A gene therapy involving adeno-associated viral (AAV) vectors for treating 

 has failed to meet the primary endpoints of the study.

A team, led by Patrick Yu-Wai-Man, Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).

Leber hereditary optic neuropathy (LHON) is caused by mutations in mitochondrial DNA (mDNA), while a recombinant AAV, rAAV2/2-NDA has shown promise providing therapeutic effects in mouse models of LHON.

The researchers conducted a randomized, double-masked, sham-controlled, multicenter. phase 3 clinical trial involving 37 individuals with LHON bearing a MT-ND4 mutation. Each participant’s right eye was randomly assigned in a 1:1 ratio for either rAAV2/2-ND4 (GS010) treatment or a sham injection. 

The investigators sought a primary endpoint of as the difference in the change in BCVA from baseline to week 48 between the 2 treatment groups.

The left eye of patients also received the treatment not allocated to the right eye.

“Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period,” the authors wrote.

The researchers found at week 96, the eye received the gene therapy showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters).

They also found a mean improvement of -0.258 LogMAR (+13 letters) in the sham-treated eyes.

However, they did not meet the primary endpoint (

= 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least 1 eye, while 29 participants (78%) had an improvement in vision in both eyes.

In addition, the investigators conducted a non-human primate trial to investigator the bilateral improvement found in the human trial. Here they found evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function following unilateral injection.

According to late-breaking data presented at the virtual 

American Academy of Ophthalmology (AAO) 2020 Conference

, low and intermediate doses of the novel adeno-associated virus retinitis pigmentosa GTPase regulator (AVV-RPGR) was well-tolerated and demonstrated sustained or increased vision improvement in patients with

The Phase 1/2 open-label, multi-center, dose-escalation trial, co-led by investigators from Janssen and MeiraGtx and presented by Michel Michaelides, MD, assessed the safety of the gene therapy (primary endpoint) as well as changes in visual function across multiple metrics and modalities.

As noted in the intermediate cohort, there were observed statistically significant differences in mean retinal sensitivity between the treated and untreated eyes (1.05 decibel [dB]; 90% CI, 0.81-1.29).

In both low and intermediate dosage cohorts, statistically significant differences were observed in central visual field progression rate between the treated and untreated eyes (low: 1.10 dB-sr/year; 90% CI, 0.10-2.10; intermediate: 1.26 dB-sr/year; 90% CI, 0.65-1.86).

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

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The researchers unexpectedly found sustained visual improvement in both eyes, despite only 1 eye being treated with AAV.

Gene Therapy Study for Monogenic Blindness Fails to Meet Endpoint

New research shows inhibition of activin type II receptor (ActRII) by the monoclonal antibody bimagrumab can cut body fat by one-fifth in obese patients, while simultaneously increasing muscle mass.

The phase 2 study was based on patients with 

 and obesity, and suggested a possible avenue for pharmacologic management of these patients.

People who are overweight or obese often experience a 

, such as insulin resistance and chronic inflammation, explained corresponding author Steven B. Heymsfield, MD, of the Pennington Biomedical Research Center at Louisiana State University, and colleagues.

Excess adiposity is reversible, but the primary method of doing so—lifestyle programs—are often unsuccessful. Other methods of solving the problem include 

, but Heymsfield and colleagues said most patients with severe obesity are not good candidates for the procedure.

That has led some investigators to consider possible pharmacologic approaches to the problem. One result of that effort is bimagrumab, a monoclonal antibody that binds to the ActRII receptor to inhibit natural ligands that negatively regulate skeletal muscle growth. 

A previous 10-week study in healthy volunteers with insulin resistance found a single dose of the antibody reduced total body fat mass (FM), increased lean mass (LM), and improved insulin sensitivity compared to placebo in subjects who were not dieting.

In the new study, Heymsfield and colleagues sought to see what impact the drug would have on body fat and insulin sensitivity over a longer stretch of time – 48 weeks.

