Press Releases from Pharmaceutical Companies and other Patient Organizations 

NOVATO, Calif., Dec. 19, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), today announced that the first patient has been dosed in the pivotal Phase 3 Aspire study (NCT06617429) evaluating the efficacy and safety of GTX-102, its investigational antisense oligonucleotide (ASO) for Angelman syndrome.

"Initiation of patient dosing in our Phase 3 Aspire study represents an important step forward in the development of an effective, and much needed, treatment for patients and families affected by Angelman syndrome,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. "Our goal with Aspire is to confirm the safety and clinical efficacy of GTX-102 in a large, randomized trial with a population that represents the majority of patients with Angelman syndrome. Additionally, the Aurora study will further assess safety and validate efficacy in patients with different genotypes and in younger and older patients."

The global Phase 3 Aspire study will enroll approximately 120 children ages 4 to 17 with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. Participants will be randomized 1:1 to receive GTX-102 by intrathecal injection via lumbar puncture or to the sham comparator group during the 48-week primary efficacy analysis period. Participants in the active treatment group will receive three, monthly 8 mg loading doses of GTX-102 followed by dosing in a maintenance period that will increase to a maximum dose of 14 mg of GTX-102 quarterly. Patients in the sham comparator group will be eligible to crossover onto treatment after Week 48 is complete. The primary endpoint will be improvement in cognition assessed by Bayley-4 cognitive raw score, and the key secondary endpoint will be the Multi-domain Responder Index (MDRI) across the five domains of cognition, receptive communication, behavior, gross motor function, and sleep.

“Angelman syndrome affects cognitive and motor function, making walking, communicating, and performing many everyday tasks more difficult for individuals living with Angelman syndrome. As a united community, ASF and FAST work together to further awareness and treatment of Angelman syndrome and are excited by all the recent progress in research and drug development. The initiation of the Phase 3 Aspire study by Ultragenyx is a significant achievement and something the community should celebrate,” stated Amanda Moore, chief executive officer at the Angelman Syndrome Foundation (ASF) and Ryan Fischer, chief operating officer at Foundation for Angelman Syndrome Therapeutics (FAST), in a joint statement.

At the 2024 Foundation for Angelman Syndrome Therapeutics (FAST) Global Science Summit in November, the company presented data from the Phase 1/2 study that confirmed the Phase 3 Aspire study dosing strategy and that the study is amply powered to establish the efficacy of GTX-102 on the primary endpoint of change in cognition, as measured by Bayley-4, or the key secondary endpoint of MDRI at the Week 48 timepoint.

U.S. residents can learn more by visiting www.ultraclinicaltrials.com.

Fiocruz and GEMMA Biotherapeutics (GEMMABio) announced last Tuesday (10/8) an agreement to sponsor research focused on gene therapy treatments for the Brazilian population within the scope of the Unified Health System (SUS). The ultimate goal of the international partnership with the company founded by gene therapy expert Jim Wilson is to obtain approval for gene therapy programs that will enable the country to increase the distribution of treatments for rare diseases at a more affordable cost.
With the support of the Ministry of Health (MS), the Foundation will invest up to US$100 million in GEMMABio over four years. The funds will be used to develop clinical research and production to expand the distribution of treatments for rare diseases in Brazil at a more affordable cost for the SUS.

"This partnership with GEMMABio reaffirms Fiocruz's commitment to innovation in health and its mission to ensure that scientific advances reach all Brazilians," said the Foundation's president, Mario Moreira. "By expanding access to gene therapies through the SUS, we are not only democratizing cutting-edge technologies, but also strengthening our ability to treat rare diseases in an affordable and effective manner. It is an important step to establish Brazil as a global reference in public health and innovation," he added.

"By combining our resources and expertise, this collaboration represents a major breakthrough in making gene therapies accessible to more patients faster and at a fraction of the usual cost," said Jim Wilson, president and CEO of GEMMABio. "We are optimistic that this agreement will serve as a global example for expanding access to advanced medical therapies, as well as for seeking non-traditional ways to capitalize biotechnology companies."

The partnership, which will be implemented through the Immunobiological Technology Institute (Bio-Manguinhos/Fiocruz), involves the transfer of technology used in GEMMABio's manufacturing processes to be replicated in Brazil. The agreement also provides for clinical development activities in Brazil for six main programs. Three of these programs focus on developing gene therapy treatments for GM1 gangliosidosis, Krabbe disease and metachromatic leukodystrophy.

GM1 gangliosidosis is an inherited disorder that progressively destroys nerve cells in the brain and spinal cord. Krabbe disease is a rare and usually fatal disorder of the nervous system. Metachromatic leukodystrophy is a rare inherited disease that causes fatty substances to accumulate in cells, particularly in the brain, spinal cord and peripheral nerves.

The disease targets for the other three programs have not yet been disclosed. In exchange for the financial support, Fiocruz will be able to license the related treatments to supply the SUS. "Brazil has the largest public health system in the world, offering health services and products to over 200 million people. We are very proud to bring this innovation to the Brazilian system. A technology that was previously restricted to those with higher incomes will now be accessible to the entire Brazilian population free of charge," said Marco Krieger, vice president of Production and Innovation in Health at Fiocruz.

GEMMABio

GEMMABio is a therapeutics company focused on speeding the research of and global access to life-changing advanced therapies for those living with rare diseases. The company will provide research and product development functions to bring gene therapy discoveries from the bench to the bedside faster and affordably. GEMMABio is led by gene therapy industry pioneer Jim Wilson and his team of experts, who previously conducted their work in academia. 

PHILADELPHIA, Oct. 8, 2024 /PRNewswire/ -- Today, GEMMA Biotherapeutics ("GEMMABio") – a new therapeutics company founded by gene therapy pioneer Dr. Jim Wilson – announced a major agreement with the Oswaldo Cruz Foundation ("Fiocruz"), a public health research institution that is part of the Ministry of Health of Brazil and has extensive experience in biomanufacturing.

GEMMABio partnered with Fiocruz – which is the main supplier of immunobiologics, biopharmaceuticals and diagnostics to the Brazilian Ministry of Health – to sponsor research that will bring gene therapy treatments to the people of Brazil under the Sistema Único de Saúde (SUS), Brazil's publicly funded health care system. Fiocruz will fund up to $100 million, which will be used to conduct clinical research and manufacturing – ultimately securing approval for programs that will allow the country to increase distribution of rare disease treatments and at a more affordable cost.

