Chelsie Derman

Karuna Therapeutics announced today the Food and Drug Administration (FDA) accepted its xanomeline-trospium (KarXT) New Drug Application for the treatment of adults with 

“If approved, KarXT could be one of the more important new product introductions in neuropsychiatry by providing a novel pharmacological approach for the treatment of schizophrenia,” said Bill Meury, president and chief executive officer of Karuna Therapeutics in a press release.

Schizophrenia affects 2.8 million in the US and hinders daily living. Characteristics of the mental illness fall into 3 domains: positive symptoms (hallucinations and delusions), negative symptoms (struggle with enjoying life and withdrawal from others), and cognitive impairment (issues in memory, concentration, and decision-making). People with schizophrenia struggle to keep jobs, live independently, and to maintain relationships. Although current schizophrenia treatment can be effective in managing symptoms, about 30% do not have improvements after therapy, and 50% only have partial improvements in symptoms.

Xanomeline-trospium acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system, believing to help positive, negative, and cognitive symptoms of schizophrenia. While other treatments of schizophrenia directly block dopamine receptors, this drug does not, offering a new approach to treating the mental illness.

If the FDA approves xanomeline-trospium, it will mark as the first pharmacological approach to treating schizophrenia since the 1970s. Within the past year, the FDA approved a New Drug Application for aripiprazole, a bi-monthly injection, that treats schizophrenia and bipolar disorder.

 Though xanomeline-trospium shows promise through the pivotal EMERGENT trial, demonstrating how xanomeline-trospium is associated with significant improvements in schizophrenia symptoms.

The EMERGENT program included 5 trials. The first 3 trials compared xanomeline-trospium with a placebo to access efficacy and safety, and 2 trials evaluating the long-term safety of the drug.

In the 3 placebo-controlled trials, xanomeline-trospium demonstrated statistically significant improvements in schizophrenia symptoms compared to placebo. Also, the drug was typically well-tolerated—the only adverse events were cholinergic and mild to moderate in severity. Unlike other antipsychotics, xanomeline-trospium was not associated with weight gain, somnolence, and movement disorders.

“Diagnosis marks the beginning of an often long and tiresome search for effective and tolerable treatment options,” said Gordon Lavigne, M.Ed., chief executive officer of Schizophrenia & Psychosis Action Alliance, in a Karuna Therapeutics press release. “The nature and magnitude of side effects often play a pivotal role in whether someone continues treatment, which is often crucial to minimize the risk of relapse and realize the life-altering benefits of long-term treatment. Potential approval of a pharmacologically distinct treatment option would be a welcome innovation for people living with schizophrenia.”

The FDA will decide on the approval of xanomeline-trospium for the treatment of schizophrenia patients by September 26, 2024.

Karuna Therapeutics Announces U.S. Food and Drug Administration Accepts New Drug Application for KarXT for the Treatment of Schizophrenia. 

https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-us-food-and-drug-administration

Kunzmann, K. FDA Approves Bi-Monthly Aripiprazole Injection for Schizophrenia, Bipolar Disorder. April 28, 2023. 

https://www.hcplive.com/view/fda-approves-aripiprazole-injection-schizophrenia-bipolar-disorder

Articles

The FDA will decide on the approval of xanomeline-trospium, a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system, for the treatment of schizophrenia patients by September 2024.

FDA Accepts Xanomeline-Trospium Drug Application for Schizophrenia Treatment

prevalence among older adults decreased in the countries Brazil, Russia, India, China, and South Africa from 1990 – 2019— but blindness and vision burdens are expected to rise by the year 2040.

Blindness and vision loss affects 2.2 billion people globally, commonly affecting older adults.

 Vision loss is associated with reduced health life expectancy and increased risk of depression, dementia, falls, hip fractures, hospitalizations, and death.

Currently, Brazil, Russia, India, China, and South Africa are transitioning to a market economy and experiencing an increase in economic, growth, population, aging, and noncommunicable diseases. But, as the population of older adults increases, the burden of blindness and vision loss will too.

A new study, led by Jianqi Chen, MD, of State Key Laboratory of Ophthalmology at Sun Yatsen University in Guangzhou, China, sought to assess the national trends in the burden of blindness and vision among adults in Brazil, Russia, India, China, and South Africa between 1990 - 2018 and predict the burden by 2040. The investigators considered older adults as individuals aged 

60 years old, and they studied trends by sex, age, and cause.

