Category Archives: Genetic Therapy

Immune checkpoint inhibitor (ICI) therapy prolonged overall survival (OS) compared with chemotherapy in patients with MET-amplified nonsmall cell lung cancer (NSCLC); however, the survival benefit did not appear to extend to patients with a MET exon 14 (METex14) mutation. These findings, from a cohort study, were published in the Journal of Thoracic Oncology.

MET alterations are heterogenic in NSCLC. Whereas some tumors harbor MET amplifications, approximately 3% to 4% harbor METex14. MET kinase inhibitors have demonstrated efficacy against tumors harboring METex14, but their role against tumors with MET amplifications is less clear. The study authors therefore sought to analyze a real-world cohort of patients with advanced NSCLC and METex14 or MET amplification.

The investigators evaluated 337 tumor specimens from patients with stage IIIB or IV NSCLC with a MET alteration who were diagnosed with NSCLC at a single center in Cologne, Germany between 2015 and 2018. Next-generation sequencing, fluorescence in-situ hybridization, and immunohistochemistry were used to assess alterations, co-occurring mutations, and PD-L1 expression.

METex14 alterations were present in 17.5% of the specimens. Of these patients, 32.2% harbored both a METex14 skipping mutation and a MET amplification; these patients were classified as having MET mutations.

MET amplifications were present in 82.4% of specimens, including 43.9% with low-level amplification (gene copy number [GCN] <4), 7.1% with intermediate-level amplification (GCN=4-5), 9.2% with category I high-level amplification (MET/CEN7 ratio 2 and GCN < 6), 12.2% with category II high-level amplification (GCN=6-9), and 10.1% with category III high-level amplification (GCN 10).

None of the tumors harbored EGFR, ALK, or ROS1 alterations, but 12 tumors carried BRAF mutations. High PD-L1 expression (50%) was found in 34.8% of the 227 patients assessed for PD-L1 status. There was no difference in expression level between specimens with METex14 vs MET amplification. Similarly, there was also no difference between the different levels of MET amplification.

For the OS analysis, patients were separated into cohorts based on MET amplification level or the presence of METex14. At a median follow-up of 34 months, the median OS was 12.0 months (95% CI, 9.4-14.6) in cohort A (MET amplification; GCN<10), 4.0 months (95% CI, 1.9-6.0) in cohort B (MET amplification; GCN10), and 10.0 months (95% CI, 6.9-13.0) in cohort C (METex14). There was no significant difference in OS between the cohorts.

Patients with MET amplifications who received ICIs either as monotherapy or in combination with chemotherapy were found to experience prolonged OS compared with patients who received chemotherapy alone. Among patients with low to high MET amplification (GCN <10), the median OS was 19.0 months with ICI therapy vs 8.0 months with chemotherapy (P <.0001). Among patients with very high levels of amplification (GCN 10), the median OS was 36.0 months with ICIs compared with 4.0 months with chemotherapy (P =.004). However, no significant difference in median OS was seen with ICI therapy or chemotherapy in patients with METex14 (16.0 months vs 10.0 months; P =.147).

Patients with MET amplification have a survival benefit with immunotherapy compared with chemotherapy alone, the study authors said, adding that future studies will have to focus on the definition of patients that benefit from immunotherapy or targeted therapy.

Disclosure: Some of the study authorsdisclosedfinancial relationships with the pharmaceutical industry and/or the medical device industry. For a full list ofdisclosures, please refer to the study.

Reference

Kron A, Scheffler M, Heydt C, et al. Genetic heterogeneity of MET-aberrant non-small cell lung cancer and its impact on the outcome of immunotherapy. J Thorac Oncol. Published online December 9, 2020. doi:10.1016/j.jtho.2020.11.017

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Immune Checkpoint Inhibitor Therapy May Have Survival Benefit in MET-Amplified NSCLC - Cancer Therapy Advisor

Dec. 30, 2020 12:00 UTC

SAN DIEGO--(BUSINESS WIRE)-- Arcturus Therapeutics, Inc.. (the Company, Arcturus, Nasdaq: ARCT), a leading clinical-stage messenger RNA medicines company focused on the development of infectious disease vaccines and significant opportunities within liver and respiratory rare diseases, today announced that it has selected ARCT-032, an aerosolized LUNAR mRNA-based therapeutic candidate, as a development candidate for Cystic Fibrosis (CF), a progressive hereditary disease.

We are pleased to have advanced ARCT-032 as a novel mRNA-based development candidate for CF Lung Disease. ARCT-032, based on our proprietary LUNAR technology, is designed to result in the efficient expression of a functional Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein in the lungs. We believe that ARCT-032 has the potential to address the root cause of CF lung disease, which is caused by the defective, or missing, CFTR protein, said Pad Chivukula, Ph.D. Chief Scientific Officer and Chief Operating Officer of Arcturus Therapeutics. While there has been progress with the recent approval of drugs for CF, many patients remain underserved. ARCT-032 has the potential to provide benefit to all CF patients, regardless of their underlying genetic mutations.

