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Articles

The application was supported by positive data of KYV-101 in patients with stiff-person syndrome treated in Germany under a named-patient treatment option. 

FDA Grants Regenerative Medicine Advanced Therapy Designation to Kyverna's KYV-101 for Refractory Stiff-Person Syndrome

Across a 12-week study, atogepant-treated patients, with and without acute medication overuse, had greater reductions in mean monthly migraine days, monthly headache days, and acute medication use days.

Atogepant Effective in Treating Chronic Migraine With Medication Overuse

Michael Soileau, MD, FAAN, talked about a panel of specialists who discussed the evolution and multidisciplinary treatment of Parkinson disease, emphasizing patient-centered care and advanced therapeutic options.

Transforming the Landscape of Parkinson Disease Care Through Patient-Centric Focus

Mind Moments®, a podcast from NeurologyLive®, brings you an exclusive interview with Douglas Wajda, PhD. [LISTEN TIME: 13 minutes]

Episode 120: Improving Gait in Multiple Sclerosis Through the Neural Sleeve

NeurologyLive joins the CMSC in mourning the loss of founder and CEO,June Halper, MSN, APC-C, MSCN, FAAN.

In Memoriam: A Loving Tribute to June Halper

Videos

The assistant professor at Hunter College talked about the approach of localization to prevent misdiagnoses of multiple sclerosis and ensure patients receive appropriate treatment. [WATCH TIME: 3 minutes]

Optimizing Localization in Multiple Sclerosis Diagnosis: Aliza Ben-Zacharia, PhD, DNP, ANP-BC, FAAN

, has been with the team since September 2022. Follow her on Twitter 

Patricia Clark, CNP, a nurse practitioner at the Cleveland Clinic, talked about a specialized program for hospitalized patients with Parkinson disease that aligns hospital protocols with home medication regimens to improve care.

A Comprehensive Program to Enhance Inpatient Care for Patients With Parkinson Disease

The neuroradiologist at Mayo Clinic discussed the categorization of biomarkers for Alzheimer disease, focusing on core biomarkers specific to the disease and those reflecting related pathologies. [WATCH TIME: 8 minutes] 

Categorizing Biomarker Criteria for Alzheimer Disease Diagnosis and Staging: Clifford R. Jack Jr., MD

NeurologyLive is your direct connection to the latest neurology news and interviews with expert neurologists in multimedia formats.

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Spotlight

ATMRD 2024

Secondary Symptoms of Parkinson Disease

Clinical Focus

Dementia/Alzheimer

Headache/Migraine

Video Series

1rem

Authors

Division Chief, Neuromuscular Disorders; Vice-Chair of Research, Virginia Commonwealth University

The division chief of neuromuscular disorders and vice-chair of research at Virginia Commonwealth University spoke to the ongoing success in the development of gene-mediated therapies and the challenges that come along with treating rare neuromuscular disease. [WATCH TIME: 3 minutes]

Successes and Challenges in the New Era of Genetic Medicine: Nicholas E. Johnson, MD, MSci

The division chief of neuromuscular disorders and vice-chair of research at Virginia Commonwealth University offered his insight into the advances in genetic approaches to LGMD. [WATCH TIME: 2 minutes]

The Revolution in Limb-Girdle Muscular Dystrophy With Gene Therapies: Nicholas E. Johnson, MD, MSci

 (CCF)'s Parkinson's Inpatient Program comprises of system and patient level interventions aimed to promote recovery in patients with Parkinson disease (PD). System level interventions took place at both enterprise and individual hospital levels. Enterprise level changes comprised electronic health record modifications including best practice alerts and notification of PD contraindicated medications. Hospital level interventions included creation of a PD inpatient census, a dedicated PD inpatient consult team, clinician education, changes in PD medication stocking/administration, and changes to Speech Therapy documentation templates.

 was an efficient and effective way to correctly identify and prevent or correct common clinical errors that could lead to lesser outcomes and further complications in hospitalized patients with PD.

 In the analysis, all charts of patients with PD admitted at CCF's Main Campus and Fairview hospitals were prospectively pulled into a census utilizing a custom EHR tool starting in January 2023. After confirmation of PD diagnosis, researchers followed the patient’s charts throughout the admission. Authors monitored their charts for PD contraindicated (CI) medications, deviations from home PD medication regimen, worsening of motor and non-motor symptoms, and other complications.

