Category Archives: Gene therapy

Catalent has appointed Behzad Mahdavi, Ph.D., MBA, as Vice President of Open Innovation, Biologics, Cell and Gene Therapy. In this new role, Dr. Mahdavi will join a team of experts in Catalents Science and Technology Group that works with customers and external innovators in both small and large molecules, to accelerate the adoption of new development and drug delivery technologies, and scalable manufacturing processes and techniques. He reports to Julien Meissonnier, Catalents Chief Scientific Officer.

Dr. Mahdavi has more than 20 years of experience in developing and implementing growth strategies in the biopharmaceutical industries. Dr. Mahdavi joins Catalent after a 13-year career at Lonza, where he held the role of Vice President Strategic Innovation & Alliances, and various board-level positions at other innovative companies. Prior to joining Lonza, he was Chief Executive Officer of SAM Electron Technologies.

As a company, Catalent continues to invest in the rapidly evolving and growing areas of cell and gene therapies and next-generation biopharmaceuticals, which are redefining the landscape of treating diseases, commented Mr. Meissonnier. I am delighted to welcome Behzad to Catalent, as he brings significant experience in leveraging accelerated innovation with strategic external sourcing, to further strengthen our strategy of delivering the therapies of tomorrow to patients faster, and more efficiently.

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Catalent Appoints Open Innovation, Biologics, Cell And Gene Therapy VP - Contract Pharma

Vivet Therapeutics and Pfizer are one step closer to bringing a gene therapy for a rare liver disorder into the clinic.

The companies announced Wednesday morning that the FDA has accepted its IND application for a Phase I/II study in the treatment of Wilsons disease. The study, evaluating a program dubbed VTX-801, is expected to launch early next year.

VTX-801 is an rAAV-based gene therapy vector designed to deliver a protein called ATP7B in the hopes of restoring copper homeostasis, reversing liver pathology and reducing copper accumulation in the brain, as it was shown to do in mouse models.

The study will be open label and not be randomized. Researchers will give a one-time IV infusion of the gene therapy in up to 16 adult patients, with the goal of evaluating three different dosage levels. Ultimately, the companies set a primary endpoint for safety and tolerability after 52 weeks.

In March 2019, Pfizer acquired a minority stake in the company, and in September, the big pharma agreed to manufacture the VTX-801 vector for this Phase I/II study. Max Gelman

Florida-based biotech Generex has inked the biggest deal (it) could even imagine, bagging $50 million from a consortium of Chinese institutions that licensed its Ii-Key vaccine tech for infectious diseases and cancer.

Comprising hybrid peptides and a suppression, the platform has spawned a vaccine candidate against SARS-CoV-2 in addition to a pipeline of immuno-oncology therapies.

We are able to generate a detailed immune activation profile of our Ii-Key vaccine candidates by screening blood samples from COVID-19 recovered patients, explained Richard Purcell, EVP of R&D.

In addition to the upfront fee for the overall deal, the unnamed partners have handed over $5 million to license the Covid-19 vaccine candidate and promised a $20 million success fee if its approved in China. Separate contracts for the other indications are being finalized. Amber Tong

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News briefing: Pfizer and Vivet get the OK to start gene therapy trial for rare liver disorder; Florida biotech inks $50M China deal - Endpoints News

By taking advantage of a natural process of gene silencing, a new gene therapy approach appears to prevent the toxicity todorsal root ganglion(DRG) a specific cluster of sensory neurons seen in non-human primates during gene therapy studies for neurological disorders, researchers report.

The approach successfully protected the primates DRG from excessive activity of the introduced gene known as a transgene and subsequent toxicity, without affecting the transgenes activity elsewhere in the nervous system.

DRG inflammation and toxicity was observed in non-human primates after spinal canal injection of AVXS-101 approved asZolgensma when given as an intravenous infusion prompting a partial hold of a Phase 1/2 trial (NCT03381729) to allow for further investigation.

That trial, calledSTRONG, is testing intrathecal (spinal canal) injection of this gene therapy in children with spinal muscular atrophy (SMA) between 6 months and 5 years old.

The study, MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates, was published in the journal Science Translational Medicine.

We believe that this new approach could improve safety in genetherapyuniversally, as well as in SMA, Juliette Hordeaux, PhD, the studys first author at University of Pennsylvanias Perelman School of Medicine (Penn Medicine) said in a press release.