“To the best of our knowledge, this is the first study to examine the temporal trends and projections of [blindness and vision loss] prevalence rates and number of cases among older adults in [Brazil, Russia, India, China, and South Africa] countries,” the investigators wrote.

The investigators collected data on blindness and vision loss, as well its related causes, from the Global Burden of Disease 2019. From there, the team calculated the age-standardized prevalence rate. They also evaluated the temporal trends by calculating the average annual percentage change using joinpoint regression analysis. Moreover, the team performed a Bayesian age-period-cohort to predict the burden of blindness/vision loss and its related causes by 2040. Unlike other prediction models, the Bayesian age-period-cohort examined population aging, birth cohorts, and time periods.

The investigators studied 19 detailed blindness and vision loss causes. Chen and colleagues defined blindness and vision loss as a visual acuity of < 6/18 on the Snellen chart and defined near vision loss as a near acuity of < 6/12 distance equivalent.

The results found Brazil, Russia, India, China, and South Africa experienced a significant decrease in age-standardized prevalence rates (

 < .05), with the most decrease in India (0.52; 95% CI, 0.54 – 0.50). Even now, the decreasing trends are projected to continue.

However, from 1990 – 2019, Russia had an increase in age-standardized prevalence rates (0.12; 95% CI, 0.11 – 0.14). In 2019, India had the highest age-standardized prevalence rates while Brazil had the lowest.

The age-standardized prevalence rates will continue to decrease in Brazil, India, China, and South Africa—all the countries except Russia, which will slightly increase by 2040. Also, by 2040, the number of blindness and vision loss cases are projected to increase by roughly 50% across the 5 countries. The predicted vision loss cases for each country are 192 million in China, 170 million in India, 25 million in Russia, 17 million in Brazil, and 7 million in South Africa. Except, blindness and vision loss causes are predicted to change in the future, specifically in India. 

The investigators also found the age-standardized prevalence rates were higher in women than men in most of the 5 countries.

The average annual percent change in most age groups was <0. But for older adults, they had a higher age-standardized prevalence rate, which demonstrates they skew the rate and are responsible for the country’s increasing vision loss burden trend. While blindness/visual loss in most age groups is predicted to decrease, the cases are predicted to increase rapidly in older age groups with an over 100% increase.

Based on the Bayesian age-period-cohort model, age-standardized prevalence rates in Russia were predicted for near vision loss, refraction disorders, age-related macular degeneration (AMD), and diabetic retinopathy; in India it was predicted for refraction disorders, AMD, diabetic retinopathy, and other causes; in China, an increase was predicted for diabetic retinopathy but a decrease for cataract.

The investigators found India and Brazil had significant declines for most causes of vision loss, while Russia had significant increases for near vision loss (0.29; 95% CI 0.25 – 0.33). China had significant increases for cataract (0.51; 95% CI, 0.27 – 0.76), and South Africa had significant increases for AMD (0.3; 95% CI, 0.25 – 0.35) and diabetic retinopathy (1.18; 95% CI, 1.10 – 1.25).

“The different trends of [blindness and vision loss’ age-standardized prevalence rates] across [Brazil, Russia, India, China, and South America] may reflect the different stages of population health transition,” the investigators wrote.

For instance, over the past few decades, Brazil has had significant economic and structural changes, such as the start of the universal Brazilian Unified Health System, as well as improving pollution and tobacco control. Meanwhile, Russia had consistent increases in blindness and vision loss, and they still have a high prevalence of smoking; they also have a high mortality rate for workers. In China, they have a rapid increase in cataract prevalence. Furthermore, in India, they have controlled tobacco use; they also started new initiatives of clean cooking gas. Finally, South Africa’s still at the beginning of their transition, but they started tobacco control efforts.

“[Brazil, Russia, India, China, and South America] countries have undergone or committed to substantial health-system reforms designed to improve the quality of medical services and financial protection, with the ultimate goal of universal health coverage,” the investigators wrote. “The rapid rise in the number of [blindness and vision loss] cases among older adults in these countries is indicative of the need for provision of corresponding medical resources for eye diseases, and inclusion of [blindness and vision loss] prevention and control in future national strategies.”

Chen J, Zhu Y, Li Z, et al. Temporal trends and projection of blindness and vision loss prevalence in older adults in BRICS countries. 

