A simplified gout remission definition was a feasible and valid option when compared with the 2016 preliminary gout remission definition when compared in a study of nurse-led and usual (general practitioner) care.

“To date, discrimination of the remission definitions between intervention groups has not been demonstrated in a clinical trial of urate-lowering therapy. Therefore, we compared the performance of the 2016 preliminary gout remission definition and the simplified gout remission definition by evaluating their discrimination between intervention groups, sensitivity to change over time, and construct validity, in a community-based clinical trial of nurse-led treat-to-target gout care versus usual general practitioner care,” lead investigator Adwoa Dansoa Tabi-Amponsah, PhD candidate, Department of Medicine, The Faculty of Medical and Health Sciences, University of Auckland, New Zealand, and colleagues wrote.

Tabi-Amponsah and colleagues analyzed data from a 2-year, parallel arm, randomized, unblinded trial involving 517 community derived participants with gout who were randomized 1:1 to receive nurse-led care or general practitioner usual care. Remission definitions were compared between the 2016 preliminary gout remission definition and a simplified gout remission definition without patient reported outcomes by binary logistic regression. They also compared Gout Impact Scale (GIS) scores with general linear models between those in remission and those not in remission using either definition.

The investigators found that participants in the nurse-led care group were more likely to achieve remission using either definition with an odds ratio (OR) at year 2 of 7.92 [95% CI, 4.86–12.92] using the 2016 preliminary definition and 11.88 [95% CI, 7.49–18.84] using the simplified definition.

Overall, 9.9% of participants achieved remission defined by the 2016 preliminary definition at Year 1 and 28.4% achieved it at Year 2 (

 <.001). More participants achieved remission according to the simplified definition (17.6% at Year 1 and 42.7% at Year 2; 

 <.001). Participants that achieved remission according to either definition had better gout outcomes via the GIS, including greater control over their gout, worry about future gout attacks, gout disease progression and its interference in future activities, and efficacy of gout medication, than those who did not.

“In summary, both remission definitions performed well in discriminating between the nurse-led care group and usual care group. The simplified definition identified more people as being in remission at Year 1 and Year 2, and also showed high construct validity using a gout specific health related quality of life instrument. The simplified definition is a feasible, sensitive, and valid option for defining gout remission,” Tabi-Amponsah and colleagues concluded.

Other recent research into gout flares and remission found that, unsurprisingly, overall urate lowering therapy 

 and less urate target achievement in people with gout. Overall, adherence as assessed by Medication Adherence Report Scale (MARS-5) questionnaire was high (median, 24; interquartile range, 22-25). Patients in the lowest MARS-5 quartile had, compared to the highest quartile,flares more often during the last year of follow-up (33.3% vs. 9.5%, 

=.004), and reached the 5-year serum urate treatment target less frequently (45.2% vs. 87.5%, 

Tabi-Amponsah AD, Doherty M, Sarmanova A, et al. Post-hoc analysis of two gout remission definitions in a two-year randomized controlled trial of nurse-led versus usual gout care. 

2024(16):152555. doi: 10.1016/j.semarthrit.2024.152555

Uhlig T, Karoliussen LF, Sexton J, et al.Non-adherence to urate lowering therapy in gout after 5 years is related to poor outcomes—results from the NOR-Gout study. 

. Published online September 18,2024;keae514. Doi: 10.1093/rheumatology/keae514

Articles

A study compared the 2016 preliminary gout remission definition with a simplified version in a trial of nurse-led versus general practitioner care. The simplified definition showed higher sensitivity and construct validity, identifying more patients in remission. Participants in nurse-led care were more likely to achieve remission with both definitions. The study highlighted the importance of adherence to urate-lowering therapy, as nonadherence was linked to more flares and less target achievement. The simplified definition is a feasible and valid option for defining gout remission in clinical settings.

Remission according to the simplified definition correlated with the 2016 preliminary gout remission definition and GIS score improvements.

Simplified Gout Remission Definition Feasible, Valid

Zobair Younossi, MD, MPH: Resmetirom’s Impact on Health-Related Quality of Life in MASH

New patient-reported outcomes data from the phase 3 MAESTRO-NASH trial highlight resmetirom (Rezdiffra)’s positive impact on health-related quality of life (HRQoL) in patients with 

metabolic dysfunction-associated steatohepatitis (MASH)

 and moderate to advanced fibrosis, building upon previous findings regarding the liver-directed thyroid hormone receptor-β agonist’s benefit for MASH resolution and fibrosis improvement.

“[MASH] is a disease that does have an impact on quality of life, specifically health-related quality of life. In that context, the more severe the disease is, the more profound the quality of life impairment,” Zobair Younossi, MD, MPH, professor and chairman of the Beatty Liver and Obesity Research Program, Inova Health System, chairman of the Global NASH Council, and lead author of the HRQoL analysis, explained to 

, describing misconceptions about MASH being an asymptomatic disease.

Younossi emphasized the importance of exploring any intervention’s “comprehensive impact,” including its clinical impact, its impact on patient experience and HRQoL, and its cost-effectiveness.

