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MedNess: bite-size biopharma and medtech news

18th February, 2020
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Drug Approvals
Tecentriq® (atezolizumab) + chemotherapy (carboplatin and etoposide) combination approved in China in 1L ES-SCLC patients based on Ph 3 IMpower133 trial results
“Small cell lung cancer is an area of major unmet need in China and one that has seen limited advances until now,” said Levi Garraway, M.D., Ph.D., Chief Medical Officer and Head of Global Product Development. “This approval makes Tecentriq the first cancer immunotherapy available in China for the initial treatment of extensive-stage small cell lung cancer less than a year after the US FDA and EMA approvals, marking a swift and important step forward for patients with this aggressive and difficult-to-treat disease.”
Regulatory News
FDA provides regulatory clarity on registration-enabling Ph 3 study design of nelipepimut-S (NPS) + trastuzumab in TNBC patients in the adjuvant setting
“We are indeed pleased with the feedback and final outcome from our discussions with the Agency, after extended interaction with them, on the optimal and mutually acceptable design of a potential registration-enabling Phase 3 clinical trial for NPS in combination with trastuzumab.  Importantly, we believe we have established an appropriate and expedient pathway to potentially bring NPS in combination with trastuzumab to patients in need as quickly as possible,” said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS.  “We believe this regulatory clarity will enhance our business development efforts to seek out-licensing opportunities to fund and conduct the future clinical development of NPS in order to maximize the potential of the program as we continue to focus all of our resources on the development of our lead asset, galinpepimut-S, which recently entered a registrational Phase 3 study in acute myeloid leukemia.” 
FDA accepts NDA and grants Priority Review for TAZVERIK™ (tazemetostat) for the Treatment of Follicular Lymphoma; PDUFA: Jun 18, 2020
“Follicular lymphoma is an incurable disease for which patients are in need of a safe, durable treatment option,” said Dr. Shefali Agarwal, chief medical officer of Epizyme. “If approved, we believe TAZVERIK could become an important new option for these patients and their physicians. We are thrilled with FDA’s acceptance of our application as an sNDA with Priority Review, for TAZVERIK for patients with relapsed or refractory FL. We look forward to working with the Agency during their review and would like to thank the many patients, caregivers and physicians whose contributions have been invaluable in bringing us to this point.”
Click Here for more Regulatory News
Trial Results
KEYTRUDA® (pembrolizumab) + Chemotherapy Met Primary Endpoint of PFS in 1L mTNBC patients in Ph 3 KEYNOTE-355 trial
“Triple-negative breast cancer is an aggressive malignancy. It is very encouraging that KEYTRUDA in combination with chemotherapy has now demonstrated positive results as both a first-line treatment in the metastatic setting with this trial, and as neoadjuvant therapy in the KEYNOTE-522 trial,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “We look forward to sharing these findings with the medical community at an upcoming congress and discussing them with the FDA and other regulatory authorities.”
Updated results announced from the Ph 1b/2 clinical trial EV-103 of of PADCEV™ (enfortumab vedotin-ejfv) + Pembrolizumab in 1L locally advanced or metastatic cisplatin-ineligible urothelial cancer patients
“Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn’t an option for many patients,” said Jonathan E. Rosenberg, M.D., Medical Oncologist and Chief, Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York. “I’m encouraged by these interim results, including a median progression-free survival of a year for patients who received the platinum-free combination of PADCEV and pembrolizumab in the first-line setting.”
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Trial/Program Status
First Patient Dosed in Ph 1b Clinical Trial of ATRC-101 in Patients with Select Solid Tumors