This approach could be used to design other gene therapy [carriers] to repress transgene [activity] in the cell types that are affected by the toxicity and not others, which is critical, because you need [such activity] everywhere else to effectively treat the disorder, added Hordeaux, who is also senior director of translational research for Penn Medicines gene therapy program.

Gene therapy works to deliver a functional version of a gene to correct or replace a faulty gene within specific cells in the body. Most therapy approaches today use a modified and harmlessadeno-associated virus(AAV) as a carrier for the working gene, a vehicle to transport it to a target cell.

But previous studies, including primate work by Penn researchers, showed that AAV-based gene therapies targeting the central nervous system (CNS; brain and spinal cord) can damage the DRG, a cluster of neurons of the spinal nerve that bring sensory information from the periphery to the spinal cord.

Notably, DRG toxicity was observed in studies regardless of the therapys route of administration (directly into the bloodstream or into the spinal canal). No reports of such toxicity in humans, including children treated in STRONG, are known.

Conventional immunosuppressive regimens were ineffective in preventing this toxicity, strongly indicating that an excessive immune response was not its cause. This led Hordeaux and her Penn colleagues to evaluate whether the damage was related to excessive levels of the transgenes product, which could cause cellular stress.

To test their idea, they took advantage of RNAi, a natural process of gene silencing, in which microRNA (miR) molecules bind to a specific messenger RNA (mRNA), targeting it for destruction and preventing the production of that protein. (mRNA is the molecule derived from DNA and used as a template for protein production.)

Since the miR183 complex is specifically produced in sensory tissues and organs such as dorsal root ganglion, the researchers introduced miR183s sequence targets at the endof the transgene sequence in an AVV. With this, any mRNA produced from the transgene would be destroyed in DRG neurons by the naturally present miR183, preventing protein production in these cells.

Researchers then compared the effects of administering AAV with a transgene containing or not containing miR183s sequence targets into the cerebrospinal fluid (the fluid that bathes the brain and spinal cord) of non-human primates.

Introducing miR183s sequence targets in the transgene were found to significantly reduce its mRNA levels and subsequent toxicity in DRG neurons, without affecting the transgenesmRNA levels elsewhere in the primates brain.

Steroids given to primates treated with unmodified AAVs, in contrast, failed to alleviate DRG damage, despite their known anti-inflammatory and immunosuppressive effects. This ineffectiveness was consistent with the proposal that immune system activity does not mediate this neuronal toxicity, the researchers wrote.

We were concerned about the DRG [toxicity] that was observed in most of our [non-human primate] studies, said James M. Wilson, MD, PhD, the studys senior author, and gene therapy program director and a professor of medicine and pediatrics at Penn Medicine.

This modified [viral] vectorshows great promise to reduce DRGtoxicityand should facilitate the development of safer AAV-based gene therapies for many CNS diseases, Wilson added.

Novartis gene therapy Zolgensma, when given directly into the bloodstream, is currently available for use in newborns and toddlers up to age 2 with any type of SMA in the U.S. and Japan, and to those with almost all types who weigh up to 21 kilograms (about 46 pounds) inEurope.

To meet aU.S. Food and Drug Administration(FDA) request for a pivotal confirmatory study of the gene therapys use with older SMA patients, who would be treated via intrathecal (IT) injection, Novartisplans to launch a new AVXS-101 IT trial.

This administration route is favored for those beyond toddler age, as it is thought to better target themotor neuronsdamaged by the disease.

According to the company, this IT trial cannot include U.S. sites until the hold on STRONG is lifted.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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Intrathecal Gene Therapy Use Might Be Safer With 'Silencing' Step - SMA News Today

For the first time, researchers at the Center for Cell-Based Therapy (CTC) in Ribeiro Preto, Brazil, have identified a non-hereditary mutation in blood cells from a patient with GATA2 deficiency.

GATA2 deficiency is a rare autosomal disease caused by inherited mutations in the gene that encodes GATA-binding protein 2 (GATA2), which regulates the expression of genes that play a role in developmental processes and cell renewal.

An article on the study is publishedin the journalBlood.

The non-hereditary mutation may have acted as a natural gene therapy which prevented the disease from damaging the process of blood cell renewal. This meant that the patient did not develop such typical clinical manifestations as bone marrow failure, hearing loss, and lymphedema.

