Category Archives: Genetic Therapy

January was a busy month for the US Food and Drug Administrations precision medicine efforts, as the agency produced guidance on ASO drugs for patients with debilitating or life-threatening genetic disorders and guidance on manufacturing considerations for certain cellular and gene therapy products during the COVID-19 pandemic.

The agency first issued a draft guidance to facilitate the development of individualized antisense oligonucleotide (ASO) drugs for patients with severely debilitating or life-threatening genetic disorders (ASO Guidance). The Food and Drug Administration (FDA) also issued a guidance, with immediate effect, on manufacturing considerations for licensed and investigational cellular and gene therapy products during the COVID-19 public health emergency (Manufacturing Guidance). Sponsors investigating or marketing these products should pay special attention to the discussion in these documents, as FDA outlines its approach to COVID-19 and development considerations with respect to these personalized therapies.

Manufacturing Guidance

The Manufacturing Guidance supplements FDAs June 2020 guidance on Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing. However, because cell and gene therapy (CGT) manufacturers may face special challenges, FDA recommends that CGT manufacturers perform risk assessments to identify, evaluate, and mitigate factors that may allow for the transmission of SARS-CoV-2 through CGT products. Any plans should take into account FDAs view that allogeneic products may be associated with a higher risk of infection compared to autologous products.

FDA specifically recommends the following:

As always, any adopted risk assessment and mitigation strategies must be documented and approved by the manufacturers quality unit, should include scientific justification and literature references, and should be submitted to FDA.

ASO Guidance

Turning away from the current COVID-19 crisis, FDA indicated that it is also looking ahead to the continued advancement of personalized therapies, issuing the ASO Guidance to assist sponsor investigators in the development of individualized ASO products for severely debilitating or life-threatening genetic diseases that are tailored to a patients specific genetic variant. As noted by FDA, the ASO Guidance is targeted to academic investigators, who may be less familiar with FDAs requirements and less experienced in interacting with FDA.

While the specific impetus for this guidance is unclear, assumedly FDA is receiving more inquiries regarding individualized ASO drugs from investigators, patients, or those acting on their behalf. Regardless of the reason, healthcare institutions where ASO products are used should familiarize themselves with FDAs requirements and processes to ensure that any use of an investigational ASO product accords with FDAs regulations. It will also be important that manufacturers supporting the use of ASO products or that later intend to work with ASO product investigators ensure that programs comply with FDAs regulations via contractual agreements and, as appropriate, due diligence.

For these programs, FDA recommends the following:

The ASO Guidance is likely a first step in the development of individualized therapies. As stated by FDA, the agency is optimistic that development of [ASO] individualized drug products may spur gene sequencing that leads to the development of additional individualized drug products. Accordingly, through the ASO Guidance, FDA aims to determine the most effective and efficient way to bring personalized drugs to patients, while ensuring the right risk-benefit balance.

Excerpt from:
FDA Issues More Guidance on Gene and Cell Therapy Products - Lexology

- First potentially disease-modifying gene therapy for GM2 gangliosidosis to enter clinical studies

- Expect to continue patient identification, screening, and enrollment in Stage 1 of the study throughout 2021

NEW YORK and RESEARCH TRIANGLE PARK, N.C., Feb. 03, 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 first patient with infantile Tay-Sachs disease has been dosed in a Phase 1/2 trial evaluating AXO-AAV-GM2,an investigational gene therapy for the treatment of GM2 gangliosidosis, also known as Tay-Sachs or Sandhoff disease.

We are proud to bring the first potentially disease-modifying treatment for GM2 gangliosidosis to the clinic, which is a milestone for Sio, for patients, and for the field of gene therapy, said Gavin Corcoran, M.D., Chief R&D Officer of Sio. By restoring lysosomal enzyme activity where it is essential, AXO-AAV-GM2 has the potential to change the course of this disease and help affected children attain and retain important neuro-developmental milestones. The prior expanded access study of AXO-AAV-GM2 provided important proof-of-concept data and we look forward to the results of the first stage of our study as we strive to develop a treatment for children suffering from this rapidly progressive and fatal disease.

