CoA Therapeutics bricht Klinische Studie für PKAN ab

CoA Therapeutics bricht Klinische Studie für PKAN ab

Schweren Herzens teilen wir der Gemeinschaft mit, dass CoA Therapeutics beschlossen hat, die klinische Studie zu BBP-671, dem Wirkstoff, den das Unternehmen als potenzielle Behandlung für Pantothenat-Kinase-assoziierte Neurodegeneration (PKAN) entwickelt hatte, einzustellen. Diese Entscheidung wurde getroffen, nachdem Studien gezeigt hatten, dass es nicht möglich war, eine Dosis für die klinische Studie zu finden, die ein angemessenes Gleichgewicht zwischen Sicherheit (Toxizität) und potenziellem klinischem Nutzen bietet.

Im März teilten wir mit, dass CoA Therapeutics eine Verzögerung ihrer klinischen PKAN-Studie bekannt gab, da zusätzliche Laborstudien zu BBP-671 erforderlich waren, um wichtige Informationen zur Dosierung und Sicherheit zu ermitteln. Eine große Herausforderung, die während dieser zusätzlichen Studien festgestellt wurde, war die große Variabilität der BBP-671-Spiegel im Blut, die bei Menschen beobachtet wurde. Personen, die die gleiche Dosis BBP-671 einnahmen, wiesen sehr unterschiedliche Blutkonzentrationen des Arzneimittels auf. Diese Inkonsistenz stellte ein erhebliches Risiko bei der Bestimmung einer angemessenen und sicheren Dosis für PKAN-Patienten dar.

Toxikologische Studien an PKAN-Tiermodellen trugen dazu bei, eine spezifische Sicherheitsgrenze bzw. einen Zielblutspiegel für BBP-671 festzulegen, der aufgrund von Sicherheits- und FDA-Vorschriften nicht überschritten werden darf. Es hat sich gezeigt, dass der für die Wirksamkeit erforderliche Zielblutspiegel gefährlich nahe an der Sicherheitsgrenze liegt.

BBP-671 wurde ursprünglich durch die Forschung des St. Jude Children’s Research Hospital in Memphis, Tennessee, entdeckt. CoA Therapeutics wird nun das Eigentum an BBP-671 und verwandten Substanzen an St. Jude zurückgeben. Alle Forschungsdaten werden ebenfalls weitergegeben, um jegliche zukünftige Forschung zu unterstützen.

Wir sind unendlich dankbar für die langjährige Partnerschaft mit CoA Therapeutics. Ihr Engagement für die NBIA-Gemeinschaft wird nicht vergessen werden. Wir schätzen ihre Leidenschaft und ihren Wunsch, eine Behandlung für unsere PKAN-Familien zu finden, und das Maß an Empathie und Entschlossenheit, das sie Jahr für Jahr im Interesse unserer Familien an den Tag legten.

CoA Therapeutics hat eine detaillierte offizielle Mitteilung veröffentlicht, die Sie zusammen mit einer herzlichen Botschaft an die Gemeinschaft lesen können:

CoA-Therapeutics-PKAN-Patient-Community-Update.pdf

Übersetzung eines englischen Artikels von Amber Denton, Präsidentin der NBIA Disorders Association, aus dem Newsletter der NBIA Disorders Associacion
https://nbiadisorders.org/news-events/nbia-newsletters/

International NBIA Symposium held in Switzerland in October 2022

International NBIA Symposium held in Switzerland in October 2022

In 2020, the last NBIA scientists' meeting only took place online due to the pandemic. In October 2022, for the first time since 2017, numerous players in NBIA research finally met again in person for three days at the 8th International NBIA Symposium in Lausanne.

Group photo with participants at the 8th NBIA Symposium 2022 in Lausanne

The conference attracted 80 official participants from 14 countries, 28 of whom were speakers. Including guests, e.g. patient representatives, 91 people took part. Even though the 2020 online symposium had significantly more participants, with 160 attendees from 26 countries, a face-to-face meeting in a confidential setting provides a much better framework for individual scientists to exchange information - even informally - about their NBIA projects and project ideas. It is not uncommon for such personal encounters to later lead to scientific collaborations.

The NBIA Disorders Association has awarded eight travel grants worth a total of 5,000 US dollars to young scientists who would otherwise not have been able to afford to attend. The young researchers were able to present their project results or disease-specific information in the form of posters at the symposium.

Participant Patricia Wood, founder and president of the NBIA Disorders Association, summarizes: "Several young scientists sent me emails afterwards telling me how valuable this experience was and that it motivated them to continue working on NBIA. It also gave them ideas for research and helped them form collaborations with other participants."