"By combining our resources and knowledge, this collaboration represents a major advancement in making gene therapies accessible to more patients quickly and at a fraction of the typical cost," said Dr. Wilson, who will serve as President and CEO of GEMMABio. "We are optimistic that this deal will serve as a global example for expanding access to advanced medical therapies as well as pursuing non-traditional ways to capitalize biotech companies."

A key component of the partnership will involve tech transfer, replicating GEMMABio's manufacturing technologies and process so that the companies can collaborate on programs and production in Brazil and for Fiocruz to utilize with other sponsors and programs. The agreement will also fund clinical development activities in Brazil for six core programs, including GM1 gangliosidosis (GM1), Krabbe Disease, Metachromatic leukodystrophy (MLD), and three unnamed programs. In return for their financial support, Fiocruz will be able to license related treatments to supply the Brazilian public health system.

"Brazil has the largest public health system in the world, offering health services and products to more than 200 million people. We are very proud to bring this innovation to the Brazilian system, a technology that was previously restricted to those with higher incomes, will now be accessible to the entire Brazilian population" said Marco Krieger, Vice President of Production and Innovation in Health, Fiocruz.

About GEMMABio
GEMMABio is a therapeutics company focused on speeding the research of and global access to life-changing advanced therapies for those living with rare diseases. The company will provide research and product development functions to bring gene therapy discoveries from the bench to the bedside faster and affordably.

GEMMABio is led by gene therapy industry pioneer Jim Wilson and his team of experts, who previously conducted their work in academia. Wilson is also the Chairperson of Franklin Biolabs, a Contract Research Organization. The collective goal of the two affiliated companies is to translate innovative scientific work into clinical trials, to then commercialize and distribute the new therapies around the world to patients who need them most. For more information, please visit gemmabiotx.com.

About Fiocruz
The Oswaldo Cruz Foundation (Fiocruz) is the largest biomedical research institution in Latin America, which also produces vaccines, medicines and in vitro diagnostics (IVD) to supply the Unified Health System (SUS, acronym in Portuguese for the Brazilian public health system). Linked to the Brazilian Ministry of Health, the Foundation was created on May 25, 1900 to initially manufacture serums and vaccines against bubonic plague. Since then, the institution has experienced an intense trajectory, which is intertwined with the development of public health in Brazil. Currently, Fiocruz is installed in 10 states, in addition to the Federal District, and has an office in Maputo, capital of Mozambique, Africa. In addition to the institutes based in Rio de Janeiro, the Foundation maintains units in the Northeast, North, Southeast and South regions of Brazil, and offices in Ceará, Mato Grosso do Sul, Piauí and Rondônia. In total, there are 16 technical-scientific units, focused on teaching, research, innovation, assistance, technological development and extension in the field of health. For more information, visit https://portal.fiocruz.br/en.

https://cureangelman.org/articles/upenn-announcement-biotech-dr-wilson

“This is a great decision by Dr. Wilson and that of The University of Pennsylvania to get the development of these gene therapies out of academia and into a well-resourced biotech environment that can execute more efficiently. This is exciting news for rare disease and for other companies that can now leverage the expertise of the 2nd company, Franklin, to help rapidly advance their bioanalytical and other contracted work. I’m thrilled!” – Dr. Allyson Berent, FAST Chief Science Officer

Read the full press release here.

The incredible academic work from The University of Pennsylvania is moving to biotech, where patients can be directly impacted. No one better to lead this effort than Dr. Jim Wilson.

The investigational gene therapy program for Angelman syndrome, known as GTP-220, is still owned by FAST and being run in collaboration with Dr. Wilson’s scientific team exactly as before. The change from an academic environment to a corporate entity will not impact the program deliverables or timelines. The money invested in the AS program is 100% being spent only on the GTP-220 program per the objectives of the sponsored research agreement, like every program we fund. Everyone is held to milestones and deliverables. FAST is continuing to closely control that program through IND and this news has no negative impact on the gene therapy program for Angelman syndrome. We expect this development will only improve efficiencies. This is good for all programs that were at UPenn, including AS.

More updates about investigational GTP-220 at the FAST Science Summit – registration is now open.

https://www.fiercebiotech.com/biotech/gene-therapy-pioneer-james-wilson-leaving-penn-launch-two-new-biotechs

After more than 30 years, gene therapy trailblazer James Wilson M.D., Ph.D., is leaving the University of Pennsylvania. He will be spearheading two new companies meant to translate the scientific discoveries made in the school’s Gene Therapy Program, where he served as director, into new treatments.

"Forming these two new entities is the next step to accelerate the future of gene therapy and deliver therapeutics to patients significantly faster," Wilson said in a July 31 release.

Wilson will be CEO of GEMMA Biotherapeutics and Franklin Biolabs, which will work in tandem to develop new gene therapies. GEMMABio will be the research and development side of things, while Franklin Biolabs, a genetic medicines contract research organization, will take on services and production duties.

Wilson is best known for the discovery and development of adeno-associated viruses as vectors for gene therapy. These viruses infect primates but don’t cause disease in humans and so can be engineered to deliver genetic material into our cells. These viruses were first noticed in 1965 just down the road from Penn, at Robert Atchison’s lab in Pittsburgh, before Guangping Gao, Ph.D., began isolating and describing them in Wilson’s group in the early 2000s. 

Penn’s Gene Therapy Program will be transitioning to the new companies, according to the release, with the majority of current employees being offered jobs at either GEMMABio or Franklin Biolabs. The companies will remain in the Philadelphia area and will focus on developing therapies for rare diseases.

According to the release, funding for both companies is imminent. GEMMABio’s cash will come from a group of multiple investors and investment groups, while Franklin Biolabs will be supported by one investor.

Wilson has long had a foot in the biotech world, with several companies spinning out of his lab including iECURE. He also serves as chief science advisor to Passage Bio. 

Register virtually to listen in: 

November 6, 2024 

Dear Angelman syndrome Community, 

We are writing to provide an update on Ionis’ Angelman syndrome (AS) program. On November 6, 2024, we announced successful alignment with the U.S. Food and Drug Administration (FDA) on our phase 3 study design for the evaluation of ION582 in AS. The announcement can be found here. Ionis will provide an update on the ION582 program at the FAST Global Science Summit on November 9th.

