Rare disease treatment and gene therapy were the topics of a State of Reform 5 Slides Were Discussing panel.

Gene therapy is a form of treatment where genes are inserted into the cells of a patient, instead of relying on drugs or surgery. The therapy may be especially promising for rare diseases.

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Rare diseases are defined as any disease, disorder, or illness that affects fewer than 200,000 people in the U.S. Cumulatively, its estimated that up to 30 million Americans have a rare disease, or nearly one in 10. About 80% of rare diseases have a genetic cause, and nearly all of them have limited or no approved treatment options. Oftentimes, these diseases emerge in childhood.

Jennifer Hodge, U.S. Rare Neurology Medical Team Lead for Pfizer, said during the panel that gene therapy could get to the root of these problems.

Were really saying what is the disease, what is the gene, where is the mutation, and how can we go in and correct it?

Two significant conversations surrounding gene therapy were discussed: cost and regulations.

Ryan Fischer, chief advocacy officer with Parent Project Muscular Dystrophy, said theres much education that needs to be done at the federal level to inform lawmakers on rare disease. At the same time, the mapping of the genome has opened new doors for research and future treatments.

At the state level, Carolina Sommer, founder of the Northwest Rare Disease Coalition, said they are trying to bring stories of people and families with rare diseases to Washington legislators. There is some promising legislation she supports, like the creation of a rare disease advisory council.

On pricing, Fischer said the current generation of gene therapy treatments all cost more than $1 million. However, pricing these treatments can be difficult due to their one-time nature. Alternative payment systems could be created, like payment upon reaching a milestone, as opposed to up front.

I often think its difficult for patient advocacy groups and patients to be put in the middle on the cost of therapies, Fischer said. I think its a question that should be asked and talked about, and we should be talking about it collaboratively.

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5 Slides: Gene therapy and rare disease treatment - State of Reform - State of Reform

Catalent, the Somerset-based clinical supply solutions company, on Tuesday said it will spend $230 million to expand its plant in Harmans, Maryland, to meet growing customer demand.

The Harmans campus includes a now fully operational, state-of-the-art U.S. FDA- and EMA-approved facility comprising 10 commercial-scale manufacturing suites. A second facility is under construction following an initial $130 million investment by Catalent in 2020, which will add five new manufacturing suites that are expected to be operational mid-2022. This latest investment, which will bring the total investment in the eight new lines to $360 million, will include the construction of three additional multiroom commercial suites, as well as expanding the sites storage capabilities for just-in-time inventory space, ultra-low temperature freezers and its water-for-injection infrastructure.

Other facilities, including multistory parking and an onsite cafeteria, are planned for the campus to support the significant anticipated growth in employee numbers. The expansion will see the creation of more than 700 new technical, scientific and operational employment positions over the next six years.

Catalent is committed to continuous improvement and growing with our customers futures in mind. This necessitates that we consistently incorporate our own learnings and the latest developments in CGMP manufacturing into our new and existing facilities and operations, to help assure quality and derisk processes, Manja Boerman, president, Catalent Cell & Gene Therapy, said in a news release. By applying the expertise we have gained from the last three years of operating our flagship gene therapy commercial facility, we are able to continue to expand our campus with a design layout that is innovative, efficient, and provides ultimate flexibility for our customers.

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Catalent invests $230M in Md. gene therapy campus - ROI-NJ.com

Mammoth Biosciences CRISPR systems technology will be used by Vertex Pharmaceuticals to develop in vivo gene-editing therapies for two undisclosed genetic diseases, in a deal that has the potential to generate as much as $695 million for Mammoth, the two companies announced today.

We are focused on developing in vivo gene-editing therapies in two indications for specific serious and/or life-threatening diseases with the Vertex team,Peter Nell, Mammoths Chief Business Officer and Head of Therapeutics Strategy, told GEN.

Mammoth and Vertex did say, however, that they will apply Mammoths CRISPR platform consisting of a proprietary toolbox of novel Cas enzymeswhat the company calls the largest toolbox of CRISPR proteins on earth.

These include Cas12, which targets double-stranded DNA; Cas13, which targets and recognizes single-stranded RNA; Cas14, which targets single-stranded DNA; and Cas, which is encoded exclusively in the genomes of huge bacteriophages.

Mammoth has exclusively licensed foundational IP around novel CRISPR Cas12, Cas13, Cas14, and Cas systems from the University of California, Berkeley, where, they were discovered in the lab of Nobel laureate and Berkeley-based researcher Jennifer Doudna, Ph.D.

