On November 4, 2021 Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) ("Aeterna" or the "Company"), a specialty biopharmaceutical company developing and commercializing a diversified portfolio of pharmaceutical and diagnostic products, reported its financial and operating results for the third quarter ended September 30, 2021 (Press release, AEterna Zentaris, NOV 4, 2021, View Source;id=215914&p=2209892&I=1206939-c7Z3G6f3m8 [SID1234594595]). The Company also provided an update on progress in its pre-clinical and clinical development programs.

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"Since January 2021, we have made a concerted effort to not only advance our clinical-stage program but to expand our development pipeline. We have delivered on that goal and are pleased with the progress made to date. The leadership and expertise we have established at Aeterna Zentaris, now coupled with a diversified portfolio of assets with the potential to address areas of significant medical need, has created an exciting time in the Company’s evolution and multiple potential avenues for value creation. We are diligently working to execute on the advancement of all our clinical and pre-clinical programs and are poised to continue building momentum and value in the near and long term," commented Dr. Klaus Paulini, Chief Executive Officer of Aeterna.

Recent Highlights:

Entered into an additional exclusive license with the Julius-Maximilians-University of Wuerzburg (the "University of Wuerzburg") for early pre-clinical development of AIM Biologics for the potential treatment of Parkinson’s disease.
Exercised its option under the agreement with the University of Wuerzburg to expand application of oral vaccine platform to second indication, chlamydia.
Pre-Clinical and Clinical Programs Update:

Diagnostics Development Pipeline

Macimorelin Diagnostic: Ghrelin agonist in development for diagnostic use in childhood-onset growth hormone deficiency ("CGHD")

Aeterna is currently conducting its pivotal Phase 3 safety and efficacy study AEZS-130-P02 (the "DETECT-trial") evaluating macimorelin for the diagnosis of CGHD. Children and adolescents from two to less than 18 years of age with suspected growth hormone deficiency are to be included. The study is expected to include approximately 100 subjects worldwide, with at least 40 subjects in pre-pubertal and 40 subjects in pubertal status. Macimorelin growth hormone stimulation test ("GHST") will be performed twice for repeatability data and two standard GHSTs will be used as controls: arginine (i.v.) and clonidine (p.o.). On April 22, 2021, the U.S. FDA Investigational New Drug Application associated with this clinical trial became active. The first clinical sites in the U.S. are open for patient recruitment. In the EU and rest of world countries, clinical trial approval procedures and site initiation activities are ongoing.

Next Steps

Conduct and complete the DETECT-trial.
Therapeutics and Vaccine Development Pipeline

AIM Biologicals: Targeted, highly specific autoimmunity modifying therapeutics for the potential treatment of neuromyelitis optica spectrum disorder ("NMOSD") and Parkinson’s disease (PD)

In January 2021, Aeterna entered into an exclusive patent license and research agreement with the University of Wuerzburg, Germany, for worldwide rights to develop, manufacture and commercialize AIM Biologicals for the potential treatment of NMOSD. Additionally, the Company has engaged Prof. Dr. Joerg Wischhusen of the University of Wuerzburg as well as neuro-immunologist Dr. Michael Levy (MGH/Boston) as consultants, who will provide scientific support and advice in the field of inflammatory CNS disorders, autoimmune diseases of the nervous system, and NMOSD.

In September 2021, the Company entered into an additional exclusive license with the University of Wuerzburg for early pre-clinical development for the potential treatment of Parkinson’s disease.

Next Steps – NMOSD

Conduct in-vitro and in-vivo assessments to select an AIM Biologicals-based development candidate.
Manufacturing process development for selected candidate.
Next Steps – Parkinson’s Disease

Design and produce antigen-specific AIM Biologics molecules for the potential treatment of Parkinson’s disease.
Conduct in-vitro and in-vivo assessments in relevant Parkinson’s disease models.
Macimorelin Therapeutic: Ghrelin agonist in development for the treatment of ALS (Lou Gehrig’s disease)

In January 2021, the Company entered into a material transfer agreement with the University of Queensland, Australia, to provide macimorelin for the conduct of pre-clinical and subsequent clinical studies evaluating macimorelin as a potential therapeutic for the treatment of ALS (Lou Gehrig’s disease). The University of Queensland researchers have filed for supportive grants and aim to conduct pre-clinical studies in multiple pre-clinical models to demonstrate the therapeutic reach of macimorelin on disease progression and disease-specific pathology. They also plan to conduct a subsequent investigator initiated clinical trial given positive pre-clinical results.