The planned phase 3 clinical trial, called REVEAL, will be a global, randomized, placebo-controlled study to establish the efficacy and safety of ION582 in AS. REVEAL will enroll approximately 200 children and adults with AS with a maternal UBE3A gene deletion or mutation. Participants will be randomized 2:1 to ION582 or placebo. The placebo-controlled analysis period will be approximately one year long. Participants will then be eligible to transition to an open-label long-term extension (LTE) phase, where everyone will receive ION582.

Over the coming weeks we plan to discuss and get alignment with additional regulatory agencies, clinicians, and the AS community as we work to initiate the REVEAL study in the first half of 2025.

We are grateful to the Angelman syndrome community, whose collaboration, support, and guidance has been critical to the development of ION582. We look forward to working with the community to advance ION582 to the next stage of development.

Sincerely, 

The Ionis Angelman Syndrome Team

For additional questions, please contact: padvocacy@ionis.com

Key Questions and Answers

1. What are next steps for the ION582 development program? Ionis is currently working to initiate REVEAL, a pivotal phase 3 clinical trial to evaluate ION582 in individuals with Angelman syndrome. The REVEAL trial is intended to establish the efficacy and safety of ION582 in Angelman syndrome and build on the evidence generated, including from the phase 1/2a HALOS trial. 

2. What is ION582? ION582 is an investigational antisense oligonucleotide (ASO) medicine designed to increase the production of the UBE3A protein in the brain. 

3. What is the current status of the phase 1/2a HALOS trial? HALOS is an open-label, three-part phase 1/2a clinical trial to evaluate safety and tolerability of ION582 in people with Angelman syndrome. Part 1 of the trial, a three-month, multipleascending dose study, is complete and all eligible participants transitioned into the Part 2 longterm extension (LTE) portion of the study, which is ongoing. The Part 2 LTE will evaluate ION582 for an additional 12 months. Once eligible participants have completed both Part 1 and Part 2, they can then transition to the Part 3 LTE portion to continue receiving ION582 for an additional three years. 

4. When will there be additional information provided about the REVEAL trial? We will update the community when appropriate as details become available. We recognize the urgent need for medical advancements in Angelman syndrome and are working to advance ION582 to the next stage of development.

Register virtually to listen in: 

• Positive End of Phase 2 discussion with FDA, including alignment on Phase 3 design

• Bayley-4 expressive communication selected as Phase 3 study primary endpoint

• Initiation of ION582 Phase 3 study planned for H1 2025

• Ionis to share ION582 program update at the FAST Global Science Summit in November

CARLSBAD, Calif., Nov. 6, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced the pivotal Phase 3 study design following successful alignment with the U.S. Food and Drug Administration (FDA) on ION582, an investigational medicine for the treatment of people living with Angelman syndrome (AS). AS typically presents in infancy and is characterized by profound intellectual disability, impaired verbal abilities and severe motor impairment.

"Following positive results for ION582 in the Phase 2 HALOS trial, we are pleased to have alignment with the FDA on the design of our Phase 3 REVEAL trial, which will address clinical endpoints that reflect the most pressing and meaningful outcomes for people living with AS and their caregivers," said Brett Monia, Ph.D., chief executive officer of Ionis. "We will enroll a broad group of individuals living with AS in the global pivotal Phase 3 trial, planned to begin in the first half of 2025. We look forward to working with the community to advance a potential new treatment targeting the underlying cause of disease in this debilitating neurological condition that has no approved medicines."

The planned global, randomized, placebo-controlled Phase 3 study will enroll approximately 200 children and adults with AS that have a maternal UBE3A gene deletion or mutation. The primary analysis will occur after approximately one year of treatment, followed by all patients transitioning into an open-label long-term extension (LTE) phase of the study. Patients will be randomized 2:1 to active therapy or placebo, and ION582 will be evaluated at two dose levels which will be dosed quarterly without a loading regimen. The primary endpoint will be improvement in expressive communication as assessed by the Bayley Scales for Infant and Toddler Development-4 (Bayley-4), an objective and direct clinician-administered assessment of clinical functioning. Deficits in expressive communication are reported to be the symptoms most challenging to caregivers of people with AS. The study will evaluate several secondary endpoints including overall disease severity, cognition, communication, sleep, motor functioning and daily living skills, in addition to other exploratory endpoints.

The End of Phase 2 meeting was supported by data from the Phase 2 open-label HALOS study. In the recently completed multiple ascending dose (MAD) portion of the study, ION582 treatment provided strong evidence of clinically meaningful improvement on all functional domains including communication, cognition and motor function. Overall, 97% of people in the medium and high dose groups assessed in the study saw an improvement in overall AS symptoms as measured by the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinicians' impressions. ION582 showed favorable safety and tolerability at all dose levels in the study.

At the FAST Global Science Summit this weekend (November 8-9), Ionis will provide an update to the community on the Phase 3 program and review data from the MAD portion of the HALOS trial.

About ION582

ION582 is an investigational antisense medicine designed to inhibit the expression of the UBE3A antisense transcript (UBE3A-ATS) and increase production of UBE3A protein, for the potential treatment of Angelman syndrome (AS). In 2022, the U.S. Food and Drug Administration (FDA) granted ION582 Orphan Drug designation and Rare Pediatric designation.

About Angelman Syndrome (AS)

AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by profound intellectual disability, balance issues, motor impairment and debilitating seizures. Most patients are unable to speak. Individuals with AS have a normal lifespan but require complete care from a caregiver. Some symptoms can be managed with existing medicines; however, there are no approved disease modifying therapies.

About Ionis' Neurology Franchise

Ionis has been at the forefront of discovering and developing leading neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUA™ (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS. The clinical-stage portfolio includes 11 therapies, of which five are wholly owned by Ionis. Ionis' investigational portfolio includes medicines for which there are few or no disease modifying treatments, such as rare diseases including Prion disease and Alexander disease and more common conditions such as Alzheimer's and Parkinson's disease.

About Ionis Pharmaceuticals, Inc.

For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients.

To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram.

Ionis Forward-looking Statements

This press release includes forward-looking statements regarding Ionis' business, and the therapeutic and commercial potential of Ionis' commercial medicines, ION582 and Ionis' additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions, or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at www.Ionis.com.

In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries.

Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc.

ION582 is an investigational medicine that has not been approved for the treatment of any disease by regulatory authorities.