The investigators recruited 75 patients, with 37 randomized into the bimagrumab group and 38 receiving placebo. A total of 58 patients completed the study. The enrollees had an average age of 60.4 years, an average body mass index (BMI) of 32.9, a mean body weight of 93.6 kg, a mean FM of 35.4 kg, and a mean Hb

The randomized trial was double-blind. Those in the bimagrumab group received intravenous (IV) infusions of the drug at a dosage of 10 mg/kg up to 1,200 mg in 5% dextrose solution every 4 weeks for 48 weeks. Those in the placebo group received only the dextrose solution at the same intervals.

At the conclusion of the study, FM had dropped 20.5% in the bimagrumab group compared to 0.5% in the placebo group. LM increased 3.6% and dropped 0.8% in the bimagrumab and placebo groups, respectively.

 levels dropped 0.76% among patients receiving the drug, compared to 0.04% in the placebo group. Body weight dropped by 6.5% in the bimagrumab group, versus 0.8% among those receiving placebo.

Heymsfield noted that earlier studies with animal models had not shown the adipose tissue signal, though the smaller human study had. He said the results of the intervention in the present study were more impressive than expected.

“The magnitude and character (fat loss and muscle gain) of this effect is unprecedented,” he said. “One learning: the best model to study these effects is in humans; typically drug developers can project efficacy from animal models to humans.”

The study also raises bigger questions about the extent to which this type of pharmacologic approach could be used more broadly to counter obesity and related conditions. Heymsfield said the results could spark a push to develop a pill form of the drug, as the formulation in the study was an intravenous infusion.

“Another outcome, already being realized, is a stimulus for basic scientists to unravel the mechanisms of these effects….something that could potentially lead to important new discoveries and drugs,” he said.

In the meantime, Heymsfield said bimagrumab’s IV formulation and the relatively high cost of monoclonal antibodies mean the drug would probably be best suited for people with high-risk obesity-related comorbidities, possibly as an alternative to bariatric surgery.

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity

A phase 2 study suggests treating the common diabetes comorbidity may be capable with the monoclonal antibody.

Bimagrumab Linked to Dramatic Weight Loss in Patients with Diabetes and Obesity

Researchers are touting a new treatment formulated in a new delivery system that shrinks the tablet, enabling researchers to put 3 doses of CTx-1301 into the size of 1 pill.

American Professional Society of ADHD and Related Disorders (APSARD) 2021 Annual Conference

, researchers showed the drug can be effective treating 

, Matthew Brams, MD, Chief Medical Officer of Cingulate Therapeutics, and Shane Schaffer, PharmD, CEO of Cingulate, said the unique formulation could be a boost for treating ADHD over the course of a day.

Bram said most drugs on the market for ADHD work effectively, but the majority have a 8-12 hour duration. CTx-1301 contains an immediate pulse, a pulse 3 hours later, and a 20% proportion that is saved for 7 hours later.

This boost given 7 hours following taking the actual treatment limits the amount of pills needed and prevents a crash.Bram said around 60% of ADHD patients require a booster dose, but with it built right into the tablet it could drastically improve the quality of life of users.

In the phase 2 study, CTx-1301 demonstrated a statistically significant higher concentration (

<0.05) compared to Focalin XR from 9-16 hours in both low and high doses.

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CTx-1301's formulation enables 3 different doses within 1 pill for ADHD.

Matthew Brams, MD: A Multidose ADHD Pill

A new study evaluating the safety and reactogenicity of trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) in older adults reported that both are acceptable to use in the prevention of 

Currently licensed in the US for adults aged 65 years and older, both vaccines have shown to be more effective than trivalent standard-dose, unadjuvanted inactivated influenza vaccines (SD-IIV3).

However, no previous research has directly compared the safety between aIIV3 and HD-IIV3 in the same trial.

To do just that, a team led by Kenneth Schmader, MD, Department of Medicine, Duke University School of Medicine, conducted a randomized, blinded, multicenter trial during the 2017-2018 and 2018-2019 flu seasons.

“The primary objective (statistical end point) was to compare proportions of participants with moderate-to-severe injection-site pain following aIIV3 vs HD-IIV3,” the investigators wrote. 

