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MedNess: bite-size biopharma and medtech news

24th February
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HIGHLIGHTS
Onco I-Analyse

Immunocore’s tebentafusp receives Breakthrough Therapy Designation for uveal melanoma
On 19th February, Immunocore announced that the US FDA has granted breakthrough therapy designation to tebentafusp (a novel bispecific TCR fused to an anti-CD3 immune-effector, specifically targeting an HLA-A*02:01 gp100 antigen) as a treatment option for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM). The designation is based on the survival data from the Phase 3 study announced in November 2020.
Background: Uveal melanoma is a relatively rare disease but is the most common form of ocular melanomas (>80% of ocular melanomas are uveal). It is the most common primary intraocular tumor with an average incidence of 5-10 people per million per year. With >40% stage III tumors metastasizing, the disease has a poor prognosis with 5-year survival of patients with distant metastases being <20%.
Currently, no treatment options are approved for distant mUV and NCCN recommends clinical trials as the preferred option. Other options include checkpoint inhibitors (CHKPTi) (Pembrolizumab, Nivolumab, Ipilimumab, Nivolumab+Ipilimumab), cytotoxics and trametinib. CHKPTi are associated with treatment-related AEs in high proportion of patients.
Details: During the initial pre-planned interim analysis, the Phase 3 of tebentafusp (versus Dacarbazine – 6%/ Ipilimumab – 12%/ Pembrolizumab – 82%) in 378 patients with previously untreated, HLA-A*0201+ mUV demonstrated superiority in primary endpoint of overall survival (HR: 0.51, p<0.0001). The estimated OS @ 1-year is 73% vs 58%, according to the K-M curve.
Final results from the study will be presented at an upcoming scientific conference and published in a peer-reviewed journal.
In April 2019, Tebentafusp was granted Fast Track Designation by the US FDA and Promising Innovative Medicine (PIM) designation under the UK Early Access to Medicines Scheme
Implications: The data reflects the first positive late-stage OS benefit for any TCR therapeutic. Immunocore will now be working with the FDA for submission of a BLA for tebentafusp in Q3 2021, followed by submission with the EMA. If approved, tebentafusp will be the first therapy approved for mUV in nearly 4 decades.
Collated by : Shilpa Rawal, PhD
COVID Special
FDA grants emergency use authorization to Eli Lilly’s bamlanivimab and etesevimab to be used together for the treatment of mild to moderate COVID-19
 In our last edition of the COVID-19 news we had covered the positive results of the combination treatment of bamlanivimab (LY-CoV555) 700 mg and etesevimab (LY-CoV016) 1400 mg in the treatment of recently diagnosed mild to moderate COVID-19. The FDA has now granted Emergency Use Authorization (EUA) for the combined use of bamlanivimab and etesevimab for the treatment of mild to moderate COVID-19 in patients aged 12 years or older and who are likely to progress to the more severe form of COVID-19 with or without hospitalization. The treatment of the combined drugs should be given as a single intravenous infusion early on after the positive COVID-19 test and within 10 days of when the symptoms first started to surface. The time of infusion of bamlanivimab by itself and in combination with etesevimab is 16 to 21 minutes. The previously authorized infusion time was 60 minutes. The EUA authorization for this combination therapy was granted to Eli Lilly and Company for the duration of the declaration or till the authorization is revoked or terminated. EUA is a form of temporary authorization and does not replace the formal review process. Currently, the use of bamlanivimab has been approved in various countries while the combination therapy also involving etesevimab is currently only authorized in Italy and United States. As per a collaboration with Amgen, Eli Lilly aim to manufacture up to 1 million doses of etesevimab for administration with bamlanivimab by the mid 2021 period. Along with the current 100,000 doses available, an additional 150,000 will be available in the first quarter of 2021. 
Etesevimab is a recombinant fully human monoclonal neutralizing antibody that binds to the spike protein receptor on the surface of SARS-CoV-2. The affinity of the antibody for the binding domain is high and prevents the binding of the virus to the ACE2 host cell surface receptors. In order to reduce the effector function, point mutation can be introduced into the native human IgG1 antibody. Etesevimab was initially developed by Junshi Biosciences and Institute of Microbiology, Chinese Academy of sciences and was later licensed by Eli Lilly. Bamlanivimab is a recombinant neutralizing human IgG1 monoclonal antibody that is directed against the spike protein of the virus. Its mechanism of action is via the blocking the viral attachment and entry into the cells. Bamlaniviab was developed from the collaboration of Eli Lilly and AbCellera. Both etesevimab and bamlanivimab are currently being studied in various ongoing clinical trials to determine their effectiveness in hospitalized COVID-19 patients and also in ambulatory patients. The EUA was based on results from the Phase 3 study of BLAZE-1 clinical study. The results from this study showed a reduced risk of COVID-19 hospitalization and a reduction in death by 70 percent. Also, the combination therapy showed consistent results when compared to those with bamlanivimab alone. The most common adverse effect associated with the study was nausea on the day of infusion. An ongoing Phase 2 study showed similar results between 700 mg bamlanivimab and 1400 mg of etesevimab and 2800 mg of each. 
"Lilly has dedicated our time, resources, and expertise to discover and develop therapies to treat COVID-19," said Daniel Skovronsky, M.D., Ph.D., Lilly's chief scientific officer and president of Lilly Research Laboratories. "Bamlanivimab alone under emergency use authorization has already provided many people with an early treatment option that could prevent hospitalizations and we are excited to now add an additional therapeutic option with a similar demonstrated clinical benefit. Additionally, with the risk of resistance emerging as various strains of the virus arise, bamlanivimab and etesevimab together could potentially allow efficacy against a broader range of naturally occurring SARS-CoV-2 variants as these new strains spread around the world." "As COVID-19 cases, hospitalizations and subsequent deaths continue to rise, we are committed to working with the U.S. government to supply our antibody therapies for use by patients across the country," Skovronsky added.
Click here for more COVID news
Collated by : Esha Sehanobish, PhD
Regulatory News
2 sBLAs submitted to FDA for PADCEV® (enfortumab vedotin-ejfv) in locally advanced/Metastatic Urothelial Cancer Based on EV-301 and Cohort 2 of EV-201 data for RTOR review
“The FDA’s review of our applications under Real-Time Oncology Review supports our efforts to expand PADCEV’s availability as a treatment option for more patients as quickly as possible,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. “Locally advanced or metastatic urothelial cancer is an aggressive disease with limited treatment options.” 

