Marco Meglio

This article was originally published in NeurologyLive.

The US Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for Idorsia’s daridorexant, an investigational dual orexin receptor antagonist, for the treatment of adult patients with insomnia, according to a recent announcement.

The NDA includes data from a comprehensive clinical and nonclinical developmental program, which demonstrated the efficacy of daridorexant on subjective sleep parameters and an improvement in daytime functioning, while maintaining a favorable safety profile. Idorsia submitted the NDA to the FDA on January 8, 2021 and noted that should they receive approval, daridorexant will launch in the first half of 2022.

"I’m very happy that this first regulatory hurdle is behind us. This was a huge NDA and the team has done an excellent job in preparing the dossier, on which the FDA can judge the properties and merits of daridorexant,” Jean-Paul Clozel, MD, chief executive officer, Idorsia, said in a statement. “We now stand-by to work with the FDA to answer any questions that might arise concerning the effect of daridorexant on sleep, daytime functioning and its safety profile.”

If approved, daridorexant would become the first sleep medication to demonstrate an improvement in sleep and daytime functioning, as measured by the Insomnia Daytime Symptoms and Impacts Questionnaire, while keeping a favorable safety profile in adult and elderly patients.

In April 2020, the company read out data from its first pivotal phase 3 study of daridorexant (NCT03545191), 

. Doses of both 25-mg and 50-mg daridorexant significantly improved sleep onset and sleep maintenance as measured objectively in a sleep lab by polysomnography. Self-reported data from daily diaries also showed the drug’s significant impact on subjective total sleep time, as well.

The double-blind, randomized, placebo-controlled, parallel-group, phase 3 study included 930 adult and elderly patients with insomnia and evaluated treatment with daridorexant over a 3-month period. In addition to improvements in sleep onset and sleep maintenance, treatment with 25-mg and 50-mg daridorexant also significantly improved total sleep time subjectivity (sTST) compared with placebo.

All 3 of these improvements were seen at both the 1- and 3-month timepoints. That study was part of a larger phase 3 registration program that included another phase 3 study and extension study. In July 2020, 

the safety and efficacy of daridorexant was confirmed

 in the publication of a second pivotal phase 3 study.

The latest data demonstrated a statistically significant improvement in sleep maintenance and subjective total sleep time at months 1 and 3 for patients, nearly 40% of whom were 65 or older, who received the 25-mg dose. Additionally, the therapy also demonstrated positive effects on daytime functioning, which were observed in the first phase 3 study as well.

The safety of the drug was consistent across both studies, with treatment-emergent adverse events (TEAEs) reported in 38.2% and 39.3% of patients treated with 10 mg or 25 mg daridorexant compared with 32.7% in the placebo group. The most common TEAEs observed were nasopharyngitis, headache, somnolence, and fatigue. Notably, no cataplexy-like events or next-morning residual effects were reported, and no suicide or self-injurious behavior was observed.

Articles

If approved, daridorexant would become the first sleep medication to demonstrate an improvement in sleep and daytime functioning.

FDA to Review Daridorexant Insomnia Treatment Application

 of this article was published online by sister publication NeurologyLive.

Findings from a new study demonstrated that pegunigalsidase alfa, or PRX-102, was well-tolerated among patients with 

Furthermore, patients were noted to be stable in their clinical presentations following treatment course.

These findings were announced last week by Protalix Biotherapeutics and Chiesi Global Rare Diseases.

The 12-month open-label, switch-over, phase 3 BRIGHT study included 30 patients with Fabry disease previously treated with a commercially available enzyme replacement therapy (ERT), such as agalsidase alfa or agalsidase beta for at least 3 years prior and were on a stable dose administered every 2 weeks.

After receiving treatment with pegunigalsidase alfa 2 mg/kg every 4 weeks, no patients developed treatment-induced anti-drug antibodies (ADA).

No Fabry clinical events were reported during the study either.