The researchers say that the findings pave the way for the use of gene therapy and changes to the process of checking family medical history and medical records for families with the hereditary disorder.

Luiz Fernando Bazzo Catto, first author of the article, said: When a germline [inherited] mutation in GATA2 is detected, the patients family has to be investigated because there may be silent cases.

The discovery was made when two sons were receiving medical treatment at the blood centre of the hospital run by FMRP-USP, both of which, in post-mortem DNA sequencing, showed germline mutations and GATA2 deficiency diagnosis. The researchers used next generation sequencing to estimate the proportion of normal blood cells in the fathers bone marrow, preventing clinical manifestations of GATA2 deficiency, and of cells similar to his childrens showing that 93% of his leukocytes had the mutation that protects from the clinical manifestations of GATA2 deficiency.

Following the sequencing of the fathers T-lymphocytes, the researchers found that the mutation occurred early in their lives and in the development of hematopoietic stem cells, which have the potential to form blood.

They also measured the activity of the blood cells, to see if they could maintain the activity of inducing normal cell production for a long time, by measuring the telomeres of his peripheral blood leukocytes. Telomeres are repetitive sequences of non-coding DNA at the tip of chromosomes that protect them from damage. Each time cells divide, their telomeres become shorter. They eventually become so short that division is no longer possible, and the cells die or become senescent.

The telomeres analysed by the researchers were long, indicating that the cells can remain active for a long time.

The researchers hypothesised that the existence of the somatic mutation in the fathers blood cells, and its restoration of the blood cell renewal process, may have contributed to the non-manifestation of extra-haematological symptoms of GATA2 deficiency such as deafness, lymphedema, and thrombosis.

Professor Rodrigo Calado, a corresponding author of the article, said: A sort of natural gene therapy occurred in this patient. Its as if he embodied an experiment and a medium-term prospect of analogous gene therapy treatment in patients with GATA2 deficiency.

The findings help us understand better how stem cells can recover by repairing an initial genetic defect.

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Non-hereditary mutation acts as natural gene therapy for GATA2 deficiency - Health Europa

Penn Medicine researchers have developed a new targeted approach to prevent a toxicity seen in the sensory neurons of dorsal root ganglia after gene therapy to treat neurological disorders. It's an important hurdle to clear, as the field works toward more safe and effective gene therapies for patients with disorders like spinal muscular atrophy.

"We believe that this new approach could improve safety in gene therapy universally," said first author Juliette Hordeaux, DVM, PhD, senior director of Translational Research in Penn's Gene Therapy Program.

The findings were reported online this week in theScience Translational Medicine.

The toxicity has not been reported in humans, but studies in nonhuman primates using adeno-associated viral (AAV) vectors to deliver corrected genes via the spinal cord fluid and intravenously have revealed problems of axonal degeneration in some tracts of the spinal cord and peripheral nerves. The cause was traced back to the dorsal root ganglion, or DRG, a cluster of neural cells on the outside of the spinal cord responsible for transmission of sensory messages.

This toxicity stems from the overexpression of an introduced gene, known as a transgene, in cells in the DRG, researchers from Penn's Gene Therapy Program found in the study. To correct that, they modified a transgene with a microRNA target designed to reduce the level of the transgene expression in the DRG. That alteration eliminated more than 80 percent of the transgene expression and reduced the toxicity in primates, the researchers report.

"We believe it is a safe, straightforward way to ameliorate the safety of AAV therapy for the central nervous system," said first author Juliette Hordeaux, DVM, PhD, senior director of Translational Research in Penn's Gene Therapy Program. "This approach could be used to design other gene therapy vectors to repress transgene expression in the cell types that are affected by the toxicity and not others, which is critical, because you need the expression everywhere else to effectively treat the disorder."

Gene transfer expert James M. Wilson, MD, PhD, director of the Gene Therapy Program, and professor of Medicine and Pediatrics in Penn's Perelman School of Medicine, served as the senior author of the paper.

After Penn researchers documented DRG toxicity in nonhuman primates, they began devising a way to overcome it. Though its asymptomatic in primates, the damage became clear under close study of histopathology in the CNS. Damage to the DRG in humans, researchers know, can lead to the breakdown of axons responsible for delivering impulses from nerves to the brain. Numbness and weakness in limbs, among other side effects, follow suit.