FDA accepts sNDA for BRUKINSA (Zanubrutinib) in Waldenström’s Macroglobulinemia
“We are pleased that the FDA has accepted the sNDA for BRUKINSA in WM, a rare disease with significant morbidity. BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue,” said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. “We look forward to continuing our communications with the FDA in the coming months and hope that BRUKINSA will become a new treatment option for patients with WM in the United States.”
 
FDA Grants Sotorasib Priority Review Designation For The Treatment Of Patients With KRAS G12C-Mutated Locally Advanced Or mNSCLC
  • PDUFA date for sotorasib: Aug. 16, 2021
  • NDA is based on the Ph 2 results from the CodeBreaK 100 trial in locally advanced or metastatic NSCLC patients whose cancer had progressed despite treatment with chemotherapy and/or immunotherapy.
  • Full results from the study were recently presented in IASLC 2020 World Conference on Lung Cancer (WCLC).
  • Sotorasib NDA was submitted on Dec. 16, 2020 and is being reviewed by the FDA under its Real-Time Oncology Review (RTOR) program.
  • Marketing Authorization Application (MAA) submitted in the EU in Dec. 2020.
  • MAAs submitted for sotorasib in Australia, Brazil, Canada and the United Kingdom in Jan 2021.
  • Sotorasib has Breakthrough Therapy Designation in the U.S. and China.
Click here for more Regulatory News
Trial Results
Ph 2/3 Trial of N-803 for BCG Unresponsive NMINC CIS shows 71% Complete Response Rate
“The high rates of complete response without serious adverse events indicates that the combination of BCG plus N-803 is a promising alternative to existing therapies and compares favorably to the other approved options valrubicin and pembrolizumab,” said presenting author Karim Chamie, M.D., Associate Professor of Urology, David Geffen School of Medicine at UCLA.

