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7th April
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MedNess This Week
HIGHLIGHTS
     Onco-I-Analyse

The FDA issued CRL for Keyturda in high-risk, early stage TNBC
On 29th March, Merck announced that it has received a complete response letter (CRL) from the US FDA regarding the sBLA application for Keytruda in high-risk, early stage Triple Negative Breast Cancer (TNBC).
Background: Early stage TNBC is an area of high unmet need with poorer outcomes and survival. Chemotherapy is the only standard of care for high-risk early stage TNBC patients. ​
Details: The decision followed ODAC’s review where the committee voted unanimously (10-0 votes) to postpone the application until longer-term data is available. The committee questioned the “clinical meaningfulness of a small improvement in pCR rate, the immaturity of the EFS data with five additional pre-specified analyses planned, and increased immune-mediated toxicity”
In July 2020, the FDA had accepted the sBLA for this indication with 29th March 2021 as the PDUFA date. The sBLA was based on the Ph 3 KEYNOTE-522 study evaluating Keyturda + chemotherapy (vs. chemotherapy) as neoadjuvant therapy, followed by Keytruda monotherapy (vs. placebo) as adjuvant therapy in 1,174 patients with early stage TNBC. The co-primary endpoint of pCR (64.8% vs. 51.2%, p<0.001) led to statistically significant and clinically meaningful improvement, regardless of PD-L1 expression with a positive trend for another co-primary endpoint of EFS.
In December 2020, FDA’s Oncologic Drugs Advisory Committee (ODAC) decided to review Merck’s sBLA on 9th February, 2021.
Implications: Following the CRL, Merck will discuss the subsequent steps with the FDA. The trial continues to evaluate EFS and the next interim analysis is in expected during Q3 2021. Both the FDA and ODAC raised the concern regarding the trial design arguing that the trial does not answer if Keytruda will be required in both settings, given the additional toxicity with checkpoint inhibitors.
In November 2020, Keytruda + chemotherapy was also granted accelerated approved for frontline, PD-L1+ (CPS≥10) TNBC. FDA’s current CRL does not influence frontline approval.
Collated by : Shilpa Rawal, PhD
    Drug Approvals
“In the Phase 3 IKEMA study, the addition of Sarclisa to carfilzomib and dexamethasone reduced risk of disease progression or death by 45%,” said Thomas G. Martin, M.D., Associate Director, Myeloma Program, The University of California, San Francisco, Professor of Medicine, Adult Leukemia and Bone Marrow Transplantation Program and co-leader of the Hematopoietic Malignancies Program, Helen Diller Family Comprehensive Cancer Center. “This approval is an important advancement for patients whose disease has relapsed and reinforces the potential for Sarclisa to become a standard of care in relapsed or refractory multiple myeloma.”
European Commission approves Cabometyx® + Opdivo® as a first-line treatment for patients living with advanced renal cell carcinoma based on pivotal Ph 3 CheckMate -9ER trial data
“Today’s EC approval for the use of Cabometyx in combination with Opdivo® provides an important new first-line treatment option for patients living with advanced renal cell carcinoma,” said Howard Mayer, Executive Vice President and Head of Research and Development, Ipsen. “At Ipsen, we’re proud that this, now approved, treatment option not only addresses key efficacy benefits, but also the need to maintain quality of life for patients. We look forward to collaborating with a broad range of European stakeholders to bring this unique combination to eligible patients living with advanced renal cell carcinoma.”
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Regulatory News
“Patients living with locally advanced and metastatic cholangiocarcinoma, or bile duct cancer, currently have a poor prognosis, particularly since there is no standard treatment after the failure of first-line chemotherapy,” said Martin J. Birkhofer, MD, Senior Vice President and Chief Medical Officer, Taiho Oncology, Inc. “We are pleased that the FDA has recognized the potential benefit of futibatinib in previously treated CCA patients. We look forward to continued dialogue with FDA and other Health Authorities as we work toward global availability of futibatinib for cholangiocarcinoma patients.”

