MeiraGTx Posts Encouraging Gene Therapy Data From Eye Disorder Trial

 

• MeiraGTx Holdings plc 
  MGTX+5.67%+ Free Alerts
   announced topline data from the Phase 1/2 study MGT009 of botaretigene sparoparvovec, gene therapy for X-linked retinitis pigmentosa (XLRP).
• Treatment with botaretigene sparoparvovec was found to be generally safe and well-tolerated.
• Significant improvements were demonstrated across retinal, visual functions, and functional vision in participants treated with botaretigene sparoparvovec compared to the randomized untreated control arm of the study at six months post-treatment.
• MeiraGTx and Janssen Pharmaceuticals Inc, a unit of Johnson & Johnson 
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  , are jointly developing botaretigene sparoparvovec.
• In the dose-escalation and expansion phases of the MGT009 study, improvements in vision were seen in subjects treated with low and intermediate doses of botaretigene sparoparvovec compared to the randomized concurrent control arm at 6 months. 
• Improvements were demonstrated in retinal sensitivity on static perimetry, functional vision in a vision-guided mobility assessment, and other visual function and functional vision measures.
• The Phase 3 Lumeos study of botaretigene sparoparvovec for XLRP with disease-causing variants in the RPGR gene is actively dosing patients.

https://www.benzinga.com/general/biotech/22/06/27883902/meiragtx-posts-encouraging-gene-therapy-data-from-eye-disorder-trial

Association of Cyberbullying Experiences and Perpetration With Suicidality in Early Adolescence

 Shay Arnon, MA¹; Anat Brunstein Klomek, PhD¹; Elina Visoki, MSc^2,3; et al

doi:10.1001/jamanetworkopen.2022.18746

Abstract

Importance  Adolescent suicidality (ie, suicidal ideation or attempts) is a major public health concern. Cyberbullying experiences and perpetration have become increasingly prevalent and are associated with mental health burden, but their roles as independent suicidality risk factors remain unclear. Data are needed to clarify their contribution to teen suicidality to inform suicide prevention efforts.

Objective  To examine whether cyberbullying experiences and perpetration are distinct stressors divergent from other forms of peer aggression experiences in their association with suicidality in early adolescence.

Design, Setting, and Participants  This cross-sectional analysis used data collected between July 2018 and January 2021 from the Adolescent Brain Cognitive Development (ABCD) study, a large, diverse sample of US children aged 10 to 13 years.

Exposures  Youth reports of cyberbullying experiences or perpetration.

Main Outcomes and Measures  The main outcome was youth-reported suicidality (past or present, as reported in the ABCD 2-year follow-up assessment). Covariates included demographics, established environmental risk and protective factors for youth suicidality, psychopathology, and experiences or perpetration of offline peer aggression.

Results  A total of 10 414 ABCD participants were included in this study. Participants had a mean (SD) age of 12.0 (0.7) years and 4962 (47.6%) were female; 796 (7.6%) endorsed suicidality. A total of 930 (8.9%) reported experiencing cyberbullying and 96 (0.9%) reported perpetrating cyberbullying. Of the perpetrators, 66 (69.0%) also endorsed experiencing cyberbullying. Controlling for demographics, experiencing cyberbullying was associated with suicidality (odds ratio [OR], 4.2 [95% CI, 3.5-5.1]; P < .001), whereas perpetrating cyberbullying was not (OR, 1.3 [95% CI, 0.8-2.3]; P = .30). Experiencing cyberbullying remained associated with suicidality when accounting for negative life events, family conflict, parental monitoring, school environment, and racial and ethnic discrimination (OR, 2.5 [95% CI, 2.0-3.0]; P < .001) and when further covarying for internalizing and externalizing psychopathology (OR, 1.8 [95% CI, 1.4-2.4]; P < .001). Both being a target and being a perpetrator of offline peer aggression were associated with suicidality (OR, 1.5 [95% CI, 1.1-2.0] for both), controlling for all covariates described earlier. Cyberbullying experiences remained associated with suicidality (OR, 1.7 [95% CI, 1.3-2.2]; P < .001, controlling for all covariates) when included with offline peer aggression experiences and perpetration.

Conclusions and Relevance  In this cross-sectional study, experiencing—but not perpetrating—cyberbullying was associated with suicidality in early adolescence. This association was significant over and above other suicidality risk factors, including offline peer aggression experiences or perpetration. These findings can inform adolescent suicide prevention strategies, and they suggest that clinicians and educational staff working with this population should routinely evaluate for adolescents’ experience with cyberbullying.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793627

FDA Releases Action Plan for Rare Neurodegenerative Diseases, Including ALS

 Today, the U.S. Food and Drug Administration unveiled its Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) – a five-year strategy for improving and extending the lives of people living with rare neurodegenerative diseases by advancing the development of safe and effective medical products and facilitating patient access to novel treatments. 