As the first and only FDA-approved MASH therapeutic, resmetirom’s clinical impact has been demonstrated across 18 clinical studies in its clinical development program. Now, its benefit on patient experiences and HRQoL has also been confirmed through an analysis of MAESTRO-NASH comparing changes in HRQoL scores from baseline in patients receiving resmetirom versus placebo and compared between patients with and without biopsy response.

Among 966 ITT patients, 323 received resmetirom 100 mg, 322 received resmetirom 80 mg, and 321 received placebo. By weeks 24 and 52, patients receiving 80 or 100 mg resmetirom experienced HRQoL improvement in the Worry domain of the Chronic Liver Disease Questionnaire-NASH (mean +0.21 to +0.24; 

<.05). At week 52, participants who met histologic endpoints after treatment with resmetirom 100 mg or 80 mg experienced an improvement in several HRQoL domains, including Worry (+0.46), Health Distress (+8.1), and Stigma (+3.5).

Of note, the improvement in HRQoL among resmetirom biopsy responders was contrasted by no similar improvement in the placebo group. Additionally, biopsy responders with stage F3 fibrosis at baseline had similar or more pronounced improvements in HRQoL in comparison to responders with F2 or F1B fibrosis at baseline.

“At the end of the day, a patient doesn’t understand their fibrosis stage or their ELF score or their FibroScan score. They may or may not really get the variables that are important to clinicians,” Younossi explained. “They want to make sure that they feel better, and ultimately, they are not going to risk bad liver disease in the future. This answers the first piece, that if you respond to this treatment, you will also have some improvement in your quality of life.”

Brooks, A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed October 8, 2024. 

https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

Madrigal Pharmaceuticals. Madrigal Pharmaceuticals Announces Publication of Positive Health-Related Quality of Life Results from the Phase 3 MAESTRO-NASH Trial of Rezdiffra™ (resmetirom). September 30, 2024. Accessed October 8, 2024. 

https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-publication-positive-health

Younossi ZM, Stepanova M, Racila A, et al. Health-Related quality of life (HRQL) assessments in a 52-Week, Double-Blind, randomized, Placebo-Controlled phase 3 study of resmetirom (MGL-3196) in patients with metabolic dysfunction associated steatohepatitis (MASH) and fibrosis. 

Videos

Resmetirom (Rezdiffra) has shown a positive impact on health-related quality of life (HRQoL) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis, as demonstrated in the phase 3 MAESTRO-NASH trial. The trial revealed significant HRQoL improvements in patients receiving resmetirom compared to placebo, particularly in the Worry, Health Distress, and Stigma domains. These findings underscore the importance of considering comprehensive impacts, including patient experience and HRQoL, when evaluating therapeutic interventions for MASH.

Younossi explains how MASH negatively impacts patients’ quality of life and describes resmetirom’s benefit across multiple HRQoL domains.

Blue Shield California has reached a deal with adalimumab biosimilar manufacturer Fresenius Kabi to offer the drug at a quarter of the price of the market reported net price of reference adalimumab (Humira).

“We will no longer take part in a pharmacy system that is designed to maximize the profit of participants instead of the quality, convenience and cost-effectiveness for consumers,” Paul Markovich, CEO, Blue Shield of California, said in a statement.

 “Every employer, health plan and payer should be asking — and challenging — their pharmacy benefit managers to offer clinically effective and lower cost alternatives at a transparent price. This is why Blue Shield decided to rebuild our pharmacy care system — so we can get medications to the right people, at the right time, at the right price.”

The agreement was reached between Fresenius Kabi, which manufactures adalimumab-aacf (Idacio) and is an operating company of Fresenius, and was facilitated by Evio Pharmacy Solutions. As part of the agreement, Blue Shield California will offer the biosimilar for $525 net price per monthly dose, compared to the market reported net price of Humira at $2,100. In a statement, Blue Shield California said that the deal was enabled by Blue Shield’s new Pharmacy Care Reimagined model and other innovations. The discount was enabled by eliminating supply chain obstacles and removes excess complexities. One of these "complexities" is the role of pharmacy benefit managers, which are sidestepped in the new agreement.

“Biosimilars are safe, effective and essential to lower the cost of biologic medicines and improve their access to patients in the United States,” Pierluigi Antonelli, president and CEO, Fresenius Kabi, added.

 “Fresenius Kabi is pleased to provide this option to Blue Shield of California and their members. By simplifying the drug’s path to patients, our collective goal is to make medicine more affordable and more accessible. This allows for prioritizing savings through overall lower net costs that can improve both premiums and patient out-of-pocket spending for their medication.”

The agreement will go into effect on January 1, 2025, on which date most Blue Shield commercial members using adalimumab-aacf will pay $0 out of pocket. The company believes that not only will the collaboration bring drug spend down, medication adherence is also expected to go up, yielding reductions in overall cost of care and benefitting member health outcomes.

“We are excited to continue the pharmacy transformation journey with Blue Shield of California, as our first health plan customer to participate in this new net price model,” Matt Seibt, head of pharmaceutical partnerships at Evio Pharmacy Solutions, added.

 “This offering will have a massive impact on reducing health care costs. Evio will continue to utilize our innovative contracting and operational model to craft additional biosimilar opportunities in the next few years.”