Macimorelin, a ghrelin agonist, is an orally active small molecule that stimulates the secretion of growth hormone from the pituitary gland. Acting via this mechanism, it is believed that macimorelin may slow the progression of certain neurodegenerative diseases like ALS.

Next Steps

Work with the University of Queensland to conduct proof-of-concept studies with macimorelin in disease-specific animal models.
Assess alternative formulations.
Formalize pre-clinical development plan.
Delayed Clearance Parathyroid Hormone ("DC-PTH") Fusion Polypeptides: Potential treatment for primary hypoparathyroidism

In March 2021, Aeterna entered into an exclusive patent and know-how license agreement and research agreement with The University of Sheffield, United Kingdom, for the intellectual property relating to DC-PTH fusion polypeptides with delayed clearance for all human uses. In consultation with The University of Sheffield, Aeterna has selected AEZS-150 as the lead candidate in its DC-PTH program. AEZS-150 is being developed with the goal of providing a potential new treatment option of primary hypoparathyroidism in adults.

Next Steps

Work with The University of Sheffield to conduct in depth characterization of development candidate (in-vitro and in-vivo).
Develop manufacturing process.
Formalized pre-clinical development of AEZS-150 in preparation for a potential IND filing for conducting the first in-human clinical study.
Vaccine Platform: Potential orally active, live-attenuated bacterial vaccine with application across multiple coronavirus types, including COVID-19 (SARS-CoV-2) and chlamydia

In February 2021, Aeterna entered into an exclusive option agreement with the University of Wuerzburg to evaluate a pre-clinical, potential COVID-19 vaccine developed at the University of Wuerzburg. In March 2021, the Company exercised its option and entered into a license agreement where the Company was granted an exclusive, world-wide, license to certain patent applications and know-how owned by the University of Wuerzburg to research and develop, manufacture, and sell a potential COVID-19 vaccine. The Company’s vaccine platform is currently undergoing pre-clinical studies for the prevention of coronavirus diseases, including COVID-19 (SARS-CoV-2) with the planned start of clinical development targeted for H1 2023.

In September 2021, the Company exercised its option under the agreement with the University of Wuerzburg on a then undisclosed field, now known to be chlamydia. Chlamydia trachomatis is a sexually transmitted bacterium infecting over 130 million subjects annually. Asymptomatic disease can spread to the reproductive tract eventually inducing infertility, miscarriage, or ectopic pregnancy, which is a life-threatening condition. Ocular infections can lead to inclusion conjunctivitis or trachoma, which is the primary source of visual impairment or infectious blindness.

Additionally, the Company has entered into a Research Agreement under which the Company has engaged the University of Wuerzburg on a fee-for-service basis to conduct supplementary research activities and pre-clinical development studies on the potential vaccines, the results of which will be included within the scope of the license agreements. Additionally, Prof. Dr. Thomas Rudel of the University of Wuerzburg was engaged by the Company in September 2021 as a scientific consultant to support development of the salmonella-based vaccine platform for the coronavirus and chlamydia vaccines.

Next Steps – Coronavirus Vaccine

Evaluate administration route, dose and immunization scheme.
In-vivo immunology experiments with antigen variant candidates in relevant mice models.
Conduct virus challenge experiments in immunized transgenic animals.
Start manufacturing process assessment / development.
Conduct pre-clinical safety and toxicology assessment.
Next Steps – Chlamydia Vaccine

Design and prepare candidate vaccine strains.
Evaluate administration route, dose and immunization scheme.
In-vivo immunology experiments with candidate strains in relevant mouse models.
Summary of Third Quarter 2021 Financial Results

All amounts in this press release are in U.S. dollars unless otherwise noted.

Financing and Warrant Exercises

During the period between January 1, 2021, and September 30, 2021, holders have exercised certain of our outstanding warrants to purchase 35,011,187 of the Company’s common shares for gross proceeds of approximately $20.0 million. On October 1, 2021, the Company received notice of exercise of 100,000 warrants at $0.45 per common share for the issuance of 100,000 common shares of the Company; such exercise was completed on October 4, 2021.

Cash and cash equivalents

The Company had $68.0 million in cash and cash equivalents at September 30, 2021 (June 30, 2021 – $69.9 million).

Results of operations for the three-month period ended September 30, 2021

For the three-month period ended September 30, 2021, the Company reported a consolidated net loss of $1.7 million, or $0.01 loss per common share (basic), as compared with a consolidated net loss of $1.1 million, or $0.02 loss per common share (basic) for the three-month period ended September 30, 2020. The $0.6 million increase in net loss is primarily from an increase in total operating expenses of $0.6 million and a decline in net finance income of $0.5 million, partially offset by an increase of $0.5 million in total revenue.