Doudna is a co-founder of Mammoth Biosciences along with CEO Trevor Martin, Ph.D.; Janice Chen, Ph.D., the companys CTO; Lucas Harrington, Mammoths CSO; and Ashley Tehranchi, Ph.D., who served as CTO until May 2019.

Cas14 and Cas are the smallest known CRISPR systems. Their sizes530 amino acids for Cas14a and 757 amino acids for Cas-2are less than half those of commonly used variants of Cas9 [1368 amino acids for SpCas9] and Cas12 [1,300 amino acids for FnCas12], offering numerous potential advantages for the therapies Mammoth plans to develop, Martintold GEN Edge last month, after the company announced the completion of $195 million in new financing completed over the past year.

The additional financingconsisting of $150 million in Series D financing and a $45-million Series C round whose investors included Amazonbrought Mammoths total capital raised from investors to more than $255 million., propelling the company to a unicorn valuation of more than $1 billion.

In addition, Mammoth said, it is building out its IP portfolio by discovering novel CRISPR systems within and beyond the foundational work. The company has yet to disclose those systems or other Cas enzymes under development.

The combination of Mammoths unique technology with Vertexs unmatched experience in serious disease research and development will only accelerate programs with the goal of reaching patients with high unmet medical need, Nell added. We believe our novel ultra-small CRISPR systems have the potential to be game-changers when it comes to systemic and targeted delivery of in vivo gene-editing therapies.

CRISPR-edited therapies have been an area of focus for Vertex. Late last year, the company and CRISPR Therapeuticsreported positive data from a pair of Phase I/II trialsfor their CRISPR-Cas9 gene-edited therapy CTX001 showing consistent and sustained positive response in 10 patients treated for a pair of blood disorders, sickle cell disease (SCD) and beta thalassemia.

The companies in April amended their collaboration agreement to give Vertex leadership in global development, manufacturing, and commercialization of CTX001 with support from CRISPR Therapeutics, in return for CRISPR receiving a $900 million upfront payment and a potential additional $200 million milestone payment upon CTX001 regulatory approval. Two months later, during the Joint European Hematology Association-American Society of Hematology (EHA-ASH) Symposium, researchers presented additional clinical data showing CTX001 to have delivered a consistent and sustained response to treatment in 22 patients in two ongoing Phase I/II trials.

We see tremendous potential for CTX001, Stuart A. Arbuckle, Vertexs executive vice president and chief commercial and operations officer, told analysts July 29 on the companys quarterly earnings call following release of second-quarter results. He cited an estimate of more than 150,000 patients in the United States and Europe, who have beta thalassemia, or sickle cell disease, approximately 32,000 of whom have severe disease; plus another 25,000 severe sickle cell disease patients, the vast majority of which were in the United States.

We believe that a gene-editing approach which holds the potential for a one-time curative treatment will be highly valued by patients, physicians, and payers, Arbuckle said. Consistent with our own internal market research, published physician surveys in the United States consistently indicate that they expect a quarter to a third of their sickle cell disease patients would be good candidates for a one-time curative approach using the current conditioning regimen, which is in line with the estimates of the numbers of severe patients.

With gentler conditioning regimens in the future, Arbuckle added, we expect CTX001 to be an attractive option for a much larger proportion of the 150,000 beta thalassemia and sickle cell disease patients.

To launch its collaboration with Mammoth, Vertex has agreed to pay the Brisbane, CA,-based company $41 million upfront, including an investment in the form of a convertible note, and up to $650 million in potential future payments tied to achieving research, development, and commercial milestones across two potential programs.

Mammoth is also eligible for tiered royalties from Boston-based Vertex on future net sales on any products that may result from the collaboration, the first one announced by Mammoth for the development of gene-edited therapies.

Vertex and Mammoth share the same commitment to developing therapies that have the potential to be transformative for people with serious diseases, stated David Altshuler, MD, PhD, Vertexs CSO. We look forward to expanding our cell and genetic therapies capabilities with the addition of Mammoths ultra-small CRISPR systems for in vivo genome editing, which will provide us with another set of tools to tackle many of the diseases were interested in.

Mammoth is also developing CRISPR-based diagnostics, having applied Cas12 in its COVID-19diagnostic effort which culminated in the SARS-CoV-2 RNA DETECTR Assay, a COVID-19 diagnostic for whichUCSF Health Clinical Laboratorieswasgranted an FDA Emergency Use Authorization (EUA)in August 2020.