Plasma lyso-Gb3 concentrations remained stable during the study with a mean change of 3.01 nM from baseline (19.36 nM) to week 52 (22.23 nM).

During the 52-week treatment period, mean absolute change of Estimated Glomerular Filtration Rate (eGFR) values remained stable, with a mean change from baseline of –1.27 mL/min/1.73 m2.

Researchers also found that patient perception of their own health remained high and stable throughout the study duration.

This was indicated by a survey using the Quality of Life EQ-5D-5L questionnaire, with overall health mean scores of 78.3 (±3.1) and 82.1 (±2.9) at baseline and week 52, respectively, on a 0 to 100 scale.

Using the short-form Brief Pain Inventory (BPI) questionnaire, approximately 75% of study participants had an improvement or no change in average pain severity at week 52, as compared to baseline. These results remained stable throughout the study, and pain-related results showed no increase and/or relapse in pain.

The most common Fabry disease symptoms observed were acroparesthesia, heat tolerance, angiokeratomas, and hypohydrosis.

Each patient received at least 1 dose of pegunigalsidase alfa, 29 of which completed the 12-month study.

Of these 29 patients, 28 received the intended regimen of 2 mg/kg every 4 weeks throughout the study, while 1 patient was switched to pegunigalsidase alfa 1 mg/kg every 2 weeks per protocol.

"The results indicate that this investigational therapy is well tolerated and potentially an effective treatment for adult patients living with Fabry disease," Einat Brill Almon, PhD, senior vice president and chief development officer, Protalix, said in a 

"We are encouraged to see that all of the patients who completed this study chose to enroll in the long-term extension study,” she continued. “Currently, 80% of the patients enrolled in the BRIGHT study have been treated with this treatment regimen for over 2 years. We look forward to advancing this study and further evaluating the results."

The treatment received fast track designation in 2018 and continued to make headlines in August 2020 when the company announced that the US Food and Drug Administration (FDA) has accepted its biologics license application (BLA).

At the time, the company announced a prescription drug user fee act (PDUFA) date for January 27, 2021, but in November, the FDA extended the action date by 3 months to April 27, 2021.3

The BLA was supported by a comprehensive set of data compiled from the company’s completed phase 1/2 clinical trial as well as the related extension study succeeding the phase 1/2 clinical trial, interim data from the phase 3 BRIDGE switch-over study, and safety data from the on-going clinical studies of pegunigalsidase alfa in patients receiving 1 mg/kg every other week.

The FDA will consider the approval of the biologics license application next month.

PRX-102 for Fabry Disease Efficacious, Well-Tolerated

, none may be more overshadowed than the changes made within the medical education system, and the adjustments the students themselves were forced to make during a time in which even those who were teaching class, were learning themselves.

A select number of those students worked on the frontlines throughout the pandemic—some out of choice, and some who were requested by their education system. In addition to continuing their daily studies, they were tasked with learning how to treat COVID-19 patients along the guides of ever-changing protocols.

Years before it’d be asked of them in a professional setting, medical students demonstrated the necessary features of clinical adaptation and resiliency. Patrick Chen, a neuro ICU fellow at Massachusetts General Hospital, saw the call to action as part of his duty.

“When we realized what COVID was, most neural ICU people were very inclined to jump in,” Chen said. “That’s just the type of personalities within our field. It’s all hands-on deck. From that standpoint, I don’t think there was any doubt that COVID was going to be a daily interaction for us.”

Chen echoed the thoughts of many frontline workers facing the brunt of the pandemic over this last year. Ahead of their time in responsibility and reliability, medical students embraced the culture and professionalism of their would-be colleagues from the very beginning of COVID-19.

Depending on the level of education, the decision to enter the frontlines may have been easier for some than others. Those who are in medical school are paying to go to school, whereas those in residency may be paid by an institution to conduct research for them.