“Dosing of the first patient in our Phase 1b study of ATRC-101 is an important milestone marking our transition to a clinical-stage company,” said John Orwin, Chief Executive Officer. “ATRC-101 has demonstrated potent single-agent anti-tumor activity in multiple preclinical solid tumor models and we believe, through both its novel target and mechanism of action, that this antibody represents an exciting potential new approach in oncology. We look forward to reporting initial data from this study in the second half of 2020.”
First Patient Enrolled in Ph 1 Trial of Galinpepimut-S (GPS) + Nivolumab (Opdivo®) in Malignant Pleural Mesothelioma (MPM) Patients
“We are pleased to be collaborating with Memorial Sloan Kettering on this Phase 1 trial and excited to have expanded the clinical evaluation of GPS in combination with nivolumab to patients with advanced MPM,” said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS. “There are few effective therapies for mesothelioma, a disease which is characterized by high expression of the WT1 antigen, and we believe that the combination of GPS and nivolumab could be promising for patients with MPM, due to the combination’s potential synergistic immune-based mechanisms for anti-tumor activity. We look forward to gaining further insights on the safety and clinical outcomes of this combination in MPM.”
Collated by : Richa Tewari, PhD
Medness Plus
FDA issues an emergency use authorization for the first 2019 novel Coronavirus diagnostic
“Since this outbreak first emerged, we’ve been working closely with our partners across the U.S government and around the globe to expedite the development and availability of critical medical products to help end this outbreak as quickly as possible. This continues to be an evolving situation and the ability to distribute this diagnostic test to qualified labs is a critical step forward in protecting the public health,” said FDA Commissioner Stephen M. Hahn, M.D. “Our collaboration with the CDC has been vital to rapidly developing and facilitating access to this diagnostic test. The FDA remains deeply committed to utilizing our regulatory tools and leveraging our technical and scientific expertise to advance the availability of critical medical products to respond to this outbreak in the most expeditious, safe and effective manner possible.”
FDA announces the approval of three drugs for nonprescription use through Rx-to over-the-counter switch
“As a result of the Rx-to-OTC switch process, many products sold over-the-counter today use ingredients or dosage strengths that were available only by prescription 30 years ago,” said Karen Mahoney, M.D., acting deputy director of the Office of Nonprescription Drugs in the FDA’s Center for Drug Evaluation and Research. “Approval of a wider range of nonprescription drugs has the potential to improve public health by increasing the types of drugs consumers can access and use that would otherwise only be available by prescription. This includes providing the millions of people that suffer with joint pain from arthritis daily over-the-counter access to another non-opioid treatment option.”
Regeneron Pharmaceuticals announces positive results from their Phase 3 trial to evaluate EYLEA® in the treatment of patients with non-proliferative diabetic retinopathy
"These data reinforce that regular EYLEA treatment can be highly effective at reducing the risk of new vision-threatening events among patients with moderately severe to severe non-proliferative diabetic retinopathy," said Charles C. Wykoff, M.D., Ph.D., PANORAMA investigator, retina surgeon and ophthalmologist with Retina Consultants of Houston. "The PANORAMA trial shows that more than half of all untreated patients developed vision-threatening events over two years, underscoring the value of treating patients proactively and regularly." "Through millions of injections and eight pivotal Phase 3 trials, EYLEA has built a substantial body of evidence and safety profile. High-dose aflibercept will hopefully build on this standard-of-care therapy and represents our ongoing commitment to ophthalmologic research and development," said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer at Regeneron. "We are eager to explore the potential of high-dose aflibercept to deliver sustained vision gains and extended duration of action in patients with wet AMD and DME.
Click Here for more MedNess Plus
Collated by : Esha Sehanobish, PhD
Medness Reviews
 