Wood reports lively discussions with many questions and ideas. The networking encouraged interest in collaborations to further explore some topics in mutual exchange. The event focused on the more common NBIA diseases such as PKAN/CoPAN, MPAN, BPAN, PLAN/INAD and FAHN.

The main topics of discussion were:
- Disease mechanisms and therapeutic approaches for NBIA diseases
- Customized animal and cell models for preclinical tests
- Specific evaluation scales for clinical studies, based on the natural course of the disease
- Clinical therapy studies

A committee of scientists headed by Thomas Klopstock from the Ludwig Maximilian University of Munich prepared the program for the symposium. In addition to Susan Hayflick from Oregon Health & Science University in Portland, Valeria Tiranti from the Neurological Institute C. Besta in Milan and Agnès Rötig from the Institute Imagine in Paris, Hoffnungsbaum Chairman Markus Nielbock and NBIA Disorders Association Chairman Patricia Wood (USA) were also members of this committee as patient representatives. On site in Lausanne, the patient organization NBIA Suisse, led by Fatemeh Mollet, organized the event, which had been postponed twice due to the pandemic, to ensure that everything ran smoothly.

Picture: NBIA Alliance representatives at the symposium
L-R: Roberta Scalise, AISNAF, Fatemeh Mollet, NBIA Suisse, Joost Schimmel, Stichting Ijzersterk, Patricia Wood, NBIA Disorders Association.

A meeting of the NBIA Alliance also took place on the fringes of the symposium. The NBIA Alliance is a network of international NBIA patient organizations that was established as part of the EU research project TIRCON and now has 10 members. The patient representatives discussed possible joint projects for the future as well as an update of the NBIA Alliance website. The NBIA Alliance also had a meeting with representatives of the US pharmaceutical company CoA Therapeutics, which is currently preparing a clinical trial for PKAN. Members of four patient associations were present in person, with the remainder attending both meetings via Zoom. For Hoffnungsbaum e.V. Chairman Markus Nielbock took part in the meetings virtually.

In addition to the NBIA Disorders Association and the Swiss Foundation for People with Rare Diseases, the three biotech sponsors Chiesi, CoA Therapeutics and Travere Therapeutics in particular made the symposium possible with their financial support. Hoffnungssbaum e.V., another sponsor, also provided €5,000. As these funds were not needed, they will be donated to the research fund of Hoffnungsbaum e.V. research fund.

Sources and further information:
December 2022 Newsletter of the NBIA Disorders Association (also image source), p. 2-4:
https://www.nbiadisorders.org/news-events/nbia-newsletters/62-2022-newsletters/477-2022-december-newsletter
Fatemeh Mollet and website of NBIA Suisse:
https://nbiasuisse.org/de/8th-international-symposium-on-nbia-2/

PKAN study with CoA-Z completed in the USA

PKAN study with CoA-Z completed in the USA

From 2019 to 2022, Oregon Health & Science University in Portland (USA) conducted the first clinical trial for PKAN patients in the USA with a new preparation called "CoA-Z" for the treatment of PKAN.

This first part of the study has now been completed and analysis of the data has begun with the aim of determining the safety and tolerability of CoA-Z and whether it could be suitable as a therapy for PKAN. To do this, hundreds of biomarker blood samples collected and frozen over the course of three years must now be analyzed in the laboratory.

The duration of the study had to be shortened in the end due to pandemic-related problems with the supply chain. However, despite the COVID-19 pandemic, this decentralized study could initially be carried out without significant adjustments, as central clinic visits were not planned and all necessary data and samples could be sent to the OHSU from the families' respective homes, which was in line with the restrictions imposed by the pandemic anyway.

From December 2019 to September 2021, 77 children and adults with PKAN were enrolled in the study. The majority of the study participants took part as subjects until the end of their two-year study period or until the end of the active part of the study in summer 2022.

Next steps are for OHSU statisticians to review all data and analyze the information, including data on complications, subject adherence to study rules, and clinical information from the PKANready natural history study, which took place in parallel with the CoA-Z study.

Meanwhile, Dutch and British PKAN research teams are working on similar clinical trials. The study in the Netherlands is already well advanced and the UK team expects to start their study this year. These trials are different from each other and the team at OHSU is hoping to gain useful information from the different trials that can help drive the development of CoA-Z.

