Hep C Meds Linked to Improved PTSD Symptoms

 The combination of the two antiviral medications glecaprevir and pibrentasvir (Mavyret) is linked to improved symptoms in posttraumatic stress disorder (PTSD), new research suggests.

A national cohort study of US Department of Veterans Affairs patients included more than 250 participants with PTSD and comorbid hepatitis C virus.

Results showed the glecaprevir/pibrentasvir (GLE/PIB) combo was more strongly associated with PTSD symptom improvement than other antiviral combinations tested in the study, including ledipasvir/sofosbuvir.

"While there are great treatments available for PTSD, there's a lot of desire in the field to find a new medication that will be helpful," lead author Brian Shiner, MD, acting associate chief of staff for research, VA Medical Center, White River Junction, Vermont, told Medscape Medical News.

"We had a great opportunity to use a novel data mining method to look in a wonderful database for a new treatment and we found something very promising," said Shiner, who is also an associate professor of psychiatry at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

The findings were published online recently in the American Journal of Epidemiology.

Common Psychiatric Disorder

PTSD is one of the most common psychiatric disorders, with an estimated lifetime prevalence of 6.4% in the United States. Yet only two drugs, the selective serotonin reuptake inhibitors sertraline (Zoloft) and paroxetine (Paxil), have been approved by the US Food and Drug Administration (FDA) to treat PTSD.

The VA recommends trauma-based psychotherapy, such as prolonged exposure and cognitive processing therapy, as first-line treatments for PTSD. However, not all patents respond to or have access to these approaches, said Shiner.

The investigators wanted to examine whether existing medications might reduce PTSD symptoms. Their previous exploratory study used "data mining" of national VA medical records.

Results from that study showed the three hepatitis C antivirals of GLE (an NS3/4A protease inhibitor), PIB (a NS5A protein inhibitor), and velpatasvir (another NS5A protein inhibitor) were associated with more than double the expected number of patients experiencing a clinically meaningful improvement in PTSD symptoms.

Sertraline was associated with only a slightly higher than expected improvement.

"SSRIs are effective, better than placebo, but the effects are not as good as we would hope," Shiner said.

He noted that GLE and PIB are always prescribed together (Mavyret), whereas velpatasvir is commonly prescribed with the NS5B polymerase inhibitor sofosbuvir under the brand name Epclusa. Sofosbuvir is also commonly prescribed with the NS5A protein inhibitor ledipasvir under the brand name Harvoni.

Strong Association

The new study included 253 VA users with a diagnosis of PTSD and hepatitis C. Of these, 54 were receiving GLE/PIB, 145 were receiving ledipasvir/sofosbuvir, and 54 were receiving sofosbuvir/velpatasvir.

Researchers compared the groups with respect to change over 8-12 weeks on the PTSD Checklist (PCL), a 20-item self-report scale.

In adjusted analyses, the largest mean improvement on the PCL was 14.9 points for the GLE/PIB group and the smallest adjusted mean improvement on the PCL was 7.5 points for the ledipasvir/sofosbuvir group (mean difference, 7.34 points; 95% CI, 1.05 - 13.63).

The adjusted proportion of patients improving by 15 points or more on the PCL was highest for the GLE/PIB group at 43.6% and lowest for the ledipasvir/sofosbuvir group at 26.3%.

Even when accounting for patients receiving trauma-based therapy or SSRIs, "it still looks like there's a strong association of the hepatitis C antivirals with PTSD symptom improvement," said Shiner.

Researchers also carried out a sensitivity analysis among only patients who were cured of HCV (over 90% of the total sample), defined as having an undetectable HCV viral load up to a year after completion of therapy. The analysis showed PTSD outcomes were still superior for participants receiving GLE/PIB.

"The sensitivity analysis was not that robust because almost everyone was cured, so it included almost everybody, but it didn't point us away from the possibility of an off-target effect," Shiner said.

Why antivirals may improve PTSD symptoms is not clear, but they may affect the immune response in patients with hepatitis C — and there may also be an immune response in PTSD, he noted. "Some of those factors may be shared, and that could explain some of the off-target effect," said Shiner.

However, he noted the GLE/PIB drug combination is costly and patients with PTSD can probably access it only through enrolling in a study.

"We are not recommending that people go out and purchase this very expensive drug to treat their PTSD at this point," Shiner said.

He added that the research team has now received funding from the Department of Defense to conduct a randomized, placebo-controlled trial of GLE/PIB as a potential treatment for PTSD.

Promising Potential Treatment

Commenting for Medscape Medical News, PTSD expert Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, DC, said the results suggest GLE/PIB is a promising potential treatment for PTSD.

"I definitely think this should be looked at further," said Ritchie, who was not involved with the research.

She noted that current PTSD therapies have drawbacks. SSRIs have side effects, the most "troubling" being sexual dysfunction. And although cognitive behavioral therapy is effective, "people have to stick with it" and studies show about two thirds of patients drop out, she said.