About ARCT-032

ARCT-032 will utilize Arcturus' LUNAR lipid-mediated aerosolized platform to deliver CFTR messenger RNA to the lungs. Expression of a functional copy of the CFTR mRNA in the lungs of CF patients has the potential to restore normal lung CFTR activity. The ARCT-032 program is supported by preclinical data in CFTR deficient murine model, ferrets and NHPs. LUNAR-CFTR can be efficiently delivered to epithelial cells in the airways and restore chloride channel activity in a CFTR KO mice model following intranasal administration of LUNAR-CFTR.

An mRNA-based replacement therapy for CF, if successfully developed, has the potential to deliver a fully functional copy of CFTR into the lungs, independent of the underlying CF genotype. The expression of functional CFTR protein is expected to restore chloride channel efflux in the airways, reducing mucus accumulation, tissue scarring, and minimizing the progressive respiratory dysfunction observed in CF patients.

About Arcturus Therapeutics

Founded in 2013 and based in San Diego, California, Arcturus Therapeutics Holdings Inc. (Nasdaq: ARCT) is a clinical-stage mRNA medicines and vaccines company with enabling technologies: (i) LUNAR lipid-mediated delivery, (ii) STARR mRNA Technology and (iii) mRNA drug substance along with drug product manufacturing expertise. Arcturus diverse pipeline of RNA therapeutic and vaccine candidates includes self-replicating mRNA vaccine programs for SARS-CoV-2 (COVID-19) and Influenza, and other programs to potentially treat Ornithine Transcarbamylase (OTC) Deficiency, Cystic Fibrosis, and Cardiovascular Disease along with partnered programs including Glycogen Storage Disease Type 3, Hepatitis B Virus, and non-alcoholic steatohepatitis (NASH). Arcturus versatile RNA therapeutics platforms can be applied toward multiple types of nucleic acid medicines including messenger RNA, small interfering RNA, replicon RNA, antisense RNA, microRNA, DNA, and gene editing therapeutics. Arcturus technologies are covered by its extensive patent portfolio (200 patents and patent applications, issued in the U.S., Europe, Japan, China and other countries). Arcturus commitment to the development of novel RNA therapeutics has led to collaborations with Janssen Pharmaceuticals, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Ultragenyx Pharmaceutical, Inc., Takeda Pharmaceutical Company Limited, CureVac AG, Synthetic Genomics Inc., Duke-NUS Medical School, and the Cystic Fibrosis Foundation. For more information visit http://www.ArcturusRx.com. In addition, please connect with us on Twitter and LinkedIn.

Forward Looking Statements

This press release contains forward-looking statements that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact included in this press release, are forward-looking statements, including those regarding the Companys development strategy, the likelihood that preclinical or clinical results will be predictive of future clinical results or sufficient for regulatory approval, the likelihood of the Company to obtain clearance from regulatory authorities to proceed with planned clinical trials, the planned initiation, design or completion of clinical trials, the likelihood of success, or of the efficacy or safety, of ARCT-032 or other product candidates, future operations, the continuation or success of collaborations with the Companys strategic partners, and our current cash position and expected cash burn. Arcturus may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in any forward-looking statements such as the foregoing and you should not place undue reliance on such forward-looking statements. Actual results and performance could differ materially from those projected in any forward-looking statements as a result of many factors including, without limitation, the impact of COVID-19 on the ability to conduct clinical trials, the availability of manufacturing capacity and raw materials, unexpected clinical results, and general market conditions that may prevent such achievements or performance. Such statements are based on managements current expectations and involve risks and uncertainties, including those discussed under the heading "Risk Factors" in Arcturus Annual Report on Form 10-K for the fiscal year ended December 31, 2019, filed with the SEC on March 16, 2020 and in subsequent filings with, or submissions to, the SEC. Except as otherwise required by law, Arcturus disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.

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Arcturus Therapeutics to Advance ARCT-032, an Aerosolized LUNAR mRNA-based Therapeutic, as a Development Candidate for Cystic Fibrosis Lung Disease -...

First gene therapy to receivefull EU marketing authorization for eligible MLD patients

One-time treatment with Libmeldy has been shown to preserve motor and cognitive function

Achievement shared with research alliance partners Fondazione Telethon and Ospedale San Raffaele

BOSTON and LONDON and MILAN, Italy, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, and its research alliance partners Fondazione Telethon and Ospedale San Raffaele, today announced that the European Commission (EC) granted full (standard) market authorization for Libmeldy (autologous CD34+ cells encoding the ARSA gene), a lentiviral vector-based gene therapy approved for the treatment of metachromatic leukodystrophy (MLD), characterized by biallelic mutations in theARSAgene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

MLD is a very rare, fatal genetic disorder caused by mutations in the ARSA gene which lead to neurological damage and developmental regression. In its most severe and common forms, young children rapidly lose the ability to walk, talk and interact with the world around them, and most pass away before adolescence. Libmeldy is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible young patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at which untreated patients show severe motor and cognitive impairments.