“A coprimary objective was to compare serious adverse events (SAEs) and adverse events of clinical interest (AECI) after each vaccine,” they continued.

The team evaluated a total of 757 patients ≥65 years old (mean age, 72). A majority were woman (55%) and White individuals (78%).

The population was then randomized 1:1 to receive either aIIV3 or HD-IIV3.

Participants who received a vaccine during the 2017-2018 flu season and were subsequently evaluated were ineligible to be evaluated during the 2018-2019 season. Therefore, all participants represented unique individuals.

The primary outcome of moderate-to-severe injection-site pain and 14 other solicited reactions were measured within 8 days of vaccination and using a noninferiority test.

Serious adverse events and adverse events of clinical interest were measured between days 1-43.

The investigators also measured health-related quality of life (HRQOL) scores before and after vaccination (days 1 and 3). These scores were then compared between study groups.

Final data indicated that the proportion of patients who reported moderate-to-severe injection-site pain following reception of aIIV3 (n = 12; 3.2%) was noninferior compared with HD-IIV3 (n = 22; 5.8% [difference −2.7%; 95% CI, −5.8 to 0.4]).

Furthermore, 10 solicited reactions (fever, chills, vomiting, diarrhea, nausea, headache, myalgia, redness, swelling, shoulder pain on side of vaccination) met noninferiority criteria for aIIV3, while 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not.

“It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3,” the investigators wrote.

Further, no participant sought medical care of a vaccine reaction. No adverse events of clinical interest were observed in this population.

The team reported that 9 participants had at least 1 serious adverse event following aIIV3 injection (2.4%; 95% CI, 1.1-4.5) and 3 participants had at least 1 severe adverse event after HD-IIV3 (0.8%; 95% CI, 0.2-2.2). And yet, the investigators determined that no severe adverse event was associated with vaccination.

Additionally, HRQOL scores were considered not clinical meaningful pre- and post-vaccination and between groups.

Schmader and his team concluded that both vaccines are acceptable to use in adults of older age.

However, they acknowledged that their study was powered for a single-outcome of injection-site pain, a limitation in their analysis. Furthermore, they did not address the safety of administering allV3 or HD-IIV3 with additional vaccines in the same visit.

“The safety of adjuvanted influenza vaccines has been a topic of public interest,” they wrote. “Similar clinical safety profiles support the conclusion that concerns about differences in safety between aIIV3 and HD-IIV3 need not be a factor when choosing between them.”

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults

The randomized, blinded trial evaluated the safety and reactogenicity of aIIV3 and HD-IIV3 in adults 65 and older. 

Study Supports Safety of Trivalent Influenza Vaccines in Older Adults

New research presented on a poster during the 

 shows the value in CTx-1301 (dexmethylphenidate) as a beneficial treatment under fasted conditions for adult patients with 

In the randomized, single-dose, four-sequence, four-period, crossover study, a team of researchers compared the drug with Focalin XR in 45 adults with ADHD.

The researchers found the study drug exhibited similar systemic d-MPH exposure to the comparison drug for up to 8 hours following administration. Plasma concentrations at 15-16 hours for CTx-1301 were also similar to the comparison drug at 12 hours.

CTx-1301 demonstrated a statistically significant higher concentration (

<0.05) compared to Focalin XR from 9-16 hours in both low and high doses, while CTx-1301 is expected to have a similar onset of action as the comparison drug (30 minutes).

Overall, the CTx-1301 tablets showed a trimodal pharmacokinetic profile with fast onset, entire active-day duration. This shows the drug has the potential to minimize crash and rebound, while eliminating the need for booster doses.

, Matthew Brams, MD, Chief Medical Officer of Cingulate Therapeutics, and Shane Schaffer, PharmD, CEO of Cingulate, explained the results and what the plans are for a phase 3 trial.

Researchers are prepared a phase 3 trial testing the treatment in adults with ADHD.

Matthew Brams, MD: Positive Results for CTx-1301 for Adults with ADHD

The coronavirus disease 2019 (COVID-19) has changed the role of many across the spectrum of medicine, including psychiatrists.