“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” said FDA Commissioner Robert M. Califf, M.D. “To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities. This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies.” 
 
The action plan is a blueprint for how the agency will move forward in aggressively tackling challenges in drug development for rare neurodegenerative diseases, including ALS, in order to improve patients’ health. Specific actions include regulatory science initiatives, enhancements to existing programs and new policy initiatives. The plan has been developed in accordance with the provisions of the Accelerating Access to Critical Therapies for ALS Act, or ACT for ALS, that President Biden signed into law on December 23, 2021. 

Within a five-year span, the plan will focus on bolstering scientific advancement and promoting innovation for rare neurodegenerative diseases by engaging in targeted activities including: 

• Establishing the FDA Rare Neurodegenerative Diseases Task Force (FY 22).
• Establishing the public-private partnership for rare neurodegenerative diseases (FY 22).
• Developing disease-specific science strategies (FY 22 – FY 26).
• Leveraging ongoing FDA regulatory science efforts.

The ALS Science Strategy is an element of the plan focused specifically on ALS. It provides a forward leaning framework for FDA activities to assess key regulatory science priorities. The focus areas of the ALS Science Strategy are to:

• Improve characterization of disease pathogenesis and natural history —including quantifying disease progression, predictive and prognostic biomarkers, and efficient translation and implementation of basic science discovery is needed.
• Facilitate patient access to new drugs whenever possible and promote greater participation in clinical trials by reducing barriers and burdens faced by diverse populations; utilizing digital health technologies and decentralized trial designs; and ensuring mechanisms for expanded access (generally outside of a clinical trial) are appropriately integrated into development programs.
• Enhance clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.

Key to the success of the FDA’s implementation of the ALS Science Strategy will be patient engagement, public workshops, research projects, coordination across FDA centers and offices and collaboration with the National Institutes of Health (NIH).

ACT for ALS also requires the Department of Health and Human Services (HHS) to implement a Public-Private Partnership for Neurodegenerative Diseases between NIH, FDA and one or more outside entities through cooperative agreements, contracts or other appropriate mechanisms to advance the understanding of neurodegenerative diseases and foster development of treatments for ALS and other rare neurodegenerative diseases. It also directs the agency to award grants and contracts to public and private entities to cover the costs of research and development of interventions that are intended to prevent, diagnose, mitigate, treat or cure ALS and other rare neurodegenerative diseases.

https://www.fda.gov/news-events/press-announcements/fda-releases-action-plan-rare-neurodegenerative-diseases-including-als

Most Pathways Can Be Related to the Pathogenesis of Alzheimer’s

 Sarah L. Morgan1,2,3, Pourya Naderi1,2, Katjuša Koler4, Yered Pita-Juarez1,2,5, Dmitry Prokopenko2,6, Ioannis S. Vlachos1,2,5, Rudolph E. Tanzi2,6, Lars Bertram7,8 and Winston A. Hide1,2*

DOI:  https://doi.org/10.3389/fnagi.2022.846902

Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and diversity of biological pathways within a corpus of 206,324 dementia publication abstracts. A total of 91% (325/335) of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways have publications containing an association via at least 5 studies, while 63% of pathway terms have at least 50 studies providing a clear association with AD. Despite major technological advances, the same set of top-ranked pathways have been consistently related to AD for 30 years, including AD, immune system, metabolic pathways, cholinergic synapse, long-term depression, proteasome, diabetes, cancer, and chemokine signaling. AD pathways studied appear biased: animal model and human subject studies prioritize different AD pathways. Surprisingly, human genetic discoveries and drug targeting are not enriched in the most frequently studied pathways. Our findings suggest that not only is this disorder incredibly complex, but that its functional reach is also nearly global. As a consequence of our study, research results can now be assessed in the context of the wider AD literature, supporting the design of drug therapies that target a broader range of mechanisms. The results of this study can be explored at www.adpathways.org.

https://www.frontiersin.org/articles/10.3389/fnagi.2022.846902/full

FDA Expands Use of Weight-Loss Drug to Adolescents

 The FDA approved a supplemental indication for phentermine/topiramate extended-release capsules (Qsymia) for chronic weight management in adolescents ages 12 and older with obesity, defined as a body mass index (BMI) in the 95th percentile or higher.