Other recent research into adalimumab biosimilars found that patients with inflammatory bowel disease (IBD) are 

satisfied with all adalimumab biosimilar and reference

 treatments, with some levels of variance. Patients using the subcutaneous injection form had the highest satisfaction with Yuflyma® (9.0; SD, 1.4), Humira (8.9; SD, 1.3) and Hulio (8.9; SD, 1.7; 

 <.05). Around one-third (n = 299; 31.8%) of all participants had injection site reactions. Over one-fifth of patients (n = 223; 23.7%) were previously treated with another adalimumab of which 32 (14.3%) discontinued treatment due to adverse events.

“Humira has drawn scrutiny for its high and inconsistent pricing from both consumers and policymakers,” Matt Gibbs, vice president of pharmacy transformation at Blue Shield of California added.

 “With our new low-cost alternative, Blue Shield offers a more affordable, yet equally clinically effective option to members and employers. This move continues our organization’s path of transparency and transforming pharmacy care for the better.”

Blue Shield of California Slashes Cost of World’s Best-Selling Drug. News release. Blue Shield California. October 1, 2024. 

https://news.blueshieldca.com/2024/10/01/blue-shield-of-california-slashes-cost-of-worlds-best-selling-drug

Caron B, Seksik P, Buisson A, et al. Patient preferences for adalimumab in inflammatory bowel disease: a nationwide study from the GETAID. 

Blue Shield California has partnered with Fresenius Kabi to offer the adalimumab biosimilar, Idacio, at a significantly reduced price compared to Humira. This initiative is part of Blue Shield's Pharmacy Care Reimagined model, aiming to enhance medication accessibility and affordability by simplifying the supply chain. The agreement, effective January 2025, will allow most Blue Shield members to access adalimumab-aacf with no out-of-pocket costs, potentially improving medication adherence and reducing overall healthcare costs. Recent studies indicate high patient satisfaction with adalimumab biosimilars, despite some adverse events.

BSC and Fresnius Kabi reached a deal facilitated by Evio Pharmacy Solutions by sidestepping pharmacy benefit managers.

Blue Shield California Offers Adalimumab Biosimilar for a Quarter of Reference Price

New research presented at CHEST 2024 suggests ensifentrine (Ohtuvayre) was associated with improved lung function, symptoms, and quality of life regardless of disease severity among patients with 

chronic obstructive pulmonary disease (COPD)

“Patients with COPD continue to suffer from impaired lung function, daily symptoms, and impaired quality of life despite available treatments,” wrote investigators.

 “Ensifentrine provides a novel mechanism of action for clinically meaningful improvements in lung function, symptoms, and quality of life regardless of COPD severity, that is complementary to existing treatment mechanisms.”

In June 2024, ensifentrine received a historic approval from the 

 for the treatment of COPD. an inhaled nonsteroidal nebulizer therapy, the dual PDE3 and PDE4 inhibitor became the first treatment with a novel mechanism of action to receive approval for COPD in more than a decade. This approval, which was awarded to Verona Pharma, was based on data from the phase 3 ENHANCE-1 and -2 trials.

In her presentation at CHEST 2024, Jessica Bon, MD, MS, of Wake Forest University School of Medicine, detailed an analysis of the trials aimed at detailing the effects of the agent on lung function, COPD symptoms, and quality of life among patients with moderate-to-severe COPD. Form the trials. Investigators obtained information from 868 patients with COPD and moderate airflow obstruction and 681 with severe airflow obstruction.

Upon analysis, results suggested use of ensifentrine was associated with a statistically significant improvement in FEV1 AUC(0-12h) relative to placebo at week 12 for both the moderate and severe subgroups (

<.05). Further analysis demonstrated ensifentrine treatment was associated with significantly improved Peak FEV1 at week 12 relative placebo in both groups (

Investigators highlighted improvements observed in E-RS Total Score with ensifentrine, with this reduction reaching statistical significance relative to placebo therapy at weeks 6, 12, and 24 among the moderate subgroup (

<.05) and week 6 among the severe subgroup. Of note, numeric improvements were observed in the severe group at weeks 12 and 24. Additionally, analysis of St. George’s Respiratory Questionnaire total scores suggested improvements in score were observed at weeks 6, 12, and 24 for both subgroups and exceeded the minimal clinically important difference at weeks 6 and 24 in both subgroups.

In addition to this analysis, 5 other presentations focused on the effects of ensifentrine at CHEST 2024. These studies, all of which leveraged data from the ENHANCE program, examined the effects across a multitude of subgroups and for several different endpoints, including quality of life, effect of background smoking history on outcomes, and associations of use with decreasing healthcare resource utilization.

“Ensifentrine is a remarkable addition to COPD therapy,” said William Stringer, MD, professor of Medicine at the David Geffen School of Medicine at UCLA.

 “It has the capacity to bronchodilate, reduce inflammation, augment mucociliary clearance, and reduce exacerbations in smokers and former smokers.”

ENSIFENTRINE IMPROVED LUNG FUNCTION, SYMPTOMS, AND QUALITY OF LIFE REGARDLESS OF COPD SEVERITY. 

Presented at: CHEST 2024. Boston, MA. October 6 - 9, 2024.