Ionis Pharmaceuticals Investor Contact: D. Wade Walke, Ph D. - IR@ionis.com - 760-603-2331

Ionis Pharmaceuticals Media Contact: Hayley Soffer - Media@ionis.com - 760-603-4679

https://www.neurenpharma.com/pdf/55d1f2f3-c118-47ea-bb9b-60aa59415a18/Phase-2-trial-shows-significant-improvements-in-Angelman.pdf 

Investors' webinar: https://www.youtube.com/watch?v=hO6z4VoEs8k 

ION582 demonstrated consistent improvements across multiple functional domains in Angelman syndrome patients

ION582 was safe and well tolerated at all dose levels

Ionis plans to move ION582 into pivotal trial

Detailed ION582 data to be presented at upcoming medical meeting

CARLSBAD, Calif., May 16, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced positive topline data from the HALOS Phase 1/2a open-label study of ION582 in Angelman syndrome. ION582 was safe and well tolerated in the study and showed encouraging and consistent benefits in individuals living with Angelman syndrome, with the most robust improvements observed in key areas of functioning including cognition, communication and motor function.

Ionis also announced that it will independently advance ION582 as part of Ionis' leading portfolio of potentially transformational medicines for serious neurological diseases. Ionis plans to review the ION582 Phase 1/2a results with regulatory authorities to align on the design of the pivotal program. Biogen has elected not to exercise its option to license ION582.

"There are currently no approved treatments for Angelman syndrome, which causes developmental delays, cognitive impairment and severe communications challenges, with most individuals unable to speak or live independently," said Lynne Bird, M.D., professor of clinical pediatrics at UC San Diego and HALOS study investigator. "We are encouraged by the positive and consistent improvements seen in the HALOS study across multiple measures, as these functional improvements could have a transformative impact in the lives of people living with Angelman syndrome and their caregivers. We are also encouraged by the favorable safety and tolerability profile observed in the study, which is particularly important when treating children. We very much look forward to further evaluation of ION582 in a pivotal program."

Angelman syndrome is caused by a loss of function in the maternal UBE3A gene. ION582 is designed to unsilence the paternal UBE3A allele in order to increase production of the UBE3A protein in the brain. Angelman syndrome affects an estimated one in 12,000 to 20,000 people globally.1 It presents as profound and severe developmental delays in motor, language and cognitive functioning, seizures and ataxia. It is a serious neurodevelopmental disorder that presents in early childhood, resulting in complete dependence on a caregiver.

"We are encouraged by the data from the HALOS study and pleased to add this promising medicine to our growing independent pipeline of neurology medicines," said Brett Monia, Ph.D., chief executive officer of Ionis. "We look forward to sharing detailed data at the upcoming Angelman Syndrome Foundation meeting and to advancing ION582 into a pivotal study. Individuals with Angelman syndrome face significant neuro-developmental challenges and have no approved therapies today. We are committed to working closely with the community, investigators and regulators to advance this promising investigational medicine."

Part 1 of the HALOS trial was a three-month, multiple-ascending dose (MAD) study in 51 patients aged 2-50, which evaluated three doses of ION582. All eligible patients transitioned into the Part 2 long-term extension (LTE) portion of the study, which is evaluating the two higher doses of ION582 for an additional 12 months. Part 3 of the study will evaluate eligible patients for an additional three years. Topline results were available for all patients at four months (one month after last MAD dose), and six months, and were consistent with preliminary findings reported at the Foundation for Angelman Syndrome Therapeutics (FAST) meeting in November 2023. Topline data included:

Safety assessment was the primary objective of the trial and ION582 was safe and well tolerated at all dose levels. Adverse events in the trial were consistent with patient medical histories, Angelman syndrome diagnosis or related to intrathecal administration.

ION582 showed consistent effects across multiple objective and subjective measures used to assess functioning in individuals living with Angelman syndrome. These include the Bayley-4, an objective physician assessment of clinical functioning, Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinicians' impressions, and the Vineland-3 and Observer-Reported Communication Ability (ORCA) measures, which are parent-reported assessment tools. These positive results correlated with positive changes in EEG activity including a reduction in slow wave delta activity.

At six months, approximately 65% of patients achieved an improvement in cognition on the Bayley-4. While no direct comparisons should be made, these improvements exceeded improvements seen in natural history studies over the same time period.

At six months, approximately 70% of patients showed improvement on Bayley-4 measures of receptive and/or expressive communication. While no direct comparisons should be made, these changes exceeded improvements seen in natural history studies over the same time period.

At six months, approximately 65% of patients showed improvements in Bayley-4 measures of fine and gross motor skills. While no direct comparisons should be made, these changes exceeded improvements seen in natural history studies over the same time period.

Ionis expects to report detailed results from the HALOS study at the Angelman Syndrome Foundation meeting in July. ION582 has received Orphan Drug designation in the U.S. The HALOS Phase 1/2a open-label trial is evaluating safety, tolerability, pharmacokinetics and pharmacodynamics in addition to certain clinical outcomes measures. ION582 is administered intrathecally into the cerebral spinal fluid with a lumbar puncture. For more information on the HALOS Study (NCT05127226), visit clinicaltrials.gov.

About Ionis' Neurology Franchise

Ionis' neurology franchise addresses all major brain regions and central nervous system cell types and currently has three Phase 3 studies ongoing with 11 therapies in clinical development, several of which Ionis plans to commercialize directly. Ionis is discovering and developing potential treatments for many neurological diseases for which there are few or no disease modifying treatments, including common diseases like Alzheimer's and Parkinson's as well as rare diseases such as amyotrophic lateral sclerosis (ALS) and Alexander disease. Ionis has discovered and developed three commercially available neurological disease medicines, including SPINRAZA® (nusinersen), the first approved treatment for spinal muscular atrophy, WAINUATM (eplontersen), a medicine to treat hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), and QALSODY® (tofersen) for SOD1-ALS.

About Ionis Pharmaceuticals, Inc.

For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients.

To learn more about Ionis, visit Ionispharma.com and follow us on X (Twitter) and LinkedIn.

Ionis Forward-looking Statements

This press release includes forward-looking statements regarding Ionis' business, financial guidance and the therapeutic and commercial potential of our commercial medicines, ION582, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2023, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available from the Company.

In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries.

Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. QALSODY® is a registered trademark of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies.

Ionis Pharmaceuticals Investor Contact: D. Wade Walke, Ph.D. - info@ionisph.com - 760-603-2331

Ionis Pharmaceuticals Media Contact: Hayley Soffer - CorporateCommunications@ionisph.com - 760-603-4679

1 Mertz LG, Christensen R, Vogel I, Hertz JM, Nielsen KB, Gronskov K, Ostergaard JR. Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A. 2013;161A:2197–203.