. Published online November 13, 2023. doi:10.1111/jgs.18672

https://www.who.int/news-room/fact-sheets/detail/blindness-and-visual-impairment

By 2040, the number of blindness and vision loss cases are estimated to increase by roughly 50% across Brazil, Russia, India, China, and South America, a new study found.

Vision Loss Will Increase in Brazil, Russia, India, China, South Africa by 2040

The US Food and Drug Administration (FDA) has issued a warning to patients and health care providers about the Phillips DreamStation 2 continuous positive airway pressure machines’s (CPAP) thermal issues—and to watch out for overheating as the device has led to fires, smoke, and burns.

The Phillips DreamStation 2 CPAP machine delivers positive airway pressure for treatment of 

 at home and in clinical settings. Recently, the FDA had been receiving  reports about the device’s overheating. Between August 1, 2023, and November 15, 2023, the FDA received 270 complaints associated with the device.

Customers received the DreamStation 2 CPAP machines as replacements for the recalled DreamStation 1 CPAP machine in June 2021. Issues with the DreamStation 2 CAP machines is still being under review. The agency does not believe the safety issues stem from the foam used in the machine, but possibly related to an electrical or a mechanical malfunction of the machine.

The FDA advises patients, caregivers, and health care providers to follow the manufacturer’s instructions. Recommendations include placing the machine on a firm, flat surface, keeping it away from the carpet, fabric, or other flammable materials, carefully cleaning the machine, emptying the machine’s water reservoir, and allowing the heater plate and water tank to cool for 15 minutes before removing the tank to prevent the risk of burns. If someone touches the heater plate, the heated water, or the humidifier water tank pan, they could burn.

The FDA recommended checking the machine before and after every use for odd smells or changes in appearance—issues may only be visible when the machine is running, so customers should inspect before going to bed.

Moreover, the FDA instructed to unplug the machine and stop using if there is a burning smell, a change in appearance of the machine, unexplained changes to the machine’s performance, water spilling into the machine, and the machine making unusual sounds.

If the user does not experience any of these issues, the FDA does not recommend discontinuing the machine. Though, if they start to experience unusual smells, sounds, and changes in appearance, then they should report to the FDA or to Philips.

The FDA is currently looking to find the underlying cause for Phillips DreamStation 2 CPAP’s overheating.

“The FDA is committed to assuring this new safety issue is resolved expeditiously. We will continue to monitor the company’s handling of this, among other safety issues, to ensure they take appropriate steps to mitigate the risk to patients,” said Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a press release. “We share the public’s concerns regarding the new and continued safety issues of CPAP machines and certain recalled medical devices manufactured by Philips. Addressing these safety concerns remains a top priority for the FDA.”

Carefully Monitor Philips DreamStation 2 CPAP Machines for Signs of Overheating: FDA Safety Communication. 

https://www.fda.gov/medical-devices/safety-communications/carefully-monitor-philips-dreamstation-2-cpap-machines-signs-overheating-fda-safety-communication

FDA Cautions Public of Safety Issue with Philips’ DreamStation 2 CPAP Machines. 

https://www.fda.gov/news-events/press-announcements/fda-cautions-public-safety-issue-philips-dreamstation-2-cpap-machines

The FDA issued a warning about the DreamStation 2 CPAP Machine, which is used to treat obstructive sleep apnea, due to reports of the device overheating and leading to fires, smoke, and burns.

FDA Warns About CPAP Machine Overheating Risk

Credit: The University of New South Wales

Despite potential difficulty of diagnosing AMD, clinicians in a new study demonstrated excellent accuracy in diagnosing 

AMD, a highly prevalent retinal disease, leads to irreversible vision loss. The disease impacts quality of life and poses a financial burden to the individual, families, and society. In Australia, AMD costs AU $750 million overall. Clinicians typically detect AMD during a regular eye exam, but if undetected, they might do a visual acuity test, ophthalmoscopy, an amsler grid test, or an eye angiogram and optical coherence tomography if they suspect a patient might have wet AMD.

AMD can be left undiagnosed—and about 25% of people with AMD do not even know they have the eye condition. Investigators of the new study suggest this could either be because of the difficulty of detecting AMD or because patients do not routinely get their eyes checked. If it is because of the difficulty of detecting AMD, the investigators explain detecting AMD can be tricky to detect due to its heterogenous appearance. AMD detections can overlap with other macular conditions like central serous chorioretinopathy, adult vitelliform, dystrophy, and malattia leventinese. People may not be receiving AMD diagnoses because of lack of clinician knowledge surrounding the diagnosis. Also, in the early stages of AMD, the individual may not experience any symptoms, so they might not think about getting their eyes checked.