Revenues

Total revenue for the three-month period ended September 30, 2021, was $0.6 million as compared with $0.1 million for the same period in 2020, representing an increase of $0.5 million. 2021 revenue was comprised of $0.52 million in licensing revenue (2020 – $0.02 million), $0.06 million in supply chain revenue (2020 – $0.09 million) and $0.02 million in royalty income (2020 – $0.02 million).
Operating expenses

The Company’s total operating expenses for the three-month period ended September 30, 2021, were $2.4 million as compared with $1.9 million for the same period in 2020, representing an increase of $0.5 million. This increase arose primarily from a $0.4 million increase in research and development costs and an increase of $0.1 million in selling expenses. This increase in total operating expenses was primarily due to the impact of the initiation of research and development projects as announced in the first quarter of 2021.
Net finance income

Net finance income for the three-month period ended September 30, 2021, was $0.1 million as compared with net finance income of $0.6 million for the same period in 2020, representing a decrease in net finance income of $0.5 million. This was primarily due to the $0.8 million decrease in the change in fair value of the warrant liability and a $0.1 million decline in the gain from changes in foreign currency exchange rates partially offset by a $0.4 million reduction in other finance costs.
Consolidated Financial Statements and Management’s Discussion and Analysis

For reference, the Management’s Discussion and Analysis of Financial Condition and Results of Operations for the third quarter of 2021, as well as the Company’s unaudited consolidated interim financial statements as of September 30, 2021, will be available on the Company’s website (www.zentaris.com) in the Investors section or at the Company’s profile at www.sedar.com and www.sec.gov.

On November 4, 2021 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies (tumor-infiltrating lymphocyte, TIL, and peripheral-blood lymphocyte, PBL), reported third quarter and year-to-date 2021 financial results and corporate updates (Press release, Iovance Biotherapeutics, NOV 4, 2021, View Source [SID1234594594]).

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Frederick Vogt, Ph.D., J.D., Interim President and Chief Executive Officer of Iovance, stated, "During 2021, we have continued to report long-term clinical data demonstrating the durability of one-time treatment with lifileucel in metastatic melanoma while broadening the potential for TIL cell therapy to address more patients in additional indications and treatment settings. We look forward to highlighting our TIL cell therapy platform at the upcoming Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting. Our top priority remains our ongoing work to address feedback from the U.S. Food and Drug Administration (FDA) regarding the potency assays for lifileucel to support our planned biologics license application (BLA) submission. We remain increasingly confident in the broad potential for TIL as the next class of paradigm-shifting therapy for cancer patients with significant unmet need."

Third Quarter 2021 Highlights and Recent Corporate Updates

Regulatory

Potency assays for lifileucel: Following FDA feedback regarding the potency assays for lifileucel, Iovance has continued ongoing work developing and validating its potency assays and has engaged in discussions with the FDA during the second half of 2021. The anticipated BLA submission for lifileucel continues to be planned for the first half of 2022. Resolution of the potency assay for lifileucel in melanoma is also a key step towards our regulatory plans in other indications.
U.S. FDA Fast Track designation for lifileucel in combination with pembrolizumab in metastatic melanoma: The FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of metastatic melanoma based on the unmet medical need and potential advantages for this combination over available care. Fast Track designation allows for potential Accelerated Approval and Priority Review as well as more frequent interactions with the FDA.
Clinical

TIL therapy in combination with pembrolizumab in advanced solid tumor cancers: Iovance is investigating TIL in combination with pembrolizumab in earlier treatment settings in metastatic melanoma, cervical cancer, non-small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC) patients who are naïve to therapy with immune checkpoint inhibitors (ICI). Data for certain indications for TIL in combination with pembrolizumab will be highlighted in an oral presentation at the upcoming SITC (Free SITC Whitepaper) annual meeting. Early clinical data previously presented in metastatic melanoma (ASCO 2021) and HNSCC (SITC 2020) suggest that the response rate for TIL in combination with pembrolizumab may be increased in patients who are ICI-naïve.
TIL therapy in NSCLC:
LN-145 clinical data in metastatic NSCLC (mNSCLC): Detailed results from Cohort 3B in the IOV-COM-202 study will be highlighted in a poster presentation at the SITC (Free SITC Whitepaper) annual meeting. As previously reported, clinical data for LN-145 showed a 21.4% overall response rate (ORR) and 64.3% disease control rate in heavily pretreated mNSCLC patients who received one or more prior systemic therapies, including anti-PD-1 therapy.
LN-145 in second-line mNSCLC: Enrollment is ongoing and more than 20 clinical sites are activated in the U.S. and Canada for the IOV-LUN-202 study of LN-145 in patients with mNSCLC.
Research