Todays EC approval of Libmeldy opens up tremendous new possibilities for eligible MLD children faced with this devastating disease where previously no approved treatment options existed, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Libmeldy is Orchards first product approval as a company, and I am extremely proud of the entire team who helped achieve this milestone. We are grateful for and humbled by the opportunity to bring this remarkable innovation to young eligible patients in the EU.

With Libmeldy, a patients own hematopoietic stem cells (HSCs) are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a self-inactivating (SIN) lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying disease with a single treatment.

The EC approval of Libmeldy comes more than a decade after the first patient was treated in clinical trials performed at our Institute, and ushers in a remarkable and long-awaited shift in the treatment landscape for eligible MLD patients, said Luigi Naldini, M.D, Ph.D., director of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Our team at SR-Tiget has been instrumental in advancing the discovery and early-stage research of this potentially transformative therapy to clinical trials in support of its registration through more than 15 years of studies supported by Fondazione Telethon and Ospedale San Raffaele, and we are extremely proud of this achievement and what it means for patients and the field of HSC gene therapy.

MLD is a heart-breaking disease that causes immeasurable suffering and robs children of the chance of life, said Georgina Morton, chairperson of ArchAngel MLD Trust. As a community, we have been desperate for a treatment for young MLD patients, and we are incredibly excited to now have such a ground-breaking option approved in the EU.

The marketing authorization for Libmeldy is valid in all 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway. Orchard is currently undertaking EU launch preparations related to commercial drug manufacturing, treatment site qualification and market access.

Data Supporting the Clinical and Safety Profile of Libmeldy

The marketing authorization for Libmeldy is supported by clinical studies in both pre- and early- symptomatic, early-onset MLD patients performed at the SR-Tiget. Early-onset MLD encompasses the disease variants often referred to as late infantile (LI) and early juvenile (EJ). Clinical efficacy was based on the integrated data analysis from 29 patients with early-onset MLD who were treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.

Clinical safety was evaluated in 35 patients with MLD (the 29 patients from the integrated efficacy analysis as well as six additional patients treated with the cryopreserved formulation of Libmeldy). Safety data indicate that Libmeldy was generally well-tolerated. The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies (AAA) reported in five out of 35 patients. Antibody titers in all five patients were generally low and no negative effects were observed in post-treatment ARSA activity in the peripheral blood or bone marrow cellular subpopulations, nor in the ARSA activity within the cerebrospinal fluid. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For further details, please see the Summary of Product Characteristics (SmPC).

About MLD and Libmeldy

MLD is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1

Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, is approved in the European Union for the treatment of MLD in eligible early-onset patients. In the U.S., OTL-200 is an investigational therapy which has not been approved by the U.S. Food and Drug Administration (FDA) for any use. Libmeldy was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.

About Orchard

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

About Fondazione Telethon, Ospedale San Raffaele and the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget)

Based in Milan, Italy, the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Ospedale San Raffaele, a clinical-research-university hospital established in 1971 to provide international-level specialized care for the most complex and difficult health conditions, and Fondazione Telethon, an Italian biomedical charity born in 1990 and focused on rare genetic diseases. SR-Tiget was established in 1995 to perform research on gene transfer and cell transplantation and translate its results into clinical applications of gene and cell therapies for different genetic diseases. Over the years, the Institute hasgiven a pioneering contribution to the field with relevant discoveries in vector design, gene transfer strategies, stem cell biology, identity and mechanism of action of innate immune cells. SR-Tiget has also established the resources and framework for translating these advances into novel experimental therapies and has implemented several successful gene therapy clinical trials for inherited immunodeficiencies, blood and storage disorders, which have already treated >115 patients and have led through collaboration with industrial partners to the filing and approval of novel advanced gene therapy medicines.

For more information:

Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, plans, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, and the therapeutic potential of Libmeldy, including the potential implications of clinical data for eligible patients. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation:: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the inability or risk of delays in Orchards ability to commercialize Libmeldy, including the risk that we may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

1 Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature.Journal of Child Neurology2010, DOI:http://doi.org/10.1177/0883073809341669

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Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) - GlobeNewswire

DetailsCategory: DNA RNA and CellsPublished on Tuesday, 22 December 2020 18:50Hits: 612

TSHA-101 to be first bicistronic vector evaluated in human clinical trials; TSHA-101 designed to deliver both HEXA and HEXB transgenes within a single AAV9 vector construct

TSHA-101 CTA is the second clinical trial clearance received, in addition to TSHA-118s open investigational new drug application for CLN1

Interim data from Phase 1/2 trial anticipated in 2021

DALLAS, TX, USA I December 21, 2020 I Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a patient-centric gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system in both rare and large patient populations, today announced that Queens University in Ontario, Canada, received Clinical Trial Application (CTA) approval from Health Canada for its investigator-sponsored Phase 1/2 trial exploring TSHA-101, Tayshas investigational AAV9-based gene therapy, for the treatment of infantile GM2 gangliosidosis.

