NBIA NEWS & INFORMATION

By: Amber Denton

It is with a heavy heart that we inform the community that CoA Therapeutics has decided to discontinue the clinical trial of BBP-671, the compound the company was developing as a potential treatment for Pantothenate Kinase-Associated Neurodegeneration (PKAN). This decision was made after studies showed they were unable to identify a clinical trial dose that adequately balanced safety (toxicity) and potential clinical benefit.

In March, we shared that CoA Therapeutics announced a delay in their PKAN clinical trial due to the need for additional laboratory studies on BBP-671 to determine critical dosing and safety information. A significant challenge identified during these additional studies was the wide variability of BBP-671 blood levels observed in humans. Individuals taking the same dose of BBP-671 showed vastly different blood concentrations of the drug. This inconsistency posed a significant risk in determining an appropriate and safe dose for PKAN patients.

Toxicology studies in animal models of PKAN helped to establish a specific safety limit, or target blood level, for BBP-671 that cannot be exceeded due to safety and FDA regulations. The target blood level needed for efficacy was shown to be dangerously close to the safety limit.

Despite multiple studies and efforts to control these large differences in human blood levels, the exact cause of these variations remains undetermined, making it impossible to predict individual responses to the drug. Some individuals may have exceeded the safety limit, while others might have fallen below the target level, resulting in no clinical benefit.

Originally discovered through research led by St. Jude Children's Research Hospital in Memphis, Tennessee, CoA Therapeutics will return ownership of BBP-671 and related compounds to St. Jude. All their research data will also be shared to support any future research.

We are immensely grateful for the long-standing partnership with CoA Therapeutics. Their dedication to the NBIA community will not be forgotten. We appreciate their passion and desire to find a treatment for our PKAN families, and the amount of empathy and determination demonstrated year after year on behalf of our families.

CoA Therapeutics has released a detailed official announcement that you can read here along with their heartfelt message to the community

By: Patricia Wood

July 2024

Photo credit: Jan Greune (LMU)

Professor Lena Burbulla, Ludwig Maximilian University, Munich, Germany

In November 2022, the NBIA Disorders Association, along with three sister organizations in Europe, awarded two Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) grants of $70,000 each. These one-year grants were awarded based on priorities set during an MPAN workshop that was part of an MPAN Landscape Analysis project also funded by these same organizations.

Prof. Lena Burbulla of the Ludwig Maximilian University of Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, recently completed their research under this funding and have both reported promising findings.

The funding was made possible through an international collaboration that included AISNAF in Italy, Hoffnungsbaum e.V. in Germany, and Stichting Ijersterk in The Netherlands.

Burbulla’s research involved human disease modeling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so, her lab used induced pluripotent stem cells (iPSCs) generated from the skin cells of people affected with MPAN.

Brains of MPAN patients show massive loss of nerve cells in specific regions, predominantly a region in the midbrain called the substantia nigra. Here, the loss of cells producing the neurotransmitter dopamine is substantial and anticipated to be responsible for the vast majority of clinical symptoms. Therefore, Burbulla’s team used stem cells from MPAN patients and converted them into midbrain-specific dopaminergic nerve cells — the type of cells that degenerate in the brains of individuals affected by MPAN — to identify mechanisms specifically affecting this vulnerable cell type.

They were able to remarkably recapitulate important aspects of the disease pathology found in patient brains making patient-derived dopaminergic nerve cells a valuable model to study disease-specific phenotypes in a dish.

They also observed an accumulation of alpha-synuclein, a presynaptic protein known to aggregate in the brains of MPAN patients, a signature of iron misregulation leading to iron overload as well as axonal swellings that have been observed in postmortem brain biopsies.

Unbiased proteomic studies revealed some key mitochondrial proteins to be dysregulated and multiple proteins related to neurotoxicity and activation of the brain’s immune response to be enhanced. This unique protein signature may give a first insight into why dopaminergic nerve cells in the brains of patients are specifically vulnerable and degenerate.

Burbulla states that one of the most promising advantages of human iPSCs is their utility as a patient-specific disease model, offering the opportunity to gain deeper insights into disease mechanisms and progression. In this study, they demonstrated that iPSC-derived MPAN patient nerve cells recapitulate aspects of human disease pathology and therefore serve as a valuable model to better understand the disease-specific mechanisms underlying loss of C19orf12 function.

Burbulla plans to publish their results and hopes to conduct further studies using patient-derived disease models to guide future rescue strategies in the hope of identifying new therapeutic approaches to combat MPAN.

Dr. Rajnish Bharadwaj, University of Rochester Medical Center, Rochester, New Jersey

Bharadwaj’s research used fruit fly models that have a gene called nazo whose human counterpart is C19orf12, the gene that causes MPAN in humans. Using these fruit flies, Bharadwaj showed that Nazo protein is required for the maintenance of lipid droplets, which are storage sites for triglycerides (fat). In its absence proteins involved in curbing the utilization of fat (by lipolysis) are diminished. The loss of the nazo gene has a significant impact on the lifespan and health of the fly.

Bharadwaj is working on gaining a deeper understanding of the alterations in lipid droplets in flies lacking the nazo gene. Interestingly, human C19orf12 protein is highly enriched in adipose (fat) tissue. Bharadwaj’s findings suggest that lipid abnormalities may contribute to neurodegeneration in humans.

Bharadwaj has already published a paper on his findings that can be found here in PLOS Genetics: Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis | PLOS Genetics

He plans to use the data accumulated with this grant to get NIH funding to carry the work forward. It is hoped that this study will provide the foundation for future investigations into the role of the human C19orf12 protein in NBIA.

The NBIA Disorders Association, along with its international NBIA Alliance partners, remains committed to advancing research that brings us closer to understanding and ultimately curing MPAN. As we celebrate these advancements of Burbulla and Bharadwaj, we look forward to further breakthroughs that will improve the lives of those affected by NBIA disorders.

NBIAcure Prepares to Submit for FDA Approval of CoA-Z Compound

March 2024

By Amber Denton

Dr. Penelope Hogarth and Dr. Susan Hayflick, NBIAcure Oregon Health & Science University, Portland, Oregon

NBIAcure, a research team led by Dr. Susan Hayflick and Dr. Penny Hogarth and based at Oregon Health & Science University (OHSU), has released a significant update to the Pantothenate Kinase-Associated Neurodegeneration (PKAN) community regarding the status of CoA-Z, a vitamin intermediate. In January, the team announced their decision to approach the U.S. Food and Drug Administration (FDA) based on the strength of gathered data rather than pursue additional studies.

The FDA will evaluate data from the clinical trial to assess the safety and tolerability of CoA-Z and its effect in altering a biological marker of PKAN in the blood. Trial results indicate that CoA-Z altered the blood biomarker in a dose-dependent manner, with higher doses yielding a greater response.

A critical outcome of the trial is demonstrating CoA-Z's safety. This involves establishing that possible side effects occur with the same frequency, whether a participant was on a placebo or one of three doses.

The initial six months of the trial were conducted in a double-blind, placebo-controlled manner to meet the most rigorous scientific requirements. This approach demonstrates to the FDA that the research was done with the greatest integrity to protect against potential bias. Analysis of this phase confirmed CoA-Z's safety and tolerability across all tested doses.

The team is finalizing the report for this phase alongside other essential information, including the manufacturing process, stability under varied conditions, and effects on animal models. The target is to submit a draft application to the FDA by the end of March, a goal that remains on track.

Although the exact timeline for the FDA's review of the draft remains uncertain, the agency has suggested that conducting a preliminary assessment before final submission could minimize future delays. The team will advocate for expedited review while valuing the time and attention given to the review process. Meanwhile, the focus will shift to analyzing data from the trial's open-label portion, where all participants received the same dose of CoA-Z for inclusion in the final submission.

In February, Dr. Penelope Hogarth, part of the NBIAcure team at OHSU, presented the clinical trial results at the 8th International Symposium on Pediatric Movement Disorders in Barcelona, Spain. Numerous PKAN specialists attended the symposium and expressed excitement about the findings.

NBIAcure and the Spoonbill Foundation partners remain hopeful that the presented data will suffice to convince the FDA that additional studies are unnecessary. The team extends their gratitude to the PKAN community for their support and encouragement throughout this process.