Kunzmann K. FDA approves Ensifentrine (ohtuvayre) for COPD. HCP Live. June 26, 2024. Accessed October 8, 2024. https://www.hcplive.com/view/fda-approves-ensifentrine-for-copd.

Verona Pharma. Verona Pharma to present six analyses of the phase 3 enhance studies in COPD at chest 2024. Verona Pharma. September 30, 2024. Accessed October 8, 2024. https://www.veronapharma.com/news/verona-pharma-to-present-six-analyses-of-the-phase-3-enhance-studies-in-copd-at-chest-2024/.

Ensifentrine, an inhaled nonsteroidal nebulizer therapy, has shown significant improvements in lung function, symptoms, and quality of life for COPD patients, regardless of disease severity. Approved by the FDA in June 2024, it is the first COPD treatment with a novel mechanism in over a decade. Data from the ENHANCE-1 and -2 trials demonstrated statistically significant improvements in FEV1 and quality of life scores. Additional studies presented at CHEST 2024 highlighted its benefits across various subgroups and endpoints, including reduced healthcare resource utilization.

New research presented at CHEST 2024 highlights ensifentrine’s effectiveness in improving lung function, symptoms, and quality of life for COPD patients, regardless of disease severity.

CHEST 2024: Ensifentrine Improves Lung Function, Quality of Life Regardless of COPD Severity

) has issued another Complete Response Letter (CRL) for dasiglucagon (Zegalogue) for the prevention and treatment of hypoglycemia in pediatric patients 7 days of age or older with 

Announced by Zealand Pharma on October 08, 2024, the company stated the FDA's CRL cited the timing of the third-party manufacturing facility inspection, which was completed in August/September 2024. Of note, issues at the manufacturing facility were cited as the reason for the initial CRL for this indication, which was announced in December 2023.

“We at Zealand Pharma are acutely aware of the significant unmet medical need for newborns and children with congenital hyperinsulinism who have either no or very limited treatment options today,” said David Kendall, MD, chief medical officer of Zealand Pharma. “We are committed to working with the FDA and our third-party manufacturing partner to bring dasiglucagon to patients living with this devastating disease in the months ahead.”

In June 2023, Zealand Pharma announced the FDA acceptance of their New Drug Application for dasiglucagon. In December 2023, Zealand Pharma announced the receipt of a Complete Response Letter from the FDA.

According to the company, the agency did not cite any deficiencies in the application related to dasiglucagon but were instead related to those identified during an inspection at a third-party manufacturing facility. In May 2024, the company noted the FDA had assigned an October 08, 2024, target action date for their resubmission.

According to the October 08, 2024 announcement of the CRL, Zealand Pharma pointed out the third-party contract manufacturing facility inspection was completed in August/September 2024 but the manufacturer had not yet received its inspection classification following ther reinspection. The company also pointed out prior deficiencies had been resolved as of this reinspection and the CRL did not state any concerns about the clinical data package or safety of dasiglucagon.

The NDA from Zealand Pharma is supported by a pair of phase 3 trials and their long-term extension trial. One phase 3 trial assessed dasiglucagon for reducing the need for intravenous glucose in newborns and infants newly diagnosed with congenital hyperinsulinism who were being treated in a hospital setting and potentially avoid pancreatectomy. The other phase 3 trial assessed dasiglucagon for reducing time in hypoglycemia for children aged between 3 months and 12 years administered in a homecare setting. The final trial used in support of the application was an ongoing long-term extension trial that enrolled 42 of the 44 patients who participated in the 2 aforementioned trials.

The first trial was a 2-arm, open-label study conducted among 32 children with congenital hyperinsulinism aged 3 months to 12 years and was conducted in a homecare setting. In the study, all participants were treated with dasiglucagon plus standard of care from week 5 until the end of the 8-week study. Results of this study suggested use of dasiglucagon did not significantly reduce the rate of hypoglycemia compared to standard of care alone when assessed by intermittent self-measured plasma glucose.

The other phase 3 trial was a 2-part study. A total of 12 neonates and infants aged 7 days to 12 months were included in the first part, which was a 48-hour crossover study. Results from this part of the study suggested use decreased the need for intravenous glucose infusion by 55% relative to placebo therapy. Part 2 was designed as a 21-day open-label study, which concluded 10 of the 12 neonates and infants were able to discontinue intravenous glucose for at least 12 hours and 7 of the 12 neonates and infants remained weaned off intravenous glucose at the end of the trial without concomitant pancreatic surgery.

Zealand Pharma. Zealand Pharma provides U.S. regulatory update on dasiglucagon in congenital hyperinsulinism. GlobeNewswire News Room. October 8, 2024. Accessed October 8, 2024. https://www.globenewswire.com/en/news-release/2024/10/08/2960183/0/en/Zealand-Pharma-provides-U-S-regulatory-update-on-dasiglucagon-in-congenital-hyperinsulinism.html.

Zealand Pharma. Zealand Pharma submits New Drug Application to US FDA for dasiglucagon in congenital hyperinsulinism. GlobeNewswire News Room. June 30, 2023. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2023/06/30/2698007/0/en/Zealand-Pharma-submits-New-Drug-Application-to-US-FDA-for-dasiglucagon-in-congenital-hyperinsulinism.html.