TSHA-101 will be the first bicistronic vector to enter a first-in-human clinical study, which is a significant milestone for Taysha and for the field of gene therapy, said Suyash Prasad, MBBS, M.SC., MRCP, MRCPCH, FFPM, Chief Medical Officer and Head of Research and Development of Taysha. GM2 is a devastating lysosomal storage disease with no approved treatments and todays CTA approval marks a formative moment for children suffering from this rapidly progressive and fatal disease.

The trial will be a single arm, open-label Phase 1/2 trial evaluating the use of TSHA-101 for the treatment of infants with GM2. The study will be sponsored by Queens University and led by Jagdeep S. Walia, MBBS, FRCPC, FCCMG, Clinical Geneticist and Associate Professor Head, Division of Medical Genetics (Department of Pediatrics) at Queens, and Director of Research (Department of Pediatrics), at the Kingston Health Sciences Centre.

Preclinical evidence to date supports our belief that TSHA-101, when given intrathecally as a bicistronic transgene packaged into a single AAV9 vector, has the potential to address the lysosomal enzyme deficiency, to change the disease trajectory and to improve patient survival, said Dr. Jagdeep S. Walia. We are pleased to have the support of Health Canada as we continue to advance TSHA-101.

Todays CTA approval is a culmination of our teams and Dr. Walias tireless efforts and a momentous occasion for children affected by GM2 along with their parents and caregivers, said RA Session II, Founder, President and CEO of Taysha. We are grateful to our partners at Queens University for their work to advance this gene therapy into the clinic.

About GM2 Gangliosidosis

GM2 gangliosidosis is a rare and fatal monogenic lysosomal storage disorder and a family of neurodegenerative genetic diseases that includes Tay-Sachs and Sandhoff diseases. The disease is caused by defects in the HEXA or HEXB genes that encode the two subunits of the -hexosaminidase A enzyme. These genetic defects result in progressive dysfunction of the central nervous system. There are no approved therapies for the treatment of the disease, and current treatment is limited to supportive care.

About TSHA-101

TSHA-101 is an investigational gene therapy administered intrathecally for the treatment of infantile GM2 gangliosidosis. The gene therapy is designed to deliver two genes HEXA and HEXB driven by a single promoter within the same AAV9 construct, also known as a bicistronic vector. This approach allows the simultaneous expression of a 1:1 ratio of the two subunits of protein required to generate a functional enzyme. It is the first and only bicistronic vector currently in clinical development and has been granted Orphan Drug and Rare Pediatric Disease designations by the U.S. Food and Drug Administration (FDA).

About Taysha Gene Therapies

Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our teams proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platforman engine for potential new cureswith a goal of dramatically improving patients lives. More information is available at http://www.tayshagtx.com.

SOURCE: Taysha Gene Therapy

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Taysha Gene Therapies Announces Queen's University's Receipt of Clinical Trial Application Approval from Health Canada for Phase 1/2 Clinical Trial of...

Over the last several years, parents from across the country have appeared on television and news outlets to raise money to develop treatments for their children with rare genetic disorders.

Many of these families, including one from Kansas City, Missouri, have pinned their hopes on one Texas researcher, Dr. Steven Gray of the University of Texas Southwestern Medical Center in Dallas, who claims to be on the verge of treating a number of rare conditions. They've raised millions of dollars to fund his research, although breakthroughs haven't happened to the extent many had hoped.

While gene therapy holds great promise, the growing trend of family-funded research concerns some medical ethicists, who say that suggestions to parents that treatments may be imminent can raise thorny ethical issues.

These are parents. They are desperate. says Mayo Clinic bioethicist Megan Allyse. They are willing to try almost anything. They are in a pretty vulnerable position for somebody to come along and say, Give me your money, and I can make this better.

Further complicating the picture is the recent entry into the field of a private company, Taysha Gene Therapies, which says it will accelerate Grays research. That has divided his supporters and raised concerns about families who might be left behind.

Kim Fry, of Kansas City, Missouri, has a video on her phone of her son, Charlie, that was made in 2018 when he was 5 months old. It shows her bright-eyed boy gently shaking in his father's lap, as if shivering from cold.

Those little tremors sent the family on a year-long odyssey that led to a frightening diagnosis. A genetic test showed Charlie had an incredibly rare mutation in a single gene, SLC6A1. The mutation typically causes intellectual disabilities and epilepsy starting around the age of three-and-a-half that can severely affect patients for the rest of their lives.