The observed toxicity in past animal studies was enough for the U.S. Food and Drug Administration to recently place a partial hold on human trials administering a gene therapy vector into the spinal cord to treat spinal muscular atrophy, the genetic disease that severely weakens muscles and causes problems with movement. In the new study, the researchers injected vectors with and without an microRNA target, first in mice and then primates. microRNA regulates gene expression and makes for an ideal target in the cells. microRNA-183 was chosen specifically because it is largely restricted to the neurons in the DRG.

Administering unmodified AAV vectors resulted in robust delivery of the new gene into target tissue and toxicity in DRG neurons. Vectors with the miRNA target, on the other hand, reduced transgene expression significantly, as well as the toxicity of DRG neurons, without affecting transduction elsewhere in the primate's brain, histological analyses of the specimens up to 90 days later showed. An immune response was first believed to be causing the toxicity; however, the researchers debunked that hypothesis through experiments that showed how immunosuppressants and steroids were unsuccessful at alleviating the toxicity.

According to the authors, toxicity of DRGs is likely to occur in any gene therapy that relies on high doses of a vector or direct delivery of a vector into the spinal cord fluid. This latest study paves a path forward to prevent that damage.

"We were concerned about the DRG pathology that was observed in most of our NHP studies," Wilson said. "This modified vector shows great promise to reduce DRG toxicity and should facilitate the development of safer AAV-based gene therapies for many CNS diseases."

Reference: Hordeaux J, Buza EL, Jeffrey B, et al. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Science Translational Medicine. 2020;12(569). doi:10.1126/scitranslmed.aba9188

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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New Approach Reduces the Toxicity of Brain-Targeted Gene Therapy - Technology Networks

Belgium-headquartered UCB has strengthened its gene therapy capabilities with a pair of deals a collaboration agreement with Lacerta Therapeutics and the acquisition of Handl Therapeutics.

Handl Therapeutics based in Leuven, Belgium specialises in adeno-associated virus (AAV) capsid technology and has a focus on developing disease modifying gene therapies to treat neurodegenerative diseases.

In addition to its own capabilities, Handl has built an international network to access expertise from a number of institutions. This includes platforms licensed from KU Leuven in Belgium, the Centre for Applied Medical Research in Spain, the University of Chile and Kings College London in the UK.

UCBs global footprint and scientific expertise in neurodegenerative diseases, coupled with our shared cultures of scientific advancement and commitment to patients, creates an exceptional environment in which we can accelerate the development of gene therapies and change patients lives, said Florent Gros, founder and chief executive officer of Handl Therapeutics.

UCB did not disclose the financial terms of the acquisition, although it did add in a statement that the Handl team will continue to be based in Handl and will work closely with UCBs international research team.

The Lacerta deal is focused on developing AAV-based therapies for patients with a central nervous system disease with a high unmet need. Like the Handl acquisition, UCB did not offer the financial details of the Lacerta research collaboration and licensing agreement.

Lacerta is set to lead research and preclinical activities as well as the early manufacturing process development, with UCB planning to lead IND-enabling studies, manufacturing and clinical development.

UCBs ambition for patients relies on our ability to innovate and deliver highly differentiated medicines, said Dhavalkumar Patel, chief scientific officer of UCB.

The acquisition of Handl Therapeutics and the new partnership with Lacerta Therapeutics offers us the potential to drive a fundamental change in how diseases are treated, by moving us from treating symptoms to disease modification and eventually towards a cure. he added.

The Handl and Lacerta deals build on UCBs previous acquisition of Element Genomics in 2018.

UCB paid $30m to access Elements platform of technologies aimed at improving the understanding of genome structure and function including CRISPR editing technologies used for genomic and epigenomic regulatory region analysis and modulation.

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UCB boosts gene therapy offering with a pair of new deals - PMLiVE

Researchers from Penn Medicine have developed a new targeted approach that modifies viral vectors and inhibits toxicities in the sensory neurons of dorsal root ganglia (DRG) that commonly occur following the use of gene therapy for neurological diseases.

