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MedNess: bite-size biopharma and medtech news

26th February, 2020
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News of the week
BioMarin’s hemophilia A candidate accepted for FDA priority review
Biomarin announced that the FDA accepted its investigational AAV5 gene therapy, valoctocogene roxaparvovec, for adults with hemophilia A. FDA has granted a priority review for the drug and not currently planning to hold an advisory committee meeting (ADCOM) to discuss the application. Further, the FDA has accepted the premarket approval (PMA) application for an AAV5 total antibody assay as a companion diagnostic test for valoctocogene roxaparvovec. With a low prevalence of pre-existing immunity to AAV5, BioMarin estimates that approximately 80% of people with hemophilia A in the US do not have preexisting immunity to AAV5 that would make them ineligible for the treatment.
Collated by : Ananda Ghosh, PhD
Drug Approvals
Japan Ministry of Health, Labor and Welfare Approves Opdivo (nivolumabin Unresectable Advanced or Recurrent Esophageal Cancer patients based on the Ph 3 ATTRACTION-3 trial data
“Alongside our partner, Ono Pharmaceutical, we are proud to offer Opdivo as an alternative to chemotherapy for patients in Japan with esophageal cancer, regardless of their PD-L1 status,” said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. “This first-ever approval of Opdivo in esophageal cancer exemplifies our commitment to advancing treatment options with the potential to extend survival for patients with difficult-to-treat gastrointestinal cancers.”
Regulatory News
FDA Issues Complete Response Letter for sBLAs for KEYTRUDA® (pembrolizumab) Six-Week Dosing Schedule
  • sBLA intended to include a 400 mg dose infused over 30 minutes every-six-weeks (Q6W) option in multiple indications
  • The submitted sBLA is based on PK modeling and simulation data (presented at ASCO 2018 Meeting)
  • Data supported the EU approval of 400 mg Q6W dosing for KEYTRUDA monotherapy indications in Mar 2019
  • Merck is reviewing the letter and will discuss next steps with the FDA
ALX148 Receives Two Fast Track Designations from FDA for the Treatment of SCCHN Patients and Patients with Gastric or GEJ Adenocarcinoma
“FDA’s decision to grant Fast Track designation to ALX148 is an important recognition of ALX Oncology’s promising clinical data. This designation reflects the potential for ALX148 to be an important advancement in the treatment of patients with HNSCC and HER2-positive gastric/GEJ cancer,” said Sophia Randolph, M.D., Ph.D., Chief Medical Officer of ALX Oncology. “We are encouraged by the initial data from our Phase 1 clinical trial that showed a 40 percent objective response rate (ORR) in checkpoint inhibitor-naive HNSCC patients whose tumors had progressed on prior platinum therapy, and a 21 percent ORR in gastric/GEJ patients where all responders’ disease had progressed upon at least one prior anti-HER2 containing regimen. We look forward to working closely with the FDA on the clinical development of ALX148 for patients with cancer.”
FDA Breakthrough Therapy Designation granted to PADCEV™ (enfortumab vedotin-ejfv) + Pembrolizumab in 1L Advanced Bladder Cancer based on  Ph 1b/2 trial EV-103 data
“This is an important step in our investigation of PADCEV in combination with pembrolizumab as a first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy,” said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics. “Based on encouraging early clinical activity, we recently initiated a phase 3 trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.”
Click Here for more Regulatory News
Trial Results
FAILED TRIAL: Ph 2 trial of cabiralizumab + Opdivo® (nivolumab) with and without chemotherapy in patients with advanced pancreatic cancer did not meet primary endpoint
“Pancreatic cancer is a difficult disease to treat, and unfortunately the combination of cabiralizumab and Opdivo with and without chemotherapy did not show any meaningful benefit over standard of care chemotherapy in this randomized, controlled Phase 2 trial,” said Helen Collins, M.D., Executive Vice President and Chief Medical Officer of Five Prime Therapeutics. “We are disappointed by this outcome and appreciate the participation of the investigators, staff, patients, caregivers, and our development partner who all contributed to the conduct and completion of this Phase 2 clinical trial.”