Iovance continues to advance the next generation of TIL and related therapies and technologies. Late preclinical programs in investigational new drug (IND)-enabling studies include a novel IL-2 analog (IOV-3001) as well as a genetically modified TIL (IOV-4001). IOV-4001 leverages TALEN technology licensed from Cellectis S.A. to inactivate PD-1 expression by the TIL product.
Iovance and the National Institutes of Health (NIH) extended their Cooperative Research and Development Agreement (CRADA) through August 2024. The CRADA focuses on emerging areas of translational and clinical research for TIL therapies.
Manufacturing

TIL manufacturing success: To date, more than 500 patients have been dosed with Iovance TIL products with more than a 90 percent manufacturing success rate.
Iovance Cell Therapy Center (iCTC): Clinical manufacturing of TIL commenced at the iCTC in September of 2021. Commercial manufacturing remains on track to commence with a potential regulatory approval. The iCTC achieved LEED Gold Certification through the U.S. Green Building Council (USGBC).
Corporate

Cash position of $660.8 million at September 30, 2021 is expected to be sufficient well into 2023.
A strong organization of more than 300 employees with an average of more than 3.5 years of cell therapy experience is in place to advance research, development, manufacturing, and commercial launch preparations.
Iovance continues to expand its intellectual property portfolio and currently owns more than 30 granted or allowed U.S. and international patents for TIL compositions and methods of treatment and manufacturing in a broad range of cancers. Iovance’s Gen 2 patent rights are expected to provide exclusivity through 2038. Iovance’s portfolio also includes patent applications and granted patents directed towards Gen 3 manufacturing, selected TIL products, stable and transient genetic TIL modifications, tumor digest and fragment compositions and methods (including cryopreservation), and combinations of checkpoint inhibitors and TIL products.
Third Quarter and Year-to-Date 2021 Financial Results

Iovance has $660.8 million in cash, cash equivalents, investments and restricted cash at September 30, 2021 compared to $635.0 million at December 31, 2020. The cash position is expected to be sufficient to fund current and planned operations well into 2023.

Jean-Marc Bellemin, Chief Financial Officer, stated, "With the continued strength of our balance sheet and focused investment on pipeline development and launch preparations, we are well positioned to execute our operating plan with no immediate need to raise additional capital. Following completion of the iCTC, we have also concluded our initial $85 million investment in constructing the facility."

Net loss for the third quarter ended September 30, 2021, was $86.1 million, or $0.55 per share, compared to a net loss of $58.6 million, or $0.40 per share, for the third quarter ended September 30, 2020. Net loss for the nine months ended September 30, 2021, was $242.9 million, or $1.60 per share, compared to a net loss of $191.2 million, or $1.41 per share, for the same period ended September 30, 2020.

Research and development expenses were $65.4 million for the third quarter ended September 30, 2021, an increase of $22.3 million compared to $43.1 million for the third quarter ended September 30, 2020. Research and development expenses were $183.4 million for the nine months ended September 30, 2021, an increase of $34.1 million compared to $149.3 million for the same period ended September 30, 2020.

The increase in research and development expenses in the third quarter 2021 over the prior year period was primarily attributable to an increase in costs associated with growth of the internal research and development team and increases in clinical trial costs and iCTC facility related costs. The increase in research and development expenses in the first nine months of 2021 over the prior year period was primarily attributable to growth of the internal research and development team and an increase in iCTC facility related costs.

General and administrative expenses were $20.9 million for the third quarter ended September 30, 2021, an increase of $5.0 million compared to $15.9 million for the third quarter ended September 30, 2020. General and administrative expenses were $59.8 million for the nine months ended September 30, 2021, an increase of $15.7 million compared to $44.1 million for the same period ended September 30, 2020.

The increases in general and administrative expenses in the third quarter and first nine months of 2021 compared to the prior year periods were primarily attributable to growth of the internal general and administrative team and higher stock-based compensation expenses.