This played “a huge factor” into the decisions of some students, said Christina Zhang-Miller. Zhang-Miller a fourth-year medical student from the University of Cincinnati. She was among a divided class: 50% wanted to help at the hospital, 50% cited family or loved ones they wanted to protect from possible transmission. What’s more, the latter group had no financial incentive to outweigh the risk.

For newcomers who entered the frontlines, the daily strain of overwhelming new cases, worsening patient conditions, and limited resources weighed heavily.

Fabio Nascimento, MD, an epilepsy fellow at Massachusetts General Hospital, shared his experiences in responding to COVID-19 deaths while continuing his education. The sensation was uniquely difficult.

“The most heartbreaking devastating scenarios are the people like you and me, who are in their 20s and 30s,” Nascimento said. “These people have no medical history at all, they come in with COVID, and are then moved to the ICU to get intubated. It’s definitely scary.”

At the beginning of the pandemic, there was a heightened sense of fear and anxiety throughout hospitals and across clinical care specialties. A lot was attributable to the unknowns of the virus and how to treat it. In this circumstance, both students and clinicians were learning together, eroding some of the mentor-mentee relationship that is common within education.

Even for those who were not in the mix of frontline care, medical school stressors became exacerbated as well. Like many aspects of life, the switch to virtual gradually adopted, and came with shortcomings. This transition resulted in greater rates of isolation, increased use of email, and struggles with establishing boundaries between work and home, which affected faculty, students, and support staff.

Applicants at every stage of schooling were greeted with a completely different interviewing process, one that does not involve shaking hands and touring facilities. Students were forced to make decisions about their future education without gaining the full experience: meeting professors, visiting laboratory settings, or connecting with future classmates and colleagues.

Zhang-Miller has been in the process of interviewing for residency programs. Specializing in anesthesiology, she has found it challenging so far. “I’ve never done in-person interviews for residency, so I have no comparison. I don’t know if it feels the same or not. They always say choose a program you vibe well with, but it’s hard to get to know the residents over Zoom.”

Virtual classes themselves have been met with reticence. Zhang-Miller is among those who questioned their long-term feasibility.

“There are a lot of ongoing discussions about it amongst applicants and residency programs,” Zhang-Miller said. “It really depends, if we start residency and feel ‘Woah, the program is being misrepresented,’ then that’s an indicator that virtual interviews didn’t work well.”

The fourth-year medical student isn’t the only one who is uncertain about the future. Others, including Chen, have no clue to what extent virtual learning will be adopted following the conclusion of the pandemic. He wondered whether institutions will recognize the current model as “the future of medicine,” or whether they’ll return to their old method—which itself faced criticism for ineffiencies.

“I wonder if the pendulum is going to swing the other way,” Chen said. “There’s something to be lost in not having that consistency of being in the hospital.”

The pandemic has also had an impact on the ability for students to stand above their peers. In the virtual setting, the grading systems can change, shifting to more pass/fail than individual grades. On top of that, some of the requirements for students have been altered as well.

The National Board of Medical Examiners (NBME) and the Federation of State Medical Boards (FSMB), the organizations that oversee the United States Medical Licensure Examination (USMLE), announced the cancelation of the Step 2 Clinical Skills (CS) exam in January.

After being on hold since May 2020, the announcement came roughly 6 months after the organizations announced they would review the exam’s purpose and endeavor to create a modified version. As is the case with any Step exam, its primary purpose was medical licensure.

Conducting clinical rotations was also an area that was impacted by the pandemic. In March 2020, the Association of American Medical Colleges (AAMC) strongly supported pausing all student clinical rotations until the schools had a better opportunity to educate its students with up-to-date information on COVID-19, and the appropriate steps in place to ensure their own and their patients’ safety.

The ability to stand out among fellow peers became a challenge both in the lab and outside of the classroom.