These findings were presented at the 3rd Annual 

Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress

, and colleagues. During the Congress, Clark, a nurse practitioner of the Center for Neurological Restoration at the Cleveland Clinic, sat down with 

 in an interview to talk about how the program accurately ensures patients with PD receive their home medication regimen while hospitalized. She also talked about the types of interventions that were most frequently required for the patients in the program. Moreover, Clark spoke about how education and awareness among hospital providers impacts the effectiveness of the program.

NeurologyLive: What specific measures did the program take to ensure that hospitalized patients with PD receive their home medication regimen accurately?

: The program is designed to improve quality and safety of care for patients that have PD who come into the hospital and are inpatient; they may be hospitalized for any reason, it's usually not because of their PD, it could be a planned surgery or an infection. It's a program that Benjamin Walter, MD, and my colleague, Shannon Shaffer, CNP, had done for a while, the intervention part. With a grant from the 

, they standardized it more, adding other changes, and are now doing an evaluation of the program.

We created an inpatient team that consists of myself and Shannon, so 2 nurse practitioners, and we have about 2 hours of our day total [dedicated to the program]. She does it 3 days a week. I do it 2 days a week. It's about 10 to 12 hours of clinician time a week. We created a census where we get a list of anybody in the hospital that has PD, Lewy body dementia— anything like that in their history, so not necessarily their admission diagnosis. What we do is confirm their diagnosis. We usually read one of their last notes from their neurologist. We'll look at their medication and see what their most recent home regimen is. Then we go to their hospital chart, and we make sure that their hospital medical record, that their schedule matches their home regimen.

Typically, medications are maybe ordered 3 or 4 times a day in the hospital, and those default to certain times. We make sure that those times are specific to the patient. One of the changes that we made is that a hospital provider has to enter those as custom times. They can't just say 3 times a day, and it defaults to hospital times. They have to specifically enter say, 9am, 1pm and 5pm. This helps keep patients on their home regimen. We try to intervene if, for example, someone is in the emergency room for several hours. We make sure that as long as it's not contraindicated, that they're still getting their home regimen and they're not missing doses. We make sure that patients aren't ordered or given any contraindicated medication.

There's a lot of medications that are used for nausea and confusion that can block patients Parkinson medication and make Parkinson symptoms worse. We look at charts every day and make sure none of those are ordered. For about 40% of those patients we get, it's really just monitoring, looking every day that nothing is contraindicated. There's nothing going on that we need to intervene with. For the remaining 60% of those patient this past year, we've actually had to intervene. This includes contacting the provider, letting them know you ordered Compazine that's actually contraindicated. Maybe suggest that they change their timetable so they're not getting their last dose when they've been asleep for 3 hours.

Then also managing things like dysphagia, making sure people are getting up and active as soon as possible, getting moving, things like constipation, recommending regimens if they can't be on their particular Parkinson regimen. And so that was about 60% of cases. We're looking at those broader hospital and system changes that we made so alerts come up, changing so providers have to enter the medication schedule regularly, and seeing if that kind of diminished over time. Because those corrections now, a lot of them are happening before we even see it.

How long was the total data collection period for the program, including the break?

We did 6 months of data collection, and then we had a break for about 2 months where we continued the intervention, but didn't collect the data. And then we did 6 more months [of data collection]. And so that data collection will be complete at the end of this month (June). Overall, we'll have 12 months of data collection. But the other thing is, the whole time we've been doing the intervention, so that is data collection, where we're talking specifically about what our intervention recording their home medication regimen. But for the whole length of the study, we'll also have data from our medical records, and we’ll be able to see their outcomes. We just don't have where we specifically discussed what our intervention was.

How important is it for patients to understand medications that contradict their PD treatments?

A big part of our intervention as well is education. So educating our providers: we'll put in a note for a particular patient with our recommendations for that specific person. Just through our intervention, we're teaching people about the program that they can access, but also mistakes to watch out for in the future. And so a lot of times, people will say, “Well, what does that say about the providers? Around 20% of your interventions were discontinuing a contraindicating medication. Why was that ordered in the first place?” But if you look at the poster, you see the reasons for why people were admitted to the hospital.