This strategy will likely have several important research and clinical implications, as investigators in the field have worked tirelessly for years to develop safer and more effective gene therapies for neurological disorders. We believe that this new approach could improve safety in gene therapy universally, said lead author Juliette Hordeaux, DVM, Ph.D., senior director of Translational Research in Penns Gene Therapy Program, in a statement.

Many gene therapies use viral vectors, but these vectors can have adverse neurological effects. While these toxicities have not yet been observed in humans, nonhuman primate studies using adeno-associated viral (AAV) vectors to deliver corrected genes via the spinal cord fluid have shown issues of axonal degeneration in spinal cord and peripheral nerve tracts. In these studies, the cause of the issues led back to the DRG, comprising a cluster of neural cells found on the outside of the spinal cord that are responsible for delivering sensory messages.

In a recent paper published in Science Translational Medicine, Dr. Hordeaux and colleagues found a way of modifying these vectors so they ultimately avoid these dangerous side effects. They first found that the toxicities appear to come from overexpression of a transgene in cells in the DRG.

The researchers altered a transgene with a microRNA target that was designed to reduce transgene expression levels in the DRG. Ultimately, this modification eliminated over 80% of the transgene expression and resulted in drastic toxicity reduction in the studied primates

We believe it is a safe, straightforward way to ameliorate the safety of AAV therapy for the central nervous system, said Hordeaux about the studied modification. This approach could be used to design other gene therapy vectors to repress transgene expression in the cell types that are affected by the toxicity and not others, which is critical, because you need the expression everywhere else to effectively treat the disorder.

Senior author of the paper was gene transfer expert James M. Wilson, MD, Ph.D., professor of Medicine and Pediatrics in Penns Perelman School of Medicine. Dr. Wilson, who left Solid Biosciences two years ago. Dr. Wilson has been discussing the potential adverse neurological effects of AAV vectors for several years.

Drs. Hordeaux and Wilson injected vectors with and without a microRNA target miRNA183 in mice and primates in the new study. The administration of unaltered AAV vectors led to robust delivery of the gene into target tissue as well as toxicities in DRG neurons. These effects occurred without impacting transduction in elsewhere in the brain, according to histological analyses conducted up to 90 days later.

The authors of the study suggest the toxicity of DRGs likely occur in a gene therapy relying on high vector doses or direct vector delivery into the fluid of the spinal cord. We were concerned about the DRG pathology that was observed in most of our nonhuman primate studies, noted Wilson. This modified vector shows great promise to reduce DRG toxicity and should facilitate the development of safer AAV-based gene therapies for many central nervous system diseases.

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New Targeted Approach Could Prevent Toxicities Associated with Neurological Gene Therapies - BioSpace

Vivet Therapeutics and Pfizer Inc. Announce FDA Authorization to Proceed with GATEWAY, the Phase 1/2 Study for VTX-801, Vivets Investigational Gene Therapy for Wilson Disease

PARIS, France and NEW YORK, N.Y.November 18, 2020 Vivet Therapeutics (Vivet), a privately held gene therapy biotech company dedicated to developing treatments for inherited liver disorders with high unmet medical need, and Pfizer Inc. (NYSE: PFE) announced today that the U.S. Food and Drug Administration (FDA) has cleared Vivets Investigational New Drug (IND) application for the GATEWAY study, a Phase 1/2 clinical trial evaluating Vivets proprietary, investigational gene therapy vector, VTX-801, for the potential treatment of Wilson disease (WD), a rare and potentially life-threatening liver disorder. The trial is expected to commence in early 2021.

We are pleased to announce Vivets first IND clearance by the FDA, which is for our GATEWAY Phase 1/2 study for VTX-801, said Jean-Philippe Combal, CEO and Co-Founder of Vivet. This is a very important milestone for the Wilson disease community for whom VTX-801 could bring significant potential therapeutic benefit. VTX-801 aims to restore copper homeostasis and the GATEWAY trial will measure relevant biomarkers to evaluate physiological restoration of copper elimination and transport in patients. We look forward to advancing VTX-801 into the clinic in early 2021.

VTX-801 is a novel, investigational rAAV-based gene therapy vector designed to deliver a miniaturized ATP7B transgene encoding, a functional protein that has been shown to restore copper homeostasis, reverse liver pathology and reduce copper accumulation in the brain of a mouse model of Wilson disease. VTX-801s rAAV serotype was selected based on its demonstrated tropism for transducing human liver cells.