Florian Eichler, M.D., Director of the Leukodystrophy Service of the Center for Rare Neurological Diseases at Massachusetts General Hospital, and principal investigator, added, To date, the current GM2 treatment landscape is limited to supportive care, underscoring the significant need for new treatment options to address this devastating pediatric neurodegenerative disease. AXO-AAV-GM2 has significant potential to address the clinical manifestations of both Tay Sachs and Sandhoff diseases, and as a result, the dosing of this patient represents a major step forward for this therapy. We look forward to evaluating the results of this study and advancing the first potentially disease-modifying treatment option for patients with GM2.

The Phase 1/2 study (NCT04669535) is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of surgical delivery of AXO-AAV-GM2 directly to the brain and spinal cord of pediatric participants with both infantile and juvenile GM2 gangliosidosis. AXO-AAV-GM2 has been granted Orphan Drug and Rare Pediatric Disease Designation by the FDA and is the first investigational gene therapy to enter clinical trials for GM2 gangliosidosis. In 2019, clinical evidence from two patients under an expanded access IND found that treatment with AXO-AAV-GM2 was generally well-tolerated and associated with improved bioactivity outcomes.

The families of children with Sandhoff and Tay-Sachs diseases show incredible bravery in choosing to participate in investigational studies of novel therapeutics like AXO-AAV-GM2. We share their hope that this treatment can halt or reverse the otherwise inexorable course of these tragic diseases, said Terence R. Flotte, MD, Professor of Pediatrics and Dean at the University of Massachusetts Medical School and principal investigator of the trial.

GM2 gangliosidosis is a set of rare, monogenic neurodegenerative lysosomal storage disorders caused by mutations in the genes that encode the enzyme -Hexosaminidase A. It can be categorized into two distinct diseases, Tay-Sachs disease, which results from a mutation in the gene encoding the alpha subunit of the -Hexosaminidase A enzyme (HEXA), and Sandhoff disease, which results from a mutation in the gene encoding the beta subunit of the -Hexosaminidase A enzyme (HEXB). Children affected by GM2 gangliosidosis suffer from a progressively debilitating disease course and reduced life expectancy.

Sue Kahn, Executive Director of National Tay-Sachs & Allied Diseases Association(NTSAD), added, This news represents the culmination of many years of work to advance this research and immense support from the GM2 community, and it underscores the dire need for new treatment options capable of providing meaningful benefits to patients and families. We are extremely excited by the progress Sio has made and the hope it brings to our community.

Sio aims to advance the program through strategic partnerships with leading research organizations. The Company has a partnership with Viralgen, an AskBio subsidiary, to support AAV-based vector manufacturing of clinical trial material for the registrational study. Additionally, through an existing genetic testing collaboration with Invitae, ongoing partnership with GM2 gangliosidosis patient groups, and collaboration with leading academic researchers at the University of Massachusetts Medical School and Massachusetts General Hospital, Sio has begun patient identification and screening activities for the ongoing clinical study.

About AXO-AAV-GM2

AXO-AAV-GM2 is an investigational gene therapy for GM2 gangliosidosis (also known as Tay-Sachs and Sandhoff diseases), a set of rare and fatal pediatric neurodegenerative genetic disorders caused by defects in the HEXA (leading to Tay-Sachs disease) or HEXB (leading to Sandhoff disease) genes that encode the two subunits of the -hexosaminidase A (HexA) enzyme. These genetic defects lead to progressive neurodegeneration and shortened life expectancy. AXO-AAV-GM2 aims to restore HexA function by introducing a functional copy of the HEXA and HEXB genes via delivery of two co-administered AAVrh8 vectors.

About Sio Gene TherapiesSio 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.

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

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 potentially, and potential, and other similar expressions are intended to identify forward-looking statements. For example, all statements Sio makes regarding costs associated with its operating activities 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 initiation and conduct of preclinical studies and clinical trials; the availability of data from clinical trials; the development of a suspension-based manufacturing process for AXO-Lenti-PD; the scaling up of manufacturing, the 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 November 13, 2020, 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.

Contacts:

Media

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

Investors and Analysts

Parag V. Meswani, Pharm.D.Sio Gene Therapies Inc.Chief Commercial Officerinvestors@siogtx.com

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Sio Gene Therapies Announces First Patient Dosed in Clinical Trial of AXO-AAV-GM2 in Patients with Tay-Sachs and Sandhoff Disease (GM2 Gangliosidosis)...

A gene therapy targeting the inherited electrical heart disorder long QT syndrome has been developed by researchers at the Mayo Clinic and has shown early success in lab-based studies.