Many of these clinicians must treat patients now dealing with enhanced feelings of stress, frustration, and self-concern, while also dealing with similar feelings for themselves.

attention deficit/hyperactivity disorder (ADHD)

, Elizabeth Ahmann, Research Director of the Springer Institute and Micah Saviet, Director of the Springer Institute, discussed how the role of the ADHD coach may not have changed much during the ongoing pandemic, but specific of what ADHD individuals need has shifted.

Ahmann said in the past a common issue for individuals with ADHD was getting to work on time. However, because of the massive shift to a work from home setting across the board, some of the current issues include how to manage the stress and potential distractions in working from home.

There are also differing challenges in terms of socialization and physical activity than there was prior to the pandemic.

However, overall coaches still need to be cognizant of how ADHD can impact the daily life of the individual.

The researchers recently presented data from a focus group on what is needed to improve ADHD coaching during the 

The role of many in psychiatry has changed during the COVID-19 pandemic.

ADHD Coaching During COVID-19

 polygenic risk scores may be the most beneficial of all related mood disorder risk scores in the assessment of 

The American Professional Society of ADHD and Related Disorders (APSARD) 2021 Annual Conference

 this weekend, a team of Massachusetts General Hospital investigators reported that such risk scores may even provide explanation into the significant comorbidity rate of ADHD and other youth mood and emotional dysregulation issues.

Presented by author Joseph Biederman, MD, the study sought to assess the available body of information available on associations between polygenic risk scores for bipolar disorder (BP-PRS) and pediatric bipolar spectrum and related disorders.

As Biederman and colleagues noted, the strong genetic basis of mood disorders could potentially provide clinicians with diagnostic insights when few avenues of care are clear.

“Because the genetic basis of complex disorders such as mood disorders is polygenic, clinically relevant information could emerge from genetic markers in aggregate in the form of polygenic risk scores,” they wrote.

Their research included an online literature search for the following grouped terms:

PRS and Bipolar Disorder, Bipolar, or Bipolar Depression

PRS and Attention, ADHD, Conduct Disorder symptoms, emotional dysregulation, aggression

The investigators additionally screened for predetermined inclusion and exclusion criteria.A litany of variables were extracted from relevant studies, including population age, study size, source of PRSs, source of clinical and genetic data, primary study outcome, assessments used, and main findings.

In their findings, Biederman and colleagues observed bipolar PRSs were significantly associated with deficits in executive functioning, ADHD diagnoses, and associated executive function deficits.

In the lone study to compare depression PRSs to bipolar PRSs directly in youths, investigators noted that, among the 40,000 children aged 6-17 years old, only depression PRSs were associated with ADHD symptoms, internalizing problems, and social problems.

ADHD PRSs, the team reported, were associated with conduct problems, depressive symptomatology, and externalizing disorders symptoms.

“Findings revealed that while higher BP-PRSs were correlated with increased hypomania scores, ADHD-PRSs were more clearly associated with emotional reactivity, emotional dysregulation, and irritability—frequent correlates of pediatric bipolar spectrum disorder,” investigators wrote.

Though depression PRSs were predictive of more severe pediatric trajectories toward major depressive disorder, their contribution toward pediatric bipolar spectrum and related disorders is still unknown; available studies did not examine such risk in observed patients.

Taken together, one form of polygenic risk scores seems to best inform interpretation of pediatric mood disorder risks and progression.

“These finding suggest that ADHD-PRSs may have the most important contribution to the development of mood related problems in youth and may begin to explain the high comorbidity between ADHD with mood and emotional dysregulation problems in the young,” Biederman and colleagues wrote.

The study, “Can Polygenic Risk Scores Help Identify Pediatric Bipolar Spectrum and Related Disorders?” was presented at APSARD 2021.

Such scores could provide insight into the significant comorbidity rate of ADHD and other youth mood and emotional dysregulation issues.

ADHD Polygenic Risk Scores May Benefit Pediatric Bipolar, Mood Disorder Understanding

A pilot study assessing the use of telemedicine in patient-reported responses to adult 

treatment showed a notable sensitivity to the impact of therapy changes on symptoms and patient functioning.