Primary Efficacy Endpoints Achieved from Ph 2 CLOVER-1 Study of CLR131 in Relapsed/Refractory B-cell Lymphomas
“The data reported today are very promising and we believe the product profile for CLR 131 can improve further with the administration of a second cycle. These results are even more impressive considering the challenging patient population tested, as all were heavily pre-treated with the vast majority being refractory to their most recent therapy,” said James Caruso, president and CEO of Cellectar Biosciences. “Based upon these compelling data and the need for new and innovative treatment options for patients, we plan to execute upon a well-defined and approvable regulatory path forward in a prioritized hematologic indication. We hope that this potentially first-in-class PLE-targeted radiotherapeutic will provide a new and meaningful treatment option for patients living with multiple myeloma and/or NHL.”
Click Here for Trial Results
Trial/Program Status
Randomized Ph 2 cohort expansion initiated in ongoing first-in-human Ph 1/2a trial of anti-CTLA-4 Probody BMS-986249 alone and in combination with Opdivo® (nivolumab)
“CTLA-4 is the prototypical checkpoint target and blocking this mechanism has proven highly effective in the treatment of melanoma and other cancer types. This exciting progress within our alliance with Bristol-Myers Squibb is aimed at the development of anti-CTLA-4 therapies to broaden the reach of this foundational pathway for cancer patients,” said Sean McCarthy D.Phil., president, chief executive officer and chairman of CytomX Therapeutics. “This ongoing work by the Bristol-Myers Squibb team complements CytomX’s own work and continued clinical progress with the combination of our anti-PD-L1 Probody, CX-072, with ipilimumab, which will further delineate the potential of our Probody therapeutic platform to deliver differentiated anti-cancer therapies.”
Ph 2 trial of VB-111 + nivolumab (Opdivo®) launched in mCRC patients
“This phase 2 study is part of our strategy to broaden the potential indications for VB-111 and to explore its activity as part of combination therapies,” said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics. “We look forward to collaborating with NCI on this clinical trial, as we continue to generate data which adds to our understanding of VB-111’s mechanism of action and therapeutic potential. We were particularly encouraged by results in ovarian cancer demonstrating the recruitment of infiltrating T cells into a tumor following treatment with VB-111, turning the tumor ‘hot’. This important finding suggests that VB-111 may be applied to other ‘cold’ tumors, in which checkpoint inhibitors show limited or no efficacy, including colorectal cancer, for which there remains a major unmet need.”
Click Here for Trial/Program Status
Collated by : Richa Tewari, PhD
Medness @HealthIT
New advocates and taskforces in the HealthIT-town
IGT: A new advocacy foundation,  the Institute for Gene Therapies (IGT), has been recently launched with the goal of modernizing the US regulatory and reimbursement framework for gene therapies to keep up with the changing scenario. US health system currently spends about 85 cents of every healthcare dollar managing the symptoms of chronic diseases over a patient’s lifetime, according to IGT. Gene therapy promises to bring long-lasting effects by altering patients’ non-functioning genes or replace absent ones. It can also reshape the way of treating thousand of diseases. 
The changes will soon demand bringing together experts across the healthcare community, including corporate leaders, patient advocacy groups, and academic and scientific stakeholders, to ensure health policies reflect the latest advancements in gene therapies. IGT will work to educate stakeholders across the healthcare system about the potential for gene therapies to treat and cure common and rare chronic diseases, and advocate for policies that help ensure patients who need gene therapies can benefit from them. Read the full story here.