The first reason is for an elective procedure, scheduled procedure, and then I think it's like cardiac. Really, none of our top 5 reasons that patients were admitted were for something neurological. These are providers that its not their main focus. The patients are thinking about the knee replacement and the other surgery, and “this is how I normally handle nausea”. And so that box for composing gets clicked, so now they see an alert. If they don't follow the alert, they get a little message or note from us. Overall, providers have been extremely receptive to the program. Admittedly, they reach out they say, “I don't know much about neurology. I don't know much about Parkinson specifically.” And so we're getting a lot of good feedback.

Another one of our interventions that I, as a former nurse, was really kind of nervous about, was medication delivery. Just because the medications were ordered to be given at the correct time doesn't necessarily mean it's given at the correct time. For most medications in the hospital, you have a 1-hour window on either side to give the medication for it could be considered on time. If the time is nine o'clock, it can be given any time between 8 and 10. A nurse normally starts with one of their first patients. By the time they get to their last patient, they're somewhere in that window.

One of the changes that we made was for Parkinson medications. If it falls 15 minutes out time of the outside of that scheduled time, a little alert pops up. From my perspective, it's just a matter of prioritizing. When you're a nurse on the floor, you get your patients, you get your patient load, and you look at everyone's blood pressures and vitals. Do they have insulin? Do they have a Parkinson medication? And so, it was just a matter of teaching nurses. This is something that needs to prioritize and be on time so well.

What were the biggest lessons learned from the study?

I think one of the biggest things I've learned in this study is that everyone really just has the patient's care and the best interest of the patient at heart. People are really receptive. I wouldn't necessarily take criticism, but they're receptive to someone who knows about the disease, getting involved and helping out. Patients are really grateful too, because they come into the hospital, they're overwhelmed, they want to do what their provider says, and in their mind, their medications are late, but they think, well, maybe my provider ordered it to be given at a different time, or maybe I'm missing it because I'm having this surgery. Overall, it's just been really a wonderful program to improve patient care.

Click here for more coverage of ATMRD 2024

REFERENCES
1. Clark PA, Brooks A, Fernandez HH, et al. Improving the Quality and Safety of Care for Hospitalized Patients with Parkinson's Disease. Presented at: ATMRD; June 22-25, 2024; Washington, DC.

Clinical

SAP Partners

Anvi Gadani, MD, talked about her presentation where she covered various advanced therapies for managing Parkinson disease and essential tremor.

Advanced Therapeutic Options for Parkinson Disease and Essential Tremor: Anvi Gadani, MD

"We focused on deep brain stimulation, which is one of our main go-to therapies now for our patients with advanced Parkinson and essential tremor. You can target the deep structures in the brain that can contribute to these disease processes and stimulate with high-frequency modulatory therapy. This helps manage these more advanced patients that have had significant disease progression and all the other oral medication therapies have started to become of limited benefit to them."

Levodopa is known as the most efficacious drug for a majority of patients with Parkinson disease (PD) and is recommended to be used as primary approach to control troublesome tremor.

 Despite levodopa optimization, deep brain stimulation (DBS) and focused ultrasound are considered first-line therapies for patients with drug-refractory PD tremor. Another highly effective therapy for medication-refractory tremor is surgery, but mostly in selected patients without motor fluctuations. These therapies require appropriate utilization and success them may depend on both the provider and the patient.

 from June 22-25, 2024, Anvi Gadani, MD, presented a talk reviewing how various therapeutic delivery systems and surgical management options such as DBS, pump therapy, and focused ultrasound impact the management of PD, essential tremor (ET), and dystonia. In her talk, Gadani presented how clinicians can communicate to their patients about the different types of treatments available, while comparing the benefits and risks, to manage their movement disorder.

Gadani, an assistant clinical professor of medicine at Medstar Georgetown University Hospital, sat down with 

 at the Congress to discuss the primary benefits and risks of deep brain stimulation for patients with PD and ET. Additionally, she spoke about how MRI-guided focused ultrasound differs from DBS in terms of invasiveness and therapeutic approach. Moreover, Gadani, who also serves as a neurologist in the department of movement disorders at Montgomery Medical Center, talked about the emerging device-aided therapies in development, and how close they are to reaching clinical settings.