“Another big part of medical school is building your application for residency. Part of that is volunteer experience, research experience,” Zhang-Miller said. “Volunteer opportunities are very limited right now. Research opportunities are limited right now because you can’t do anything in person. There’s a lot of anxiety for first- and second-year medical students in terms of whether or not their applications are going to be ‘good enough’ for residency.”

For some students, their research was severely impacted by the pandemic. Especially during the earlier stages, a number of studies in the clinical lab setting were put on hold. For Dustin Shaw, the ability to not conduct experiments delayed his work; however, he felt as though he is in a more fortunate position than others.

“I’m at the end. For me, the delay is probably not as severe as a student who’s just starting out, who just had 6 months of their time that they could be using getting their PhD cut off,” Shaw said.

Shaw, an MD/PhD candidate at the University of Chicago, is in his final year before he goes back to medical school. He currently has not committed to his next program. To get over the endeavors of the pandemic, he spent 6 weeks over the summer working in a clinical lab that obtained and processed COVID-19 samples for subsequent analysis.

He said that only a small subset of students were allowed to go into the buildings for COVID-19-specific projects, or to maintain valuable operations that contained years of data and work.

Becoming a doctor is not just reading charts, understanding electroencephalogram (EEG) data, or soaring to the top of your class with highest honors. There’s an aspect of maturing and gaining confidence in front of the patients you’re one day going to treat.

“Examining people is really important. That’s a huge hole in the education portion of residency training. For me, being in my fourth year of residency, it doesn’t influence me as much because I’ve already done a lot of inpatient rotations,” Nascimento said. “But for people that are just starting residency, it’s definitely a huge change. You do lose a lot as far as interacting with patients and having attendings around you showing you how to do certain things and exam. There’s a huge loss there.”

Within certain specialties, the need to interact with patients becomes even more important. Nascimento pointed out that those who may be doing a movement disorders fellowship would be at a disadvantage to begin with, because the in-person work is not comparable to the virtual setting.

Throughout the different levels of education, students begin to develop and share a special bond with their colleagues. In a non-COVID environment, students would spend time congregating in small-group interactions, laboratory sessions, simulations, and technology sessions. There would be a mutual level of sympathy for the amount of work that’s on a student’s plate, as well as the mental stresses they may be facing.

While many will remember the COVID-19 pandemic as a source of disruption, it may be also be viewed as a catalyst for the transformation of medical education—changes that had been brewing for the past decade. There’s also something to be said for the unequivocal educational experience gained from helping respond to a pandemic.

The pandemic also provided an opportunity for learners to realize the dynamic nature of medical knowledge: key concepts in human biology, sociology, psychology, and system science proved essential for caregivers at every level responding to this novel threat.

Town halls led by translational scientists, epidemiologists and public health officials, health system leaders and frontline clinicians demonstrated the necessary diverse skill sets a clinician must need, while also showed that multidisciplinary action can help solve complex health care problems.

Schools and learners also pilot tested new methods of instruction, rethought their approach to assessment, identified different methods to build community, and adopted new strategies for recruitment and admission in a travel-constricted world.

Some students are excited about the changes made to education. “Despite all the tragic aspects the pandemic brought us, from an education standpoint, there’s a lot of newer methods that have been created or improved,” Nascimento said.

On top of everything, Nascimento believed the number of educational platforms available to students has grown. He noted the number of videos, podcast, teaching sessions, and tutorials have helped close some of the educational gaps that lie within virtual learning.

To Nascimento’s point, students adapting to a more virtual setting coincides with the direction medicine was trending anyway. The use of telemedicine has grown exponentially over the past decade, and was further exacerbated by the pandemic.

Amid the greatest adoption of telehealth in the history of medicine, these students will have a firsthand perspective at the optimal usage of these techniques and provide input on ways to evolve it for the better.

Decades down the road, some students will be able to answer that they were not on the sidelines of the COVID-19 pandemic, but rather a part of the response needed to help uplift the country out of its dark time. As a whole, the lessons learned from today’s medical students will continue to be a key cog in how medication education, and therefore clinical care itself is constructed in the future.