In March 2019, the companies announced that Pfizer had acquired a minority equity interest in Vivet and secured an exclusive option to acquire all outstanding shares. In September 2020, Vivet and Pfizer announced the signing of an agreement for the manufacture by Pfizer of the VTX-801 vector for the GATEWAY study.

The FDA clearance of Vivets IND marks an important milestone for the VTX-801 program, which we believe has the potential to become a transformational therapy for people with Wilson disease, said Seng Cheng, Chief Scientific Officer, Rare Disease Research Unit, Pfizer. Pfizer has begun manufacturing clinical material for the GATEWAY study and look forward to the studys commencement.

This IND is a recognition of the expertise of Vivets research team led by our CSO and Co-Founder, Dr. Gloria Gonzlez-Aseguinolaza, research collaborations, notably with la Fundacin para la Investigacin Mdica Aplicada (FIMA), and experienced development team. We believe that our global development expertise, together with our collaboration with Pfizer, places us in a strong position to rapidly execute and bring this potentially transformational therapy to patients with high unmet medical needs, added Jean-Philippe Combal.

About GATEWAY - Phase 1/2 Clinical Trial of VTX-801 in Wilson disease

The GATEWAY trial is a multi-center, non-randomized, open-label, Phase 1/2 clinical trial designed to assess the safety, tolerability and pharmacological activity of a single intravenous infusion of VTX-801 in adult patients with Wilson disease, prior to and following background WD therapy withdrawal.

Six leading centers in the United States and Europe are expected to participate in the GATEWAY Phase 1/2 trial. The trial is expected to enroll up to sixteen adult patients with Wilson disease and will evaluate up to three doses of VTX-801. Patients will participate in a pre-dosing observational period and will be administered a prophylactic steroid regimen.

The primary endpoint of the GATEWAY trial is to assess the safety and tolerability of VTX-801 at 52 weeks after a single infusion. Additional endpoints include changes in disease-related biomarkers, including free serum copper and serum ceruloplasmin activity, as well as radiocopper-related parameters and VTX-801 responder status to allow standard-of-care withdrawal.

Vivet Therapeutics expects to enroll the first patient in early 2021.

More details on:

https://clinicaltrials.gov/ct2/show/NCT04537377?term=VIVET&draw=2&rank=1

About Vivet Therapeutics

Vivet Therapeutics is an emerging biotechnology company developing novel gene therapy treatments for rare, inherited metabolic diseases.

Vivet is building a diversified gene therapy pipeline based on novel recombinant adeno-associated virus (rAAV) technologies developed through its partnerships with, and exclusive licenses from, the Fundacin para la Investigacin Mdica Aplicada (FIMA), a not-for-profit foundation at the Centro de Investigacin Medica Aplicada (CIMA), University of Navarra based in Pamplona, Spain.

Vivets lead program, VTX-801, is a novel investigational gene therapy for Wilson disease which has been granted Orphan Drug Designation (ODD) by the Food and Drug Administration (FDA) and the European Commission (EC). This rare genetic disorder is caused by mutations in the gene encoding the ATP7B protein, which reduces the ability of the liver and other tissues to regulate copper levels causing severe hepatic damages, neurologic symptoms and potentially death.

Vivets second gene therapy product, VTX-803 for PFIC3, received US and European Orphan Drug Designation in May 2020.

Vivet is supported by international life science investors including Novartis Venture Fund, Roche Venture Fund, HealthCap, Pfizer Inc., Columbus Venture Partners, Ysios Capital, Kurma Partners and Idinvest Partners.

Please visit us on http://www.vivet-therapeutics.com and follow us on Twitter at @Vivet_tx and LinkedIn.

About Pfizer: Breakthroughs That Change Patients Lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at http://www.Pfizer.com. In addition, to learn more, please visit us on http://www.Pfizer.com and follow us on Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

Pfizer Disclosure Notice

The information contained in this release is as of November 18, 2020. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about Vivet Therapeutics (Vivet) investigational gene therapy, VTX-801, and Pfizers collaboration with Vivet on the development of VTX-801, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, risks related to the ability to realize the anticipated benefits of the collaboration, including the possibility that the expected benefits from the collaboration will not be realized or will not be realized in the expected time; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities;whether regulatory authorities will be satisfied with the design of and results from the clinical studies; whether and when any applications may be filed in any jurisdiction for VTX-801; whether and when any such applications may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the products benefits outweigh its known risks and determination of the products efficacy and, if approved, whether VTX-801 will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of VTX-801; uncertainties regarding the impact of COVID-19 on Pfizers business, operations and financial results;and competitive developments.