Led by Sharon Ho, of the centre for eye health at The University of New South Wales in Sydney, Australia, the investigators conducted a prospective diagnostic accuracy study of community optometrists practicing in Australia.

“In the current study, the diagnostic accuracy of community optometrists for AMD was estimated as ‘excellent’ with an [receiver operating characteristics curve] of 0.86, sensitivity of 84.5% and specificity of 88.0%,” the investigators wrote.

The study included 5 practicing optometrists, with 60% being female (n = 3), and the mean age being 30.2 years old. Over half (60%) worked in an independently owned practice, and 40% in a corporate practice. Clinical practices were located either in a major city (60%) or a regional centre (40%) in New South Wales.

The 5 optometrists examined 1023 images obtained from color fundus photographs to identify AMD. The team unidentified images so they could not be linked to a patient’s age, gender, history, or other clinical characteristics. They also created 5 image datasets by random assigning.

Of the images, 226 featured AMD and 797 featured other ocular conditions or no abnormal findings. The investigators found 27% of the images with AMD had other significant ocular condition like other posterior diseases, anterior eye diseases, and glaucoma. For images without AMD, 62.2% had other significant ocular conditions like other posterior eye disease, glaucoma, and anterior eye disease. About half (52%) of the images were from females (n = 536), and the mean age of patients in the images was 61.2 years old.

The investigators assessed diagnosis accuracy by the area under the receiver operating characteristics curve (aROC). They also calculated specificity, as well as positive and negative predictive values. For each image, they had to say if AMD was present with a yes or no. If they answered “yes,” they had to identify the stage of AMD in the image as either early, intermediate, late geographic atrophy, or late neovascular AMD). The optometrists had 4 weeks to go through the images with an option of a 2-week extension.

Using the receiver operating characteristics curve, diagnostic performance was characterized as: no discrimination (aROC = 0.5), poor (0.5 < aROC < 0.7), acceptable (0.7 

The receiver operating characteristics curve for community optometrists’ diagnosis of AMD was 0.86 (95% CI, 0.83 – 0.89), making it an excellent score. When testing for diagnosis sensitivity and specificity, the investigators received 84.5% for sensitivity (95% CI, 79.1 – 89.99) and 88% for specificity (95% CI, 5.5 – 90.1).

The team also tested the diagnosis accuracy for each stage of AMD, receiving 0.82 (95% CI, 0.73 – 0.91) for early AMD, 0.76 (95% CI, 0.72–0.81) for intermediate AMD, 0.69 (95% CI, 0.49 – 0.90) for late geographic atrophy AMD, and 0.55 (95% CI, 0.34 – 0.75) for late neovascular AMD.

“Wide 95% CIs indicated that performance ranged from ‘no discrimination’ to ‘excellent’ for diagnosing late geographic atrophy AMD and ‘no discrimination’ to ‘acceptable’ for diagnosing late neovascular AMD,” the investigators wrote. “This is likely due to the small participant sample size (n = 5) and small number of late AMD images in the study dataset (n = 10) for late geographic atrophy AMD, n = 9 for late neovascular AMD).”

The investigators noted optometrists often underestimate AMD severity, which can slow down patient care. Clinical guidelines recommend referral within 1 week of a treatable neovascular lesion—but if patients are undiagnosed, AMD vision loss will continue to worsen. While the study had a small sample size, the results still demonstrated clinician’s accuracy in AMD diagnosis.

“Therefore, future studies involving more participants and larger balanced test datasets are required to explore this issue,” the investigators concluded.

Ho S, Doig GS, Ly A. Diagnostic accuracy of community optometrists for age-related macular degeneration using colour fundus photographs: A pilot evaluation. 

 Published online November 3, 2023. doi:10.1111/opo.13242

https://stanfordhealthcare.org/medical-conditions/eyes-and-vision/macular-degeneration/diagnosis.html. Accessed November 28, 2023.

https://www.hopkinsmedicine.org/health/conditions-and-diseases/agerelated-macular-degeneration-amd

Of 1023 color fundus photograph images, the 5 optometrists in the study were able to accuracy diagnosis 226 images with AMD.