The therapy involves a two-stage process of silencing the genetic error that causes the electrical dysfunction and then replacing it with a functional protein using a short hairpin RNA vector.

As reported in the journal Circulation, the research is still at an early stage, but shows promise in a lab-based cardiac cell model.

Although the first gene therapy trials happened more than 30 years ago, several deaths and adverse effects from these original therapies, combined with sometimes limited efficacy, led to delays in further research and development in this area.

However, things have changed over the last few years. Since the eye gene therapy Luxturna was approved by the FDA in 2017, more than double the number of new therapies for different genetic diseases have gone into development than before and there have been notable successes in developing therapies for various retinal, neurological and immune disorders.

The possibility of developing gene therapies for heart disease has not been explored in depth until recently and is still in its early stages. More widespread heart diseases with polygenic causes are complicated to target with gene therapies and incur high costs. But many rarer arrythmias, such as long QT syndrome, have a genetic cause and are therefore potential gene therapy targets.

Gene therapy is an emerging area of interest for treating a variety of genetic heart diseases in general and long QT syndrome in particular, says Michael Ackerman, M.D. Ph.D., a Mayo Clinic cardiologist and director of Mayo Clinics Windland Smith Rice Comprehensive Sudden Cardiac Death Program, who led the research.

Long QT syndrome is caused by an electrical heart problem that can cause irregular heartbeat, and under conditions of stress, or exertion, can cause the heart to stop beating suddenly. It occurs in approximately 1 in 7,000 people and most often has a genetic cause, although in some cases it can be acquired as a side effect of certain medications or as a result of other illnesses.

Ackerman and team designed and developed the first suppression and replacement KCNQ1 gene therapy approach for the potential treatment of patients with type 1 long QT syndrome. The KCNQ1 protein is involved in potassium channel function and mutations in this gene are common in people with long QT syndrome.

The therapy designed by the Mayo Clinic team involved cloning two short hairpin RNAs one for silencing purposes and one to replace the faulty protein into a single gene therapy construct.

When tested in beating cardiac cells from long QT patients and controls in the lab, the therapy successfully normalized the electrical function of the long QT cells, providing proof of principle to continue development of the therapy.

If the therapeutic efficacy of this disease-in-the-dish gene therapy trial with KCNQ1 can be replicated in a nonhuman, animal model of long QT syndrome, then suppression-replacement gene therapy may be a promising strategy for long QT syndrome in general and in theory almost any sudden death-predisposing autosomal dominant genetic heart disease, says Ackerman.

Of course, we still have a long way to go from nearly curing a patients heart cells in the dish to effectively treating the whole person. Nevertheless, we are excited by this first critical milestone and look forward to the next step.

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Prototype Gene Therapy for Long QT Heart Condition Developed - Clinical OMICs News

First participant dosed in the RESOLUTESM trial, a Phase 1/2 dose-escalation study of SPK-3006

Enrollment of approximately 20 total study participants is ongoing

PHILADELPHIA, Feb. 01, 2021 (GLOBE NEWSWIRE) -- Spark Therapeutics, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY) and a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced the dosing of the first participant in the Phase 1/2 RESOLUTESM trial of SPK-3006, an investigational liver-directed adeno-associated viral (AAV) vector gene therapy for late-onset Pompe disease (LOPD), a rare, inherited lysosomal storage disorder.

Dosing the first participant in the Phase 1/2 RESOLUTE trial of investigational SPK-3006 for late-onset Pompe disease is an important milestone and first step to what we hope will ultimately allow us to bring an innovative gene therapy to these patients, said Gallia G. Levy, M.D., Ph.D., chief medical officer of Spark Therapeutics. We are deeply appreciative of the ongoing collaboration of the Pompe disease community as we continue to enroll participants in this Phase 1/2 study.

The RESOLUTE trial is an open-label Phase 1/2, dose-escalation gene transfer study designed to evaluate the safety, tolerability and efficacy of a single intravenous infusion of investigational SPK-3006, an AAV vector-based gene therapy, developed in collaboration with Genethon, in adults with clinically moderate LOPD currently receiving enzyme replacement therapy. The study is expected to enroll approximately 20 participants receiving the investigational gene therapy in sequential, dose-level cohorts. Additional details are available on ClinicalTrials.gov (NCT04093349).

We are honored to have the first participant dosed in this clinical trial, which we hope will lead us to introduce a novel therapeutic option for patients living with late-onset Pompe disease, said Principal Investigator Tahseen Mozaffar, M.D., University of California Irvine Health.