Doctors told Kim and Nate there was no treatment available to help their son.

At that moment, you just feel crushed and kind of begin grieving for the life you think your childs going to have, Kim said.

Rare genetic disorders have generally received little attention from biotech companies because the markets for treatments are so small.

But shortly after the diagnosis, Kim met Amber Freed, a mother from Denver who seemed to have found a solution. After her son, Maxwell, was diagnosed with the same mutation a year earlier, Freed met Gray, a molecular biologist who had focused on gene therapy while doing a post-doctoral fellowship at UNC Chapel Hill.

Gray was developing treatments or even possible cures for conditions caused by single-gene mutations, and he had agreed to work on SLC6A1. But it would be up to Freed to provide Gray with the millions of dollars he would need to do this work.

With the possibility of a treatment suddenly on the table, Kim and Nate immediately joined Amber in raising money through the organization she started, SLC6A1 Connect, and their own campaign, A Cure For Charlie. Their goal was to create a treatment and bring it to clinical trial before Charlie turned three-and-half, hoping to block the severe effects of the mutation and giving him a chance to live a regular life.

Once the funding is there, then all the science is going to move into place, so really the only hurdle that were facing right now between us and the cure is the funding, Nate said in fall of 2019.

Family fundraisers

Family fundraisers are a departure from how medical research is usually funded, typically through the National Institutes of Health, large foundations and advocacy groups.

Nevertheless, families like the Frys have appeared on news outlets and in publications throughout the country in recent years, from Good Morning America and ABC News to People magazine and countless local news shows, to raise money for research.

The children have been diagnosed with many different genetic disorders, but their stories are similar. They all have rare gene mutations that will lead to serious mental or physical declines or early death, and their parents are pinning their hopes on Gray to develop treatments.

They call themselves the Steve Gray Parents.

Gray himself has appeared in articles and videos, including one produced by UT Southwestern about Willow Canaan, a girl from Mississippi who has multiple sulfatase deficiency.

A lot of the families that we interact with, they are coming to us with really sick kids. I think knowing their story, knowing that one child, gives us a face, gives us a mission that if we can move fast enough theres hope that we could treat and we make things different for that specific child, Gray said in one video.

Gray became a go-to researcher for rare disease families after his treatment of Hannah Sames, a girl from New York with a degenerative genetic disorder called giant axonal neuropathy.

In a 2016 clinical trial, Sames was injected with a manufactured virus that contained a working copy of the gene that was mutated. Through this adeno-associated virus delivery method, the normal gene would take over from the mutated one and stop the degeneration from happening.

The treatment slowed the progress of Hannahs disease, according to Gray, but it wasnt a cure. In a 2019 interview on Connecticut Public Radio, Hannahs mother, Lori, said the family was seeking additional treatment.

But Gray thinks the same method could be used to treat and possibly cure all kinds of genetic disorders, including the SLC6A1 mutation

Were due for another leap in technology, Gray told KCUR in 2019. Were going to have a better virus technology, better ways to deliver genes, and I can see that just making a further leap for the whole field.

Gray, who says he has been involved in developing treatments for two dozen diseases, has accepted money from families to pay for the high costs of manufacturing viruses, doing toxicology studies and running clinical trials. Many of these family groups had raised more than a $1 million each from their friends, relatives and neighbors.

Though these families have been effective at raising money, bioethicist Allyse worries that without the peer review process that traditional funders use, they may not be in the best position to decide what research is likely to get results.

The potential problem with going around that process is that its possible to sort of go down avenues that are less supported by the literature, that are less in line with the scientific consensus, Allyse said.

But those doubts have done little to discourage dedicated parents like Amber Freed.

In early December 2019, Freed hosted the second annual SLC6A1 research symposium in a hotel conference room in downtown Baltimore. Freed quit her job in finance after her sons diagnosis to dedicate herself to advancing a treatment, and she began organizing annual SLC6A1 research symposiums in 2018 to drum up interest in the work.

Shes also held charity golf tournaments, set up fundraising campaigns with companies like Amazon and Pizza Hut, and helped arrange the creation of genetically altered mice in China for research.

During the last two years, Freed has cultivated relationships with genetic researchers from all over the world, and as the sleepy scientists who traveled to Baltimore to take part in the symposium wandered into the conference room early on a Friday morning, she greeted them like family, with big hugs and smiles.

Alex Smith

Despite Freeds seemingly endless enthusiasm, she made clear in her welcoming speech to the scientists that, unlike them, her involvement in SLC6A1 research didnt happen by choice.

But to be honestI dont want to be here, read a slide projected behind her at the end of her remarks.

Some improvements but no 'home run'

Toward the end of the day, Gray took the podium to deliver an update on research from his lab. For many in the audience, this was the days main event.