A further description of risks and uncertainties can be found in Pfizers Annual Report on Form 10-K for the fiscal year ended December 31, 2019 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned Risk Factors and Forward-Looking Information and Factors That May Affect Future Results, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available atwww.sec.govandwww.pfizer.com.

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Vivet Therapeutics and Pfizer Inc. Announce FDA Authorization to Proceed with GATEWAY, the Phase 1/2 Study for VTX-801, Vivet's Investigational Gene...

While the US Food and Drug Administration (FDA) is still receiving investigational new drug applications (INDs) for cell and gene therapies, officials are concerned about the impact of the COVID-19 pandemic on clinical trials.Its clear that COVID-19 has adversely affected all aspects of development of cell and gene therapies, said Peter Marks, director of FDAs Center for Biologics Evaluation and Research (CBER), said at the Alliance for Regenerative Medicines Meeting on the Mesa. For some of the studies that are ongoing there are some real challenges to overcome in terms of endpoints that may have been missed.The pandemic also has disrupted global harmonization efforts around gene therapies, Marks said.We were on the cusp, in fact, working with global regulators trying to get towards more harmonization of gene therapy programs in different countries, he said. Were trying to keep it moving but its a challenge to do.Marks noted that before COVID-19 he spent about 75% of his time on cell and gene therapies, but the pandemic has forced him to shift priorities. Some things have less policy demands at this point in time. At this point in time its very much reversed and its probably 80% of my time on COVID-related activities.Marks also noted that CBERs Office of Tissues and Advanced Therapies (OTAT) has been struggling to keep up with its workload even before the pandemic. With the influx of applications for cell and gene therapies over the last five years, Marks said the office, Should have doubled in size and its only modestly larger, 15-20% larger in size.Marks said he is not satisfied with the level of dialogue the agency has been able to have with gene therapy developers. Especially early on, we should be able to have this dialogue that really facilitates setting things up well so that our knowledge of the entire fieldwe help leverage that for every sponsor.Weve been so strapped in terms of personnel that its hard to do that, Marks said, noting that COVID-19 has exacerbated things even further. Because the number of gene therapy applications hasnt fallen off dramatically, some of the trials may not be moving as quickly, but the applications keep coming in. Marks said that OTAT has also had to shift priorities during the pandemic and that he hopes the next user fee cycle will bring in the resources necessary to staff up further.Speaking on a separate panel with members of industry, OTAT Director Wilson Bryan echoed Marks sentiment.We were stretched thin before the pandemic, and with the flood of work that came in, it really had an impact, he said. Sometimes folks dont like to admit this, but we all know weve had delayed meetings, weve had to delay review of some applications because of giving priority to the pandemic.However, Bryan said the office is getting its balance and is working to catch up on some of its delayed activities.Bryan expressed some worry about the financial well-being of some of the smaller companies his office works with. Were hearing a lot about their struggles to stay afloat and continue and finish off their development programs and whether or not those development programs are going to be sufficient to meet regulatory standards, he said.One of the challenges, said Timothy Schroeder, CEO of CTI Clinical Trial & Consulting, will be dealing with gaps in data from clinical trials. The question is going to be how do sponsors, how do regulatory authorities and how do companies such as ourselves fill those gaps?On the regulator side, Bryan said his office is working with companies on an individual basis to sort out those issues, which differ from one indication to the next.Bryan added that one positive to come of the pandemic is greater interest in remote outcome assessments in clinical trials. If we have an energy now to develop outcome measures and validate outcome measures that allow us to reliably capture information from patients in remote locations, that will ultimately facilitate development, he said.The pandemic also has significantly disrupted FDAs ability to conduct surveillance and preapproval inspections. While the agency has resumed some domestic inspections and mission-critical foreign inspections, it also is leveraging other sources of information, including inspection reports from other regulators, and requesting documents from applicants and facilities in lieu of on-site inspections where possible. (RELATED: FDA issues pandemic inspections FAQ guidance, Regulatory Focus 19 August 2020).Were considering virtual inspections, particularly for companies where the site has a track record, but if its a site that is brand new with no track record or if its a site with that has a bad track record, were hesitant to do that, Bryan said.Bryan also raised the prospect of FDA inspectors tagging along remotely for an inspection being conducted by other regulators. Is it possible that we could have an inspection by European inspectors and have US regulators going along for a virtual inspection at the same time? We think about those things, I dont know that weve done them yet, Bryan said, adding that he is not sure whether FDA inspectors would be comfortable with the information they would get.Curran Simpson, chief operations and technology officer at REGENXBIO, said he sees promise in virtual audits and believes the level of documentation a site provides can be indicative of its compliance.How often have I walked into a manufacturing facility thats well-run but has terrible documentation? Almost never. I think virtual audits, if you do a risk-based approach and the audit partner has the ability to send documentation in an efficient way and you have experienced people doing this, I think youre going to get the same flavor of an audit very quickly from the level of the documentation, he said.Of course, youll want to accompany that to the extent possible with imaging of the facility, Curran said, To see if those practices are being followed, the overall cleanliness of the facility and the management of material movement If you dont get a good impression from the documentation that youre working through, its probably a bigger issue that you want to escalate.Amy DuRoss, co-founder and CEO of Vineti, an enterprise software company specializing in advanced therapies, expressed some doubts about the current potential for fully remote audits.Certainly our piece of the chain because were enterprise software is readily auditable remotely, but I would say that the overall system and in manufacturing, Im not sure weve evolved as a species yet to adapt our remote techniques to get a full picture I dont think were there yet, she said.