The drug originally received FDA approval in July 2012 for adults with overweight or obesity and at least one comorbidity related to weight, and is recommended alongside an increase in physical activity and a reduced-calorie diet in both adults and teens.

According to the CDC, 19.7% of adolescents ages 12 to 19 have obesity, which has negative impacts on their present health, as well as their future health.

The FDA noted that children with obesity often reach adulthood with obesity. While lifestyle modification is initially recommended, medication may be considered in cases where interventions are unsuccessful.

The efficacy and safety of phentermine/topiramate were evaluated in a 56-week, double-blind, placebo-controlled study of 223 adolescents ages 12 to 16 with a very high BMI, who were unsuccessful at losing weight or maintaining weight loss with exercise and diet alone.

Participants were randomized to receive phentermine/topiramate 7.5 mg/46 mg (n=54), phentermine/topiramate 15 mg/92 mg (n=113), or placebo (n=56) once a day after a titration period. Participants also received counseling in lifestyle modifications, including reducing calories and increasing physical activity.

At the end of the study, participants on the 7.5 mg/46 mg dose lost on average 4.8% of their BMI, and those on the 15 mg/92 mg dose lost on average 7.1% of their BMI. Those who were given placebo gained 3.3% of their BMI on average.

Patients starting this drug are advised to take a pregnancy test before use, and to continuously use contraceptives during treatment, since the drug is associated with fetal harm.

Phentermine/topiramate is also not recommended for those with glaucoma, hyperthyroidism, or those who are currently taking or have taken monoamine oxidase inhibitors in the prior 2 weeks.

Common adverse events experienced by adolescents included depression, fever, flu, joint pain, dizziness, and ankle sprain, while adults often experience dizziness, dry mouth, constipation, a pins-and-needles sensation, altered sense of taste, and insomnia. The drug has also been associated with increased heart rate and suicidal ideation.

https://www.medpagetoday.com/pediatrics/obesity/99488

89bio’s home run fails to excite

 Targeting fibroblast growth factors in cardiometabolic diseases has not always gone smoothly. But 89bio has prevailed in a mid-stage study in severe hypertriglyceridaemia with its sole project, the subcutaneous FGF21 analogue pegozafermin.

The company immediately followed the news with a $75m offering, helping explain this morning's muted stock market response – 89bio shares rose just 3% at the open. But investors might also have an eye on a readout next year in a bigger opportunity, Nash – and here 89bio has plenty of competition.

Data Entrigue

The phase 2 Entrigue trial evaluated various doses of pegozafermin in patients with severe hypertriglyceridaemia, defined as triglyceride levels of 500mg/dl or greater. Around half of patients were on background therapy, including statins and prescription fish oils.

The primary endpoint was the change in triglycerides from baseline, versus placebo, at eight weeks.

Before the readout, SVB Securities analysts had said a triglyceride reduction of 40-50% or more would be considered a “home-run scenario”. This was achieved at all weekly doses, with the highest dose tested, 27mg weekly, looking particularly impressive. These figures also look good when compared with the 27% decline in triglycerides seen with Amarin’s Vascepa.

Source: Company presentation

However, there are reasons to be cautious about the 27mg/week dose of pegozafermin: the trial’s two treatment-related discontinuations came in this cohort, one due to abdominal cramps and one due to nausea and vomiting. Overall, 22% and 17% of patients in this dose group experienced nausea and diarrhoea respectively.

89bio has not yet said which dose it will take forward into a phase 3 study, slated to start in the first half of next year. If this is successful, the group plans to seek approval based on triglyceride lowering – it believes that it will not need a cardiovascular outcomes trial.

SVB reckons that pegozafermin sales in severe hypertriglyceridaemia could peak at around $650m – while this is a substantial sum it is dwarfed by the $3bn the analysts have forecast for the project in Nash.

There are good reasons for investors to be jittery about Nash, which has proven a tough indication to crack. And frayed nerves might not have been helped by 89bio recently making several changes to its Enliven mid-stage trial in Nash, including skewing enrolment towards high-dose arms and adding secondary composite histology endpoints to try to “help stabilise the placebo response”.

A competitor might soon provide an indication of whether Enliven has a chance: Akero Therapeutics is due to report data from the Harmony trial of its FGF21 stimulant in Nash next quarter.

However, other FGF21 projects have already disappointed, with Bristol Myers Squibb last year discontinuing pegbelfermin, which it had been developing for Nash. Novo Nordisk also shelved NN9499 in obesity, although it is still pursuing an FGF21 asset in Nash.