Cision View original content to download multimedia:https://www.prnewswire.com/news-releases/ionis-announces-positive-topline-results-from-phase-12a-trial-of-ion582-for-angelman-syndrome-302147385.html

SOURCE Ionis Pharmaceuticals, Inc. 

Listen to the host investors call here:

https://event.webcasts.com/starthere.jsp?ei=1666809&tp_key=36c30d5344

Download the slides from the presentation here:

https://ir.ultragenyx.com/events-presentations

https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-interim-phase-12-data-patients 

Expansion Cohorts showed rapid, clinically meaningful improvement across multiple domains; improvements consistent or exceeding Dose-escalation Cohorts data at Day 170

Additional long-term data in Dose-escalation Cohorts showed increasing and sustained clinical benefitthrough Day 758

Company will host investor call at 8:00 a.m. ET

NOVATO, Calif., April 15, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced new data from the Phase 1/2 study of GTX-102 for the treatment of Angelman syndrome. Patients in Expansion Cohorts A & B treated with a set dose and regimen of GTX-102 showed rapid and clinically meaningful improvement across multiple domains consistent with or exceeding Dose-escalation Cohorts 4-7 data at Day 170. Treatment of the Dose-escalation Cohorts 4-7 showed long-term increasing and sustained clinical benefit far exceeding Natural History data at Day 758. These data will be discussed in more detail in a corporate presentation being hosted by the company today at 8:00 a.m. ET and will also be presented by Kemi Olugemo, M.D., FAAN at the 76th Annual American Academy of Neurology Meeting (AAN) in Denver on Tuesday, April 16. 

“There is currently no approved disease modifying treatment for Angelman syndrome, which results in profound impairment in individuals living with this disease,” said Erick Sell, M.D., director of the Angelman clinic at the Children’s Hospital of Eastern Ontario, and a principal investigator on the Phase 1/2 study. “The multidomain improvement in the Bayley-4 and ASA measures are significant and in line with the clinically meaningful change observed by patient families. These kids have continued to make functional gains over time, which may ultimately lead to more independence.”

New Expansion Cohorts A & B data include Day 170 results on 24 patients, and long-term Dose-escalation Cohorts 4–7 data include up to Day 758 results on 15 patients.

Expansion Cohorts at Day 170:

• Cognition assessed by Bayley-4 showed rapid and clinically significant improvement compared with Natural History data. Day 170 data were consistent with the treatment benefit observed in the Dose-escalation Cohorts at a similar timepoint. 

• Behavior assessed by the Angelman Severity Assessment (ASA) showed rapid improvement exceeding the treatment benefit observed in the Dose-escalation Cohorts at Day 170.

• Hyperactivity and noncompliance assessed by the Aberrant Behavior Checklist-Community (ABC-C) showed rapid and clinically significant improvement at Day 170 compared with Natural History data, providing further insight into one of the most commonly reported behavioral issues.

• Sleep assessed by ASA showed rapid and clinically meaningful improvement exceeding treatment benefit observed in the Dose-escalation Cohorts at Day 170. 

• Receptive communication assessed by Bayley-4 showed rapid improvement compared with Natural History data.  Day 170 data were consistent with the treatment benefit observed in the Dose-escalation Cohorts at a similar timepoint. Gross Motor function assessed by ASA showed rapid improvement exceeding the treatment benefit observed in the Dose-escalation Cohorts at Day 170.

• Gross motor assessments as measured by Bayley-4 were not performed at Day 170 in the Expansion Cohorts to reduce patient testing burden and are not included in this analysis at this timepoint.

• Multi-domain Responder Index (MDRI) analysis across the four domains of Cognition, Receptive Communication, Behavior and Sleep resulted in a total net response of +2.0 (p-value <0.0001). The majority of patients had already achieved a total net response of +2 to +4 domains, demonstrating improvement exceeding the minimally important difference (MID) threshold in several domains even at this early Day 170 timepoint.

Dose-escalation Cohorts up to Day 758:

• Cognition assessed by Bayley-4 showed continuing long-term improvement compared with Natural History data and exceeded the threshold of clinical significance by many-fold in many patients.

• Behavior assessed by ASA showed continuing clinically meaningful improvement.

• Sleep assessed by ASA showed sustained clinically meaningful improvement. Receptive communication measured by Bayley-4 showed sustained and clinically significant improvement compared with Natural History data.

• Gross motor function assessed by Bayley-4 showed continued and clinically significant improvement compared with previously reported Natural History data.

• MDRI analysis across the four domains of Cognition, Receptive Communication, Behavior and Sleep resulted in a total net response of +2.0 (p-value = 0.0007) at Day 338. The majority of patients had a total net response of +2 to +4, as well as a 2- to 5-fold improvement over the MID threshold in several domains.

“The totality of these interim data demonstrates that treatment with GTX-102 resulted in rapid, multi-domain improvements that continued during maintenance dosing. These broad developmental gains are having a meaningful impact on patients and their families. For example, we’re hearing about children who are now able to routinely communicate their needs to family members, which greatly improves their ability to interact with their caregivers. We have also heard from families about their children who are accumulating additional developmental gains such as running, swimming and independent eating,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “Our next step is an end of Phase 2 meeting with the FDA and interactions with other health authorities to enable timely initiation of a Phase 3 pivotal study.” 

There were no unexpected serious adverse events. Three patients had serious adverse events (mild to moderate) of lower extremity weakness assessed as related to study treatment; one in Cohort 7, two in Cohorts A & B; none reported in Cohorts C–E to date. All resolved rapidly without sequelae and remain in the study without ongoing safety concerns. The five original patients affected by lower extremity weakness from Cohorts 1–3 have been re-dosed safely multiple times and are receiving maintenance treatment without recurrence. The Cohort 7 patient has also been re-dosed safely multiple times and is receiving maintenance treatment without recurrence. The two patients in Cohorts A & B remain in study and are expected to continue dosing. The FDA and other regulatory agencies were notified of all safety events and raised no issues nor required additional actions. The foregoing safety information is current as of April 5, 2024.

Conference Call and Webcast Information

Ultragenyx will host a conference call at 8:00 a.m. ET today to discuss the new efficacy and safety data from the GTX-102 Phase 1/2 clinical study. The live and replayed webcast of the call will be available through the company’s website at https://ir.ultragenyx.com/events-presentations.