His teams early research using the treatment showed some improvements in motor and behavioral skills in young, genetically altered mice that were treated before symptoms had appeared. But there was no change in mice that already had symptoms.

I think treating at an early age, were seeing some signs of improvements and some nice signals that our vector is doing something positive, but, you know, its not a home run, Gray explained.

Though it wasnt the result Freed dreamed of, she was encouraged that the research appeared to be on the right path.

Gray insisted he had tried to be careful about managing expectations for families funding his work, but between symposium talks, he also said he had recently shifted course on working with them.

Im really having to say no a lot now, Gray told KCUR. Im kind of moving into a point where we were trying not to say no, and we were trying to work on everything that the science made sense. But there is a point where you just have to say, You know Ive got to focus on what Im doing, and theres a limit.

While Grays work did lead to a treatment for Hannah Sames, similar breakthroughs havent come in time for other families.

Laura King Edwards of Charlotte, North Carolina, started working with her family to raise money for Grays work after her baby sister, Taylor, was diagnosed with a form of a rare disorder called infantile Batten disease in 2006.

The family didnt have a lot of hope the research would lead to a treatment in time to help Taylor, and she died two years ago at age 20.

Edwards says that looking back, she sometimes regrets all the time she spent running a fundraising organization.

Id spend hours up at night dealing with tech issues on our website, for example, or responding to emails from people all over the world, knowing that thats time that maybe I couldve spent with my little sister while she was still here, Edwards says.

Nevertheless, even after Taylor was gone, her family continued to support Grays work through their organization, Taylor's Tale.

A new player

Not long after the conference in Baltimore, however, the race for a SLC6A1 treatment slowed to a crawl.

When the COVID-19 pandemic hit, scientific studies and medical trials across the country were stopped and research funds were directed to coronavirus research.

The therapists who work with Amber and Kims sons were unable to meet with them in person, and the boys started to backslide on some of their developmental progress.

Then, after the initial waves of the coronavirus subsided, hopes for Grays research came roaring back to life when a new company, Taysha Gene Therapies, announced it would partner with UT Southwestern, offering a boost to the research and development beyond what families could provide.

They could get it to a certain place, said Taysha founder R.A. Session II, But when it needs to get to kind of the meaningful level in order to get it into late-stage clinical trials, this is where they just dont necessarily have the capability. And so I think this is where you would see programs then transitioning into a companys hands in order to kind of pursue them and move them forward.

In April, Taysha announced a partnership with UT Southwestern that would fund Grays research and work to move it more quickly into clinical trials and possible treatment. Gray was named chief scientific officer.

The company said the family fundraising would no longer be needed.

For some parents, like Doug and Kasey Woleben of Dallas, that was great news. Theyve raised around $1 million for research to treat Leigh syndrome, which affects their 8-year-old son, Will.

We were excited, thrilled to know that were now off the hook for millions and millions and millions of dollars. And that Taysha and UT Southwestern are trying to push this program and move it forward as quickly as possible. So for us, it was a miracle, Kasey said.

But Taysha's involvement and its timeline have brought disappointment for other families. The company's first clinical trials, to treat a mutation that causes Tay Sachs disease, were planned to start in Canada at the end of 2020 but only received approval from the Canadian government this week.

The company says it plans to seek permission to test treatments for three other conditions, including the SLC6A1 mutation, by the end of 2021, but it has not announced any dates for beginning trials.

For Amber Freed and Kim Fry, Tayshas timeline is problematic. Both of their sons were expected to exhibit epilepsy symptoms before the end of next year and so they would see little benefit from treatment initiated after that.

Im very disappointed, Freed said in September. If you had asked me this time last year, I would have fully expected to be in a clinical trial right now.

Different priorities

Session insists that Tayshas timeline and priorities on are based on what the research shows is safe and effective.

Weve allowed the science to kind of move forward at the pace the science moves, Session says. Then we move it forward into the clinic based on that science.

But to Freed, the goal of fast-tracking to trial, even one that would have only resulted in a slight improvement for her son, appears much less likely now that Taysha is involved.

Once you hand over the reins to a biotech, you lose decision-making power as a nonprofit organization, and you abide by their timeline and not necessarily your own, Freed said. In my case, we are racing to get this therapy into children like Maxwell and Charlie as quickly as possible, so we need it done tomorrow.

For other Gray supporters, however, the future is even less clear. Tayshas development pipeline does not include treatments for some of the conditions that Gray had previously been working with families to develop, including Charcot-Marie Tooth, Krabbe disease and multiple sulfatase deficiency.

UT Southwestern researchers will continue to research those conditions, according to a university spokesman, and Taysha says it plans to expand its pipeline in the future.

Terry Pirovolakis, who had enlisted Grays help to develop a treatment for spastic paraplegia 50, which affects his son, Michael, will not be involved with Tayshas work. Hell only continue to work with UT Southwestern directly.