February of 2020 will be remembered for two historical publications in the field of Immuno-oncology (IO)

CRISPR Engineered T-Cells In Patients With Refractory Cancer
The off-target effect of CRISPR and Cas9 immunogenicity and adopting the system in clinical settings kept the skeptics at bay for some time now. However, the latest work from Carl June's group at UPENN, seemed to have clarified some doubts, and this is only the beginning of an era. Things are going to be better from this point on. 
They reported in Science the first in human phase I trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells of three patients with refractory cancer using NY-ESO-1 TCR engineered T cells in patients. The transgenic TCR is specific for NY-ESO1 tumor antigen in patients with myeloma, sarcoma, and melanoma. 
The T cell receptor complex is central to successful anti-tumor responses. The key instrument for T cell-mediated immunotherapy, are patients own T cells that are genetically engineered to recognize the tumor and initiate an immune reaction to kill the cancer cells. A technique pioneered by June's group that ushered the era of cancer immunotherapy. However, CAR T Immunotherapy has certain limitations, such as: 

  1. Unwanted immune reactivity that can be harmful to the patients.
  2. Using endogenous TCR can lead to mispairing of the TCR alpha and beta chain, leading to reduced cell surface expression and generates self- reactive TCR. 
  3. Adoptively transferred T Cells are known to have T cell exhaustion and hence, reduced efficacy

To overcome these shortcomings, the group targeted TCRAC, TCRBC, and PDCD1 (PD1) using multiplex CRISPR-Cas9 genome editing.  
Some of the key results that will govern the evolution of CRISPR based therapies in the future are: 

  1. Sustained persistence of the engineered cells in the blood of all three patients. The cells were stable from 3-9 months after infusion. 
  2. Minimal immunogenicity of Cas9
  3. Absence of cytokine release syndrome
  4. Tri-genic editing using CRISPR-Cas9 had a similar number of translocation, as was observed in digenic translocation using TALENS in preclinical and clinical studies. Rearrangements were detected in approximately 4% of cells.
  5. The absence of PD-1 showed no autoimmunity nor T cell genotoxicity so far.
  6. Stable disease in 2 patients

In short, this first phase I pilot study confirms the possibility of multiplex CRISPR-Cas9 technology at a clinical scale. However, to fully assess the safety of the technology, studying several patients having infusions with higher editing infusions will need to be performed. 

Use Of CAR-Transduced Natural Killer Cells In CD-19 Positive Lymphoid Tumors
The second study from Dr. Katayoun Rezvani's group at the M.D. Anderson Cancer center developed engineered Natural killer (NK) cells that were modified to express an anti CD19. Anti CD19 CAR T cell therapy that changed the treatment for B cell cancers can cause substantial cytokine release syndrome as a devastating side effect. 
In their recently reported phase I and phase II studies at the New England Journal of Medicine, Dr. Rezvani's group engineered NK cells derived from cord blood with relapsed or refractory CD 19 positive Non-Hodgkin's lymphoma or chronic lymphocytic leukemia, using a retroviral vector carrying anti CD19 CAR, IL15 and an inducible Caspase 9 as a safety switch. 
The cells were expanded ex vivo and administered to patients after lymphodepleting chemotherapy. 
Key Results: 

  1. No cytokine release syndrome observed
  2. No neurotoxicity, GVHD or increase in the inflammatory cytokines were observed
  3. Out of 11 patients that received the treatment eight responded to the treatment of which 7 had complete remission
  4. CAR NK cells were found to expand and persisted for up to one year. 
"We have shown that it is possible to produce more than 100 doses of CAR NK cells from a single cord-blood unit. This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients,”
Needless to say that both the studies are landmark studies that will tremendously impact the way genome editing and immunotherapy will evolve in the next decade.
Collated by : Ananda Ghosh, PhD
Medness Business
Onco-News
Elicio Therapeutics and Natera To Collaborate in Phase I/II Pancreatic Cancer Study of ELI-002
“This study addresses an unmet need in the adjuvant setting for PDAC patients,” said Christopher Haqq, M.D., Ph.D., Elicio’s Executive Vice President, Head of Research and Development, and Chief Medical Officer. “Pancreatic cancer remains one of the deadliest forms of cancer, with a high rate of relapse post-surgery and 90% of patients are affected by KRAS mutations. ELI-002 brings the common KRAS mutated peptides together with a powerful immune activating adjuvant and Elicio’s proprietary lymph node targeting technology. Potent immune responses from sending the T cells for education in the lymph node hold promise to stop recurrence. We are excited to partner with Natera to select and monitor patients using breakthrough Signatera technology.”
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 
Concept and Design: Ananda Ghosh and Nisha Peter
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