, investigators from Massachusetts General Hospital reported outcomes from an online survey-based assessment of adults with ADHD asked to gauge real-time response to psychopharmacology.

They observed a likely correlation to patient sensitivity and mobile ADHD symptom monitoring following changes in treatment status.

The Shire and Takeda-supported trial, presented by author Craig Surman, MD, included 90-plus patients aged 18-80 who self-identified a taking stimulant therapy for ADHD. Participants recorded their demographic information, medication use history and patterns, and their symptoms associated with ADHD.

Surman and colleagues used mobile phone surveys and messaging systems from RedCAP to remotely monitor patients. Their hypothesis was that personalized surveys via mobile messaging could be sensitive to ADHD-specific therapy effects.

“Technology opens the possibility of using measurements by mobile messaging to inform clinical care,” they wrote. “We know that ADHD symptoms respond rapidly to some forms of psychopharmacology as measured on well-validated rating scales. In clinical practice, individuals may find particular symptoms easier to recognize and report on than others.”

Investigators used the Weiss Functional Impairment Rating Scale (WFIRS) and the Adult ADHD Self Report Scale v1.1 (ASRS) to gauge patient-reported therapy effects.

Participants identified medication-sensitive items, and received such items as queries during selected time periods in the morning and evening. From this, investigators inferred “on” and “off” medication statuses for analyses.

In their outcome, the research observed that data confirmed self-reported ADHD symptom severity discriminated “on” versus “off” stimulant therapy status.

Investigators also noted sensitivity thresholds for symptom reporting, as well as reporting patters: within-day and between-day differences.

“Mobile monitoring of ADHD symptoms and functional impact is likely sensitive to changes in treatment status,” they concluded. “Future research may validate the clinical utility of using personalized self-reported mobile-messaged items in treatment optimization.”

The study, “Sensitivity of Electronic Patient Reported Outcome Measures to Medication Effects in Adult ADHD – A Pilot Study,” was presented at APSARD 2021.

Personalized, daily self-reporting for patients could influence future therapeutic strategies.

ADHD Treatment Change Impacts Remote Patient Monitoring 

Virtual Behavioral Parent Training (BPT) appears to be an acceptable alternative for parents of children with 

 2021 American Professional Society of ADHD and Related Disorders (APSARD) Annual Virtual Meeting

A team, led by Nguyen Tran, Seattle Children’s Research Institute, administered online surveys to assess parent satisfaction with new telegroup formats due to the effects of the

 coronavirus disease 2019 (COVID-19) pandemic

“We assessed the acceptability of online BPT as an alternative to in-person groups since the start of COVID-19,” the team wrote. “Given increased stress and social isolation for parents during the pandemic, telegroups are hypothesized to be an acceptable alternative for parents of children with ADHD.”

An Assessment of Remote Behavioral Parent Training

Tran and colleagues thus evaluated a total of 75 parents (74.3% female) of children with externalizing behaviors. The sample was taken across 12 groups and 5 BPT programs: Incredible Years, Superparenting, ADHD 101, First Stem, and Lifestyle Enhancement for ADHD Program (LEAP).

Some of the programs had met in-person prior to the pandemic, while others—including LEAP—were conducted entirely through virtual means.

Surveys on acceptability and satisfaction were administered following 1 year of attendance to these programs.

These included the Telegroup Feedback Survey (TFS), which inquired into parents’ experiences with technological features of the group as well as the group itself, and the Client Satisfaction Questionnaire (CSQ), which surveyed general satisfaction with the group.

Therefore, of the total surveyed, 88% reported overall satisfaction with the telegroup format.

Most reported a preference for having virtual groups as opposed to a cancellation or discontinuation of them. Further, 80% reported that they are able to actively participate in the sessions.

Even more, LEAP attendance was significantly higher in a virtual setting (95.7%; 112 out of 117 encounters) compared with a previous in-person group. The investigators reported an increase in attendance by 11.5%.