 
Data interoperability taskforce: A new taskforce has been organized under the Office of the National Coordinator for Health IT (ONC) to support the convergence of clinical and administrative data to improve data interoperability to support clinical care, reduce burden and improve efficiency—furthering implementation of “record once and reuse”. To achieve the vision, it strives to produce information and considerations related to the merging of clinical and administrative data, their transport and protection structures, and the electronic prior authorizations. Read the details on the taskforce’s overarching charges here.
Launching of Vanderbilt Clinical Informatics Center
Vanderbilt University Medical Center (VUMC) has launched the new Vanderbilt Clinical Informatics Center (VCLIC), which will promote and support collaborations in clinical informatics across the institution. According to Adam Wright, the director of clinical decision support, “The primary idea driving clinical informatics is that we should use computerized information systems to help people make better clinical decisions”. 
VUMC has one of the largest biomedical informatics departments in the country that is recognized as a leader in applying computer and information science to care delivery services. The launch of VCLIC adds to VUMC’s efforts to advance clinical informatics in healthcare. In November 2017, the institution shut down key decision support systems and adopted commercial software from Epic Systems. VCLIC will aim to pave the way for clinical informatics initiatives, educating researchers and staff about how to build and evaluate interventions, how to access data, and how to disseminate results within and beyond VUMC. Read the full story here.
Collated by : Debarati Banik
Medness Reviews

Machine Learning Aids Scientists Discover Powerful New Antibiotic
In the first of its kind antibiotic discovery, an AI system has identified a powerful new antibiotic compound.
Using deep learning algorithms, scientists from MIT trained the AI system to identify potential antibiotic compounds using various mechanisms to those of existing antibiotics. Specifically, they fed the program information on the atomic and molecular features of 2,500 drugs and natural compounds and their efficacy against E.coli growth.
The new antibiotic dubbed Halicin, after the Hal 9000 system, was identified after the AI system analyzed a library some 6,000 compounds that were under investigation for treating human diseases. This library was used to make the AI systems look for potential candidate molecules that would be effective but unlike existing antibiotics. This would boost the chance for the drug to overcome antibiotic resistance.
Tests showed that Halicin showed antibiotic effect toward M.tuberculosis, strains of Enterobacteriaceae resistant to carbapenems. Halicin also cleared C. difficile and multidrug resistant Acinetobacter baumannii infections in mice.
This study is milestone for the use of AI in new drug discovery. Click here for a detailed report by STAT news.
Researchers Uncover role of Targeted deletion of PD-1 in Myeloid cells 
In an interesting study, researchers from the Harvard Medical School have uncovered an unappreciated role of the cell death protein PD-1 expressed on myeloid cells.
PD-1, a cell checkpoint receptor and target of cancer immunotherapy, is expressed T cells and myeloid cells. Earlier, the role PD-1 ablation in antitumor immunity specific to myeloid cells versus T had been unclear because most studies used either PD-1–blocking antibodies or complete PD-1 KO mice. In this study, the researchers generated conditional knockouts for the PD-1 specific to either T cells or Myeloid cells and compared effects on tumor suppression.
They found that compared with T cell–specific PD-1 ablation, myeloid cell–specific PD-1 ablation more effectively decreased tumor growth in mice. Notably, the myeloid cell–specific PD-1 ablation also induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite PD-1 expression in T cells.  They also observed metabolic reprogramming of emergency myelopoiesis in PD-1 deficient myeloid progenitors that lead to their differentiation into inflammatory macrophages and dendritic cells. The results of this study serve to be better understand and analyze how PD-1 centric therapies work.