Encouraging results observed in Ph 1 trial of cabozantinib + nivolumab +/- ipilimumab in patients with refractory metastatic genitourinary (GU) tumors
“We see a significant level of anti-tumor activity with an acceptable tolerability profile for the combination of cabozantinib with nivolumab or nivolumab and ipilimumab for this early phase trial across a broad range of GU malignancies,” said Andrea Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health and the principal investigator of the trial. “This phase 1 study’s early results provided important information for the development of the phase 3 CheckMate -9ER study sponsored by Bristol Myers Squibb, of cabozantinib plus nivolumab versus sunitinib that recently reported improved progression-free survival, overall response, and overall response rate, leading to last month’s U.S. approval of the combination therapy of cabozantinib and nivolumab in first-line advanced renal cell carcinoma. The additional activity seen in other GU tumors support further research into the potential of cabozantinib combinations with immune checkpoint inhibitors in other advanced, intractable GU cancers.”

Positive Results announced for CABOMETYX® (cabozantinib) in Patients with Metastatic Papillary Renal Cell Carcinoma in SWOG S1500/PAPMET Study
“We’re excited to build on the demonstrated history of CABOMETYX’s clinically meaningful and statistically significant benefits for patients with renal cell carcinoma with these data that support its efficacy in patients with papillary renal cell carcinoma, who are often not the focus of major clinical trials for kidney cancer,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “The ability of CABOMETYX to inhibit MET, which is frequently altered in this tumor type, encouraged additional research into its potential benefits. It’s gratifying to see these positive results of the PAPMET trial, which may help physicians choose an appropriate therapy for their patients with advanced papillary renal cell carcinoma.”
Trial/Program Status
Ph 2/3 study of bempegaldesleukin (NKTR-214, BEMPEG) + KEYTRUDA® (pembrolizumab) in 1L metastatic or unresectable recurrent PD-L1+ve SCCHN patients to be initiated in H2, 2021  
"We are excited to advance the combination of BEMPEG plus KEYTRUDA to a Phase 2/3 study in first-line squamous cell carcinoma of the head and neck," said Jonathan Zalevsky, PhD, Chief R&D Officer at Nektar.  "Earlier studies of BEMPEG in combination with immune checkpoint inhibitors, also known as ICIs, evaluated in patients with immune-sensitive cancers have shown the potential to increase and deepen treatment responses as compared to historical rates for ICIs alone.  This collaboration with Merck will enable us to further explore the combination of BEMPEG with the leading checkpoint inhibitor therapy in the setting of advanced head and neck cancer." 
OlympiA Ph 3 trial of Olaparib will move to early primary analysis and reporting following IDMC’s recommendation
Andrew Tutt, Global Chair of the OlympiA Phase III trial and Professor, Institute of Cancer Research and Kings College London, said: “We are delighted that our global academic and industry partnership has been able to help investigate a possible personalised treatment for women with hereditary breast cancer. The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 genes which also may cause the disease to develop at a significantly earlier age than is usual. The OlympiA trial has allowed us to go beyond using genetic testing to identify patients who are at risk of this disease and explore the potential of Lynparza to prevent disease recurrence for these patients. We look forward to analysing and presenting the full results of the trial at a forthcoming medical meeting.”
 