Targeting fibroblast growth factors in liver and cardiometabolic diseases
Project	Company/ies	Description	Details
Phase 2
Pegozafermin (BIO89-100)	89bio	Glycopegylated FGF21 analogue	Entrigue in SHTG toplined Jun 2022; Enliven in Nash, data due Q1 2023
Efruxifermin	Akero Therapeutics (via Amgen)	Fc-FGF21 fusion protein	Harmony in non-cirrhotic Nash, data due Q3 2022; Symmetry in cirrhotic Nash, ends Oct 2023
BOS-580	Boston Pharmaceuticals (via Novartis)	FGF21 analogue	NCT04880031 in Nash, completes Nov 2022
Aldafermin	NGM Bio	FGF19 analogue	Failed Alpine 2/3 in F2/F3 Nash; Alpine 4 in F4 Nash, data due H1 2023
NNC0194-0499 (NN9500)	Novo Nordisk	FGF21 analogue	NCT05016882 + semaglutide in Nash, ends May 2024
MK-3655 (NGM313)	Merck & Co/NGM Bio	FGFR1c/KLB agonist antibody	NCT04583423 in pre-cirrhotic Nash, ends May 2024
Fallen by the wayside
Pegbelfermin	Bristol Myers Squibb	Pegylated FGF21 analogue	Discontinued Nov 2021 following Falcon trials in Nash
Nash=nonalcoholic steatohepatitis; SHTG=severe hypertriglyceridemia. Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/trial-results/89bios-home-run-fails-excite

Axsome Advances MDD Drug, Explores New ADHD Treatment

 Three months after striking a deal to acquire the excessive daytime sleepiness drug Sunosi from Jazz Pharmaceuticals, Axsome Therapeutics is planning to assess the dual-acting dopamine and norepinephrine reuptake inhibitor in a Phase III attention deficit hyperactivity disorder (ADHD) study.

On Tuesday, Axsome hosted an investor day event to provide an update on plans for Sunosi following the $53 million deal that brought it into the company's portfolio. Additionally, Axsome provided updates on other developmental assets, including major depressive disorder (MDD) treatment AXS-05 (dextromethorphan-bupropion), which is under review by the U.S. Food and Drug Administration. 

In a Monday filing with the U.S. Securities and Exchange Commission, Axsome announced that the FDA provided the company with proposed labeling for AXS-05 related to a New Drug Application filing. Axsome said it was reviewing the proposed labeling and is expected to reply to the FDA to secure a final agreement. 

AXS-05 is an NMDA receptor antagonist that uses a proprietary formulation and dose of dextromethorphan and bupropion. Earlier this month, the company presented new data from the Phase III GEMINI study on MDD that showed AXS-05 provided "substantial and statistically significant improvement in depressive symptoms and induction of remission."

That notification from the FDA is significantly good news for Axsome since it had hoped that AXS-05 would already have a year's worth of approval. The company expected potential approval in 2021, but the FDA announced that its review of the data would not be completed by the time the initial PDUFA date had been set. 

In its year-end financial report in March, Axsome said it has answered all CMC questions the regulatory agency raised about that delay. AXS-05 is under Priority Review.

For Sunosi, the company outlined its vision to achieve approval for a supplemental New Drug Application in ADHD, a common, chronic neurodevelopmental disorder. During the investor event, Stephen V. Faraone, a professor in the departments of psychiatry and neuroscience and physiology at SUNY Upstate Medical University, explained that throughout the lifetime of a patient, ADHD increases the risk of multiple psychiatric disorders, including depression and suicide, as well as occupational failure and addiction. 

While there are several medications approved for ADHD, there are problems with many of them, including concerns over non-adherence and the fact that some of the drugs are stimulants that can be misused and abused. Axsome believes that Sunosi can play a unique role in treating ADHD and meeting some of the unmet needs of that patient population. 

Sunosi is a dual-acting dopamine and norepinephrine reuptake inhibitor. Amanda Jones, senior vice president of clinical development at Axsome, noted that both dopamine and norepinephrine are implicated in the pathophysiology of ADHD. She also explained that as a non-stimulant, Sunosi has a low potential for abuse. The company plans to conduct a four-week Phase III study in this indication to assess its potential. 

Additionally, the company intends to conduct a study assessing if Sunosi can improve cognitive outcome measures in patients with excessive daytime sleepiness associated with obstructive sleep apnea (OSA). About 40% of OSA patients complain of cognitive difficulties. 

Data from both of these Sunosi studies are expected later this year. Axsome believes that Sunosi has significant upside in additional indications and intends to explore those options to maximize returns on its investment.

https://www.biospace.com/article/axsome-explores-new-indications-for-sunosi-sees-light-at-the-end-of-the-tunnel-for-experimental-mdd-drug/