Zealand Pharma. U.S. Food and Drug Administration Issues Complete Response Letter for Dasiglucagon in congenital hyperinsulinism for up to three weeks of dosing due to inspection findings at third-party manufacturing facility. GlobeNewswire News Room. December 23, 2023. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2023/12/23/2800891/0/en/U-S-Food-and-Drug-Administration-issues-Complete-Response-Letter-for-dasiglucagon-in-congenital-hyperinsulinism-for-up-to-three-weeks-of-dosing-due-to-inspection-findings-at-third-.html.

Zealand Pharma. Zealand Pharma announces financial results for the first quarter of 2024. GlobeNewswire News Room. May 16, 2024. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2024/05/16/2883075/0/en/Zealand-Pharma-Announces-Financial-Results-for-the-First-Quarter-of-2024.html.

Zealand Pharma. Zealand Pharma announces data from the first phase 3-trial with dasiglucagon in Congenital Hyperinsulinism (CHI) Z. GlobeNewswire News Room. December 2020. Accessed October 8, 2024. https://ml-eu.globenewswire.com/Resource/Download/157a5a09-f74e-4e14-a760-2f50c3172402.

Zealand Pharma. Zealand Pharma announces positive results from phase 3 trial of Dasiglucagon in pediatric patients with congenital hyperinsulinism (CHI) . GlobeNewswire News Room. May 19, 2022. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2022/05/19/2446817/0/en/Zealand-Pharma-Announces-Positive-Results-from-Phase-3-Trial-of-Dasiglucagon-in-Pediatric-Patients-with-Congenital-Hyperinsulinism-CHI.html#xd_co_f=ODdkNGE0YmItYWE1Ni00ZmE2LTg0OGYtNzE4ZGZkMjE1YTkz~.

Zealand Pharma. Zealand Pharma Announces Global License and Development Agreement with Novo Nordisk for Zegalogue® (dasiglucagon). GlobeNewswire News Room. September 7, 2022. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2022/09/07/2511078/0/en/Zealand-Pharma-Announces-Global-License-and-Development-Agreement-with-Novo-Nordisk-for-ZEGALOGUE-dasiglucagon.html.

The FDA issued a Complete Response Letter (CRL) for dasiglucagon, citing issues at a third-party manufacturing facility, not deficiencies in the drug's application. Zealand Pharma remains committed to addressing these issues to meet the unmet medical needs of pediatric patients with congenital hyperinsulinism. The New Drug Application is supported by phase 3 trials, which showed mixed results in reducing hypoglycemia and intravenous glucose needs. The company aims to resolve manufacturing issues and bring dasiglucagon to market, emphasizing its potential benefits for affected children.

The FDA's decision to issue a CRL was announced on October 08, 2024 and cites issues with the timing of the facility inspection.

FDA Issues Second CRL for Dasiglucagon (Zegalogue) in Congenital Hyperinsulinism

 month in review for September 2024 is any indication, recent advancements in gene therapies and treatments for vision-related conditions could significantly improve patient outcomes and quality of life.

In September, ATSN-101 gene therapy demonstrated notable safety and efficacy in patients with Leber congenital amaurosis 1, while Nanoscope Therapeutic's MCO-010 gene therapy received US Food and Drug Administration (FDA) support for its Phase 3 trial targeting Stargardt disease. Additionally, oral gildeuretinol acetate showed significant reductions in geographic atrophy (GA) growth associated with age-related macular degeneration (AMD), and phentolamine ophthalmic solution provided rapid reversal of mydriasis, leading to FDA approval. Meanwhile, studies underlined the psychological impacts of vision loss, highlighting a higher risk of depression in retinitis pigmentosa patients and suggesting that correcting vision impairment could prevent nearly 20% of dementia cases in older adults.

ATSN-101 Gene Therapy Reports Positive Data in Phase 1/2 Trial

ATSN-101 subretinal gene therapy showed a strong safety profile and significant improvements in visual function in patients with Leber congenital amaurosis 1 (LCA1) due to GUCY2D mutations, according to Phase 1/2 trial data. High-dose ATSN-101 treatment resulted in an average 20 dB improvement in dark-adapted full-field stimulus test (FST), with two patients experiencing over 40 dB improvements. These results indicate the potential efficacy of gene therapy for patients with LCA1, even after years of blindness.

Nanoscope Reports Positive End-of-Phase 2 Meeting for MCO-010 Gene Therapy

On September 12, 2024, Nanoscope Therapeutics announced a successful End-of-Phase 2 meeting with the FDA for its MCO-010 gene therapy targeting severe vision loss caused by Stargardt disease. The FDA's support enables the initiation of a Phase 3 trial, which will assess the safety and efficacy of a single dose of MCO-010 compared to a sham injection. This advancement represents a potential breakthrough in providing a restorative treatment for patients with Stargardt disease, moving beyond traditional vision rehabilitation approaches.

SAGA: Oral Gildeuretinol Achieves Meaningful Reduction in GA Growth Rate

On September 17, 2024, Alkeus Pharmaceuticals announced that oral gildeuretinol acetate (ALK-001) significantly reduced lesion growth in patients with GA secondary to AMD after 24 months. The Phase 3 SAGA trial also demonstrated a statistically significant slowing of low-luminance visual acuity (LLVA) decline, a key secondary endpoint, with a favorable safety profile. These findings will be presented as a late-breaking abstract at the 128th Meeting of the American Academy of Ophthalmology (AAO) in Chicago.