Source: December 2022 Newsletter of the NBIA Disorders Association, p. 11:
https://www.nbiadisorders.org/news-events/nbia-newsletters/62-2022-newsletters/477-2022-december-newsletter/

8th International Symposium on NBIA in Switzerland

8th International Symposium on NBIA in Switzerland

NBIA scientists will meet to share their research from October 13-15 in Lausanne, Switzerland, at the 8th International NBIA Symposium. More than 20 scientists and physicians from all over the world will present the results of their NBIA projects and learn about the latest developments in current NBIA research. The high-calibre program includes presentations on the most common NBIA variants PKAN, BPAN, MPAN, PLAN and FAHN and beyond, followed by discussions on the necessary next steps in the various branches of NBIA research.

 

In a confidential atmosphere, the symposium also offers the opportunity for researchers to get to know each other personally and to network, also with a view to future cooperation on research projects. Clinically active physicians, most of whom also have research experience in NBIA, can also share their experiences with treatment options for NBIA patients and thus take new findings back into their everyday clinical practice.

Hoffnungsbaum e.V. is one of the sponsors of this important NBIA event, the first face-to-face meeting of NBIA researchers since 2017, with €5,000. In 2020, the symposium was only held online due to the pandemic. Our US partner organization, the NBIA Disorders Accociation, is contributing $5,000 in the form of travel grants for young scientists.

The symposium is being organized by the Swiss NBIA patient organization NBIA Suisse under the leadership of its chair Fatemeh Mollet. Under the chairmanship of Prof. Dr. Thomas Klopstock, Head of the NBIA Centre at the Friedrich Baur Institute in Munich, a five-member scientific committee has taken on the task of designing the program. For Hoffnungsbaum e.V. our Chairman Markus Nielbock worked on the committee as a patient representative.

Website of the symposium: https://nbiasuisse.org/8th-international-symposium-on-nbia/

Research project leads to a stem cell model of FAHN

Research project leads to a stem cell model of FAHN

A German team of scientists, who received a $45,000 research grant from the NBIA Disorders Association in 2020, has successfully produced a stem cell model of FAHN to help researchers better understand the disease and test potential therapies for it.

FAHN (Fatty Acid Hydroxylase-associated Neurodegeneration) is a rare form of NBIA. The type of stem cell produced by the researchers is an induced pluripotent stem cell that can be programmed to develop into any type of human cell. The team developed the stem cells from skin fibroblasts of FAHN patients. This tissue contained copies of the mutated FA2H gene that causes the disease. The special ability of a stem cell to transform into any type of cell in the body now enables the researchers to generate central nervous system cells affected by FAHN .

The team was led by Dr. Andreas Hermann, together with Dr. Moritz Frech, Dr. Jan Lukas and PhD student Fatima Efendic from Rostock University Hospital. They worked together with Dr. Sunita Venkateswaran from the University of Ottawa. She provided the skin fibroblast cell lines for the research.

Researchers working on FAHN research at Rostock University Hospital,
From left to right: Dr. Jan Lukas, Dr. Moritz Frech, Fatima Efendic and Dr. Andreas Hermann.

The research project was entitled "In vitro disease modeling of fatty acid hydroxylase-associated neurodegeneration (FAHN): Patient-specific induced pluripotent stem cells and their neuronal derivatives as human models for FAHN".

Due to the COVID-19 pandemic, there have been delays in completing the work, which are still ongoing. Third-party funding from the Center for Transdisciplinary Neurosciences Rostock at the Rostock University Medical Center will enable the project to continue until April 2023. 

The researchers are planning to produce further induced pluripotent stem cell lines, each carrying different disease-relevant mutations. One focus is the development of protocols for the differentiation of these cells into oligodendrocytes. 

Image: Wikipedia

Oligodendrocytes form the myelin sheath in the central nervous system, which surrounds the axons of the nerve cells and thus ensures rapid signal transmission. As degeneration of the myelin sheath occurs in FAHN patients, the team wants to investigate the causes of these myelin sheath disorders using the newly established model system.
With a better understanding of the abnormal changes in cell function that occur during disease progression, researchers can test potential therapies to see if they can reverse the effects of FAHN .

A published article on the work, "Generation of the human iPSC line AKOSi010-A from fibroblasts of a FAHN patient carrying the heterozygous mutation p.Gly45Arg/p.His319Arg", is available online for download: https://www.sciencedirect.com/science/article/pii/S1873506122002124
The latest results of the project will be presented at the 8th International Symposium on NBIA, which will take place in Lausanne, Switzerland, from October 13 to 15, 2022.

(Publication and translation courtesy of the NBIA Disorders Association. The English original appeared in the NBIA Disorders Association Newsletter, September 2022, translated with the free version of https://www.deepl.com/translator)

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