Webcast and Conference Call

Iovance will host a conference call today at 4:30 p.m. ET to discuss the third quarter 2021 financial results and corporate updates. The conference call dial-in numbers are 1-(844) 646-4465 (domestic) or 1-(615) 247-0257 (international) and the access code is 7286232. The live webcast can be accessed in the Investors section of the company’s website at View Source The archived webcast will be available for a year in the Investors section at www.iovance.com.

On November 4, 2021 Four UniSA researchers reported that have collectively won $5.2 million in Federal Government funding to tackle some of the biggest health issues facing Australia today (Press release, University of South Australia, NOV 4, 2021, View Source [SID1234594575]).

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Centre for Cancer Biology researchers Dr Guillermo Gomez, Professor Yeesim Khew-Goodall and Professor Claudine Bonder, along with Professor Allison Cowin from UniSA’s Future Industries Institute, will share the NHMRC Ideas Grants funding, announced today.

The money will fund three-year research projects into glioblastoma, breast cancer, diabetic foot ulcers and multiple myeloma.

Dr Guillermo Gomez has been awarded $2 million to develop a new treatment for glioblastoma, the most aggressive form of brain cancer with a survival rate of just 15 months.

Dr Gomez will apply cutting-edge technologies, including artificial intelligence, to identify how tumours reprogram healthy cells in the brain to support their growth.

"A significant feature of glioblastoma is its capacity to invade surrounding healthy brain tissue, leading to such a poor prognosis for patients," Dr Gomez says.

"By analysing how this happens we hope to develop new drugs which target this interaction and make tumours less resistant to therapies.

"The survival rate for glioblastoma has remained the same for the past 30 years, highlighting a desperate need for new treatment options, and hopefully we can lay the foundations for that."

A $1.1 million project awarded to UniSA Professor Yeesim Khew-Goodall will help younger women diagnosed with the most aggressive form of breast cancer to overcome chemotherapy resistance, improving their survival chances.

Prof Yeesim Khew-Goodall will collaborate with University of Melbourne researchers to develop new, non-toxic drugs to fight triple negative breast cancer (TNBC).

TNBC accounts for about 40 per cent of breast cancer-related deaths each year, with approximately 1200 Australian women losing their lives.

"Triple negative breast cancer is the most challenging breast cancer to treat," says Prof Khew-Goodall.

"It is not fuelled by estrogen and progesterone, or by the HER2 protein, so it doesn’t respond to medicines targeting hormones or the protein receptors. Many TNBC patients relapse, even after initially responding to chemotherapy.

"For these patients the treatment options are limited and so their prognosis is poor."

Prof Khew-Goodall and her team have identified a new driver of chemotherapy resistance in triple negative breast cancer which they hope to exploit, developing a more effective drug for patients.

Professor Allison Cowin will use her $1.2 million grant to develop biochemical tools which can predict whether diabetic patients will develop chronic foot ulcers, which affect approximately 165 million people worldwide.

"We aim to develop a simple blood-based prognostic device that will provide an early indication of foot ulcer risk for people living with diabetes," Prof Cowin says.

"If these ulcers are not diagnosed early and quickly treated, it can result in amputation, which is an outcome that nobody wants."

Professor Claudine Bonder has been awarded $908,000 to develop better prognostic tools for more effective treatments for multiple myeloma, an incurable aggressive bone marrow cancer that arises from plasma cells.

"Approximately 2000 people are diagnosed in Australia each year with multiple myeloma and fewer than half will survive beyond five years," Prof Bonder says.

"Myeloma affects multiple places in the body, causing bone pain, fractures, tiredness, infections, kidney damage and hypercalcaemia. It is a chronic, relapsing and remitting disease that is difficult to treat and impossible tot cure."

Prof Bonder and Assoc Prof Craig Wallington-Beddoe from Flinders Medical Centre have teamed up to investigate a single cell surface protein that is upregulated in approximately 20 per cent of myeloma patients who are then three times more likely to die within six years of diagnosis.

The four UniSA research projects are among 248 announced today across Australia, collectively awarded $239 million in funding to further research into a wide range of health and medical issues.

On November 4, 2021 VolitionRx Limited (NYSE AMERICAN: VNRX) ("Volition"), a multi-national epigenetics company developing simple, easy to use, cost effective blood tests to help diagnose and monitor a range of cancers and other life-altering diseases in both humans and animals, reported that it is presenting two abstracts at the 2021 Veterinary Cancer Society (VCS) Virtual Annual Conference, which takes place from Thursday, November 4 through Saturday, November 6 (Press release, VolitionRX, NOV 4, 2021, View Source [SID1234594574]).