The 45-minute test is designed to detect nucleic acid from SARS-CoV-2 in upper respiratory specimens. The test extracts, isolates, and purifies SARS-CoV-2 nucleic acid for simultaneous reverse transcription into cDNA, followed by amplification using loop-mediated amplification (RT-LAMP).

The SARS-CoV-2 RNA DETECTR Assay was co-developed by Mammoth through itspartnership with UCSF professor Charles Chiu, MD, PhD, who is also director of the UCSF-Abbott Viral Diagnostics and Discovery Center, and a member of the companys Scientific Advisory Board. Mammothin 2019exclusively licensed two U.S. patentsgranted to the regents of the University of California that cover CRISPR collateral cleavage diagnostic systems.

In July 2020, Mammoth won funding for its development of a scalable COVID-19 test, when the company wasawarded $23.1 millionof $248.7 million in contracts to the first seven lab-based and point-of-care tests diagnostics developersfunded through the NIHs Rapid Acceleration of Diagnostics (RADx) initiative. The testing system can be adapted to detect for other viruses, though Mammoth has not made public which ones.

Two months earlier in May 2020, Mammoth launched a collaboration with GlaxoSmithKlines GSK Consumer Healthcare to develop a handheld test designed to apply the DETECTR platform at point of need. Mammoth has disclosed few details since the initial announcement, with Martin saying last month: I cant say too much about it, but definitely weve made huge strides.

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Vertex Taps Mammoth's CRISPR Tech in Gene Therapy Deal Worth up to $695M - Clinical OMICs News

Led by Ben Philpot, PhD, and Matt Judson, PhD, the new therapy was generally well-tolerated and prevented key signs of the condition in animal models.

CHAPEL HILL, NC Scientists at the UNC School of Medicine have reported in the journal JCI Insight encouraging early tests of a gene therapy strategy against Angelman syndrome, a neurodevelopmental disorder that features poor muscle control and balance, hard-to-treat epilepsy, and intellectual disabilities.

Angelman syndrome affects roughly one in every 20,000 children, and in the US alone it is thought that there are more than 15,000 people with the condition. There is no specific treatment, but scientists led by Ben Philpot, PhD, Kenan Distinguished Professor of Cell Biology and Physiology at UNC School of Medicine and Associate Director of the UNC Neuroscience Center, previously suggested that the best way to treat the disorder would be to restore function of the UBE3A gene in neurons, which has been lost in the brains of people with Angelman syndrome.

The genetics of Angelman syndrome are more complicated than classic single-gene disorders such as cystic fibrosis and sickle-cell anemia. Humans inherit one maternal and one paternal copy of most genes. Angelman syndrome arises in children whose maternal UBE3A copy has somehow been mutated or deleted. For reasons that arent fully clear, mature neurons normally express only the maternal copy of UBE3A; the paternal copy is effectively silenced. Thus, when the maternal copy is lost, the genes function is absent in neurons. Because UBE3A encodes a protein that helps regulate the levels of other important proteins, its absence severely disrupts brain development.

Compounding the complexity, neurons express two different variants or isoforms of UBE3A that vary slightly in length a short form and a long form in a ratio of about three short forms for every one long form.

Philpots team was able to craft a version of UBE3A that, when expressed by neurons, yields short and long forms of the UBE3A protein at a near-normal ratio. The scientists inserted their therapeutic UBE3A gene into a virus-derived carrier, or vector, engineered for reliable delivery to neurons. They injected a solution of this vector into hollow spaces, called ventricles, in the brains of newborn Angelman syndrome model mice, which lack the maternal copy of the mouse Ube3a gene. Like humans with Angelman syndrome, these mice fail to express UBE3A protein in their neurons and develop motor deficits, seizures, and other neurological symptoms in the first months of life.

Philpot and colleagues verified that vector-borne UBE3A became active in neurons throughout the Angelman model mouse brain just days after injection, at a level similar to that of the normal gene. This treatment restored motor skill-learning and the essential mouse behaviors of digging, burrowing, and nest-building. Untreated mice developed the usual Angelman-like impairments. The treated mice also did not become as susceptible as their untreated counterparts to experimentally induced epileptic seizures, and importantly, did not suffer any obvious negative side effects.

This was a proof-of-concept study, but if these early results were translated to the clinic, they would represent big improvements in the quality of life for individuals with Angelman syndrome, said study lead author Matt Judson, PhD, a research associate in the Philpot Lab, who performed most of the experiments.

