s Galleri test correctly identified the presence of cancer in 51.5% of cases from among more than 2,800 people already diagnosed with the disease. In addition, the test was able to identify the organ sites of the tumors upto 88.7% of the time, giving clinicians a head-start in targeting the disease for treatment and helping them choose the most effective follow-up diagnostics.

Following its initial launch, and before Grail pursues a full FDA approval in 2023, it is expected the Galleri test could be used to help screen as many as 50 million people.
Click here for more on MedNess Reviews
MedNess Business
Onco-News
Alpine Immune Sciences to Collaborate with Merck on Immuno-Oncology Study to Evaluate ALPN-202 in Combination with KEYTRUDA®
“We are extremely pleased to collaborate with Merck, one of the world’s leading immuno-oncology companies,” said Stanford Peng, M.D., Ph.D., President and Head of R&D of Alpine. “Our prior preclinical studies demonstrated that the combination of ALPN-202 and a PD-1 inhibitor can be particularly advantageous, and this collaboration will greatly enable our ability to pursue this opportunity in the clinic. This study, in conjunction with NEON-1, ALPN-202’s ongoing first-in-human monotherapy trial, will provide insights across a broad spectrum of cancers and lines of therapy.”
Business Review
Intellia’s positive interim results make stock market friendly towards gene editing
On June 26th, 2021, Intellia Therapeutics (Intellia; Cambridge MA) announced positive interim results from the phase I dose-escalation trial of its gene-editing program, NTLA-2001, being tested as a treatment for transthyretin (ATTR) amyloidosis. ATTR amyloidosis occurs when liver cells generate mutated TTR proteins that misfold, leading to the accumulation of protein adducts as amyloids. An increase in amyloid formation leads to systemic complications such as neuropathy and cardiomyopathy. NTLA-2001 is designed as a single-dose gene therapy for ATTR amyloidosis to knock out the mutated TTR gene in liver cells
Interim trial data from six patients reveal a mean reduction of 87% in serum TTR levels by day 28 of treatment, with a maximum serum reduction of 96%. This compares favorably with current pharmaceutical treatments for the disease- RNA-silencing therapy from Alnylam and protein stabilizing small molecule therapy from Pfizer, which achieve around 80% reduction. The most well-received (by the stock market) results from the interim data are possibly the sustained lack of side effects, including liver toxicity and immune system overdrive, in ATTR patients. Secondly, the systemic administration of the gene therapy, as opposed to viral vector-based site-specific delivery used by other CRISPR companies such as Editas, indicates easier clinical adoption of the therapy.
Since Intellia’s announcement, the stock market speculation has pivoted from cautious to overtly positive across the spectrum of gene-editing companies, increasing share prices of Intellia by 45% along with others such as Editas, Beam Therapeutics, and CRISPR Therapeutics by 10-15%. Intellia’s market capitalization rose to USD 11 billion from the previous USD 9 billion in a single trading session. A lot of this confidence comes from the relief that gene editing can be safe. There has been a general queasiness about tinkering with genes and their potential unwanted (and possibly irreversible) ramifications that has led even the FDA to take a cautious approach to sanctioning gene-editing based human trials. The Intellia trials have recruited patients from New Zealand and Luxemburg, and not the USA. Intellia’s results are now speculated to open doors for FDA approvals to gene editing. The lack of risk now associated with gene editing only augments its potential to achieve life-long treatments to diseases with unmet needs, including cancer.
Another compelling aspect of the single-dose therapy is the reduction of cost to treatment that is attractive to health insurers. Alnylam’s Onpattro requires three weekly infusions by a clinician, Pfizer’s Vyndamax is a daily-once oral medication costing USD 25,000 annually. NTLA-2001 requires no healthcare infrastructure beyond the single injection, for lifelong treatment. Backing from insurers will give an edge to gene therapy products over competitors, despite the latter’s longer market presence. Interestingly the share price of Anlnylam is down by 10%, since the NTLA-2001 news, while Regeneron- Intellia’s partner for commercializing NTLA-2001- has seen a 4% increase in share price, amid the speculation that Regeneron may eventually acquire Intellia’s gene-editing pipeline and that Alnylam’s ATTR offering will be faced out by Intellia’s program.
In terms of revenue, NTLA-2001 is poised to be a blockbuster speculated to generate upwards of USD 15 billion annually for Intellia. ATTR amyloidosis has been a profitable market for companies generating between USD 306 million (Alnylam’s Onpattro) to USD 429 million (Pfizer’s Vyndamax) annually. One only hopes that NTLA-2001 continues being safe and effective, even against patients with previous exposure to other ATTR therapies (not evaluated in the clinical trials).
Collated by: Richa Tewari, PhD and Divyaanka Iyer
Editors' Desk
Richa Tewari, PhD
Oncology News
Shilpa Rawal, PhD
Onco I-Analyse
Arundithi Ananthanarayanan
MedNess Reviews
Divyaanka Iyer
Business Review
Debarati Banik
HealthIT
Darpan Chakraborty
Social Media Manager
Nisha Peter, PhD
Managing Editor
Abhi Dey
Consulting Editor
Rinki Saha
BioPharma News
Managing Editor
Shalini Roy Choudhury
Genes and Therapy
Managing Editor
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The sponsors do not have any influence on the nature or kind of the news/analysis reported in MedNess. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Medness. Examples of analysis performed within this article are only examples. They should not be utilized in real-world analytic products as they are based only on very limited and dated open source information. Assumptions made within the analysis are not reflective of the position of anyone volunteering or working for Medness. This blog is strictly for news and information. It does not provide medical advice, diagnosis or treatment nor investment suggestions. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
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Content Editors: Richa Tewari , Esha SehanobishRinki Saha ,  Shilpa Rawal, PhD ,  Debarati Banik  , Divyaanka Iyer , Arundithi Ananthanarayanan and Abhinav Dey 
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