Click here for more Trial Status
Collated by : Richa Tewari, PhD
MedNess Plus
FDA approves BOTOX® for the treatment of bladder muscle overactivity associated with neurologic conditions in pediatric patients
 FDA recently granted approval to BOTOX® (onabotulinumtoxinA) for the treatment of detrusor (bladder muscle) overactivity associated with a neurologic condition in pediatric patients 5 years and older. These are patients who are either inadequately treated or are intolerant to anticholinergic medication. The approval was granted to Allergan, an AbbVie company. 
The condition neurogenic detrusor overactivity is often characterized by frequent and unexpected urine leakage. Due to ineffective communication between the bladder and the spinal cord, neurogenic detrusor overactivity can occur. This can also be accompanied with spinal cord injuries or conditions such as spina bifida. As a result of this ineffective communication, there can be involuntary bladder muscle contraction thus reducing the bladder capacity and increasing the pressure in the bladder. If the condition is left unattended, the elevated bladder pressure may lead to kidney damage over time. BOTOX® was the first approved botulinum toxin type A treatment. It has also been approved for 12 different therapeutic indications. The approval for BOTOX® was based on results from a Phase 3 randomized, double-blind study. The aim of this study was to determine the safety and efficacy of BOTOX® in pediatric patients with neurogenic detrusor overactivity. It included 100 such patients. The results showed that administration of 200 Units of BOTOX® reduced the daytime urinary inconsistencies, which was the primary endpoint of the study. The medication was also able to lower maximum bladder pressure and resulted in increased bladder capacity at week 6. The most common adverse effects associated with this study was bacteriuria, urinary tract infection, leukocyturia and hematuria. 
"BOTOX® is the first neurotoxin approved for use in treating neurogenic detrusor overactivity in children who are not adequately managed with anticholinergic medication. While always satisfying to bring forth new indications, it is particularly rewarding when we can help advance care for pediatric patients with BOTOX®," said Mitchell F. Brin, M.D., Senior Vice President, Chief Scientific Officer, BOTOX® & Neurotoxins, AbbVie. "This milestone marks the 12th approved therapeutic indication for BOTOX®, adding another approved use to the pediatric portfolio. Building upon our 30-year heritage in BOTOX® research and development, we remain steadfast in our pursuit of neurotoxin innovation to address unmet medical needs across therapeutic areas."
FDA approves the first-of-its-kind implant for the treatment of avascular necrosis (AVN) a rare bone disease
 FDA approves the first-of-its-kind implant to replace the bone in the ankle joint that connects the leg and the foot (talus bone) for the treatment of avascular necrosis (AVN). The Patient Specific Talus Spacer 3D-printed talus implant was approved for humanitarian use and is expected to provide a joint-sparing alternative to other surgical interventions commonly used in the late-stage AVN. The data was reviewed through the humanitarian device exemption (HDE) method. Humanitarian Use Device (HUD) intends to benefit patients by treating or diagnosing conditions that affect not more than 8000 individuals per year in the US. The HDE approval was granted to Additive Orthopedics, LLC. 
Avascular necrosis (AVN) of the ankle joint is a progressive and debilitating condition that causes the death of bone tissues due to lack of blood supply to the area. It can originate from injuries such as dislocated joints, broken bone or tissue damage over time that prevents the blood supply to the damaged area. As a result of this the tissues become necrotic in nature. In case of bones of joints such as the ankle, the degradation of cartilage that prevents the friction between bones, can lead to pain and arthritis. In some cases, such as the later stages of AVN, there can be a complete collapse of the talus bone. One of the common modes of treatment is a surgery that fuses the joints in the foot and the ankle together which eliminates motion in the joints, or below-the-knee amputation. However, the Patient Specific Talus Spacer is talus bone 3D printed implant that can be used in talus replacement surgery. The talus spacer is personalized for each patient based on the CT imaging and is fitted to the patient’s anatomy. The implant is made from cobalt chromium alloy which during the replacement surgery is put in place of the talus bone of the patient. The approval for this implant was based on a study from 31 patients and 32 talus replacement surgeries. After a period of three years, the pain reduced from moderate to severe before surgery to mild, after surgery. The average range of the ankle joint movement was also improved. Subjective scoring systems for pain and functionality were used. 
“Avascular necrosis of the ankle, while a rare condition, is a serious and potentially debilitating one that causes pain and can lead to inhibited motion of the ankle joint, and in some cases, removal of part of the leg,” said Capt. Raquel Peat, Ph.D., M.P.H., USPHS, director of the FDA’s Center for Devices and Radiological Health’s Office of Orthopedic Devices. “Today’s action provides patients with a treatment option that could potentially reduce pain, retain range of motion of their joint and improve quality of life.”
Click here for more MedNess Plus
Collated by : Esha Sehanobish, PhD
MedNess @ HealthIT
 