The researchers plan to further develop their strategy, first with more tests in mice and monkeys to optimize dose and delivery methods, and ultimately, pending promising safety results, human clinical trials. If such a therapy were available, the researchers expect it might be able to deliver benefits to individuals of any age, but perhaps with varying benefits.

The range from birth to four years is probably ideal, but we think that whenever we can reinstate this genes function in the brain, were likely to see some improvements, Philpot said.

Along with Judson and Philpot, who was recently ranked as the worlds leading Angelman syndrome researcher, the JCI Insight paper was co-authored by Charles Shyng, Jeremy Simon, Courtney Davis, Mattijs Punt, Mirabel Salmon, Noah Miller, Kimberly Ritola, Ype Elgersma, David Amaral, and Steven Gray.

The research was supported by the Angelman Syndrome Foundation, and the National Institutes of Health (R01HD093771, R01MH120229, R01NS114086).

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Gene Therapy Shows Early Promise as Angelman Syndrome Treatment | Newsroom - UNC Health and UNC School of Medicine

Dive Brief:

Only a handful of gene therapies for inherited diseases are approved worldwide. Bluebird, holding two of them, has been one of the leading developers.

So Bluebird's struggles in Europe are notable for the dozens of other biotech companies advancing gene-based treatments for uncommon diseases like cerebral adrenoleukodystrophy or severe beta thalassemia.

The company's decision also reflects the differences in how therapies approved in Europe are paid for, with decisions on reimbursement left up to the governments of individual EU member states. Compared to the U.S., European countries can be more aggressive in demanding lower prices and, as many have single-payer healthcare systems, are better able to negotiate for larger discounts.

While Bluebird set a $1.8 million price for Zynteglo, the company proposed having countries reimburse for treatment over five years. Payments were linked to continued patient benefit.

Germany, however, countered with an initial price of $790,000 per patient, rising to roughly $950,000 if patients were benefiting from treatment several years later, according to an April report from STAT News.

That proved unpalatable to Bluebird, which pulled Zynteglo from Germany before later announcing a broader withdrawal from Europe.

"Bluebird's decision to focus on the U.S. market is driven by the challenges of achieving appropriate value recognition and market access for Zyntegloin Europe, which makes bringing its transformative gene therapies like Zyntegloand Skysona to patients and physicians in Europe untenable for a small innovative company at this time, said Andrew Obenshain, head of severe genetic diseases at Bluebird, in an August statement.

Along with the withdrawal of Skysona from Europe, Bluebird is also pulling back an application for approval in the U.K., according to a Thursday filing with U.S. securities regulators. Withdrawal of Zynteglo from the EU and U.K. will be complete by early 2022.

Bluebird said it will continue long-term follow-up of patients treated in clinical trials in Europe, but will not carry out further study of the treatments there.

While specific numbers aren't available, few patients ever received Zynteglo. The first patient ever treated commercially only received the therapy in February of this year, after manufacturing difficulties had delayed Bluebird's launch of the drug.

Neither Zynteglo or Skysona were expected to be widely used given the small patient populations they were approved to treat. But clinical testing had shown both to be effective therapies, meaning their withdrawal leaves patients in Europe with one less treatment option.

Bluebird recently asked the Food and Drug Administration for approval of Zynteglo in the U.S. and plans to do the same for Skysona by the end of this year.

The company is also in the midst of splitting in two, with its cancer research and programs set to be spun out into a new independent company called 2seventy bio.

Continued here:
Bluebird, winding down in Europe, withdraws another rare disease gene therapy - BioPharma Dive

Life sciences company Catalent said Tuesday that it is planning to invest $230 million to expand its campus for manufacturing gene therapy treatments near BWI Airport.

With this investment, Catalent plans to add three viral-vector manufacturing suites to its facility in the Anne Arundel County town of Harmans, adding capacity for the company to produce treatments that transfer genetic material into cells to fight rare diseases.

At the facility, Catalent Cell and Gene Therapy offers contract manufacturing for firms that develop and commercialize new treatments in an area of medicine that is coming of age. With FDA clearance, it is producing treatments at commercial scale that are designed to be used in late-stage trials and in the clinic.

An initial building at the site that opened in 2019 has 10 manufacturing suites. In 2020, the company invested $130 million to expand a second building, which has five manufacturing suites. With the latest investment, three more suites with room for multiple bioreactors will be added to that building to maximize capacity for production. Catalent also plans to add storage capacity, including space for just-in-time inventory and low-temperature freezers. In all, the company expects to have 18 suites operational on the 350,000-square-foot campus at the end of 2022.