From my perspective, it was, thats great. Tayshas gonna come in and maybe save the world, but I dont want to be part of it 'cause theyve got a lot of stuff they gotta work out, and Im not going to wait around for them to figure it out, Pirovolakis said.

Pirovolakis, who lives in Toronto, has raised more than $1.5 million since May 2019 through his online campaign, Cure Michael, which was the most successful GoFundMe campaign in Canada last year.

Expectations vs. reality

He says that while he has been comfortable working with Gray, he believes that drug companies, which depend on the involvement of families for rare disease research, can mislead parents about what might be possible for their children.

The industry, as a whole, I think, maybe sets expectations that are higher than reality," Pirovolakis said. "We see these presentations at the conferences of these kids doing amazing things, like a 4-year-old that has no brain function pretty much, going to school two years later. Its remarkable.

"But that was five or 10 years of research. So I think that expectations from the industry are maybe what cloud us as parents in the hope that something amazing is gonna happen for our kids.

CureCMT4J, a foundation created to advance research on Charcot-Marie Tooth by parent advocate Jocelyn Duff, an early supporter of Gray, also is no longer involved with the researchers work. Duff said the organization had moved in a different direction, but she declined the provide details. The group had raised $1.3 million as of fall 2020.

Some ethicists have also raised questions about the costs of rare disease treatment, and they point to a drug previously developed by members of the Taysha team as a prime example of their concern.

Several members of the Taysha team, including Session, directors Sean Nolan and Phillip Donenberg, and others, earned their reputation for success as part of a AveXis, a company that developed the breakthrough treatment for spinal muscular atrophy, Zolgensma.

Zolgensma was introduced by drug giant Novartis last year with a price tag of more than $2.1 million, making it the most expensive drug in the country.

On the one hand, you could say thats a winning team, said Megan Allyse. On the other hand, you could say is that the team you want to be on if what youre trying to do is generate not just effective treatments, but accessible treatments?

Session says that Taysha currently has no plans regarding the pricing or accessibility of any treatments the company might develop.

We should be so blessed to be able to have a discussion on pricing because then were talking about an approved therapy, Session says. But were not there yet. So what I would say is the company is focused on getting these drugs into patients effectively and safely as efficiently as possible.

Taysha announced in November that it raised more than $275 million in private financing and an initial public offering.

For Kim Fry and Amber Freed, however, the focus is still very much on what can be done for their sons.

The women are continuing to raise money, but they have shifted to other researchers and technologies. And they have adjusted their expectations.

Frys son, Charlie, started having more significant seizures earlier in the year and is now taking medication to reduce them.

She still thinks a treatment within the next year or two could help her son and others like him, although not in the way she had once imagined.

It may not be a 100% home run where they live 100% the life we hoped. But theyll still have a better life than they are living today, Fry said. I lose sleep every night over the thought that it might be too late, but Im still hopeful that there will be benefit for them.

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These Families Raised Millions To Fund Treatment For Their Kids' Genetic Disorders. It Hasn't Happened. - KCUR

Amryt Granted Orphan Drug Designation by the FDA for AP103

DUBLIN, Ireland, and Boston MA, December 23, 2020, Amryt (Nasdaq: AMYT, AIM: AMYT), a global, commercial-stage biopharmaceutical company dedicated to developing and commercializing novel therapeutics to treat patients suffering from serious and life-threatening rare diseases, is pleased to announce today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for AP103 for the treatment of Dystrophic Epidermolysis Bullosa ("DEB"). AP103 is based on Amryt'sgene-therapy platform technology and offers a potential treatment for patients with DEB, a subset of EB.The FDAsOffice of Orphan Products Development (OOPD) grants orphan drug designation to support the development of medicines for rare diseases, that affect fewer than 200,000 people inthe United States. Orphan drug designation may allowAmrytto be eligible for a seven-year period of U.S. Marketing exclusivity upon approval of AP103 and a waiver of the Prescription Drug User Fee Act (PDUFA) filing fees, subject to certain conditions.

AP103 is based on a new gene therapy delivery platform, in-licensed by Amryt in March 2018, that utilises a non-viral delivery vector, HPAE (Highly Branched Poly -Amino Ester), designed to deliver the correct collagen VII gene into skin cells.

Joe Wiley, CEO of Amryt Pharma, commented:"Receiving an orphan drug designation from the FDA for our gene-therapy candidate, AP103, is a significant development for patients suffering fromEB and provides additional momentum to our development pipeline.Unlike other gene therapies that rely on viral vectors, AP103 is based on a novel polymer-based topical delivery platform, which we believe offers potential advantages in the gene-therapy field and haspotential to be used in other genetic skin conditions.

