 joined the MJH Life Sciences team in October 2020. Follow her on Twitter 

Victoria Johnson

Data from a recent study suggest that sleep profile may be able to 

predict the trajectory of cognitive function

 in patients with mild-to-moderate Alzheimer disease (AD).

Investigators found a significant difference of –1.51 (95% CI, 2.43 to –0.59) in the Mini-Mental State Examination (MMSE) after 12 months of follow-up between deep and light sleepers. Sleep depth and cognitive decline exhibited a dose-response relationship (

-trend = .02). A similar relationship was seen between sleep depth and processing speed as measured by the Stroop words test (SWT; 

 = .016) and executive function as measured by the verbal fluency test (VFT; 

“This is the first study to report an association between sleep and cognitive decline after the diagnosis of Alzheimer’s disease. Accordingly, the sleep profile may have a predictive role in relation to the cognitive function of mild-moderate Alzheimer’s disease patients after 12 months of follow-up,” first author Adriano D. S. Targa, MD, Centro de Investigación Biomédica, Red de Enfermedades Respiratorias, Spain, and colleagues wrote.

Targas and colleagues analyzed data from 125 patients with a median age of 75.0 years (interquartile range [IQR], 72.0-80.0) as part of an ancillary study of a prospective trial (NCT02814045) designed to evaluate the influence of obstructive sleep apnea (OSA) on the cognitive decline of patients with AD after 1 year of follow-up. The patients had a median MMSE score of 23.0 (IQR, 22.0-25.0). They were mostly women (57.6%). The most common comorbidities were hypertension (59.2%) and dyslipidemia (41.6%).

Late-Life Depression May Forecast Cognitive Impairment in the Elderly

The investigators confirmed the differences in MMSE between deep and light sleepers by performing a sensitivity analysis adjusted for confounding factors. This analysis yielded a significant difference of –1.20 (95% CI, –1.33 to –0.12). Further stratification into deep, moderate, and light sleepers yielded a mean change of –0.89 (95% CI, –2.10 to 0.30) in deep sleepers, –1.59 (95% CI, –2.84 to –0.34) among moderate sleepers and -2.35 (95% CI, –3.71 to –1.01) among light sleepers. A linear trend test demonstrated a significant change of –0.72 (95% CI, 1.33 to –0.12) after adjusting for confounding factors.

Further differences were found between deep and light sleepers after controlling for sex, age, and educational level, with a significant –1.3 (95% CI. –2.35 to –0.26) difference in SWT score and –1.04 (95% CI, –1.94 to –0.14) in VFT score. These remained significant after sensitivity analyses.

A –1.15 (95% CI, -2.29 to –0.01) difference on the Stroop color test and –1.23 (95% CI, –2.42 to –0.04) difference on trail-making test-A scores were also seen, but these were not significant after sensitivity analyses.

“Further studies will be necessary to investigate whether relationships of causality between the observed associations are present and to evaluate whether the predictive role of sleep is maintained after longer periods of follow-up. In case of a positive response, sleep-based interventions could be considered to prevent a marked cognitive decline,” Targas and colleagues wrote.

 previously spoke with Christian Agudelo, MD, Evelyn F. McKnight Neurocognitive Scholar, University of Miami Miller School of Medicine, about a study he served as lead investigator for that found a link between poor sleep patterns and cognitive decline.

While the effects of poor sleep have yet to be determined in different race or age populations, Agudelo noted that there could be neurodevelopmental issues that stem from poor sleep, but also that behavioral tendencies and the lack of prioritizing sleep may have an impact as well. He also stressed that these associations should additionally be observed in younger populations and that the need for diversifying study populations is crucial to further justify broader implications.

1. Targas ADS, Benitez ID, Dakterzada F, et al. Sleep profile predicts the cognitive decline of mild-moderate Alzheimer’s disease patients. 

 May 2021. zsab117. doi: 10.1093/sleep/zsab117
2. Agudelo C, Tarraf W, Wu Benson, et al. Actigraphic sleep patterns and cognitive decline in the Hispanic Community Health Study/Study of Latinos. 

Articles

While the relationship between sleep and cognition needs to be further studied, sleep-based interventions may be a future approach to help prevent cognitive decline. 

Sleep Profiles May Predict Cognitive Decline in Alzheimer Disease

 and efficacy in the phase 2b VISION-DMD study (NCT03439670) in the treatment of individuals with Duchenne muscular dystrophy (DMD).