It will also mean hiring. Currently, Catalent employs 900 people at the site. The company plans to add 700 new employees in scientific, technical and operational roles over the next six years. With the employee growth, it is also adding facilities like an onsite cafeteria and parking garage with the latest investment.

Catalent is committed to continuous improvement and growing with our customers futures in mind. This necessitates that we consistently incorporate our own learnings and the latest developments in [Current Good Manufacturing Practice] manufacturing into our new and existing facilities and operations, to help assure quality and de-risk processes, said Dr. Manja Boerman, president of Catalent Cell & Gene Therapy, in a statement. By applying the expertise we have gained from the last three years of operating our flagship gene therapy commercial facility, we are able to continue to expand our campus with a design layout that is innovative, efficient, and provides ultimate flexibility for our customers.

Somerset, New Jersey-based Catalent provides development and manufacturing services to pharma, biotech and other health companies producing new treatments at facilities around the world. Its presence in the area dates to 2018, when it acquired Baltimore-founded Paragon Bioservices in a deal worth $1.2 billion. The Harmans campus opened right around the time that the acquisition was announced, and Paragon became part of what is now Catalent Cell and Gene Therapy. It continues to have a facility at the University of Maryland BioPark in downtown Baltimore where it works on manufacturing for developmental phases, and added a facility in Rockville in 2019.

Together, the Maryland facilites form a network under Catalent Cell and Gene Therapy, which has grown since the Paragon acquisition in 2019. With innovation continuing to progress rapidly and companies bringing new treatments to market, Catalent is growing its footprint as its customers grow, too.

It shows continued investment in the manufacturing portion of the states biotech footprint. Maryland has a concentration of researchers and scientists at universities and federal labs that make the discoveries that lead to new treatments, and start companies. The state is also increasingly a place where companies are opening facilities to manufacture treatments after they are developed and approved for market.

Along with Catalents investment, this year also brought news of forthcoming production facilities in Frederick from home COVID-19 test maker Ellume, as well as a new site for multiple companies helmed by VaLogic. Kite Pharma also opened a new biomanufacturing facility in Frederick Countys Urbana.

Funding from investors is a well-tracked metric of a communitys growth, but these moves indicate its also worth considering what the growth investments made directly by companies show about the innovation economy.

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Catalent is investing $230M to expand its gene therapy manufacturing campus near BWI - Technical.ly

27 October 2021

Morrison & Foerster LLP

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On September 30, 2021, the U.S. Food and Drug Administration(FDA)announcedfinal guidance titled "Interpreting Sameness of Gene Therapy Productsunder the Orphan Drug Regulations." The guidance finalizesthe January 2020 draft guidance and provides FDA's currentperspective on certain criteria that help determine sameness ofhuman gene therapy products for orphan drug designation andexclusivity purposes. In the Federal Register notice announcing thefinal guidance, FDA noted that it received comments on the draftguidance that "generally supported the approach described inthe guidance." FDA considered these comments and requests foradditional clarification when finalizing the guidance, "addingclarification and examples, as feasible."

The Orphan Drug Act (ODA) seeks to incentivize the developmentof drugs for rare diseases, defined in the ODA as those affectingfewer than 200,000 people in the United States. The incentivesinclude a 25% tax credit on applicable research and developmentexpenditures, waived user fees when submitting applications to FDA,and the potential for a seven-year period of orphan drugexclusivity for the approved indication. Manufacturers must requestand be granted designation before they are eligible for anyincentives.

When FDA grants marketing approval for a designated orphan drugfor a use or indication within the designation disease orcondition, FDA will determine if the drug is eligible for orphandrug exclusivity. Orphan drug exclusivity is product and indicationspecific, meaning FDA cannot approve a drug containing the sameactive moiety for the same intended use or indication during theperiod of marketing exclusivity.

FDA uses different criteria in determining sameness formacromolecule and small molecule drugs 1.The FDAdefines "same drug" for macromolecule drugs as "adrug that contains the same principal molecular structural features(but not necessarily all of the same structural features) and isintended for the same use as a previously approved drug, exceptthat, if the subsequent drug can be shown to be clinicallysuperior, it will not be considered to be the same drug."2

If a sponsor requests orphan drug designation for a drug that isthe same as a drug already approved for the same use or indication,the sponsor must provide a plausible hypothesis that its drug isclinically superior to the already approved drug. Designation asclinically superior is based on greater efficacy, safety, or amajor contribution to patient care. In order to receive theseven-year market exclusivity, a sponsor must demonstrate that itsproduct is actually clinically superior.