About AmrytAmryt is a biopharmaceutical company focused on developing and delivering innovative new treatments to help improve the lives of patients with rare and orphan diseases. Amryt comprises a strong and growing portfolio of commercial and development assets.

Amryts commercial business comprises two orphan disease products.

Amryt's lead development candidate, FILSUVEZ (Oleogel-S10) is a potential treatment for the cutaneous manifestations of Epidermolysis Bullosa (EB), a rare and distressing genetic skin disorder affecting young children and adults for which there is currently no approved treatment. FILSUVEZ has been selected as the brand name for the product. Amryt does not have regulatory approval for FILSUVEZ to treat EB. In September and October 2020, Amryt reported positive results from its pivotal global Phase 3 trial in EB. The product has been granted Rare Pediatric Disease Designation and has also received a Fast Track Designation from the U.S. Food and Drug Administration.

Myalept / Myalepta (metreleptin) is approved in the US (under the trade name Myalept) as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy (GL) and in the EU (under the trade name Myalepta) for the treatment of leptin deficiency in patients with congenital or acquired GL in adults and children two years of age and above and familial or acquired partial lipodystrophy (PL) in adults and children 12 years of age and above for whom standard treatments have failed to achieve adequate metabolic control. Metreleptin is also approved for lipodystrophy in Japan. Generalised and partial lipodystrophy are rare disorders characterised by loss or lack of adipose tissue resulting in the deficiency of the hormone leptin, produced by fat cells and are associated with severe metabolic abnormalities including severe insulin resistance, diabetes, hypertriglyceridemia and fatty liver disease.

Juxtapid/ Lojuxta (lomitapide) is approved as an adjunct to a low-fat diet and other lipid-lowering medicinal products for adults with the rare cholesterol disorder, Homozygous Familial Hypercholesterolaemia ("HoFH") in the US, Canada, Columbia, Argentina and Japan (under the trade name Juxtapid) and in the EU and Brazil (under the trade name Lojuxta). HoFH is a rare genetic disorder which impairs the body's ability to remove low density lipoprotein ("LDL") cholesterol ("bad" cholesterol) from the blood, typically leading to abnormally high blood LDL cholesterol levels in the body from before birth - often ten times more than people without HoFH - and subsequent aggressive and premature cardiovascular disease.

In March 2018, Amryt in-licensed a pre-clinical gene-therapy platform technology, AP103, which offers a potential treatment for patients with Dystrophic Epidermolysis Bullosa, a subset of EB, and is also potentially relevant to other genetic disorders. For more information on Amryt, including products, please visitwww.amrytpharma.com.

This announcement contains inside information for the purposes of article 7 of the Market Abuse Regulation (EU) 596/2014. The person making this notification on behalf of Amryt is Rory Nealon, CFO/COO and Company Secretary.

Forward-Looking Statements

This press release may contain forward-looking statements containing the words "expect", "anticipate", "intends", "plan", "estimate", "aim", "forecast", "project" and similar expressions (or their negative) identify certain of these forward-looking statements. The forward-looking statements in this announcement are based on numerous assumptions and Amryt's present and future business strategies and the environment in which Amryt expects to operate in the future. Forward-looking statements involve inherent known and unknown risks, uncertainties and contingencies because they relate to events and depend on circumstances that may or may not occur in the future and may cause the actual results, performance or achievements to be materially different from those expressed or implied by such forward-looking statements. These statements are not guarantees of future performance or the ability to identify and consummate investments. Many of these risks and uncertainties relate to factors that are beyond each of Amryt's ability to control or estimate precisely, such as future market conditions, the course of the COVID-19 pandemic, currency fluctuations, the behaviour of other market participants, the outcome of clinical trials, the actions of regulators and other factors such as Amryt's ability to obtain financing, changes in the political, social and regulatory framework in which Amryt operates or in economic, technological or consumer trends or conditions. Past performance should not be taken as an indication or guarantee of future results, and no representation or warranty, express or implied, is made regarding future performance. No person is under any obligation to update or keep current the information contained in this announcement or to provide the recipient of it with access to any additional relevant information that may arise in connection with it. Such forward-looking statements reflect the Companys current beliefs and assumptions and are based on information currently available to management.

Contacts

Joe Wiley, CEO, +353 (1) 518 0200, joe.wiley@amrytpharma.com

Rory Nealon, CFO/COO, +353 (1) 518 0200, rory.nealon@amrytpharma.com

Edward Mansfield, Shore Capital, NOMAD, +44 (0) 207 468 7906, edward.mansfield@shorecap.co.uk

Tim McCarthy, LifeSci Advisors, LLC, +1 (212) 915 2564, tim@lifesciadvisors.com

Amber Fennell, Consilium Strategic Communications, +44 (0) 203 709 5700, fennell@consilium-comms.com

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Amryt Granted Orphan Drug Designation by the FDA for AP103 - GlobeNewswire