About GTX-102

GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS. Nonclinical studies have shown that GTX-102 reduces levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS. Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition. GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA, and Orphan Designation and PRIME designation from the EMA.

About the Phase 1/2 study

The Phase 1/2, open-label, multiple-dose, dose-escalating study is evaluating the safety and tolerability of GTX-102 administered by intrathecal (IT) injection to pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study is also assessing clinical response as measured by a panel of efficacy assessments for the functional domains impacted in Angelman syndrome. The study has enrolled and treated 74 patients in both dose-escalation and expansion cohorts. Patients in Cohorts 4-7 (dose-escalation) are receiving long-term maintenance dosing. Data from the expansion cohorts will be used to verify the GTX-102 dose and treatment regimen for the pivotal Phase 3 study.

About the Angelman Syndrome Natural History Study

The Angelman Syndrome Natural History Study (NCT00296764) is a multisite, prospective, observational study. The study data are combined with clinic and registry data and stored in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) database platform, which is managed by Boston Children’s Hospital and spans different Angelman syndrome cohorts. The Natural History study populations analyzed for comparative purposes to GTX-102 are a subset of the larger populations, and only include 4- to 17-year-old gene deletion patients. These data are illustrative only; differences exist between study designs, subject characteristics and geographical regions and caution should be exercised when comparing data across studies. Natural history data are not available for the ASA assessments.

About Angelman Syndrome

Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. The maternal-specific inheritance pattern of Angelman syndrome is due to genomic imprinting of UBE3A in neurons of the central nervous system (CNS), a naturally occurring phenomenon in which the maternal UBE3A allele is expressed and the paternal UBE3A is not. Silencing of the paternal UBE3A allele is regulated by the UBE3A antisense transcript (UBE3A-AS), the intended target of GTX-102. In almost all cases of Angelman syndrome, the maternal UBE3A allele is either missing or mutated, resulting in limited to no protein expression. This condition is generally not inherited but instead occurs spontaneously. It is estimated to affect ~60,000 people in commercially accessible geographies.

Individuals with Angelman syndrome have a lifelong neurodevelopmental disorder including cognitive impairment, motor impairment, balance issues, and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. Anxiety and disturbed sleep can be serious challenges in individuals with Angelman syndrome. Although individuals with Angelman syndrome have a normal lifespan, they require continuous care and are unable to live independently. Angelman syndrome is not a degenerative disorder, but the loss of the UBE3A protein expression in neurons results in abnormal communications between neurons. Angelman syndrome is often misdiagnosed as autism or cerebral palsy. There are no currently approved therapies for Angelman syndrome; however, several symptoms of this disorder can be reversed in adult animal models of Angelman syndrome suggesting that improvement of symptoms can potentially be achieved at any age.

About Ultragenyx Pharmaceutical Inc.

Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com.

Ultragenyx Forward-Looking Statements and Use of Digital Media

Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding the clinical benefit, tolerability and safety of GTX-102 and the corresponding impact on patients, the anticipated dosing of the Phase 2 study for GTX-102 and the timing for initiation of a Phase 3 study for GTX-102 and associated regulatory meetings are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, the ability of the Company to successfully develop GTX-102, the Company’s ability to achieve its projected development goals in its expected timeframes, the risk that results from earlier studies may not be predictive of future study results, risks related to adverse side effects, risks related to reliance on third-party partners to conduct certain activities on the Company’s behalf, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the Company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and product candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements.

For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 21, 2024, and its subsequent periodic reports filed with the SEC.

In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/).

Contacts
Ultragenyx Pharmaceutical Inc.
Investors
Joshua Higa
+1-415-475-6370
ir@ultragenyx.com

Media
Carolyn Wang
+1-415-225-5050
media@ultragenyx.com

https://www.prnewswire.com/news-releases/family-advocates-urge-congress-support-during-inaugural-angelman-syndrome-as-congressional-advocacy-day-302081451.html

WASHINGTON, March 7, 2024 /PRNewswire/ -- The Angelman Syndrome Foundation (ASF) and the Foundation for Angelman Syndrome Therapeutics (FAST) are hosting the inaugural Angelman Syndrome (AS) Congressional Advocacy Day in Washington, D.C.

Angelman syndrome advocates from all corners of the country will head to Capitol Hill to educate Members of Congress about the critical need to invest federal resources in AS specific priorities and programs at the Department of Defense (DoD), Food and Drug Administration (FDA), and the National Institutes of Health (NIH). This marks a significant day as these two prominent organizations come together to advance legislative and policy priorities for AS.

Angelman syndrome is a rare, neurological disorder that impacts approximately 1:15,000 individuals. Common characteristics of AS include a happy demeanor, frequent laughter and many smiles, but there are also significant challenges that most individuals living with AS face such as being non-verbal, prone to seizure activity, disrupted sleep, and difficulty with gross and fine motor activities.  Current research and future potential treatments have the chance to improve the quality of life for those living with AS.

Ryan Fischer, COO of FAST highlights the importance of this step for the AS community, stating, "This event marks a historic day for the community, as it is the first ever organized Hill day for Angelman syndrome. We must ensure those representing us in Washington D.C. understand the need for increased federal focus and funding for AS. This is just the start of our collective movement to drive policy and legislation forward to improve the lives of all those diagnosed with Angelman syndrome and their families."

As the community comes together in the nation's capital, advocates are highlighting the urgent need for federal funding of AS research programs. Included in this year's requests:

• Have Angelman syndrome included in the Department of Defense peer-reviewed medical research program;

• Push FDA to include more sensitive outcome measures, growth scale values, and expanded research on clinical endpoints and biomarkers;

• Have NIH convene stakeholders to prepare a roadmap for clinical outcome measures and biomarkers for Angelman syndrome;

• A non-policy priority of the event is relationship building with congressional offices and bringing awareness to the disease.

Amanda Moore, CEO of ASF, comments on the monumental nature of the event and partnership, "As the Angelman syndrome community gathers in Washington, D.C., we emphasize the critical importance of federal funding for research programs. By uniting our voices and advocating for inclusion in vital departments such as the Department of Defense and the National Institutes of Health, we strive to bring hope and progress to our community. Together, with determination and collaboration, we aim to create a future with more smiles and fewer struggles for individuals affected by Angelman syndrome."