Phentolamine Ophthalmic Solution 0.75% Achieves Rapid Reversal of Mydriasis

Results from the Phase 3 MIRA-2 and MIRA-3 trials showed phentolamine ophthalmic solution 0.75% (RYZUMVI™) effectively and safely reversed pharmacologically-induced mydriasis within 60 to 90 minutes. The trials demonstrated a statistically significant reduction of 3 to 4 hours in time to return to baseline pupil diameter compared with placebo. These results formed the basis for FDA approval, highlighting the clinical benefit of phentolamine ophthalmic solution for patients requiring faster recovery from pupil dilation.

Retinitis Pigmentosa Diagnosis Intensifies Risk of Depressive Disorder

A nationwide cohort study in Korea found that patients with retinitis pigmentosa (RP) had a higher incidence of newly diagnosed depressive disorder compared with the general population. The 10-year cumulative incidence of depressive disorder in these patients was around 18%, with a higher rate among women and those aged 40 and older. These findings emphasized the importance of integrating mental health care into the overall management plan for patients with RP, particularly given the progressive nature of the condition and its notable impact on quality of life.

Correcting Vision Impairment May Prevent Dementia in Older Adults

A recent study in JAMA Ophthalmology found nearly 20% of dementia cases in US adults aged 71 and older could potentially be prevented by addressing correctable vision impairments. The analysis showed that contrast sensitivity impairment had the highest impact on dementia risk, with a population attributable fraction of 15%, compared to distance and near visual acuity. The investigative team emphasized the importance of incorporating vision health into dementia prevention strategies to address modifiable risk factors.

Recent advancements in ophthalmology, particularly in gene therapies and treatments, show promise in improving patient outcomes. ATSN-101 gene therapy demonstrated safety and efficacy for Leber congenital amaurosis 1, while MCO-010 received FDA support for Stargardt disease trials. Oral gildeuretinol acetate reduced geographic atrophy growth in AMD, and phentolamine ophthalmic solution reversed mydriasis rapidly, gaining FDA approval. Studies highlighted the psychological impact of vision loss, with increased depression risk in retinitis pigmentosa patients and potential dementia prevention through correcting vision impairments in older adults.

This September 2024 month in review highlights recent advances in gene therapies and therapies demonstrating the potential for improved vision outcomes.

Ophthalmology Month in Review: September 2024

Gerald Maguire, MD: The Future of Acetylcholine and Muscarinic Receptors

xanomeline trospium chloride capsules (Cobenfy)

 treatment by improving positive, negative, and cognitive symptoms while minimizing adverse events.

At the Southern California Psychiatry Conference on September 13, 2024, Gerald A. Maguire, MD, director of residency training in Psychiatry at College Medical Center in Long Branch, California, and chief medical officer at AdhereTech, presented the session, “Rethinking Systems in Schizophrenia: Acetylcholine and Muscarinic Receptors.”

The presentation took place a couple of weeks before the US Food and Drug Administration (FDA) approved xanomeline trospium chloride capsules, formerly KarXT, for schizophrenia.

 spoke to Maguire about the role of acetylcholine and muscarinic receptors. Historically, schizophrenia medications targeted dopamine receptors, but lately, research has been showing the combination of xanomeline, an M1 and M4 agonist, and trospium, a peripheral antagonist improves symptoms of schizophrenia.

“We've had some inkling that dopamine and acetylcholine play a balance in schizophrenia,” Maguire said.

The interplay between dopamine and acetylcholine has been observed for years, back when investigators studied pathways leading to Parkinson’s. It also has been known for a while antipsychotic medications lead to too much dopamine blockage.

“There's also been this understanding that too much blockade of acetylcholine, too much of the muscarinic blockade, can lead to what looks like psychosis,” he said. “We've all remembered the concern about anticholinergic crisis, where one could be dry as a bone and hot as a hair and mad as a hatter, blind is a bat, et cetera. So that's been in our minds.”

It was later discovered xanomeline could improve symptoms of schizophrenia, but it led to many adverse events such as gastrointestinal issues

“So, the idea of adding a trospium, a peripheral anti-muscarinic compound, was a novel idea to add to the xanomeline such that you may be able to maintain that effect in the brain and develop more of a tolerable delivery throughout the body,” Maguire said.

The addition of trospium allows individuals to achieve the same benefit as a muscarinic agonism but without the peripheral anticholinergic or anti-muscarinic events.

“We may treat schizophrenia now not by just blocking dopamine two receptors, but in another way that actually addresses the real underlying pathophysiology, which is the presynaptic dopamine activity and decreasing that presynaptic dopamine activity as explained through agonism of the m1 and the m4 receptors,” he said.