Human gene therapy products may qualify for orphan drugdesignation if they are intended for the treatment of a raredisease or condition and the sponsor sufficiently establishes abasis for expecting the drug to be effective in treating the raredisease. The existing regulations do not describe how the"same drug" definition applies specifically to genetherapy products for orphan drug designation and exclusivity.Mirroring the January 2020 draft guidance, FDA's final guidanceprovides some insight into the current interpretation of how the"sameness" criteria applies to gene therapies.

Assuming that two gene therapy products are intended for thesame use or indication, FDA will consider the "principalmolecular structural features" of the gene therapy productswhen determining "sameness." In the final guidance, FDAstates its intention to generally "consider certain keyfeatures such as transgenes and vectors used in gene therapyproducts to be 'principal molecular structural features'under this regulation." However, FDA does not intend toclassify two gene therapy products as different based solely onminor differences in the transgenes and/or vectors, and willdetermine whether differences are minor differences on acase-by-case basis.

For two gene therapy products intended for the same use orindication, if the products express different transgenes, FDAgenerally intends to consider them to be different drugs becausethey will not contain the same principal molecular structuralfeatures. This would be the case regardless of whether the two genetherapy products at issue have or use the same vector. FDA alsointends to consider vectors from a different viral group to bedifferent for purposes of determining "sameness."Additionally, FDA clarified in the final guidance that it willconsider two gene therapy products from the same viral group to bedifferent "when the differences between the vectors impactfactors such as tropism, immune response avoidance, or potentialinsertional mutagenesis." FDA intends to determine whethervariants of a vector from the same viral group are the same ordifferent on a case-by-case basis.

In a case where two gene therapy products express the sametransgene and have/use the same vector, FDA may also consideradditional features of the final product when determining"sameness," such as regulatory elements (e.g., promotersor enhancers). In these instances, FDA generally intends todetermine "sameness" of gene therapy products on acase-by-case basis.

Footnotes

1. 21 CFR 316.3(b)(14).

2. 21 CFR 316.3(b)(14)(ii).

Because of the generality of this update, the informationprovided herein may not be applicable in all situations and shouldnot be acted upon without specific legal advice based on particularsituations.

Morrison & Foerster LLP. All rights reserved

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On October 13th our friends over at STAT broke the news [sorry, Paywall] about a "warranty" pilot program from Pfizer that offers both patients and health plans (including Medicare Part D plans) the opportunity to receive a refund ...

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FDA Finalizes Guidance On Interpretation Of Orphan Drug - Mondaq News Alerts

Angelman syndrome affects roughly 1 in every 20,000 children and it has no approved treatment.

Researchers recently published results of early tests of a gene therapy strategy for Angelman syndrome, a rare neurodevelopmental disorder that features poor muscle control and balance, hard-to-treat epilepsy, and intellectual disabilities.

Angelman syndrome affects roughly 1 in every 20,000 children. In United States there may be more than 15,000 people with the condition and it has no specific treatment.

The genetics of Angelman syndrome are more complicated than classic single-gene disorders such as cystic fibrosis and sickle cell anemia. Humans inherit 1 maternal and 1 paternal copy of most genes. Angelman syndrome arises in children whose maternal UBE3A copy has somehow been mutated or deleted.

For reasons that arent fully clear, mature neurons normally express only the maternal copy of UBE3A; the paternal copy is effectively silenced. Thus, when the maternal copy is lost, the genes function is absent in neurons. Because UBE3A encodes a protein that helps regulate the levels of other important proteins, its absence severely disrupts brain development.

Compounding the complexity, neurons express 2 different variants or isoforms of UBE3A that vary slightly in lengtha short form and a long formin a ratio of about 3 short forms for every 1 long form.

Researchers created a version of UBE3A that, when expressed by neurons, yields short and long forms of the UBE3A protein at a near-normal ratio. The scientists inserted their therapeutic UBE3A gene into a virus-based vector engineered for reliable delivery to neurons. They injected a solution of this vector into hollow spaces, called ventricles, in the brains of newborn Angelman syndrome model mice, which lack the maternal copy of the mouse Ube3a gene. Like humans with Angelman syndrome, these mice fail to express UBE3A protein in their neurons and develop motor deficits, seizures, and other neurological symptoms in the first months of life.