Both the low (2 mg/kg/day) and high dosages (6 mg/kg/day) showed strong efficacy in the study’s primary and secondary end points. The primary end point was superiority in change of time to stand from supine positioning to standing (TTSTAND) velocity with the high dose of vamorolone compared to placebo. The treated group had a difference of 0.06 (95% CI, 0.02-0.10) rises per second from baseline (

 = .002). This is a clinically relevant improvement in TTSTAND from 6.0 to 4.6 seconds in the treated group and a corresponding deterioration in the placebo group from 5.4 to 5.5 seconds.

“Today’s news is a tremendous milestone for patients and Santhera as we further advance vamorolone as a foundational treatment option in DMD. The treatment effect translates into the potential to delay disease progression by about two years and indicates disease modifying potential of vamorolone,” Dario Eklund, chief executive officer, Santhera, said in the company’s announcement. “We now look forward to working with regulatory authorities to bring vamorolone to DMD patients, first in the US and subsequently in Europe.

The secondary end points were also met, including TTSTAND velocity in the low-dose group (

 = .02), 6-minute walk test in the high-dose (

 = .009), and time to run/walk 10 m test in the high-dose group (

 = .002). No statistically significant differences were observed between vamorolone high dose and prednisone on the secondary end points.

Pamrevlumab, Vamorolone, and Others Headline Robust Pipeline in Duchenne Muscular Dystrophy

“We are thrilled about the positive results of the VISION-DMD study as it represents a culmination over a decade of scientific research,” Eric Hoffman, PhD, president and CEO, ReveraGen BioPharma and professor, Pharmaceutical Sciences, Binghamton University–State University of New York, added to the statement. “We are grateful to have been able to gather such important data and would like to thank all VISION-DMD participants, their families and caregivers, as well as investigators and study personnel, for their commitment to this ongoing program.”

The investigational agent from Santhera and ReveraGen is a first-in-class dissociative steroid that aims to retain the anti-inflammatory activity of corticosteroids while decreasing the deleterious adverse events (AEs). If successful, vamorolone may be a promising alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD. The significant systemic AEs associated with high-dose corticosteroids diminish patient quality of life, so addressing these AEs is of high priority. Santhera noted that it plans to file a new drug application with the FDA in the first quarter of 2022, requesting priority review.

“The strength of evidence for both efficacy and safety of vamorolone over such a wide dose range from 2 to 6 mg/kg/day allows clinicians to individually tailor treatment of Duchenne patients by starting at the higher 6 mg/kg/day dose of vamorolone with equivalent efficacy to daily prednisone and titrate the dose according to how well the treatment is tolerated whilst maintaining optimal efficacy. I am enthusiastic that this approach may allow patients to avoid side effects that currently lead to discontinuing steroid treatment, meaning they are able stay on for longer,” Craig McDonald, MD, professor and chair, Department of Physical Medicine & Rehabilitation and Director of Neuromuscular Disease Clinics, UC Davis Health, said in the statement.

Vamorolone showed a favorable safety and tolerability profile over prednisone. The 24-week study was completed by 114 of 121 patients (94%). Both the high- and low-dosages showed favorable safety and tolerability profiles. No patients treated with vamorolone discontinued the study due to treatment-emergent AEs (TEAEs). The vamorolone-treated group had 96 TEAEs in the low-dose group and 91 TEAEs in the high-dose group compared to 120 TEAEs in the prednisone-treated group. Vamorolone high dose was found to be significantly superior to prednisone (

 = .02) in a prespecified analysis of clinically relevant AEs.

Vamorolone did not show stunting of growth as reported with conventional corticosteroids in previously published results of 2.5-year (113 patient years) open-label studies. These results were validated in the double-blind study in which high dose vamorolone showed a significant difference in growth velocity compared to 0.75 mg/kg/day prednisone (

“Stunting of growth is a major concern of families and patients treated with corticosteroids, and we are delighted to see this superiority of vamorolone proven in this double-blind study,” Paula Clemens, MD, study co-chair and vice chair, VA Affairs; and professor, Neurology, University of Pittsburgh School of Medicine, added to the statement.

Santhera and ReveraGen announce positive and statistically highly significant topline results with vamorolone in pivotal VISION-DMD study. News release. Santhera. June 1, 2021. https://www.globenewswire.com/news-release/2021/06/01/2239124/0/en/Santhera-and-ReveraGen-Announce-Positive-and-Statistically-Highly-Significant-Topline-Results-with-Vamorolone-in-Pivotal-VISION-DMD-Study.html

Santhera and ReveraGen announced findings of the phase 2b VISION DMD study of the investigational therapy. 

Vamorolone Efficacious in Treatment of DMD, Superior to Prednisone in Safety

This content originally appeared on our sister site, GeneTherapyLive. Read it 

The first patient has been dosed in BlueRock Therapeutics' phase 1 study (NCT04802733) of DA01 for the treatment of Parkinson disease (PD), Bayer, the holding company of BlueRock, recently announced. Asklepios BioPharmaceutical (AskBio), another subsidiary of Bayer, is also enrolling patients in its phase 1b clinical study (NCT04167540) of glial cell line-derived neurotrophic factor (GDNF) gene therapy for PD.