The International Pompe Association has been proud to collaborate with Spark Therapeutics to enhance the Pompe disease communitys understanding of gene therapy research, said Tiffany House, International Pompe Association Board Chairman. We look forward to the progress in the Phase 1/2 RESOLUTE trial, as well as the ongoing work aimed at developing gene therapies that have the potential to help individuals living with genetic diseases.

Pompe disease is a rare, inherited lysosomal storage disorder. It is a progressive, often life-limiting disease caused by the buildup of a complex sugar, glycogen, in the bodys cells. Mutations in the gene encoding acid alpha-glucosidase (GAA) result in deficiencies of the GAA enzyme and limit the breakdown of glycogen. For patients living with LOPD, the respiratory system, locomotion and maintenance of gait are the most critically impacted. These symptoms commonly result in patients becoming wheelchair bound and requiring respiratory support, which may result in reduced life-expectancy.

About SPK-3006 for Pompe diseaseSPK-3006is an investigational liver-directed AAV gene therapy for the potential treatment of late-onset Pompe disease (LOPD).SPK-3006has been engineered to produce a modified enzyme (secretable GAA) that is produced by the liver, which may result in sustained GAA plasma levels and could potentially provide greater uptake in muscle tissue. The transgene integrates technologies designed at and licensed from Genethon, where the in-vivo proof of concept in pre-clinical models was demonstrated. Spark Therapeutics retains global commercialization rights toSPK-3006.

About Spark Therapeutics AtSpark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challengethe inevitability of genetic diseases,includingblindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases.We currently have four programs in clinical trials.At Spark, a member of the Roche Group, we see the path to a world where no life is limited by genetic disease. For more information, visit http://www.sparktx.com, and follow us on Twitter and LinkedIn.

Media Contact:Kevin Giordanocommunications@sparktx.com(215) 294-9942

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Spark Therapeutics Announces First Participant Dosed in Phase 1/2 Study of Investigational Gene Therapy for Late-Onset Pompe Disease - GlobeNewswire

Among the logistical challenges facing public health agencies that are struggling to vaccinate the masses against COVID-19 is that the two mRNA shots on the market, from Moderna and Pfizer, need to be stored at ultra-cold temperatures. Now, an alternative technology for shielding patients from the novel coronavirusone that doesnt pose that storage challengeis showing early promise.

Two vaccine candidates built from gene-therapy technology and developed by Mass General Brigham scientists elicited strong immune responses in mouse and nonhuman primate models, the researchersreported on the journal preprint site bioRxiv. The team received a grant of up to $2.1 million from the Bill & Melinda Gates Foundation to further develop the vaccine technology, called AAVCOVID.

The vaccines, which remain stable when stored at room temperature, use an adeno-associated virus (AAV) vector to deliver genetic sequences of SARS-CoV-2, the virus that causes COVID-19. That generates antigens of the viruss signature spike protein, in turn prompting an immune response.

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This series will identify obstacles that stifle appropriate patient diversity in trials; unpack the organizational overhaul needed; share how sponsors, patients & investigators have come together to overcome hurdles; and explore how policy innovations can move the industry forward.

A single injection of either of the AAVCOVID vaccine candidates induced neutralizing antibodies in one mouse model of obesity and another of agingtwo conditions that have been linked with poor COVID-19 outcomes. The response lasted for at least three months, according to the study. In the monkey models, the immune response lasted for five months.

All animals also showed memory T-cell responses, which are believed to be critical for maintaining long-term immunity to COVID-19.

RELATED: Biopharma tackles COVID-19, HIV and other viruses with gene and cell therapies

Although the demand for the mRNA vaccines from Pfizer and Moderna is strong, the shots present some hurdles. The need for cold storage will make distributing the vaccines in developing countries difficult. And both vaccines require two doses to confer full immunity, which only adds to the logistical challengesand the costthe Mass Gen researchers argued in their study.

Because AAVs are already widely used to deliver gene therapies like Novartis Zolgensma for spinal muscular atrophy, the Mass Gen team was able to ramp up its preclinical studies quickly. To accelerate the effort, the researchers formed early partnerships with gene therapy specialists at the University of Pennsylvania and with Novartis, which agreed to manufacture the AAVCOVID vaccines for clinical trials.