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Dr. Tom Butera, Chief Executive Officer of Volition Veterinary Diagnostics Development, LLC said "Being able to use the Nu.Q Test to not only screen for cancer and help identify disease earlier, but also to monitor the disease progression as an early indication that a dog is coming out of remission, will meet a real unmet need in the market. We expect this disease monitoring product will be our second Nu.Q Vet product . We believe that this product has significant potential to help improve the treatment and the quality of life for dogs as well as providing valuable additional information to inform the clinical decision-making process for the veterinarian and pet owner. Whilst the veterinary commercial team has been busy negotiating global licensing and distribution arrangements, I’d like to commend the hard work and joint research efforts of the Texas A&M University and Volition team; we are delighted to present these two studies at the world’s leading veterinary oncology conference."

"The data demonstrate that Nu.Q Vet may serve as a more sensitive measurement of both minimal residual disease and remission and could be a useful monitoring test for dogs with cancer. Given Nu.Q is a simple blood test it would be incredibly useful in the clinic and general practitioner veterinarian’s office," said Dr. Heather Wilson-Robles, Professor at Texas A&M University, Chief Medical Officer of Volition Veterinary Diagnostics Development LLC, and President of the VCS.

Dr. Robles added, "The second poster reports our first study using Nu.Q Capture, Volition’s enrichment tool, to better understand the types of circulating nucleosomes and their genome patterns in the plasma of dogs with lymphoma. It was exciting to see that once again the animal data shows similar findings to human studies in that canine lymphoma patients have circulating nucleosomes lacking linker DNA (i.e., shorter nucleosomes) that are not detected in plasma from healthy canines and that Nu.Q Capture is capable of enriching canine cancer-associated nucleosomes in plasma of lymphoma patients. We look forward to expanding our research in this area."

View Source

An interview with Dr. Heather Wilson-Robles, Chief Medical Officer of Volition Veterinary Diagnostics Development LLC.

The Abstracts

Evaluation of plasma nucleosome concentrations as a tool for treatment and disease monitoring in cancer bearing dogs.

Wilson-Robles, H[1], Miller, T[1], Miller, P[1], Jarvis, J[1], Butera, T[2], Matsushita, M[1], Terrell, J[2], Kelly, TK[2]

Texas A&M University College of Veterinary Medicine & Biomedical Sciences[1]; Volition America and Volition Veterinary Diagnostics[2]

To view the abstract presentation, click HERE or download the Poster, click HERE

Enrichment tools to better understand the types of circulating nucleosomes and their genome patterns in the plasma of dogs with lymphoma.

Bourne, K[1], Miller, T[1], Jarvis, J[1], Butera, T[2], Kelly, TK[2], Davis, B[1], Wilson-Robles, H[1]

Texas A&M University College of Veterinary Medicine & Biomedical Sciences[1]; Volition America and Volition Veterinary Diagnostics[2]

On November 4, 2021 Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) reported a summary of corporate accomplishments and reports its third quarter 2021 financial results (Press release, Synta Pharmaceuticals, NOV 4, 2021, View Source [SID1234594573]).

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Paul Friedman, M.D., Chief Executive Officer of Madrigal, stated, "Throughout the third quarter, the Madrigal team continued to progress MAESTRO-NASH, the pivotal serial liver biopsy study and a key component of the Phase 3 program for resmetirom for patients with non-alcoholic steatohepatitis, NASH. We remain on track to complete the double-blind portion of our Phase 3 non-invasive imaging and biomarker study, MAESTRO-NAFLD-1, and report topline data by year-end, with additional topline data rollout in early 2022. We will also be presenting additional data from the open-label portion of this study at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting on November 12-15th."

Becky Taub, M.D., Chief Medical Officer and President of Research & Development at Madrigal stated, "Data from the recently completed 52 week open-label arm of the MAESTRO-NAFLD-1 study will be presented at AASLD and provides our most informed insights to date regarding the effects of resmetirom in presumed NASH patients, using a variety of non-invasive tests relevant to clinical practice. The double-blinded MAESTRO-NAFLD-1 and MAESTRO NASH studies readouts over the forthcoming months will further inform our understanding of how to identify and monitor NASH patients with significant fibrosis."

Dr. Taub added, "In October, in recognition of Liver Awareness Month, we announced our alliance with the Fatty Liver Foundation, a leading patient advocacy organization focused on the diagnosis, treatment and support of individuals with non-alcoholic fatty liver disease or NAFLD and NASH. Our alliance with the Foundation is in support of their NAFLD Screening Fund and aligns with our commitment to advance the use of non-invasive techniques to improve the diagnosis and staging of NAFLD and NASH and identify people at risk of NASH earlier in the course of their disease."