The scientists verified that vector-borne UBE3A became active in neurons throughout the Angelman model mouse brain just days after injection, at a level similar to that of the normal gene. This treatment restored motor skill-learning and the essential mouse behaviors of digging, burrowing, and nest-building. Untreated mice developed the usual Angelman-like impairments. The treated mice also did not become as susceptible as their untreated counterparts to experimentally induced epileptic seizures, and importantly, did not suffer any obvious negative side effects.

This was a proof-of-concept study, but if these early results were translated to the clinic, they would represent big improvements in the quality of life for individuals with Angelman syndrome, said study lead author Matt Judson, PhD, a research associate in the Philpot Lab at the University of North Carolina School of Medicine.

Results were published in the journal JCI Insight.

The researchers plan to further develop their strategy in additional animal models to optimize dose and delivery methods, and ultimately human clinical trials. If such a therapy were available, the researchers expect it might be able to deliver benefits to individuals of any age, but perhaps with varying benefits.

Reference

Judson MC, Shyng C, Simon JM, et al. JCI Insight. Published online October 22, 2021. doi:10.1172/jci.insight.144712.

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Early Results of Gene Therapy for Angelman Syndrome Look Promising - AJMC.com Managed Markets Network

NEW YORK and DURHAM, N.C., Oct. 21, 2021 (GLOBE NEWSWIRE) -- Sio Gene Therapies Inc. (NASDAQ: SIOX), a clinical-stage company focused on developing gene therapies to radically transform the lives of patients with neurodegenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation to AXO-AAV-GM1, its adeno-associated viral vector (AAV)9-based gene therapy candidate for the treatment of Type I (early infantile-onset) and Type II (late infantile-onset and juvenile-onset) GM1 gangliosidosis. The Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

Receiving Fast Track Designation is a critical step in our mission to develop the first potential treatment for all pediatric forms of this rare, terminal disease. This designation joins both the Orphan Drug Designation and Rare Pediatric Disease Designation assigned to AXO-AAV-GM1 by the FDA, which we believe further demonstrates the potential impact of this work on the patient community, said Pavan Cheruvu, M.D., Chief Executive Officer of Sio Gene Therapies. Building on the recently presented data at ESGCT demonstrating normalization of key disease biomarkers in the high-dose cohort with no serious adverse events attributed to AXO-AAV-GM1, this designation will help us accelerate clinical development of this promising investigational therapy for children and families.

The current Phase 1/2 study (NCT03952637) is designed to evaluate the safety, tolerability, and potential efficacy of AXO-AAV-GM1 gene therapy delivered intravenously in children with early infantile, or Type I, and late infantile and juvenile, or Type II, GM1 gangliosidosis. Stage 1 of the study is a dose-escalation study in which the low-dose cohort is evaluating 1.5x1013 vg/kg and the high-dose cohort is evaluating a dose of 4.5x1013 vg/kg. Stage 2 of the trial will then evaluate the efficacy and safety of the optimal dose identified in Stage 1.

Story continues

GM1 gangliosidosis is a progressive and fatal pediatric lysosomal storage disorder caused by mutations in the GLB1 gene that cause impaired production of the -galactosidase enzyme. Currently, there are no FDA-approved treatment options for GM1 gangliosidosis.

About AXO-AAV-GM1

AXO-AAV-GM1 delivers a functional copy of the GLB1 gene via an adeno-associated viral (AAV) vector, with the goal of restoring -galactosidase enzyme activity for the treatment of GM1 gangliosidosis. The gene therapy is delivered intravenously, which has the potential to achieve a broad central and peripheral biodistribution. Preclinical studies in murine and a naturally-occurring feline model of GM1 gangliosidosis have supported AXO-AAV-GM1s ability to increase -galactosidase enzyme activity, reduce GM1 ganglioside accumulation, improve neuromuscular function, and extend survival.

AXO-AAV-GM1 has received both Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA and is the only gene therapy in clinical development for all pediatric forms of GM1 gangliosidosis.

In 2018, Sio licensed exclusive worldwide rights from UMass Chan Medical School for the development and commercialization of gene therapy programs for GM1 gangliosidosis and GM2 gangliosidosis, including Tay-Sachs and Sandhoff diseases.