About the hosting organizations

The Angelman Syndrome Foundation (ASF) and the Foundation for Angelman Syndrome Therapeutics (FAST) are two organizations united in their commitment to making a significant impact in the Angelman syndrome community.

ASF's mission is to advance awareness and treatment of Angelman syndrome through education, research, clinical care and unwavering support for individuals with AS, their families, and all concerned parties. They are dedicated to improving lives and fostering understanding. (angelman.org)

FAST, as the leading patient advocacy organization, has one goal: to cure Angelman
syndrome. The largest funder of Angelman syndrome research in the world, their mission is to
drive forward transformative research and development programs as quickly as possible for
those living with Angelman syndrome — regardless of age or genotype. (cureangelman.org) (cureangelman.org)

Together, ASF and FAST combine their strengths and expertise, creating a powerful force that drives progress, offers support, and seeks cures for Angelman syndrome. Our collaborative efforts epitomize our shared dedication to making a lasting difference in the lives of those we serve.

Contact: Meghan Edberg, meghan.edberg@cureangelman.org or 952-567-1190

SOURCE Foundation for Angelman Syndrome Therapeutics (FAST)

https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-prime-designation-european-medicines-agency 

NOVATO, Calif., Feb. 05, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced that the European Medicines Agency (EMA) has granted Priority Medicine (PRIME) designation to GTX-102 for the treatment of Angelman syndrome (AS). GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and is designed to target and inhibit expression of UBE3A antisense transcript (UBE3A-AS). The EMA granted this designation in response to compelling early clinical data from the extension cohorts in the Phase 1/2 study of GTX-102 demonstrating clinically meaningful improvements in several neurodevelopmental domains including cognition, receptive communication and gross motor skills in individuals with Angelman syndrome.

"By granting PRIME designation, the EMA is recognizing the potential for GTX-102 to address the critical need for new treatments for children and families impacted by Angelman syndrome in the EU,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “Our team is working with urgency on the development of GTX-102 for Angelman syndrome and looks forward to working closely with regulators in the U.S. and EU to bring this innovative treatment to patients.”

PRIME designation is granted by the EMA to provide early and proactive support to developers of promising medicines that may offer a major therapeutic advantage over existing treatments or benefit to patients without treatment options. These medicines are considered priority medicines by the EMA, whose aim is to optimize development plans and speed up evaluations so these medicines that address significant unmet medical needs can reach patients faster.

About the Phase 1/2 study

The Phase 1/2, open-label, multiple-dose, dose-escalating study is evaluating the safety and tolerability of GTX-102 administered by intrathecal (IT) injection to pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study is also assessing clinical response as measured by a panel of efficacy assessments for the functional domains impacted in Angelman syndrome. Patients in the earlier extension cohorts (Cohorts 4-7) of the study have moved into long-term maintenance dosing, and the study has completed enrollment for the new expansion cohorts to verify the GTX-102 dose range and treatment regimen that will be used in the Phase 3 program.

About Angelman Syndrome
Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. The maternal-specific inheritance pattern of Angelman syndrome is due to genomic imprinting of UBE3A in neurons of the central nervous system (CNS), a naturally occurring phenomenon in which the maternal UBE3A allele is expressed and the paternal UBE3A is not. Silencing of the paternal UBE3A allele is regulated by the UBE3A antisense transcript (UBE3A-AS), the intended target of GTX-102. In almost all cases of Angelman syndrome, the maternal UBE3A allele is either missing or mutated, resulting in limited to no protein expression. This condition is generally not inherited but instead occurs spontaneously. It is estimated to affect one in 12,000 to one in 20,000 people globally.

Individuals with Angelman syndrome have developmental delay, balance issues, motor impairment and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. Anxiety and disturbed sleep can be serious challenges in individuals with Angelman syndrome. Although individuals with Angelman syndrome have a normal lifespan, they require continuous care and are unable to live independently. Angelman syndrome is not a degenerative disorder, but the loss of the UBE3A protein expression in neurons results in abnormal communications between neurons. Angelman syndrome is often misdiagnosed as autism or cerebral palsy. There are no currently approved therapies for Angelman syndrome; however, several symptoms of this disorder can be reversed in adult animal models of Angelman syndrome suggesting that improvement of symptoms can potentially be achieved at any age.

About GTX-102
GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS. Nonclinical studies have shown that GTX-102 reduces levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS. Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition. GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA, and Orphan Designation and PRIME designation from the EMA.

About Ultragenyx Pharmaceutical Inc.
Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com.

https://www.globenewswire.com/news-release/2024/01/03/2803223/20739/en/Ultragenyx-Announces-Completion-of-Enrollment-in-Global-Phase-1-2-Trial-of-GTX-102-in-Pediatric-Patients-with-Angelman-Syndrome.html

NOVATO, Calif., Jan. 03, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel therapies for serious rare and ultrarare genetic diseases, today announced the completion of patient enrollment in its Phase 1/2 clinical trial of GTX-102 for the treatment of pediatric patients with Angelman syndrome (AS). The dose-expansion cohorts (Cohorts A-E) have enrolled 53 patients for a total of 74 patients enrolled globally in the Phase 1/2 trial. GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and is designed to target and inhibit expression of UBE3A antisense transcript (UBE3A-AS).

“With completion of enrollment in the Phase 1/2 trial, we remain on track to report results in the first half of 2024 from at least 20 expansion cohort patients on therapy for a minimum of 6 months. We are confident that the cumulative safety and efficacy data will allow for dose and endpoint selection to support our Phase 3 program,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “We appreciate the support of the Angelman community, including the patients, families and healthcare providers, as we urgently work together to develop a new treatment option that may be able to improve the quality of life of those impacted by this devastating disease.”

In October 2023, interim data from the extension cohorts (Cohorts 4-7) of the ongoing Phase 1/2 study were announced and showed improvements across multiple domains compared to natural history data, where available, and clinical changes were associated with quantitative changes in EEG. Long-term data showed patients who stopped and restarted treatment reacquired previously gained developmental skills when they were re-dosed with the current regimen. As of the data cut-off, there have been no additional treatment-related SAEs, including lower extremity weakness, since November 2022.

About the Phase 1/2 study

The Phase 1/2, open-label, multiple-dose, dose-escalating study is evaluating the safety and tolerability of GTX-102 administered by intrathecal (IT) injection to pediatric patients with Angelman syndrome with a genetically confirmed diagnosis of full maternal UBE3A gene deletion. The study is also assessing clinical response as measured by a panel of efficacy assessments for the functional domains impacted in Angelman syndrome. Patients in the earlier extension cohorts (Cohorts 4-7) of the study have moved into long-term maintenance dosing, and the study has completed enrollment for the new expansion cohorts to verify the GTX-102 dose range and treatment regimen that will be used in the Phase 3 program.