REFERENCES
1. Pirker W, Katzenschlager R, Hallett M, Poewe W. Pharmacological Treatment of Tremor in Parkinson's Disease Revisited. J Parkinsons Dis. 2023;13(2):127-144. doi:10.3233/JPD-225060

The assistant clinical professor of medicine at Medstar Georgetown University Hospital talked about her presentation at ATMRD where she covered various advanced therapies for managing Parkinson disease and essential tremor. [WATCH TIME: 5 minutes]

Jeffery Cohen, MD, talked about recent findings on long-term impact of ozanimod in patients with relapsing-remitting multiple sclerosis.

Ozanimod's Consistent Efficacy in Long-Term Treatment for Multiple Sclerosis: Jeffery Cohen, MD

"In the long term extension, the effects on relapses in MRI lesion activity increased and reached the same level as those patients that had been on ozanimod, previously. Then, when we looked at those results as a function of age, there was very little difference in the groups based on their age.”

In phase 3 randomized trials (SUNBEAM, NCT02294058; RADIANCE, NCT02047734) ozanimod (Zeposia; BMS), an approved disease-modifying therapy, was associated with lower adjusted annualized relapse rate (ARR) and fewer gadolinium-enhancing (GdE) lesions and new/enlarging T2 lesions compared with interferon (IFN) beta-1a in patients with relapsing multiple sclerosis (RMS). Participants who completed phase 1‒3 trials investigating ozanimod were eligible to enroll in an open-label extension (OLE) trial (DAYBREAK, NCT02576717). In the phase 3 trials, adults with RMS received oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN beta-1a 30 µg/wk for at least 12 or 24 months, and in the OLE participants received ozanimod 0.92 mg/d.

In a recent ad hoc analysis of the phase 3 trials and OLE, findings showed that clinical and radiologic measures of disease activity remained stable or improved in ozanimod-treated patients with RMS over 7‒8 years of continuous treatment regardless of age category.

Among 2257 patients from SUNBEAM/RADIANCE enrolled in the OLE, 760 continued on ozanimod 0.92 mg. In the parent trials and OLE, the adjusted ARR was less than 0.2 on ozanimod, and adjusted mean number of GdE lesions remained lower than at parent trial baseline after 7 to 8 years on ozanimod treatment, both regardless of age category.

These findings were presented at the 2024 

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum

, February 29 to March 2, in West Palm Beach, Florida, by senior author 

, director, Mellen Center for MS Treatment and Research, 

® in an interview to discuss how ozanimod’s efficacy in reducing relapses and MRI lesion activity holds up in long-term treatment for patients with MS. He also talked about the role that age may play in the evolving MS disease process and the impact of medications like ozanimod. Despite the positive findings from the analysis, Cohen shared a notable limitation that the study acknowledges, and how it can affect result interpretation.

Click here for more coverage of ACTRIMS 2024.

REFERENCES
1. Cree BA, Selmaj KW, Steinman L, et al. Long-term Efficacy of the Sphingosine 1-Phosphate Receptor Modulator Ozanimod by Age Category in Patients With Relapsing Multiple Sclerosis: Final Results From Two Phase 3 Trials and an Open-label Extension Trial. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. P091.

The director of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research talked about recent findings on long-term impact of ozanimod in patients with relapsing-remitting multiple sclerosis presented at ACTRIMS Forum 2024. [WATCH TIME: 4 minutes]

Ozanimod's Consistent Efficacy in Long-Term Treatment for Multiple Sclerosis: Jeffrey Cohen, MD

A recently published meta-analysis using more than 20 studies with nearly 1400 patients showed that subcutaneous immunoglobulin (SCIG) provides a more feasible alternative for treating chronic demyelinating polyneuropathy (CIDP) than intravenous immunoglobulin (IVIG). Overall, SCIG showed more considerable cost reductions over time, was more preferred by patients, and demonstrated comparable, and sometimes superior, health outcomes.

the systematic review comprised 50 studies up till 2024, with 22 involved in the meta-analysis. Included studies offered clinical data on patients with CIDP, mostly from western Europe and the US, representing nearly 10% of their entire CIDP populations. Almost all studies included considered SCIG to be a maintenance therapy in their context, and thus, the primary goal of those studies was to reduce relapse rate and sustain or enhance neuromuscular functions.