“The potential of BlueRock and AskBio’s clinical candidates to treat PD could be immense,” said Wolfram Carius, head, cell and gene therapy, Bayer, in a statement.

 “For the first time, it might be possible to stop and reverse this degenerative disease and truly help patients with their high unmet medical need. The start of clinical trials represents the beginning towards a truly breakthrough treatment option to dramatically improve the lives of patients.”

-derived dopaminergic neurons designed to innervate the putamen to reverse the regenerative process and potentially restore motor function in people with PD. Unlike standard-of-care symptomatic treatments like levodopa, whose effects diminish over time, BlueRock aims to target PD at its root cause with DA01.

The trial will enroll 10 patients at sites in the US and Canada who will undergo surgical implantation of the DA01 cells. The primary end points of the study are safety and tolerability at 1 year post-transplant. Secondary end points are transplanted cell survival and motor effects at 1- and 2-years post-transplant, as well as continued safety and tolerability and feasibility of transplantation.

Glial Cell Line-derived Neurotrophic Factor

The GDNF study, supported by the California Institute for Regenerative Medicine, dosed its first patient with an infusion of GDNF in August 2020. Ten patients have been enrolled since then into the study to assess safety and preliminary efficacy. The one-time treatment provides a continuous production of GDNF, an advantage over intermittent protein infusions. The therapy is designed to promote the survival and functioning of vulnerable brain cells that degenerate in PD.

SenSight Directional Lead System Approved for DBS Therapy

“I’ve been investigating therapeutic gene therapy approaches for PD for nearly 30 years, and [this trial] marks a significant milestone for the field and may lead to major therapeutic opportunities for those suffering with this devastating condition, along with their families,” said Krystof S. Bankiewicz, MD, PhD, chief executive officer, Brain Neurotherapy Bio, part of Asklepios Bio, in an earlier statement.

 “We thank the current and future participating patients and the Neurology and Neurosurgery teams conducting the clinical study at The Ohio State University, the University of California San Francisco and the University of California Irvine medical centers.”

Previous research has shown that GDNF, delivered via the adeno-associated virus serotype 2 (AAV2) vector, achieved sustained expression that can promote regeneration of midbrain neurons and significant motor recovery in mouse and nonhuman primate studies. AAV2-GDNF targets brain cells within the putamen to produce and release GDNF protein. The GDNF payload consists of a human GDNF DNA sequence attached to regulatory sequences to ensure long-term stability of the payload. The treatments is administered in an MRI-guided, convection-enhanced infusion into the brain.

“There is an urgent need in the clinic for a treatment that may alter course of disease progression for patients with PD,” said Amber Van Laar, MD, movement disorder neurologist and Senior Director for Clinical Affairs of BNB. “GDNF gene therapy, if proven safe, is one such therapeutic that may mitigate and possibly reverse such clinical features of Parkinson disease,” added Adrian Kells, PhD, BNB’s Chief Operating Officer.

1. Bayer to advance two first-of-its-kind cell and gene therapies for Parkinson’s disease. News release. Bayer. June 8, 2021. 

https://www.media.bayer.com/baynews/baynews.nsf/id/Bayer-to-advance-two-first-of-its-kind-cell-and-gene-therapies-for-Parkinsons-disease?Open&parent=news-overview-category-search-en&ccm=020


2. Brain Neurotherapy Bio, Inc. announces treatment of first patient in new GDNF gene therapy trial for Parkinson’s disease. News release. Brain Neurotherapy Bio. August 25, 2020. https://e674c233-41f6-46e5-a454-6ee455f25619.usrfiles.com/ugd/e674c2_4ee7cd0693a9413cbb10b0a666f48fe4.pdf

Bayer provided an update on their phase 1 and 1b studies of dopaminergic neurons and GDNF gene therapy, respectively, for the treatment of PD.

Gene Therapy Studies Underway in Parkinson Disease

Data from the solriamfetol titration & administration (START) study presented at the 

, June 10-13, suggest that solriamfetol (Sunosi; Jazz Pharmaceuticals) is efficacious in patients switching narcolepsy medications and is easily titrated for these individuals.

“Pharmacotherapy for excessive daytime sleepiness (EDS) associated with narcolepsy is diverse, with factors such as efficacy, side effects, and tolerance influencing treatment decisions,” first author Michael J. Thorpy, MD, director, Sleep-Wake Disorders Center, Montefiore and professor of neurology, Albert Einstein College of Medicine, and colleagues wrote.

 Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS in adults with narcolepsy or obstructive sleep apnea (OSA) in the US and EU.

The START study consisted of a quantitative retrospective patient chart review among US-based physicians prescribing solriamfetol de novo, in transition from, or in addition to existing medications. Altogether, 26 physicians with 70 patients with narcolepsy participated. Most patients had narcolepsy type 2 (NT2; n = 46) while 24 had type 1 (NT1). Patients had a mean age of 40 years (standard deviation [SD], 11), 57% were women, and 6 also had OSA. Most cases of EDS were moderate (59%) or severe (36%). Comorbidities included obesity (n = 22; 31%), migraine headaches (n = 12; 17%), depression (n = 10; 14%), and cardiovascular disorders (n = 10; 14%).

The first presentation from the meeting investigated characteristics of real-world patients with narcolepsy starting solriamfetol and prescribers’ rationales for initiating treatment in a virtual, descriptive study. Solriamfetol initiation was mostly transition (n = 31; 44%) followed by add-on (n = 20; 29%), and de novo (n = 19; 27%).

Solriamfetol and the Impact of Residual Excessive Daytime Sleepiness

Patients transitioning to solriamfetol were taking 1 (n = 29; 94%) or 2 (n = 2; 7%) prior EDS medications. Patients adding solriamfetol were taking 1 (n = 16; 80%), 2 (n = 3; 15%) or 3 (n = 1; 5%). Most patients transitioning were taking wake-promoting agents (n = 22; 71%) and patients adding were most frequently taking sodium oxybate (n = 11; 55%). 

Solriamfetol’s efficacy profile was the primary reason for prescription de novo (n = 12; 63%), while need for better efficacy/augmenting effects of other medications was the primary reason for transitioning (n = 18; 58%) and add-on therapy (n = 19; 95%). At the time of data collection, 63 (90%) patients were on a stable solriamfetol dose. A small number of discontinuations occurred due to lack of efficacy (n = 3) and adverse events (n = 3).

The next study presented characterized real-world dosing and titration of solriamfetol. Most patients (86%) started solriamfetol at 75 mg; 11% started at 37.5 mg and 3% started at 150 mg. The final dose was 150 mg for 53 (76%) patients and 75 mg for 17 (24%). Most patients (67%) had 1 dose adjustment to reach their final dose; 4% had 2 adjustments, 4% had 3 adjustments, and 24% had none. Mean time to reach a stable dose was 15.1 days (SD, 11.8) overall, 19.4 days (SD, 9.3) with de novo treatment, 15.0 days (SD, 13.7) for transition, and 11.9 days (SD, 8.6) for add-on.

Physicians most frequently considered EDS severity (44%) when titrating. Fourteen of 22 transitioning patients (64%) taking a wake-promoting agent (WPA) discontinued it abruptly and 5 of 9 (56%) taking a stimulant were tapered off. Physicians were overall likely (n = 33; 47%) or very likely (n = 30; 43%) to recommend their approach for similar patients. 

"Jazz continues to be committed to deepening our understanding of sleep disorders and delivering transformational medicines to those with lifelong and chronic sleep conditions," said Robert Iannone, MD, MSCE, executive vice president, research and development and chief medical officer, Jazz Pharmaceuticals, in a statement.

 "There remains a large unmet need for people living with sleep disorders, including narcolepsy and idiopathic hypersomnia, and we look forward to showcasing the latest research and results from our portfolio during SLEEP 2021 as we work to help people with sleep disorders live fuller lives."

1. Jazz Pharmaceuticals Presents 18 Abstracts in Sleep Medicine at SLEEP 2021. News release. Jaz Pharmaceuticals. June 9, 2021. 

https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-presents-18-abstracts-in-sleep-medicine-at-sleep-2021-301308898.html


2. Thorpy M, Hyman D, Parks G, et al. Solriamfetol titration & administration (START): Characteristics of patients with narcolepsy and solriamfetol prescriber rationale. Presented at SLEEP 2021; June 10-13. Abstract 481.
3. Thorpy M, Hyman D, Parks G, et al. Solriamfetol titration & administration (START): Dosing and titration strategies in patients with narcolepsy starting solriamfetol. Presented at SLEEP 2021; June 10-13. Abstract 482.

Results from the START study of medication switching in narcolepsy were presented at the 2021 SLEEP Annual Meeting. 

Victoria Johnson

Articles

Sleep Profiles May Predict Cognitive Decline in Alzheimer Disease

Vamorolone Efficacious in Treatment of DMD, Superior to Prednisone in Safety

Gene Therapy Studies Underway in Parkinson Disease

Solriamfetol Efficacious, Easily Titrated in Patients Initiating Treatment for Narcolepsy