About Angelman Syndrome

Angelman syndrome is a rare, neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene. The maternal-specific inheritance pattern of Angelman syndrome is due to genomic imprinting of UBE3A in neurons of the central nervous system (CNS), a naturally occurring phenomenon in which the maternal UBE3A allele is expressed and the paternal UBE3A is not. Silencing of the paternal UBE3A allele is regulated by the UBE3A antisense transcript (UBE3A-AS), the intended target of GTX-102. In almost all cases of Angelman syndrome, the maternal UBE3A allele is either missing or mutated, resulting in limited to no protein expression. This condition is generally not inherited but instead occurs spontaneously. It is estimated to affect 1 in 12,000 to 1 in 20,000 people globally.

Individuals with Angelman syndrome have developmental delay, balance issues, motor impairment, and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. Anxiety and disturbed sleep can be serious challenges in individuals with Angelman syndrome. While individuals with Angelman syndrome have a normal lifespan, they require continuous care and are unable to live independently. Angelman syndrome is not a degenerative disorder, but the loss of the UBE3A protein expression in neurons results in abnormal communications between neurons. Angelman syndrome is often misdiagnosed as autism or cerebral palsy. There are no currently approved therapies for Angelman syndrome; however, several symptoms of this disorder can be reversed in adult animal models of Angelman syndrome suggesting that improvement of symptoms can potentially be achieved at any age.

About GTX-102

GTX-102 is an investigational antisense oligonucleotide delivered via intrathecal administration and designed to target and inhibit expression of UBE3A-AS. Nonclinical studies show that GTX-102 reduces the levels of UBE3A-AS and reactivates expression of the paternal UBE3A allele in neurons of the CNS. Reactivation of paternal UBE3A expression in animal models of Angelman syndrome has been associated with improvements in some of the neurological symptoms associated with the condition. GTX-102 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA.

https://www.prnewswire.com/news-releases/ionis-shares-positive-clinical-update-from-ongoing-trial-of-ion582-for-angelman-syndrome-301985239.html 

MIAMI, Nov. 11, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced the completion of enrollment and positive preliminary findings from Part 1 of the ongoing HALOS Phase 1/2a study of ION582 (BIIB121) in Angelman syndrome. ION582 was generally well tolerated in the study and showed encouraging electroencephalogram (EEG) activity trends and early signals of positive clinical improvement, which will need to be confirmed upon analysis of the full data set in mid-2024. The findings were presented today at the FAST (Foundation for Angelman Syndrome Therapeutics) Summit; the presentation is available here. Part 1 of the HALOS trial is a three-month, open-label, multiple-ascending dose study. Part 2 is a long-term extension study, which will evaluate ION582 for an additional 12 months.

Angelman syndrome is caused by a loss of function in the UBE3A gene. ION582 is designed to unsilence the paternal UBE3A allele in order to increase production of the UBE3A protein in the brain. Angelman syndrome affects an estimated one in 12,000 to 20,000 people globally1. It presents profound and severe developmental delays in motor, language and cognitive functioning, seizures and ataxia. It is a serious neuro-developmental disorder that presents in early childhood, resulting in complete dependence on a caregiver. There are no treatments specifically approved for Angelman syndrome.

"We are encouraged by the completion of enrollment in the HALOS trial in Angelman syndrome as well as the positive preliminary clinical findings," said Frank Bennett, Ph.D., executive vice president and chief scientific officer of Ionis. "We look forward to reviewing results from the study mid-year next year, which will help us define the next stage of development for ION582. This community has an urgent need for new treatment advances given the significant neuro-developmental delays and challenges faced by people with Angelman syndrome and their caregivers. We look forward to working with the community, investigators, regulators and our partners at Biogen on continued progress."

HALOS preliminary clinical findings shared at the meeting included:

• • HALOS is now fully enrolled with 51 patients at 11 global sites.

  • To date, ION582 has been generally well tolerated at all dose levels. Adverse events in the trial were consistent with patient medical histories, Angelman diagnosis or related to intrathecal administration.

  • In patients evaluable one month after the last Part 1 dose, exploratory clinical findings included:

  • A majority of patients showed an improvement in EEG activity. Angelman syndrome is characterized by an increase in slow Delta brain wave activity. Approximately 70% of patients showed a reduction in slow-wave EEG delta activity and over 80% showed an increase in faster frequency rhythms. While no direct comparisons should be made, this improvement in EEG activity exceeds that observed in natural history studies over the same time period.

  • A majority of patients showed improvement in overall functioning on the Angelman Syndrome Clinical Global Improvement Change (SAS-CGI-C) scale, which evaluates clinicians' impressions across 9 key functional areas.

  • A majority of patients showed improvement on the total Bayley score, which is a direct assessment of clinical functioning. While no direct comparisons should be made, these changes went beyond those seen in natural history studies over the same time period.

ION582 has received Orphan Drug Designation in the U.S. and is being developed by Ionis under a strategic collaboration with Biogen. The HALOS Phase 1/2a trial is evaluating safety, tolerability, pharmacokinetics and pharmacodynamics in addition to certain clinical outcomes measures. ION582 is administered intrathecally into the cerebral spinal fluid with a lumbar puncture. For more information on the HALOS Study (NCT05127226), visit clinicaltrials.gov.

About Ionis Pharmaceuticals, Inc.

For more than 30 years, Ionis has been a leader in RNA-targeted therapy, pioneering new markets and changing standards of care. Ionis currently has four marketed medicines and a promising late-stage pipeline highlighted by cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision to become the leader in genetic medicine, utilizing a multi-platform approach to discover, develop and deliver life-transforming therapies.

To learn more about Ionis visit www.ionispharma.com and follow us on Twitter @ionispharma.

Ionis' Forward-looking Statements
This press release includes forward-looking statements regarding Ionis' business and the therapeutic and commercial potential of ION582, Ionis' technologies, and other products in development. Any statement describing Ionis' goals, expectations, financial or other projections, intentions, or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2022, and most recent Form 10-Q, which are on file with the Securities and Exchange Commission. Copies of these and other documents are available at www.ionispharma.com.  

Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc.