Neurosyphilis

Pictured: Tinfoil crumpled into the shape of a human brain/iStock, wildpixel The research landscape for neurodegenerative diseases has undergone a monumental shift in the past year with the FDA approval of Eisai and Biogen’s Leqembi in Alzheimer’s disease and a regulatory decision for Eli Lilly’s donanemab expected by the end of 2023. While Alzheimer’s patients and researchers celebrate this momentum, another group is also heartened: researchers studying Parkinson’s disease. Both Alzheimer’s and Parkinson’s are progressive diseases that affect proteins in the brain, though it’s traditionally thought that the similarities end there. But experts told BioSpace that the rising tide in Alzheimer’s research has the potential to accelerate the study and treatment of Parkinson’s disease by drilling down into biological mechanisms of neurodegeneration, mainstreaming the use of biomarker data and uncovering potential shared mechanisms. These advances, they say, could inform clinical trial design and analysis in Parkinson’s and usher in a funding environment that could spell progress for a notoriously intractable condition. “There’s a lot of optimism now in the field that this is a breakthrough in neurodegeneration itself, not just in Alzheimer’s disease,” said Joanne Taylor, senior vice president of research at Gain Therapeutics. Biological Cascades Parkinson’s disease is characterized by a loss of dopamine-producing neurons in a region of the brain called the substantia nigra. Most people with Parkinson’s also have deposits of abnormal alpha-synuclein protein, which forms into clumps called Lewy bodies inside the neurons. These irregular deposits cause many of the motor and cognitive symptoms associated with the disease. Tracking disease progression quantitatively over time, however, is still an open area for research, said Akihiko Koyama, a leader at The Eisai Center for Genetics Guided Dementia Discovery. Recently—beginning with Alzheimer’s—scientists have made progress toward a biological understanding of neurodegeneration, Koyama told BioSpace. “One big change happening . . . is that we are defining the disease biologically when before we were defining it symptomatically,” he said. This means that instead of relying exclusively on one readout, researchers can study multiple biomarkers, including amyloid beta protein, tau protein and neuroimaging results from MRI scans in the case of Alzheimer’s. Gene Kinney In Parkinson’s disease, one biomarker of interest is alpha-synuclein protein, Gene Kinney, CEO of Prothena, told BioSpace. This “likely plays a very important role” in the development of the disease, even before a person might present with clinical symptoms, Kinney said. In collaboration with Roche, Prothena is testing an investigational Parkinson’s treatment, prasinezumab, that targets alpha-synuclein to stop it from spreading between neurons. Roche has fully enrolled participants for a Phase IIb study, Kinney said, with top-line data expected in 2024. The shift from symptom- to biology-based definitions via the use of biomarkers is not exclusive to Alzheimer's and Parkinson’s. Biogen’s Qalsody (formerly tofersen) for SOD1-ALS won FDA accelerated approval in April based largely on data showing a reduction in the biomarker neurofilament light chain (NfL)—this after the drug failed to meet the clinical endpoint in Phase III. Now, Taylor said, companies with investigational Parkinson’s drugs are looking to apply these same insights. “The availability of biomarkers is becoming very important because these diseases really start happening a long time before symptoms start to appear,” she said. Incorporating biomarker readouts into clinical trials for Parkinson’s is appealing for several reasons. One, Taylor said, is that it allows enrollment earlier in the disease process since people who develop motor and neurologic symptoms of Parkinson’s may already have had changes occurring in their brains years before the onset of these symptoms. Preventing the disease cascade may prove to be more attainable than reversing changes decades in the making, Taylor noted. Second, she said that collecting multiple biomarkers for trial participants increases the odds that researchers can identify a significant signal that a drug is working, which can also shed light on how it works. Finally, biomarkers can act as preliminary signals as to whether to continue a long and costly trial for a Parkinson’s drug candidate. Such encouraging preliminary signs aren’t just a boon for researchers—this feedback can also encourage investors, Taylor said. “If we can show an effect on biomarkers, it’s a reason to believe that this drug will work on the disease. We think that investors will be very excited about that.” Shared Mechanisms The key protein biomarkers in Alzheimer’s and Parkinson’s—amyloid beta and alpha-synuclein, respectively—likely share an important characteristic. Both are pathological, Kinney said, meaning they are each thought to drive disease progression as opposed to indicating the disease process. While they are distinct proteins that may affect neurons in their own ways, Koyama said further research into the causes of Alzheimer’s might clarify a shared mechanism for how incorrectly folded, disease-causing forms arise and spread. While the target of the protein might be different, “There could be a very similar mechanism happening.” The reciprocal benefits of neurodegenerative research go the other way too. Gain’s disease-modifying compounds for Parkinson’s, belonging to the class of small-molecule structurally targeted allosteric regulators (STARs), have also shown early signs of acting on Alzheimer’s, Taylor said. Because the compounds improve lysosomal health, they may act upstream of the changes that occur in both diseases. In cellular models of Alzheimer’s, Gain’s compounds prevented amyloid beta toxicity as well as tau hyperphosphorylation. “It could be that, just by improving the lysosomal health, we could have an effect on pretty much all of these diseases where protein misfolding is involved,” Taylor said. A Boon for Collaborations Success in Alzheimer’s clinical trials is a proof point not only for the basic science but also for the research collaborations behind it, Kinney said. Massive studies under the umbrella of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) bridge academia, industry and government research institutions. The Parkinson’s Progression Markers Initiative (PPMI), led by the Michael J. Fox Foundation, aims to achieve the same level of collaboration. In 2021, the consortium announced plans to triple enrollment numbers in its longitudinal clinical study. One of the initiative’s goals is to identify biomarkers across each stage of Parkinson’s—work that Kinney said will undoubtedly help drug developers. A final cross-therapeutic lesson, Kinney said, is that the moonshot for Parkinson’s should be a combination of effective drugs rather than any single magic bullet. The approval of a landmark Alzheimer’s therapy has sparked renewed investor interest in Parkinson’s research, with the hope that bets on multiple drugs will eventually pay off. “When we think about medicine, that first breakthrough is a signal of good things to come,” Kinney said. “What we're seeing today is the tip of the iceberg with respect to where this field can go.” Maddie Bender is a freelance science journalist based in Honolulu, HI. You can contact her through her website, maddiebender.com.

Data from the RESKUE Phase 1/2 clinical trial continues to demonstrate safety and efficacy post-FBX-101 systemic administration in patients recently receiving hematopoietic stem cell transplantation (HSCT), including normalization of motor function and brain development First FBX-101 patient dosed in the REKLAIM Phase 1b clinical trial for patients more than 90 days post-HSCT Dr. Maria Escolar to present the updated FBX-101 clinical data on Saturday, February 25, 2023, during the 9:00-10:00 a.m. ET session at the WORLDSymposium in Orlando, Florida COLUMBUS, Ohio--(BUSINESS WIRE)-- Forge Biologics, a genetic medicines development and manufacturing organization, announced today that Maria Escolar, M.D., Chief Medical Officer, will present updated data from the RESKUE Phase 1/2 clinical trial for FBX-101, the Company’s novel AAV gene therapy for the treatment of patients with Krabbe disease, during the 19th Annual WORLDSymposium being held February 22-26, 2023, in Orlando, Florida. Forge has also dosed the first FBX-101 subject in the REKLAIM Phase 1b clinical trial at the University of Michigan Medical Center. This press release features multimedia. View the full release here: Dr. Maria Escolar, Chief Medical Officer, Forge Biologics (Photo: Business Wire) Patients with infantile Krabbe disease have mutations in the gene encoding the lysosomal enzyme galactocerebrosidase (GALC), which is essential for normal metabolism of myelin components. Absence of GALC results in the accumulation of psychosine, a toxic substrate in cells making myelin, which then causes inflammation, rapid nerve demyelination, and progressive deterioration of the central nervous system (CNS) and peripheral nervous system (PNS). This results in progressive motor disease and often early death of patients by two years of age. “We are encouraged by the continued safety and efficacy observed in FBX-101 treated patients. Notably, some of the patients were identified by newborn screening, which enabled early disease intervention,” stated Dr. Escolar. “All patients to date have exhibited normal motor function and brain development six and 12 months post-FBX-101 administration, which would not be anticipated in the absence of systemic gene transfer of the GALC gene. We also observed up to 170-fold and 10-fold increases in plasma and cerebrospinal fluid (CSF) GALC levels, respectively, during the six and 12 months follow-up milestones, demonstrating sustained, high expression of the GALC transgene. Importantly, no treatment-related serious adverse events, liver enzymes elevations, nor development of anti-AAVrh10 antibodies have been observed after FBX-101 systemic administration. These results are very encouraging and provide hope for the families impacted by Krabbe.” Forge has also dosed one subject in the REKLAIM Phase 1b clinical trial for FBX-101 at the University of Michigan Medical Center. The REKLAIM trial is evaluating the safety and efficacy of FBX-101 in asymptomatic infantile or symptomatic late infantile Krabbe disease patients that received HSCT at least 90 days before FBX-101 administration. Children assessed in REKLAIM have received the standard of care (HSCT) and are partially or fully immuno-competent, but are at risk of developing progressive peripheral nerve disease. Dr. Escolar’s presentation, “First in Human Phase 1/2 Trial of Intravenous FBX-101 (AAVrh10.hGALC) During Hematopoietic Stem Cell Transplantation Increases GALC Activity, Supports Brain Development and Improves Motor Function in Patients with Infantile Krabbe Disease: RESKUE Clinical Trial,” will be delivered at the WORLDSymposium on Saturday, February 25, 2023, during the 9:00-10:00a.m. ET session. The session is also available on demand after February 27, 2023, for people registered who are not able to attend the meeting. A digital poster version will be on display Saturday, February 25, 2023, during the 3:00-4:00 p.m. ET session. For more details on the conference, please visit: . About Krabbe Disease Krabbe disease is a rare neurodegenerative disease affecting about 1-2.5 in 100,000 people in the U.S. Krabbe disease is caused by autosomal recessive mutations in the galactocerebrosidase (GALC) gene, an enzyme responsible for the breakdown of certain types of sphingolipids, such as psychosine, associated with myelination of the nervous system. Without functional GALC, psychosine accumulates to toxic levels in cells, specifically in cells insulating the nerves in the brain and peripheral nervous system, causing rapid demyelination. Krabbe disease initially manifests in young patients as irritability, developmental delay, and progressive muscle weakness. Symptoms rapidly advance to difficulty swallowing, breathing, and regression of neurodevelopment followed by seizures, vision and hearing loss. Infantile Krabbe disease (0-12 months of age at onset) usually leads to death in untreated patients by two years of age. Late Infantile patients (12-36 months of age at onset) usually die by the age of six. The current standard of care, hematopoietic stem cell transplantation (HSCT), has been shown to stabilize cognitive decline and significantly improve long-term neurological outcomes when performed prior to symptom onset. However, HSCT does not correct the peripheral neuropathy that is progressive as the patient grows, leading to loss of gross motor skills and eventually death. Early diagnosis is key for treating patients with Krabbe disease before symptoms are evident and significant neurological damage has occurred. Currently, 10 states in the U.S. are conducting newborn screening for Krabbe disease. Infants who screen positive due to insufficient GALC activity undergo psychosine testing and mutation analysis to confirm the diagnosis and determine which infants need immediate treatment because they are at high risk to progress. About FBX-101 FBX-101 was developed to treat children with Krabbe disease. FBX-101 is an adeno-associated viral serotype rh10 (AAVrh10) gene therapy that is delivered intravenously after HSCT infusion. The vector delivers a functional copy of the GALC gene to cells in both the central and peripheral nervous system, and has shown to functionally correct the central and peripheral neuropathy, improve myelination and gross motor function, and significantly prolong lifespan in animal models. This approach also has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies and extend the duration of gene transfer. The FDA has granted FBX-101 Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation; the EMA has granted FBX-101 Orphan Drug Designation and Priority Medicines (PRIME) designation. About the RESKUE Trial RESKUE is a Phase 1/2 clinical trial to investigate the safety and efficacy of FBX-101 in patients with infantile Krabbe disease. It is a nonblinded, non-randomized dose escalation study in which subjects receive a single intravenous infusion of FBX-101 within 21 to 60 days of HSCT, the current standard of care. Data from extensive natural history subjects will be used to compare as the control group. More information on the RESKUE trial can be found online at . About the REKLAIM Trial REKLAIM is a Phase 1b, nonblinded, non-randomized dose escalation clinical trial currently enrolling children with asymptomatic infantile and symptomatic late infantile Krabbe disease to investigate the safety and efficacy of a single intravenous infusion of FBX-101 administered more than 90 days after HSCT, the current standard of care, when the patient is partially or fully immuno-competent. Data from extensive natural history subjects will be used to compare as the control group. More information on the REKLAIM trial can be found online at . About Forge Biologics Forge Biologics is a hybrid gene therapy contract manufacturing and clinical-stage therapeutics development company. Forge’s mission is to enable access to life-changing gene therapies and help bring them from idea to reality. Forge’s 200,000 square foot facility, the Hearth, utilizes 20 cGMP suites in Columbus, Ohio, to serve as its headquarters. The Hearth is a custom-designed cGMP facility dedicated to AAV manufacturing and hosts scalable, end-to-end manufacturing services. Offerings include process and analytical development, plasmid DNA manufacturing, viral vector manufacturing, final fill, as well as regulatory consulting support to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing. By taking a patients-first approach, Forge aims to accelerate the timelines of these transformative medicines for those who need them the most. To learn more, visit .

-Statistically Significant Results in Performance of the Upper Limb PUL 2.0 (p=0.02) Extended to 18 Months, Demonstrating Long-Term Benefit in Skeletal Muscle Function- -Results Continue to Suggest Potential Disease Modification in Duchenne Muscular Dystrophy (DMD)- SAN DIEGO, CA, USA I January 25, 2023 I Capricor Therapeutics (NASDAQ: CAPR), a biotechnology company focused on the development of transformative cell and exosome-based therapeutics for the treatment and prevention of muscular and other select diseases, today announced positive 18-month results from its ongoing HOPE-2 open label extension (OLE) study in patients with later-stage Duchenne muscular dystrophy (DMD). Data from the OLE study continues to show evidence for disease modification with statistically significant differences in the Performance of the Upper Limb (PUL version 2.0) scale in the CAP-1002 original treatment group when compared to the original placebo group from HOPE-2 (p=0.02). In addition, disease progression is attenuated equally in both groups once patients begin treatment in the OLE. “DMD is a progressive disease associated with loss of function over time and there is a critical need for treatment options to slow the rate of decline and preserve upper limb function to enable key everyday activities,” said Dr. Craig McDonald, national Principal Investigator and University of California, Davis, Professor and Department of Physical Medicine and Rehabilitation Chair. “We are encouraged by the improvements in upper limb function in the treatment group at 18-months and will continue to treat and follow these patients to further evaluate the disease modifying potential of CAP-1002. Taken together, these data build on the impressive results from HOPE-2 and suggest that patients accumulate benefit over time with steady preservation of skeletal muscle functions, which underscore the potential long-term benefit of CAP-1002.” The study met its primary endpoint at the one-year timepoint and continues to show statistically significant improvements (p=0.02) on the Performance of the Upper Limb scale for patients treated with CAP-1002 at 18-months. In the study, CAP-1002 was made available to the original 20 patients enrolled in the HOPE-2 study. Of those, 13 entered and 12 completed 18-months of study follow-up. The breakdown of patients included seven from the original placebo group and six from the original CAP-1002 treatment group. All patients were off CAP-1002 or placebo for a mean of approximately one-year before resumption or initiation of therapy under the HOPE-2 OLE program. As in HOPE-2, CAP-1002 was administered quarterly and current results are from the 18-month analysis. CAP-1002 treatment during the open-label portion of the study continues to yield a consistent safety profile and has been well-tolerated throughout the study. The HOPE-2 OLE study is ongoing, and all participants continue to be monitored for safety and functional performance. Linda Marbán, Ph.D., CEO of Capricor, commented, “In the OLE phase of the HOPE-2 study, we observed statistically significant slowing of the progression of disease across patients treated with