Several abstracts summarizing data from the open-label arms of the MAESTRO-NAFLD-1 study have been accepted for presentation at AASLD’s The Liver Meeting 2021. Madrigal will host a webcast and conference call on Tuesday, November 16th at 8.00 AM ET to summarize and discuss the data that are being presented.

AASLD Presentations

Friday, November 12, 2021: Late-breaker Poster Presentation (abstract #LP21)
Biomarkers, imaging and safety in resmetirom 52 week non-cirrhotic NASH Phase 3 clinical trial, completed open-label arm of MAESTRO-NAFLD-1
Friday November 12, 2021: Poster Presentation (abstract #1922)
Liver volume reduction in resmetirom treated non-cirrhotic and cirrhotic NASH patients
Friday, November 12, 2021 (1:00-2:00pm EST): Virtual Product Theatre
Live presentation by Manal Abdelmalek, MD, Professor of Medicine, Duke University School of Medicine and Mazen Noureddin, MD, Director, Cedars-Sinai Medical Center, Karsh Division of Gastroenterology and Hepatology entitled: NASH with Fibrosis: Updates from the MAESTRO Phase 3 Clinical Program
Sunday, November 14, 2021: Oral Presentation (4:00pm EST) (abstract #118)
Presentation by Mazen Noureddin, MD, Director, Cedars-Sinai Medical Center, Karsh Division of Gastroenterology and Hepatology entitled: Utilization of the MAST (MRI-PDFF-MRE-AST) score to predict NASH on liver biopsy in MAESTRO-NASH and access response to resmetirom in MAESTRO-NAFLD-1
Leadership Team Expanded

Stephen Dodge, PharmD, MBA, has joined Madrigal as Senior Vice President and Global Head of Medical Affairs. Prior to joining Madrigal, Dr. Dodge was Senior Vice President, Cholestasis Program Head at Intercept Pharmaceuticals. Prior to Intercept, he held a number of leadership positions in medical affairs at Merck, Novo Nordisk and Novartis. His experience includes over 20 new product launches in new therapeutic areas, spanning over 20 years, with 10 years in liver and GI diseases. Dr. Dodge received an MBA from Washington University in St. Louis, his PharmD – Doctor of Pharmacy from the University of The Pacific School of Pharmacy and a B.S., Biology from California State University.

Kia Motesharei, PhD, has joined Madrigal as Senior Vice President Business & Corporate Development. Dr. Motesharei’s 20 plus years of industry experience includes over 100 business development transactions and corporate strategy initiatives including therapeutic product licensing and alliances, R&D collaborations, commercial product partnerships, royalty financing and M&A activities with companies in the United States, Europe, Japan, China, Latin America and the Middle East. Prior to joining Madrigal, Dr. Motesharei was Chief Business and Strategy Officer at NeuBase Therapeutics. Since 2004, he has held similar positions with Akcea Therapeutics, EMD Serono (Merck KGaA), Dyax Corporation, Genfit, and Activx Biosciences. Dr. Motesharei completed his Postdoctoral training as a National Institutes of Health fellow at The Scripps Research Institute and received his Doctorate degree from UCLA.

Financial Results

As of September 30, 2021, Madrigal had cash, cash equivalents and marketable securities of $299.1 million, compared to $284.1 million at December 31, 2020. The increase in cash and marketable securities was due to net proceeds of $151.2 million from sales of common stock via our at-the-market (ATM) program, partially offset by cash used to support operations of $135.9 million.

Operating expenses were $63.2 million and $177.9 million for the three and nine month periods ended September 30, 2021, compared to $58.8 million and $147.1 million in the comparable prior year periods.

Research and development expenses for the three and nine month periods ended September 30, 2021 were $54.9 million and $152.3 million, compared to $53.3 million and $131.4 million in the comparable prior year periods. The increase is attributable primarily to additional activities related to the Phase 3 clinical trials, and an increase in head count.

General and administrative expenses for the three and nine month periods ended September 30, 2021 were $8.3 million and $25.6 million, compared to $5.5 million and $15.8 million in the comparable prior year periods. The increase is attributable primarily to increases in commercial preparation activities, including an increase in headcount and an increase in non-cash stock compensation.

Interest income for the three and nine month periods ended September 30, 2021 was $0.1 million and $0.3 million, compared to $0.8 million and $3.9 million in the comparable prior year periods. The decrease in interest income was due primarily to decreased interest rates.