PRIME designation for AUTO1 for the treatment of adult ALL
“We are pleased to have received PRIME designation for AUTO1 as it will accelerate the review of a promising therapy targeting unmet medical need,” said Dr. Christian Itin, chairman and chief executive officer of Autolus. “The designation comes soon after we presented compelling activity and safety data from the ALLCAR Phase 1 clinical trial at the 62nd American Society of Hematology (ASH) Annual Meeting. We believe AUTO1 could change standard of care by offering a potentially curative therapy for r/r ALL.”
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Trial Results
"In COMMODORE, patients receiving gilteritinib lived longer than those receiving salvage chemotherapy, confirming the overall survival benefit seen in the Phase 3 ADMIRAL trial," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development. "For these patients, who have limited treatment options, the new findings provide additional evidence supporting gilteritinib as a treatment option."
Data from Ph 1/2 OVATION 2 Study of Intraperitoneal GEN-1 + Neoadjuvant Chemotherapy [NACT] to be presented
“Currently advanced ovarian cancer has a low survival rate and a lack of effective therapies. PARP inhibitors have made an important contribution in a subset of patients. For the majority of patients there is hope that an immunotherapy such as GEN-1 will provide a valuable new treatment option to improve both the quality of life and the life expectancy for these women,” commented Dr. Thaker. “OVATION 2 Study data now show R0 resections in 14 of 17 patients, or 82%, in the GEN-1 + NACT arm, compared with seven of 12 patients, or 58%, in the NACT alone arm. We view R0 resections as a good predictor of survival, and R0 resections in the GEN-1 + NACT arm are encouraging thus far,” Dr. Thaker added.
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Trial/Program Status
“Following the promising final results of a phase 1b trial evaluating this triplet combination in advanced genitourinary tumors, this milestone in the phase 3 pivotal trial brings us a step closer to understanding whether cabozantinib in combination with nivolumab and ipilimumab may improve outcomes for patients with previously untreated advanced kidney cancer,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “We look forward to sharing initial results from the event-driven analysis of COSMIC-313 when available and to learning more about the potential of cabozantinib in combination with immunotherapies.”
DESTINY-Lung02 Ph 2 Trial of ENHERTU® Initiated in Patients with HER2 Mutated mNSCLC
“Identification of the HER2 mutation as a distinct molecular target in non-small cell lung cancer has opened up a new and exciting area of research. Our initial research of ENHERTU in the DESTINY-Lung01 trial has shown impressive early results in patients with HER2 mutated metastatic non-small cell lung cancer,” said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. “Building on these results, we are initiating the DESTINY-Lung02 trial to further explore the safety and efficacy of two different doses of ENHERTU in this specific type of non-small cell lung cancer.”
Click here for more Trial Status
Collated by : Richa Tewari, PhD
MedNess @ HealthIT
 

Surges in COVID-19 case numbers directly linked to variants through genetic data
While we get more informed on the emergence of COVID-19 variants, it is important to keep the perspective of the work behind identifying them. A study published in Scientific Reports established the occurrence of surges in case numbers due to COVID-variants. The virus contains 15 genes, which can accumulate mutations making them less or more transmissible than the original virus, as identified by Whole genome sequences (WGS) analysis. To gather data for this study, they initially analyzed the genomes of 150 SARS-CoV-2 strains from outbreaks in Asia prior to March 1, 2020.
Outbreaks have been classified by stage: index (no outbreak), takeoff, exponential growth, and decline. The ease of transmission of a virus is set by the value R or reproductive number, where R is the average number of new infections caused by each new person. The team then combined the genetic and stage information into a metric called GENI, or pathogen genome identity. Compared GENI scores with the phase of an epidemic, the team found that an increase in genetic variation came immediately before a significant spike in cases.