The fact that theres an established industry out there around AAV made it easy for us to step into the existing [manufacturing] capacity, rather than having to build it, said lead investigator Luk Vandenberghe, Ph.D., an associate professor at Harvard Medical School and director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, in an interview with Fierce Biotech last year.

Vandenberghes team is now planning to start clinical trials of the vaccines overseas.

The researchers acknowledged in the study that several other vaccine candidates are nearing approval. But they believe the AAVCOVID shots will prove valuable because of other attributes that will likely be critical to achieving the desired long-lasting herd immunity at a global population scale, they wrote. Many of these considerations are logistical in nature and seek to reduce the cost, time, and complexity of vaccine distribution using available infrastructure around the world.

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One-dose COVID-19 vaccine candidate that can be stored at room temperature prompts immunity in animals - FierceBiotech

London, Feb. 02, 2021 (GLOBE NEWSWIRE) -- Roots Analysis has announced the addition of Gene Therapy Market (4th Edition), 2020-2030 report to its list of offerings.

Success of approved gene therapies has resulted in a surge in interest of biopharmaceutical developers in this rapidly evolving domain. Presently, the ability of gene therapies to treat diverse disease indications is considered among the most prominent drivers of this market. In addition, promising clinical results of pipeline candidates are anticipated to draw in more investments to support product development initiatives.

To order this 720+ page report, which features 220+ figures and 375+ tables, please visit this link

Key Market Insights

Around 800 gene therapies are currently being developed across different stages Apart from 10 approved products, most of the aforementioned therapies (65%) are in the early stages of development (discovery / preclinical), while the rest are being evaluated in clinical trials. It is worth mentioning that more than 40% of clinical stage candidates are intended for the treatment of oncological disorders.

Over 65% of innovator companies focused on gene therapy development, are based in North AmericaInterestingly, more than 75 players based in the same region, are start-ups, while over 35 are mid-sized players, and 10 are large and very large firms. Since the majority of gene therapy developers are headquartered in the US, it is considered a key R&D hub for such advanced therapy medicinal products.

There are 400+ registered gene therapy focused clinical trials, worldwideClinical research activity, in terms of number of trials registered, is reported to have increased at a CAGR of 12% during the period 2015-2020. Of the total number of trials, close to 25% have already been completed, and 35% claim to be actively recruiting.

USD 25.4 billion has been invested by both private and public investors, since 2015So far, a significant proportion of the capital raised has been through secondary offerings (USD 12.9 billion). On the other hand, around USD 5 billion was invested by venture capital investors, representing 20% of the total amount.

Close to 20,000 patents have been filed / published related to gene therapies, since 2016Around 30% of the total number of applications were related to gene editing-based therapies, while the remaining were associated with gene therapies. Further, majority of the patent assignees were industry players, however, the contribution of non-industry players in the overall patent filing activity has increased considerably (CAGR of 16%), over the past few years.

There have been several mergers and acquisitions in this market during the period 2015-2019 In fact, M&A activity is reported to have increased at a CAGR of more than 40%. Key drivers of the acquisitions mentioned in the report include, therapeutic area expansion, access to a novel technology / platform, drug class consolidation and drug class expansion.

North America and Europe are anticipated to capture over 90% of the market share, in terms of sales revenues, in 2030In vivo gene therapies currently represent a significant share of the market, and this trend is unlikely to change in the foreseen future, as several such candidates are being evaluated in late stages. In addition, more than 130,000+ patients are projected to use gene therapies in 2030 and the demand for gene therapies is expected to grow at an annualized rate of 29% and 31% during the periods 2020-2025 and 2025-2030, respectively.

To request a sample copy / brochure of this report, please visit this link

Key Questions Answered

The USD 14.6 billion (by 2030) financial opportunity within the gene therapy market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom, gene therapies exhibit the potential to become a promising alternative for the treatment of genetic disorders. The report includes detailed transcripts of discussions held with the following experts:

The research includes brief profiles of key players (listed below) engaged in the development of gene therapies; each profile features an overview of the therapy, current development status, clinical trials and its results (if available), target indication, route of administration, and recent developments (if available).

For additional details, please visit https://www.rootsanalysis.com/reports/view_document/gene-therapies-market/268.html or email sales@rootsanalysis.com

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The gene therapy market is projected to be worth USD 14.6 billion in 2030, growing at a CAGR of 30%, over the next decade, claims Roots Analysis -...