About Sio Gene Therapies

Sio Gene Therapies combines cutting-edge science with bold imagination to develop genetic medicines that aim to radically improve the lives of patients. Our current pipeline of clinical-stage candidates includes the first potentially curative AAV-based gene therapies for GM1 gangliosidosis and Tay-Sachs/Sandhoff diseases, which are rare and uniformly fatal pediatric conditions caused by single gene deficiencies. We are also expanding the reach of gene therapy to highly prevalent conditions such as Parkinsons disease, which affects millions of patients globally. Led by an experienced team of gene therapy development experts, and supported by collaborations with premier academic, industry and patient advocacy organizations, Sio is focused on accelerating its candidates through clinical trials to liberate patients with debilitating diseases through the transformational power of gene therapies. For more information, visit http://www.siogtx.com.

Forward-Looking Statements

This press release contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as "expect," "estimate," "may" and other similar expressions are intended to identify forward-looking statements. For example, all statements Sio makes regarding costs associated with its operating activities, funding requirements and/or runway to meet its upcoming clinical milestones, and timing and outcome of its upcoming clinical and manufacturing milestones are forward-looking. All forward-looking statements are based on estimates and assumptions by Sios management that, although Sio believes to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Sio expected. Such risks and uncertainties include, among others, the impact of the Covid-19 pandemic on our operations; the actual funds and/or runway required for our clinical and product development activities and anticipated upcoming milestones; actual costs related to our clinical and product development activities and our need to access additional capital resources prior to achieving any upcoming milestones; the initiation and conduct of preclinical studies and clinical trials; the availability of data from clinical trials; the occurrence of adverse safety events during our current and future trials; the development of a suspension-based manufacturing process for AXO-Lenti-PD; the scaling up of manufacturing; the outcome of interactions with regulatory agencies and expectations for regulatory submissions and approvals; the continued development of our gene therapy product candidates and platforms; Sios scientific approach and general development progress; and the availability or commercial potential of Sios product candidates. These statements are also subject to a number of material risks and uncertainties that are described in Sios most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on August 12, 2021, as updated by its subsequent filings with the Securities and Exchange Commission. Any forward-looking statement speaks only as of the date on which it was made. Sio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Contacts:

Media

Josephine Belluardo, Ph.D. LifeSci Communications(646) 751-4361jo@lifescicomms.com info@siogtx.com

Investors and Analysts

Parag V. MeswaniSio Gene Therapies Inc.Chief Commercial Officerinvestors@siogtx.com

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Sio Gene Therapies Announces Granting of FDA Fast Track Designation for Investigational AXO-AAV-GM1 (AAV9-GLB1) Gene Therapy in Patients with GM1...

SOUTH SAN FRANCISCO, Calif., October 21, 2021--(BUSINESS WIRE)--Graphite Bio, Inc. (Nasdaq: GRPH), a clinical-stage, next-generation gene editing company focused on therapies that harness targeted gene integration to treat or cure serious diseases, announced today that members of the management team will participate in a fireside chat at the Jefferies Gene Therapy/Editing Summit on Thursday, Oct. 28, 2021, at 4:30 p.m. ET.

The fireside chat will be webcast live from Graphite Bios website at http://www.graphitebio.com in the Investors section. A replay of the webcast will be archived and available for one month following the event.

About Graphite Bio

Graphite Bio is a clinical-stage, next-generation gene editing company harnessing high efficiency targeted gene integration to develop a new class of therapies to potentially cure a wide range of serious and life-threatening diseases. Graphite Bio is pioneering a precision gene editing approach that could enable a variety of applications to transform human health through its potential to achieve one of medicines most elusive goals: to precisely "find & replace" any gene in the genome. Graphite Bios platform allows it to precisely correct mutations, replace entire disease-causing genes with normal genes or insert new genes into predetermined, safe locations. The company was co-founded by academic pioneers in the fields of gene editing and gene therapy, including Maria Grazia Roncarolo, M.D., and Matthew Porteus, M.D., Ph.D.

Learn more about Graphite Bio by visiting http://www.graphitebio.com and following the company on LinkedIn.

View source version on businesswire.com: https://www.businesswire.com/news/home/20211021005108/en/

Contacts

Company: Stephanie YaoVP, Communications and Investor Relations443-739-1423syao@graphitebio.com

Investor Relations: Stephanie AscherStern IR, Inc.212-362-1200ir@graphitebio.com

Media: Christy CurranSam Brown, Inc.615-414-8668media@graphitebio.com

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Graphite Bio Announces Participation in Upcoming Jefferies Gene Therapy/Editing Summit - Yahoo Finance