Led by Mostafa Ramzi Shiha, of Cairo University, meta-analysis showed that SCIG significantly improved muscle strength and sensory function, had fewer and milder adverse events (AEs), reduced relapse rates, and received a strong preference. On muscle strength, a collection of 18 studies comprising 542 individuals with CIDP demonstrated a significant improvement in muscle strength post-SCIG treatment. Overall, the pooled standardized mean difference in Medical Research Council Scale (MRC) scores was 0.68 points (95% CI, 0.28-1.08), with statistically significant enhancement (

When evaluating muscle strength by dose level, results showed that the high dose subgroup showed a significant effect (SMD, 2.39; 95% CI, 0.79-3.98) and high heterogeneity (I2 = 95%), whereas there was no significant effect in the low dose subgroup (SMD, –0.05; 95% CI, –0.22 to 0.14). The medium dose subgroup showed a small but not statistically significant effect (SMD, 0.18; 95% CI, –0.04 to 0.40).

Overall, treatment with SCIG was associated with a 22% decreased risk of AEs compared with IVIG (

<.0001). An analysis of 2 studies found a significant difference in headache occurrence in the SCIG group (OR, 0.14; 95% CI, 0.07-0.30; 

<.0001). Infusion site reactions, a concern for subcutaneous treatments, were not significantly more common with SCIG in 2 studies, with an OR of 1.75 (

= .50). In addition, there was no significant between-group differences in severe AEs as well (OR, 0.23; 

As to why SCIG leads to fewer AEs relative to IVIG, investigators attributed this to the "slower absorption into the bloodstream with SCIG, which avoids the high peak levels of immunoglobulin G seen after IVIG administrations."

The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, developed in 2001, was used as an assessment for overall function and disability. Across 5 studies with available data comprising 67 patients, treatment with SCIG led to a significant improvement in sensory function as measured by INCAT Sensory Score. The pooled mean difference showed a reduction of 1.73 points (95% CI, –2.29 to –1.17), which was statistically significant (

<.00001). This improvement indicated enhanced sensory function following SCIG therapy.

On INCAT results, there was high heterogeneity (I2 = 92%) among the included studies. "For impaired functional mobility, no worsening was observed in the analysis of 9-hole peg test and timed meter walk test scores, indicating that patients preserved their functional mobility upon SCIG maintenance treatment,” Shiha et al wrote.

In terms of relapse rate reduction, patients with CIDP treated with SCIG had significant reductions observed, with a risk ratio of 0.146 (95% CI, 0.090-0.202; 

<.001) across 8 included studies. In comparison with conventional IVIG treatment, a previous 52-week open-label study found that IVIG administered as maintenance therapy resulted in a relapse rate of 10.5%, similar to the results of high-dose SCIG treatment in the 48-week, open-label PATH extension trial relapse rate of 10.8%. Overall, the findings from the meta-analysis indicated that both IVIG and SCIG might have comparable efficacy in terms of relapse rates.

Quality of life and health status also remained stable after treatment with SCIG, which was consistent with IVIG treatments. Interestingly, 2 included studies that used a more IgG treatment oriented scale like LQI that considers many items related to patients’ convenience, comfort, and independence, according to the IgG route of administration, showed better quality of life measures after SCIG. In addition, patients’ treatment preferences, when analyzed, unanimously demonstrated a preference for SCIG across all studies.

REFERENCE
1. Ramzi A, Maya S, Balousha N, et al. Subcutaneous immunoglobulins (SCIG) for chronic inflammatory demyelinating polyneuropathy (CIDP): A comprehensive systematic review of clinical studies and meta-analysis. 

Published online June 28, 2024. doi:10.1007/s10072-024-07640-3

Across all studies, including 2 of the largest recorded for CIDP, patients unanimously demonstrated a preference for SCIG over IVIG.

Subcutaneous Immunoglobulin Shows Superiority Over IVIG in Treating CIDP, Meta-Analysis Shows

Martin Tolar, MD, PhD, talked about a novel Alzheimer disease drug that shows promising early results in reducing key biomarkers and stabilizing cognitive function in a challenging patient population. 