CAP-1002. We are extremely pleased by the robust and consistent results observed to date, which, together with the favorable safety/tolerability profile, suggest that CAP-1002 holds promise as a potential anchor therapy for DMD patients. Further, the long-term efficacy and potential disease modification effect will augment our clinical package as we continue on our regulatory pathway towards potential approval of CAP-1002 for treatment of patients with DMD. We thank the patients, their families, caregivers, and the broader Duchenne community for working with us on this promising therapy.” Capricor is currently conducting a pivotal Phase 3 trial, HOPE-3, designed as a randomized, double-blind, placebo-controlled study with approximately 70 patients and enrollment criteria similar to HOPE-2. The Phase 3 study is currently enrolling subjects ( NCT05126758 ). Furthermore, in 2022, Capricor entered into a partnership for the exclusive commercialization and distribution of CAP-1002 for DMD in the United States with Nippon Shinyaku Co., Ltd. (U.S. subsidiary: NS Pharma , Inc.), subject to regulatory approval. Webinar Details Capricor will host a webinar in conjunction with PPMD today, January 25, at 1:00 p.m. ET to discuss the data findings. To listen to the webinar, please click the following link: http://join.parentprojectmd.org/webinar . For additional details, please visit www.parentprojectmd.org . A replay of the webinar will be made available on PPMD’s website. About HOPE-2 Open Label Extension (OLE) Study HOPE-2 was a randomized, double-blind, placebo-controlled, Phase 2 clinical study of Capricor’s lead investigational therapy, CAP-1002, in boys and young men who have DMD and are non-ambulant, the later stage of the disease process. The study was conducted at nine sites across the United States. Study patients were treated via intravenous delivery with either CAP-1002 (150 million cells per infusion) or placebo every 3 months. Data from a total of 20 patients was analyzed (12 placebo and 8 treated) at the 12-month time-point and the results were published in The Lancet . The study met its primary efficacy endpoint, PUL 1.2 mid-level dimension, showing a mean 12-month change from baseline in mid-level PUL 1.2, favoring CAP-1002 over placebo (2.6 point difference; (p=0.014). Cardiac MRI assessments showed improvements in heart function and structure with CAP-1002 treatment. Left ventricular ejection fraction (LVEF), a global measure of cardiac pump function, decreased in the placebo group over time, but improved in the CAP-1002 group, showing a 107% slowing of progression of cardiac disease (p=0.002). After the completion of the HOPE-2 study, all patients stopped treatment for approximately 392 days (mean, range [239, 567]), which is referred to as the gap phase. Then all eligible patients who wished to remain on treatment re-entered the OLE study where they received CAP-1002 (150 million cells per infusion) every three months over the course of 18 months. Patients continued through the gap phase (off treatment for both groups) and the OLE Phase (on treatment for both groups). Patients in the study were evaluated using the Performance of the Upper Limb (PUL 2.0), a validated tool specifically designed for assessing high (shoulder), mid (elbow) and distal (wrist and hand) function, with a conceptual framework reflecting the progression of weakness in upper limb function. About Duchenne Muscular Dystrophy Duchenne muscular dystrophy is a devastating genetic disorder characterized by progressive weakness and chronic inflammation of the skeletal, heart and respiratory muscles. Patients suffering from DMD typically lose their ability to walk in their teenage years and generally die of cardiac or respiratory complications by age 30. It occurs in one in every 3,600 live male births across all races, cultures and countries. DMD afflicts approximately 200,000 boys and young men around the world. Treatment options are limited, and there is no cure. About Capricor Therapeutics Capricor Therapeutics, Inc. (NASDAQ: CAPR) is a biotechnology company focused on the development of transformative cell and exosome-based therapeutics for the treatment and prevention of muscular and other select diseases. Capricor’s lead candidate, CAP-1002, is an allogeneic cardiac-derived cell therapy that is currently in late-stage clinical development for treating Duchenne muscular dystrophy. Capricor is also developing its exosome technology as a next-generation therapeutic platform. Capricor’s current focus is on developing exosomes capable of delivering nucleic acids, including mRNA, as well as proteins to treat or prevent a variety of diseases. For more information, visit capricor.com , and follow Capricor on Facebook , Instagram and Twitter. SOURCE: Capricor Therapeutics