Emerging therapies like xanomeline trospium chloride capsules represent a significant advancement in schizophrenia treatment by addressing positive, negative, and cognitive symptoms with fewer adverse effects. Historically, schizophrenia medications focused on dopamine receptors, but recent research highlights the role of acetylcholine and muscarinic receptors. Xanomeline, an M1 and M4 agonist, combined with trospium, a peripheral antagonist, offers a novel approach by maintaining brain effects while minimizing peripheral side effects. This method targets presynaptic dopamine activity, potentially addressing the underlying pathophysiology of schizophrenia.

HCPLive spoke with Maguire about the benefits of acetylcholine and muscarinic receptors for the treatment of schizophrenia.

In the month of September, several notable news stories in the field of pulmonary health were covered by the team at 

. The pulmonology field saw a variety of advancements in September, including 2 

 approvals and the introduction of the Respiratory Report series.

The review also covers new findings on treatment options for 

 and breathlessness. The following highlights of the team’s coverage represent a broad overview of the month of September’s most significant pulmonology-related stories:

FDA Approves Dupilumab (Dupixent) for Treatment of COPD

A September announcement by Regeneron highlighted the approval of dupilumab (Dupixent) treatment for patients with chronic obstructive pulmonary disease (COPD). The approval decision by FDA officials followed positive findings from the BOREAS and NOTUS trial programs.

“This latest FDA approval for (dupilumab) represents new hope for the hundreds of thousands of COPD patients in the U.S. who can sometimes struggle just to breathe during their everyday lives,” George D. Yancopoulos, MD, PhD, the president and chief scientific officer at Regeneron, and principal inventor of dupilumab, said in a statement. “...This latest approval represents an important next chapter for (dupilumab), giving those with COPD a novel option that has demonstrated the unprecedented ability to help patients experience fewer exacerbations, while also helping them breathe better and improve quality of life in Phase 3 trials.”

FDA Approves Benralizumab for Eosinophilic Granulomatosis with Polyangiitis

Another FDA approval announced in September was that of benralizumab for adults with eosinophilic granulomatosis with polyangiitis (EGPA). This decision by the agency was based upon the phase 3 findings of the MANDARA study published in the New England Journal of Medicine.

This research had compared benralizumab to the only FDA-approved medication available for EGPA at the time, which was mepolizumab (Nucala). It was also described by AstraZeneca as the first head-to-head non-inferiority study of biologics among those with EGPA.

“Patients often rely on long-term oral corticosteroids, which can cause serious and lasting side effects,” Michael Wechsler, MD, MMSc, MANDARA investigator and professor of Medicine and director of The Asthma Institute at National Jewish Health, said in a statement. “Benralizumab is a much-needed treatment option, with data showing that not only is remission an achievable goal for EGPA patients, but benralizumab can also help patients taper off steroid therapy.”

In another September article, the new quarterly newsletter from 

 was introduced. The series features updates from pulmonary investigators who are supported by the American Lung Association Research Institute, with each issue available at HCPLive.com as well as through the email newsletter list.

The Respiratory Report provides an introduction to the development of practice-changing research described by the investigators leading the research. Each iteration of the series includes video interviews and written articles describing a wide array of topics, such as asthma, COPD, rare interstitial diseases, and respiratory viruses. It is also described as similar to the 

Positive Phase 3 Findings Identified for Depemokimab Treatment of Severe Asthma

Depemokimab, a drug formulated as an ultra-long-acting biologic option for patients with severe asthma, was shown in a new study to reduce serious asthma attacks by over 50%. The study also found a 72% reduction of exacerbations resulting in hospitalization. The drug is administered to patients 2 times per year at intervals of 6 months. These new data were the conclusion of the late-stage SWIFT-1 and SWIFT-2 studies.

“These results add to the established body of evidence that targeted inhibition of IL-5 plays a key role in reducing type 2 inflammation that drives severe asthma exacerbations,” Kaivan Khavandi, the GSK global head of Respiratory/Immunology R&D, said in a statement. “Depemokimab could offer the possibility of sustained inhibition of this pathway, with a dosing schedule of just two injections per year.”

Mirtazapine Fails to Ease Breathlessness in New Study Despite Previous Hopes

New phase 3 findings on mirtazapine suggest that the antidepressant does not improve breathlessness among individuals with respiratory disease. Previously, it had been suggested that antidepressants could modulate respiratory sensation even without a mood disorder, as it raises levels of serotonin in respiratory control and other regions.

“Despite being a widespread issue, we still don’t have effective treatments available,” first author Irene Higginson, FFPHM, from King’s College London, said in a statement. “As such, many doctors turn to off-label prescribing, trying to help their patients.”

Survey Provides Updated Expert Opinions on Severe AATD Assessment, Monitoring

Another study covered in September was a compilation of opinions from pulmonologists from across 15 different European countries related to the assessment and management of severe alpha-1 antitrypsin deficiency (AATD). The investigators sought to inform a standardized treatment pathway and to help improve outcomes seen among patients.

“Discordance currently exists among published guidelines for the assessment and management of patients with severe AATD,” Marc Miravitlles, MD, PhD, ​​a pulmonologist and senior researcher at the Vall d’Hebron University Hospital and the Vall d’Hebron Research Institute in Spain, and colleagues wrote. “To our knowledge, this is the first study that attempts to establish a consensus for the treatment and monitoring of patients with AATD using Delphi consensus methodology.”