They then analyzed 20,000 sequences of SARS-CoV-2 viruses collected from February to April 2020 in the UK, while comparing them with data from cases. They found that the GENI variation score rose consistently with the number of cases. GENI score continued to rise even when national lockdown was imposed, and the number of cases stabilized.
The results of this study hope to provide a recipe of identifying an early indication of a new outbreak, as well as identify super-spreader events, while measuring virus variation and link it to the local transmission rate. Access to open-source data continues to be critical for the successful implementation of such a tool, asking for a collaboration from the health officials. “Leveraging shared resources opens unexpected collaboration and avenues for applying relevant bioinformatic and disease modelling opportunities across the scientific community to solve global public health problems very quickly,” according to the researchers.
MedNess Reviews

Experimental therapy for parasitic heart disease may also help treat COVID-19
A drug that was originally developed for a neglected tropical disease may hold the key to the treatment of COVID-19.
Chagas disease, the leading cause of heart failure in Latin America is spread by "kissing bugs" carrying the parasite Trypanosoma cruzi. These parasites produce an enzyme called cruzain that helps them replicate and evade the human immune system.
A team of researchers from the University of California San Diego McKerrow's looks for inhibitors of cruzain -- small molecules that might form the basis for new anti-parasitic medicines. One particularly effective cruzain inhibitor is called K777.
When the COVID-19 pandemic began to sweep through the United States, studies reported that that SARS-CoV-2, the coronavirus that causes COVID-19, can't dock on and infect human cells unless a human enzyme called cathepsin L cleaves the virus' spike protein.
The UC San Diego team quickly realized that cathepsin L looks and acts a lot like cruzain and found that low concentrations of K777 inhibit cathepsin L can reduce SARS-CoV-2's ability to infect four host cell lines, without harming the cells. The study is published in ACS Chemical Biology."
Selva Therapeutics, a privately held biotechnology company, has licensed K777 from UC San Diego. In a parallel study, the company has also found that the K777 therapeutic prevented lung damage in COVID-19 animal models and was well-tolerated by people who participated in a Phase I clinical trial to assess safety. Selva is planning a Phase IIa clinical trial in non-hospitalized COVID-19 patients for late 2021.
MedNess Business
Servier completes its acquisition of Agios Pharmaceuticals’ commercial, clinical, and research-stage oncology portfolio for up to $2 billion plus royalties
“We are pleased to welcome an exceptionally talented team that will allow us to strengthen our strategic focus in oncology and expand our scientific capabilities in cellular metabolism,” said Olivier Laureau, President of Servier. “It is an important milestone in Servier’s oncology strategy as it significantly reinforces the Group’s presence in the U.S. Together, with this expanded team, we remain committed to addressing the unmet needs of patients living with cancer across the globe.”
Huyabio International Announces Global Clinical Trial Collaboration With Bristol Myers Squibb In Melanoma
"This Phase 3 trial follows our open label Phase 2 study which showed impressive clinical results for the combination of Opdivo and HBI-8000 to treat melanoma," said Dr. Mireille Gillings, CEO & Executive Chair of HUYABIO. "HBI-8000 has been shown to enhance the efficacy of Opdivo through one of its mechanisms of action that controls acetylation and nuclear transportation of PD-L1."
Collated by : Richa Tewari, PhD
Editors' Desk
Richa Tewari, PhD
Oncology News
Esha Sehanobish, PhD
MedNess Plus
Arundithi Ananthanarayanan
MedNess Reviews
Divyaanka Iyer
BioPharma News
Shilpa Rawal, PhD
Onco I-Analyse
Debarati Banik
HealthIT
Rinki Saha
Managing Editor
Shalini Roy Choudhury
Managing Editor
Nisha Peter, PhD
Consulting Editor
Abhi Dey
Consulting Editor
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Content Editors: Richa Tewari , Esha Sehanobish , Rinki Saha ,  Shilpa Rawal, PhD ,  Debarati Banik  , Divyaanka Iyer , Arundithi Ananthanarayanan and Abhinav Dey 
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