Up to 69% of attendants (N = 9) in the LEAP group rated the service as ‘excellent,’ and 31% rated it as ‘good.’

According to the CSQ, 84% (N = 11) reported that most or all of their needs were met by the program.

Across all programs, only a few parents reported technical issues (n = 3), and some (n = 5) noted that telegroup can make discussions more challenging than in-person meetings.

“The COVID-19 pandemic has had a negative impact on families of children with ADHD or disruptive behaviors,” Tran and colleagues wrote. “Our data shows that parents generally found the telegroup format to be acceptable but some gaps remain, including around technical issues and participation.”

They acknowledged that additional research on acceptability is warranted. In terms of future directions, they noted a need for randomized controlled trials that could more effectively evaluate the efficacy of telegroup verices versus in-person services. 

The study, “Assessing the Transition to Remote Videoconference Group Parent Training Interventions for ADHD During the COVID-19 Pandemic,” was presented at APSARD 2021.

Randomized controlled trials are needed to evaluate their efficacy in comparison with in-person group meetings. 

Surveys Show Remote Behavioral Parent Training for ADHD is Acceptable Option 

Investigators have observed a significant and direct link between pediatric 

 and a likelihood of alcohol problems at adulthood.

 this weekend, a team of US-based investigators report an evolved understanding of developmental-based alcohol problem risks among young patients with ADHD—one which may better inform preventive intervention that would limit alcoholism and other substance abuse into such a patients’ 30s and beyond.

Presented by study author Christine Walther, PhD, of the University of Houston-Clear Lake, the trial was driven by participant- and guardian-reported metrics of ADHD symptoms, education marks, delinquency, social impairment, and alcohol use. All trial participants came from the Pittsburgh ADHD Longitudinal Study, who were interviewed at 3 age-based intervals between 14 and 30.

Past studies have described the mediational pathways in which ADHD symptom persistence, delinquency, and social and academic impairment partially explain the increased risk of substance abuse with pediatric ADHD—with stronger links observed between adolescents with low parental knowledge about their daily activities.

But such research has not expanded to observe risks as patients progress into young adulthood and their 30s.

“This study investigated the extent to which adolescent and young adult mediators continued to account for ADHD-related risk for problematic alcohol use at age 30 and whether the associations differed as a function of parental knowledge in adolescence,” they wrote.

The trial included 142 participants, 53% of whom had pediatric ADHD, 85% were white, and 92% were male. Participants were interviewed during ages 14-17, 25, then age 30.

Investigators measured adolescent and adulthood metrics including:

Age-25 and -30 participant-reported alcohol problems

The team tested adolescent-reported parent knowledge as a moderator of each of the mediated pathways, with adjustments for race, gender, age 17 alcohol use, parent psychopathology, and childhood socioeconomic status.

Walther and colleagues reported a significant association between childhood ADHD and alcohol problem likelihood in adulthood, in assessment of the model with adolescent and young adult delinquency as mediators (

Interaction between childhood ADHD and adolescent parental knowledge was also significantly associated with delinquency in adolescence (

“However, parental knowledge, the interaction between childhood ADHD and parental knowledge, and delinquency were not associated with age 30 alcohol problems,” they wrote.

Childhood ADHD and adolescent social impairment, adolescent and age 25 social impairment, and age 25 social impairment and increased alcohol problems at age 30 were all associated with one another in the model with adolescent and young adult social impairment as mediates.

“These findings suggest that factors explaining ADHD-related risk of alcohol problems appear to shift developmentally,” Walther and colleagues wrote. “In addition, parental knowledge effects in adolescence do not appear to transcend the transition to adulthood.”

The new findings could have significant implication for developing preventive measures of care designed to decrease adulthood drinking risks, such as programs designed to improve social skills for patients with ADHD.

The study, “Problematic Alcohol Use in Adulthood as a Function of Childhood ADHD, Adolescent and Young Adult Impairment, and Parental Knowledge During Adolescence,” was presented at APSARD 2021.

Investigators have observed a development-related shift in risks from teenaged ADHD and alcohol use risks in the patients' 30s.

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