Google’s association with Mayo clinic is bolstered via its new office in Rochester, Minnesota
The strategic partnership between Mayo clinic and Google was initiated in September 2019 to utilize healthcare cloud computing, data analytics, machine learning, and AI for the betterment of care delivery. So far, the utility of their association has been manifested with Mayo researchers being able to move data in cloud and physicians to plan radiotherapy better. The search for a physical space to work together ever since has now come to fruition through Collider Coworking in the historic Conley-Maass-Downs building in downtown Rochester. According to the Minnesota governor Tim Walz, “This partnership with the Mayo Clinic reinforces Minnesota’s reputation as a welcoming state for innovation and economic opportunity. We welcome Google to our community.” Notably, Google has assisted in $7.29 billion of economic activity for 22,200 Minnesota businesses, nonprofits, publishers, creators, and developers, as well as $7.3 million of free advertising to Minnesota nonprofits through the Google Ads program.  
Deep learning tool gets closer in predicting lung cancer survival expectancy
Predicting survival expectancy through early diagnosis offers the benefit of plan resources, care levels, and treatment timelines, and therefore has been sought as a readout in past machine learning programs. A new study conducted in Penn State (The Big Data Lab, Division of Engineering and Information Science) and published in the International Journal of Medical Informatics, gets to a higher level of accuracy (71%) in the prediction, compared to the past tools. The study utilized a large amount of data, such as, types of cancer, size of tumors, speed of tumor growth, and demographic data, which were collected from the lung cancer section of Surveillance, Epidemiology, and End Results (SEER) cancer registry. They were then analyzed via three popular deep learning architecture (Artificial Neural Networks or ANN, Convolutional Neural Networks or CNN, and Recurrent Neural Networks or RNN). As one of the largest registries on the early diagnosis information for cancer patients (accounting for ~35% of cancer cases in the US), SEER includes about 800K-900K entries. Finding conclusive association between them is a daunting task that has been accomplished by AI in this study. Success of the tool warrants future advancement into other disease/cancer domains, as well as further improvements to the tool, although it does not substitute for medical opinion of the oncologists/care givers. Read it on Twitter.
MedNess Reviews

Sanofi and i2O Therapeutics enter into a Research Collaboration with Sanofi to Enable Oral Delivery of Nanobody-based Medicines
Sanofi has entered into research collaboration with i2O Therapeutics to investigate the oral delivery of Sanofi's Nanobody®-based medicines, which are currently administered through intravenous or subcutaneous injections.
Nanobodies are therapeutic proteins based on camelid-derived immunoglobulin single variable domains. They have potential uses in the treatment of a range of serious and life-threatening diseases and are being developed in many therapeutic areas including inflammation, hematology, immuno-oncology, oncology and rare diseases. The molecules are typically administered via injections, but advocates of the modality see scope for oral, inhaled and ocular delivery.
I20’s key technology is based on an ionic liquid technology plastform designed to both protect drugs from the conditions they encounter when given orally and get more of the active substance across the epithelial lining.
Earlier in 2020, Sanofi Ventures recognized the potential of i20s technology and lead a $4 million seed financing in the company.
In 2018, Sanofi acquired nanobody pioneer Ablynx five billion dollars. Now, Sanofi has teamed up with i20 to explore whether the ionic liquid platform can enable the oral delivery of nanobodies.

Scientists Develop a Hydrogel-Based Delivery Platform for mRNA Vaccines for use in Cancer Immunotherapy
Before the successful development of vaccines against COVID-19 based on the mRNA technology, scientists were exploring technology's potential for use in cancer therapeutics, but were met with limited success.
Now, scientists at the China’s National Center for Nanoscience and Technology (NCNST) have developed a hydrogel to deliver an mRNA vaccine with an immune-stimulating adjuvant. According to the study, when mice with melanoma were injected with the vaccine, the vaccine stayed active for at least 30 days, inhibiting tumor growth, and preventing metastasis. This potential long-lasting effect of the hydrogel delivery system plays a key role in making the technology more suitable for cancer immunotherapy.
The COVID-19 mRNA based vaccines carry the genetic information that instructs the body to produce a specific viral protein to trigger the desired immune response. However, in cancer, the vaccines are typically designed to translate tumor-associated antigens so the immune system can recognize and eliminate the cancer.
Historically, the shortcoming of the mRNA technology was due to the unstable nature of mRNA. For its FDA-authorized COVID-19 shot BNT162b2, BioNTech used lipid nanoparticles to protect the core mRNA information. The nanoparticles degrade and release the mRNA
Collated by :  Arundithi Ananthanarayanan 
Medness Business
SHEPHERD Therapeutics and Oncoheroes Biosciences to collaborate on Oncology Therapeutics For Rare Cancers
"We are excited about this partnership between two mission-driven companies determined to address high unmet medical needs in the rare oncology space. We are confident that SHEPHERD's technology, combined with Oncoheroes' expertise in the pediatric oncology space, will deliver new therapeutics options to children and adolescents with cancer," stated Ricardo Garcia, CEO of Oncoheroes.
 
 
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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