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FDA officials, experts discuss impact of COVID-19 on cell and gene therapies - Regulatory Focus

Gene therapies are some of the hottest areas of investment in the biotech world, as are artificial-intelligence-assisted research methodologies, and Dynos right there at the intersection of these two things, Dyno CEO Eric Kelsic said.

Potential partners have been trying to get in on the action since the company's founding two years ago. Now, Cambridge, Massachusetts-based Dyno unveils its third partnership in the last five months: a pact with Roche and its Spark Therapeutics unit to develop central nervous system (CNS) and liver-directed gene therapies.

All told, the deal could exceed $1.8 billion in clinical and sales milestones, but the companies kept mum on how much Dyno's getting in an upfront fee and research funding.

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A big challenge with gene therapies is ensuring the payloads are delivered effectively and safely via their delivery vehicles. Traditionally, adeno-associated virus(AAV) vectors have limitations because they are difficult to manufacture, can only carry a limited payload and can only target certain tissue types. What's more, gene therapies delivered by AAV may not work in people who have developed a natural immunity to this type of virus.

The second challenge lies in the creation of new capsids, or the protein shell that coats viral vectors and targets cells.

There's this analogy of the protein universe. And capsids are like stars in the galaxy; most of the space is empty. We would like to find the most interesting areas to have the best capsids for in vivo gene therapy, but the space is so large that it can't search it all, Kelsic said.

Thats where Dynos AI-powered approach comes in. We do experiments to gather information about that space, then using machine learning, we build an app, and using those machine learning models, we navigate to the most interesting areas of that space, say the galaxies or the certain solar systems, which have the most interesting stars for gene therapy, he said.

RELATED: Novartis, Sarepta tap Dyno to unearth new gene therapy vectors

The partnership will play to each organizations strengths, Kelsic said, with Dyno focusing on designing, developing, testing and validating capsids using AI, and Roche and Spark adding their own payloads, advancing development and commercializing the gene therapies.

Now, with its third partnership under its belt, Dyno is working in the four areas where theres the most activity in gene therapy according to Kelsic: CNS and liver disorders with Roche, eye disorders with Novartis and muscle disorders with Sarepta Therapeutics.

As for whats next for Dyno, the company has already started the work of designing experiments for both the CNS and liver and is continuing to build its team, which has already grown from 20 to 40 employees over the last five months in what Kelsic calls a hyper-growth trajectory.

We've been making significant progress both in terms of building the team and building the platform, he said, but also building up these technologies, these tools, and applying them against a really challenging, but important problem.

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Dyno, Roche to tackle CNS, liver disease in gene therapy deal worth up to $1.8B - FierceBiotech