Rose S. Medical student education in the time of COVID-19. 

Published online March 31, 2020. doi: 10.1001/jama.2020.5227

USMLE Step 2 CS canceled: what it means for medical students. News release. AMA. February 4, 2021. Accessed March 1, 2021. 

https://www.ama-assn.org/residents-students/usmle/usmle-step-2-cs-canceled-what-it-means-medical-students

Important guidance for medical students on clinical rotations during the Coronavirus (COVID-19) outbreak. News release. AAMC. March 17, 2020. Accessed March 1, 2021. 

https://www.aamc.org/news-insights/press-releases/important-guidance-medical-students-clinical-rotations-during-coronavirus-covid-19-outbreak

Lucey CR, Johnston SC. The transformational impact of COVID-19 on medical education. 

Published online August 26, 2020. doi: 10.1001/jama.2020.14136.

Students share their experience in the virtual classroom, navigating new requirements, and the lessons learned from their position in a global pandemic.

The Transformational Impact of COVID-19 on Medical Education

A recent study failed to show tumor necrosis factor receptor 1 (TNF-TNFR1) signaling inhibition can prevent or delay the risk or age at onset of Parkinson disease (PD).

Lead author Xioying Kang, MPH, BSc, department of medical epidemiology and biostatistics, Karolinka Institut, and colleagues found that TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating C-reactive protein [CRP], 0.99; 95% CI, 0.91–1.08) or age at onset (0.13 years later onset; 95% CI, –0.66 to 0.92).

To the authors’ knowledge, this was the first Mendelian randomization (MR) study to address whether exposure to TNF inhibitors affect PD.

"Human genetics provides valuable guidance for therapeutic programs because the chances of successful drug development are substantially improved when genetic evidence links a drug’s target to an indication for therapeutic use,” Kang et al wrote. “Hence, our findings should be considered as part of discourse on the repurposing potential of TNF inhibitors for PD prevention and treatment, particularly if/when selective inhibitors of TNF-TNFR1 signaling become available.”

A total of 23 single nucleotide polymorphisms (SNPs) in the vicinity of the gene 

which encodes TNFR1, the principal effector of pro-inflammatory signaling following TNF agonism were present in the CRP data (genome-wide association studies [GWAS], n = 204,402).

The effects of TNF-TNFR1 inhibition were estimated for PD risk (Ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson’s Disease Genomics Consortium and 23andMe, Inc.

Researchers found, however, that genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease (OR, 0.75; 95% CI, 0.65–0.86) and ulcerative colitis (OR, 0.84; 95% CI, 0.74–0.97), and increased the risk of multiple sclerosis (MS; OR, 1.57; 95% CI, 1.36–1.81), as the authors noted was expected.

In secondary analyses, the more liberal linkage disequilibrium (LD) clumping yielded 4 correlated SNPs associated with CRP at false discovery rate-corrected (

<.05), 1 of which was not associated with either white blood cell count (WBC; 

The other 3 variants were associated with all 3 inflammatory markers for secondary MR models.

Using adapted inverse variance weighting (IVW) methodology to account for correlations between the variants, MR estimates based on the 3 SNPs remained consistent with the main results that neither PD risk nor age at onset were predicted to be affected by TNF-TNFR1 blockade.

Kang and colleagues also found that there were no associations of the genotypes of implicated functional variant (rs1800693) with PD risk (OR, 1.00 per TNF-inhibiting allele; 95% CI, 0.98–1.02) or age at onset (0.05 years of increase per TNF-inhibiting allele; 95% CI, –0.13 to 0.24), despite strong associations of this SNP with other inflammatory traits.

Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study

Genetically-indexed inhibition of TNF-TNFR1 signaling was predicted to reduce the risk of Crohn’s disease and ulcerative colitis, and increased the risk of multiple sclerosis.