About Resmetirom
Thyroid hormone, through activation of its β-receptor in hepatocytes, plays a central role in liver function impacting a range of health parameters from levels of serum cholesterol and triglycerides to the pathological buildup of fat in the liver. Thyroid hormone receptor (THR)-β action in the liver is key to proper function of the liver, including regulation of mitochondrial activity such as breakdown of liver fat and control of the level of normal, healthy mitochondria. Patients with NASH have reduced levels of thyroid hormone activity in the liver with resultant impaired hepatic function, in part due to the inflamed state of the liver that causes degradation of thyroid hormone.

To exploit the thyroid hormone receptor (THR)-β pathway for therapeutic purposes in liver and cardio-metabolic diseases, it is important to avoid activity at the THR-α receptor, the predominant systemic receptor for thyroid hormone that is responsible for activity outside the liver including in heart and bone. The lack of selectivity of older thyromimetic compounds, chemically-related toxicities and undesirable distribution in the body led to safety concerns. Madrigal recognized that greater selectivity for thyroid hormone receptor (THR)-β and liver targeting might overcome these challenges and deliver the full therapeutic potential of THR-β agonism. Resmetirom has been shown to be highly selective based on 1) THR-β receptor functional selectivity based on both in vitro and in vivo assays and 2) specific uptake into the liver, its site of action, virtually avoiding any uptake into tissues outside the liver. In short- and long- term human and animal studies, resmetirom has been confirmed to be safe and devoid of activity at the THR-α receptor and without impact on bone or cardiac parameters. Resmetirom does not impact the thyroid axis hormones, including the central thyroid axis. Madrigal believes that resmetirom is the first orally administered, small-molecule, liver-directed, truly β-selective THR agonist.

About the Phase 3 Registration Program for the Treatment of NASH (Non-alcoholic steatohepatitis)
Madrigal is currently conducting two Phase 3 Clinical trials, MAESTRO-NASH and MAESTRO-NAFLD-1, to demonstrate the safety and efficacy of resmetirom for the treatment of NASH.

MAESTRO-NASH is a Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom in patients with liver biopsy confirmed NASH and was initiated in March 2019. The study targets enrollment of 900 patients with biopsy-proven NASH (fibrosis stage 2 or 3, at least 450 fibrosis stage 3), randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. After 52 weeks of treatment a second biopsy is performed. The primary surrogate endpoint on biopsy will be NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score), and with no worsening of fibrosis. Two key secondary endpoints are liver fibrosis reduction of at least one stage, with no worsening of NASH on liver biopsy, and lowering of LDL-cholesterol [ClinicalTrials.gov/NCT03900429]. Madrigal announced achievement of the planned target enrollment on June 30, 2021.

The first 900 patients in the MAESTRO-NASH study will continue on therapy after the initial 52-week treatment period; and up to another 1,100 patients are to be added using the same randomization plan and the study is expected to continue for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events.

MAESTRO-NAFLD-1 is a 52-week Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom, and was initiated in December 2019 in patients with non-alcoholic fatty liver disease (NAFLD), presumed NASH. The primary endpoint for this study is to evaluate the safety and tolerability of resmetirom. Completion of enrollment of over 1,200 patients into the study was announced in November 2020. Top-line data from the study is targeted by end of year 2021.

Patients in MAESTRO-NAFLD-1 are randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. MAESTRO-NAFLD-1 also includes a 100 mg resmetirom open label arm. 52 week data were presented from the open label arm at The International Liver Congress 2021 in June and demonstrated that resmetirom is safe and well-tolerated at 100mg per day [view press release here]. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), does not include a liver biopsy and represents a "real-life" NASH study. NASH or presumed NASH is documented using historical liver biopsy or non-invasive techniques including FibroScan and magnetic resonance imaging, proton density fat fraction (MRI-PDFF) respectively. Using non-invasive measures, MAESTRO-NAFLD-1 is designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular and liver related endpoints. These key secondary endpoints include LDL-cholesterol, apolipoprotein B and triglyceride (TG) lowering; reduction of liver fat as determined by MRI-PDFF; and reduction of PRO-C3, a NASH fibrosis biomarker. [ClinicalTrials.gov/NCT04197479]. Additional secondary and exploratory endpoints will be assessed including reduction in liver enzymes, FibroScan scores and other fibrosis and inflammatory biomarkers.

Data from the 52 week portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1 and other data, including safety parameters, will form the basis for a potential subpart H submission to FDA for accelerated approval for the treatment of NASH.