Early Biomarker Evaluation and Cognitive Stabilization in Alzheimer Treatment: Martin Tolar, MD, PhD

"The APOE4 genotype specifically impairs the clearance for amyloid through the RP1 receptor, and the patients with 2 copies will almost all have the brain pathology by age 65 and most will have clinical disease."

ALZ-801 (Alzheon) is an investigational oral disease-modifying therapy in development for the treatment of early Alzheimer disease (AD). In prior studies, ALZ-801 has shown both potential for clinical efficacy in the highest-risk and most fragile Alzheimer population, patients with 2 copies of the apolipoprotein ε4 allele (

 homozygotes), and favorable safety with no increased risk of vasogenic brain edema. This patient population is the focus of Alzheon’s pivotal 78-week APOLLOE4 phase 3 trial (NCT04770220), which is the company noted is fully enrolled and expects topline data in the third quarter of 2024.

The previously completed phase 2 study (NCT04693520) assessing ALZ-801 in 

 carriers with early AD achieved its primary efficacy end point of reduction in plasma p-tau181 over 2 years.

= .045) in plasma p-tau181 was reported at 13 weeks and sustained at every visit through 104 weeks. Notably, memory scores showed improvement from baseline at 26 weeks and continued to display minimal decline from baseline at 104 weeks. Additional findings showed that these cognitive effects were significantly associated with decreased hippocampal volume atrophy (

, the founder, president and CEO at Alzheon, recently sat down with 

® in an interview to discuss the most notable takeaways for the clinician community from the phase 2 data such as how the treatment impacts brain volume and phosphorylated tau levels in patients. He also talked about the main outcomes and measures being evaluated in the ongoing placebo-controlled phase 3 study. Furthermore, Tolar spoke about how the 

 genotype affects the progression and treatment response in patients with AD.

REFERENCES
1. A Two Peer-Reviewed Scientific Publications Describe Fluid Biomarker, Brain Preservation and Clinical Benefits Following 2 Years of Treatment in Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease. News release. Alzheon. June 25, 2024. Accessed July 19, 2024. https://alzheon.com/two-peer-reviewed-scientific-publications-describe-fluid-biomarker-brain-preservation-and-clinical-benefits-following-2-years-of-treatment-in-phase-2-trial-evaluating-oral-alz-801-valiltramiprosate-i/
2. Hey JA, Abushakra S, Blennow K, et al. Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease. Drugs. Published online June 20, 2024. doi:10.1007/s40265-024-02067-8
3. Hey JA, Yu JY, Abushakra S, et al. Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model. Drugs. Published online June 20, 2024. doi:10.1007/s40265-024-02068-7

The president and CEO at Alzheon talked about a novel Alzheimer disease drug that shows promising early results in reducing key biomarkers and stabilizing cognitive function in a challenging patient population. [WATCH TIME: 10 minutes]

According to a recent announcement, patient dosing has commenced for part 2 of a phase 1 study (NCT05804383) assessing Allyx Therapeutics investigational, synapse-targeted agent ALX-001 as a potential treatment for Alzheimer disease (AD). In its release, the company noted that they are ready to proceed to phase 2 clinical development, and is not restricted by completion of ongoing studies.

This second phase, which evaluates the safety of ALX-001 dosed twice daily at either 50 mg or 100 mg vs placebo, features patients with AD between 50 and 80 years of age. It builds off previously completed single- and multiple-ascending dose portions that assessed the efficacy and safety of ALX-001, a silent allosteric modulator of mGluR5, in healthy, cognitively normal volunteers.

ALX-001, which has been in development for more than a decade, is a first-in-class compound that selectively blocks the pathogenic activation of the receptor while preserving the normal physiological glutamate signaling that is requiring for cognition. To date, studies have shown that mGlur5 is essential for mediating synaptic dysfunction and loss caused by multiple misfolded extracellular protein species, and as such, represents a novel approach to treating AD and Parkinson disease (PD).

Stephen Bloch, MD, chief executive officer and co-founder at Allyx, said in a statement, "Administering the first dose in patients is a watershed moment for a new therapeutic, and we are pleased to begin research in patients with Alzheimer disease as we continue to advance clinical development of ALX-001 to become the first-ever disease-modifying small molecule for neurodegenerative diseases."