September saw significant advancements in pulmonary health, including two FDA approvals and the launch of a new series, The Respiratory Report. Dupilumab was approved for COPD, offering a novel treatment option, while benralizumab was approved for eosinophilic granulomatosis with polyangiitis, providing an alternative to long-term corticosteroids. Positive findings emerged for depemokimab in severe asthma, showing a significant reduction in exacerbations. However, mirtazapine failed to alleviate breathlessness in a new study. A survey highlighted the need for standardized treatment pathways for severe alpha-1 antitrypsin deficiency.

This Month in Review article featured a variety of notable updates in the field of pulmonology covered in September 2024.

Pulmonology Month in Review: September 2024

Unmet Needs, Future Research in Schizophrenia and Muscarinic Agonists

xanomeline and tropsium chloride capsules (Cobenfy, formerly KarXT)

, signals a transformative shift in psychopharmacology, ushering in what leading subject matter experts are calling the "third wave" of drug development. Historically, the field has evolved from the introduction of tricyclic antidepressants and typical antipsychotics in the 1950s to the atypical antipsychotics of the 1980s, which focused on improved tolerability and safety.

As Andrew Cutler, MD, notes in the segment, this new generation leverages innovative mechanisms—particularly targeting acetylcholine alongside dopamine—aiming to address the heterogeneous nature of schizophrenia. With a range of muscarinic agonists in development, there is hope for better management of cognitive impairments and negative symptoms that have long been inadequately treated.

“We're entering an era that I'm calling the ‘muscarinic wars’ right now, which is like the old atypical wars that I lived through before Rishi entered the field, probably in the 90s, when we had a number of these atypicals,” Cutler said. “It was terrific because they're all different. Some patients we know do better with one than another, and I think the same will hold true here.”

Rishi Kakar, MD, echoed this same sentiment—noting, in his 15 years conducting studies, he has noticed more enthusiasm among clinicians with the paradigm shift.

“Let's ride the wave and see where we go,” said Kakar, on entering this new era in management.

Mechanism of Action of Xanomeline and Trospium Chloride Capsules

Applying EMERGENT Trial Results to Real-World Clinical Practice for Schizophrenia

Balancing the Benefits and Risks of Xanomeline and Trospium Chloride Capsules

(Moderator) is a former practicing psychiatrist and is the founder and chief executive officer of Terran Biosciences.

is a clinical associate professor in the Department of Psychiatry and Behavioral Sciences at SUNY Upstate Medical University and the chief medical officer of the Neuroscience Education Institute.

is a psychiatrist based out of southern Florida as well as the medical director and chief scientific officer of Segal Trials. Kakar served as the principal investigator on the pivotal EMERGENT trials.

Relevant disclosures for Cutler include Karuna, Bristol Myers Squibb, and 

. Relevant disclosures for Kakar include Karuna, Bristol Myers Squibb, and others. Relevant disclosures for Clark include Terran Biosciences.

The approval of new schizophrenia treatments, such as xanomeline and tropsium chloride capsules, marks a significant advancement in psychopharmacology, heralding a "third wave" of drug development. This new generation of treatments targets acetylcholine alongside dopamine, aiming to address cognitive impairments and negative symptoms inadequately treated by previous medications. Experts like Andrew Cutler and Rishi Kakar highlight the potential for diverse patient responses, similar to the "atypical wars" of the 1990s. The enthusiasm among clinicians suggests a promising future for schizophrenia management.

In part 5 of 5, experts discuss ongoing unmet needs and future research priorities in schizophrenia management.

In this segment of our latest HCPLive Special Report on the 

recent approval of xanomeline and tropism chloride capsules (Cobenfy)

, conversation shifts to the critical issue of medication adherence in patients with schizophrenia. Research has indicated that adherence rates for oral medications have dropped below 50%. Rishi Kakar, MD, lead investigator of the EMERGENT trials, opened the conversation by emphasizing the multifaceted reasons behind nonadherence, highlighting that medication frequency, tolerability, and caregiver perspectives play significant roles.

Andrew Cutler, MD, expanded on the topic, explaining that factors such as inadequate efficacy, intolerable adverse events, and anosognosia can contribute to low adherence rates in patients with mental illness.

The conversation also touched on the advantages of long-acting injectable (LAI) antipsychotics, which are increasingly being adopted in clinical practice. Cutler and Kakar discuss the benefits of LAIs in terms of convenience and improved tolerability, especially for patients who struggle with daily medication reminders. They acknowledge the potential for new muscarinic agonists to be developed into LAIs, while also stressing the importance of maintaining oral medication options for patients who may not prefer injectables.

The discussion centers on the challenges of medication adherence in schizophrenia, with adherence rates for oral medications falling below 50%. Factors such as medication frequency, tolerability, and caregiver perspectives are highlighted as contributing to nonadherence. Long-acting injectable (LAI) antipsychotics are presented as a beneficial alternative, offering convenience and improved tolerability. The potential for developing new muscarinic agonists into LAIs is acknowledged, while maintaining oral options for those who prefer them. The conversation involves experts with relevant disclosures from pharmaceutical companies.

In part 4 of 5, experts discuss medication adherence to schizophrenia treatments, particularly of xanomeline and trospium choloride capsules for schizophrenia.

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