Pancreatic ductal cancer now made sensitive to PD-1 immunotherapy
Dr. Vinod P. Balachandran’s group at Memorial Sloan Kettering Cancer Center describes successful treatment of pancreatic ductal cancers (PDACs) through immunotherapy in  Nature. This is of significance, as PDACs are aggressive cancers with poor long-term survival and no effective treatments. The key findings are:

  1. PDACs can be made susceptible to anti-PD1 immunotherapy by targeting Group 2 innate lymphoid cells (ILC2s) in pancreatic tumors
  2. ILC2s, relieved of PD-1 repression, proliferate to Interlukin-33 (IL-33) signals and aid CD8+ T cells in anti-tumor activity
  3. IL-33 receptors are limited to pancreatic ILC2s (ILC2s bear unique immunophenotypes in different organs) and the mechanism is pancreas specific

ILC2s are antigen independent in eliciting inflammatory reaction to pathogens through the secretion of chemo-attractants. Therefore, their co-occurance with CD8+ T lymphocytes in different cancers is interesting but unexplained. 
In the context of orthotopic PDAC models, the co-dependency of ILC2s and CD8+ T cells is now clear. The tumor microenvironment is IL-33 rich and achieves expansion of IL-33 receptor bearing ILC2s, increasing inflammatory chemokine signalling with a positive effective on CD8+ tumor infiltration. However, PD-1 limits this proliferation. Dual therapy of recombinant IL-33 along with anti- PD-1 has a synergistic effect in tumor regression (<0.001) compared to individual treatments. This is the first study to explore ILC2s in immunotherapy and provides exhaustive characterisation of the immunophenotype and interactions of ILC2s in PDACs, which can be accessed here.
Since 60% of PDACs have the co-occurrence of PD-1+ ILC2s and CD8+ T-cells, this new approach to immunotherapy holds promise for treating pancreatic cancers. A novel paradigm of considering resident ILC2s in different cancers is now open, and understanding ILC2 cytokine requirements to provide a pro-inflammatory environment within a tumor may hold the key to the successful immunotherapy in other cancers.
Medness Business
Onco-News
Tocagen merging with Forte Biosciences
"We are excited about the opportunities created by this merger, as it positions us to become a global leader in inflammatory skin diseases with the funding needed to advance our pipeline towards regulatory approval and potential commercial launch," said Paul Wagner, president and chief executive officer of Forte. "Our team and advisors are committed to providing new treatment options, particularly for pediatrics with atopic dermatitis, for which few treatment options exist, and we look forward to delivering on this as we advance through development."
Immatics and GSK Partner to Develop Novel Adoptive Cell Therapies
“We are delighted to enter into this strategic collaboration with GSK – a partner who is already committed to adoptive cell therapies and TCR-T approaches,” said Harpreet Singh, Chief Executive Officer of Immatics. “By combining Immatics’ world-leading target and TCR discovery platforms with GSK’s advanced manufacturing, development capabilities and a commitment to next-generation TCR-T technologies, both companies are joining forces to enable the development of effective novel therapies for cancer patients with high unmet medical need.”
Five Prime Therapeutics Licenses Antibodies to Seattle Genetics for Use in Novel Antibody Drug Conjugate (ADC) Programs
“We are pleased to enter into this license agreement with Seattle Genetics, a global leader that develops and commercializes transformative targeted cancer therapies that utilize its industry-leading ADC technology,” said William Ringo, Chairman and interim Chief Executive Officer of Five Prime Therapeutics. “This agreement allows Five Prime to realize value from our pre-clinical pipeline while prioritizing our clinical investments based on upcoming data readouts for our programs. Looking to the future, we will continue to seek strategic partnerships that allow us to maximize the value of our assets and the long-term potential of the company.”
Collated by : Richa Tewari, PhD
Editors' Desk
Richa Tewari, PhD
Oncology News
Esha Sehanobish, PhD
MedNess Plus
Arundithi Ananthanarayanan
MedNess Reviews
Debarati Banik
HealthIT
Divyaanka Iyer
MedNess Reviews
Nisha Peter, PhD
Managing Editor
Mayur Vadhvani, PhD
Consulting Editor
Abhi Dey
Consulting Editor
Ananda Ghosh, PhD
Founder
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The editors take care to share authentic information.  In case of any discrepancies please write to medness.newsletter@gmail.com
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 Sehanobish , Mayur Vadhvani and Abhinav Dey 
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