To date, ALX-001’s clinical program has acquired more than $20 million in grant funding from the National Institutes of Health, the U.S. Government’s highly competitive Small Business Innovation Research programs, the Alzheimer’s Association, and the Michael J. Fox Foundation for Parkinson’s Research, among others. The molecule was originally identified by Bristol Myers Squibb, but the mechanism of action for neurodegenerative diseases was discovered by Allyx scientific founder and Yale University professor Stephen Strittmatter, MD, PhD. In 2021, Allyx officially licensed the agent from Bristol Myers Squibb.

"Every neuroscientist hopes for the moment that an asset they believe in and fight for advances to the critical stage of testing in patients,” Strittmatter said in a statement.

 "The unique mechanism of action of ALX-001 and its promising early data have brought us to this point, and bolster our hope that it has the potential to be a difference-maker in Alzheimer disease."

Intensive Multimodal Lifestyle Intervention Improves Cognition and Function in Randomized Controlled Trial

Previous data form the phase 1b study, presented at the AD/PD 2024 Conference earlier this year, showed that ALX-001 was safe, with no clinically significant changes in cognitive or psychological symptom scales. The study comprised of 32 participants who completed the single-ascending dose portion who were then randomly assigned 6:2 to either twice daily ALX-001 or placebo. Across the 50, 100, 150, or 225 mg groups, findings showed that the agent maintained a 2.5-fold safety margin relative to the no observed adverse effect level.

Additional findings revealed that 50 mg BID of ALX-001 achieved a 2-fold coverage of IC80 mGluR5 receptor and 100 mg BID mean Ctrough provided a 6-fold coverage of IC80 mGluR5 receptor occupancy. All adverse events (AEs) reported were supposedly mild and patients fully recovered.

Following the positive reported data, Tim Siegert, PhD, chief operating officer and co-founder of Allyx, 

, stating, “For ALX-001, we are able to measure target engagement by imaging receptor occupancy with PET. This takes the guesswork out of dose translation and selection, which has been a challenge in CNS diseases. This is significant because our preclinical studies showed that 80% occupancy of the mGluR5 receptors rescued learning and memory deficits and reversed synapse loss in transgenic and knock-in mouse models of Alzheimer’s disease. From our human phase 1a receptor occupancy study, we know achieving 136 ng/mL plasma concentration results in 80% receptor occupancy (defining the IC80 concentration). This indicates that, even at the lowest dose (50mg BID), ALX-001 can be expected to demonstrate a therapeutic effect."

In terms of how this drug differs from previously approved antiamyloid therapies, he added that “We think we can do better by directly protecting the synapse from the toxic presence of amyloid-b oligomers. Many Alzheimer programs are now focused on more highly selective amyloid-b oligomer targeted monoclonal antibodies, but clinical benefits are likely to be limited due to selectivity, dosing and safety challenges. This has been reinforced by slow clinical adoption of new therapies so far. Allyx’s approach is different. ALX-001 is a first-in-class oral therapy for neuroprotection from toxic oligomers. Instead of targeting amyloid-b oligomers, ALX-001 blocks amyloid-β oligomer synaptic receptor signaling to protect synapses and halt dysfunction and loss. ALX-001 avoids the known risks of direct amyloid binding, increasing the likelihood of better efficacy and safety in an oral therapy."

REFERENCES
1. Allyx Therapeutics announces first Alzheimer’s disease patient treated with lead compound ALX-001. News release. June 11, 2024. Accessed July 2, 2024. https://www.globenewswire.com/news-release/2024/06/11/2896705/0/en/Allyx-Therapeutics-Announces-First-Alzheimer-s-Disease-Patient-Treated-with-Lead-Compound-ALX-001.html
2. Siegert T, Simms P, Post S, Mecca A, van Dyck C, Strittmatter S. A phase 1b multiple ascending dose study of the safety, tolerability, and pharmacokinetics of ALX-001, an mGluR5 silent allosteric modulator, in healthy older adults. Presented at: AD/PD 2024.

ALX-001, a first-in-class compound, will be assessed in an additional cohort of patients with Alzheimer disease as the company continues to plan for phase 2 studies.

Nicholas E. Johnson, MD, MSci

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