Potentially effective PTSD treatment approaches include "self-soothing" or "self-regulating" techniques such as exercise, meditation, yoga, and working with animals, she added.

Ritchie pointed out the numbers of participants in the study were relatively small, including two groups that had only 54 patients each.

And while the GLE/PIB combination should be explored further, cost, availability and side effects of this medication need to be taken into consideration, she said.

Ritchie added she is not overly concerned that the mechanism of action for the combination on PTSD may not be well understood. She noted several psychiatric medications fall into that category, including electroconvulsive therapy and lithium.

"When lithium was first found to be effective against bipolar disorder, we had no clue why," she said. "So I would not discount the antiviral based on us not knowing how it works."

However, "we're a long way off" from starting a patient with PTSD on an antiviral, said Ritchie, adding there are "a lot of steps to go through" to get FDA approval.

The study was funded by the National Institute of Mental Health. The cohort used for this study was developed through support from the Department of Defense. Shiner is a co-inventor on a provisional patent application covering the use of glecaprevir, pibrentasvir, and velpatasvir for PTSD and other psychiatric indications. Ritchie has reported no relevant financial relationships.

Am J Epidemiol. Published online June 11, 2022. Abstract

https://www.medscape.com/viewarticle/980211

White House May Ask For $25B Emergency Funding For COVID-19, Monkeypox

 

• The White House is seeking $44.5 billion in emergency funding from Congress for Covid-19 and monkeypox and back Ukraine, the Wall Street Journal reported citing administration officials.
• The White House is asking about $22.4 billion for Covid-19 vaccines, trials, and testing; $3.9 billion to fight against monkeypox; and $4.5 billion to prepare for and recover from natural disasters.
• The administration is also asking for $13.7 billion to continue supporting Ukraine. 
• Last month, the White House Covid-19 Response Coordinator said the Biden administration would stop buying COVID-19 vaccines and treatments as the U.S. plans to get out of the crisis phase.
• Congress must vote on a spending bill by the end of September to avoid a partial government shutdown as the lawmakers expect to use a stopgap funding measure that will help maintain funding levels for the short term.
• Spending bills require 60 votes, and in the 50-50 Senate, at least 10 Republicans would need to back any bill that contained the administration’s request.
• In May, Congress passed a nearly $40 billion military and economic aid package to help Ukraine, and lawmakers expect further funding needs as the war continues.

https://www.benzinga.com/general/biotech/22/09/28737209/white-house-may-ask-for-25b-as-emergency-funding-for-covid-19-monkeypox

Vertex Announces U.S. FDA Approval for ORKAMBI for child cystic fibrosis

 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced the U.S. Food and Drug Administration (FDA) approved expanded use of ORKAMBI® (lumacaftor/ivacaftor) to include children with cystic fibrosis (CF) ages 12 to <24 months who are homozygous for the F508del mutation (F/F genotype) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. ORKAMBI® was previously approved by the FDA for use in people with CF ages 2 years and older with two copies of the F508del mutation.

https://www.businesswire.com/news/home/20220902005252/en/Vertex-Announces-U.S.-FDA-Approval-for-ORKAMBI%C2%AE-lumacaftorivacaftor-in-Children-With-Cystic-Fibrosis-Ages-12-to-24-months

FDA Data Link Diabetes Drug Class to Gallbladder Disease

 An analysis of FDA's reporting system for adverse events turned up three dozen cases of acute gallbladder disease in patients taking glucagon-like peptide-1 (GLP-1) receptor agonists for diabetes or weight loss, including three deaths.

From 2005 to 2016, postmarketing cases of acute cholecystitis were identified in 21 patients taking exenatide (Byetta), in seven taking dulaglutide (Trulicity), in seven on semaglutide (Ozempic), and in one patient taking lixisenatide (Adlyxin), reported Daniel Woronow, MD, and colleagues from the FDA in Silver Spring, Maryland.Thirty of the cases were treated with cholecystectomy and two resolved with ursodeoxycholic acid treatment and discontinuation of the GLP-1 receptor agonist. Of the three patients who died, two had pancreatitis and one died from fatal liver necrosis.

In 42% of the cases, patients experienced disease onset within 90 days from the time of treatment initiation, according to the findings in JAMA Internal Medicine.

The case series complements results of a recent meta-analysis of 76 randomized trials that detected an association between cholecystitis and GLP-1 receptor agonists, the group said, explaining that "potential mechanisms include weight loss, suppression of cholecystokinin secretion, and reduced gallbladder emptying."

Prescribing information in the U.S. for these products "has recently been revised to include warnings and precautions about this risk," the group noted, based on the "mechanistic plausibility," along with the small-yet-consistent imbalances of acute gallbladder events in placebo-controlled trials of GLP-1 receptor agonists and the current series from the FDA Adverse Event Reporting System (FAERS).

Woronow's group explained that at the time of initial approval, only some GLP-1 receptor agonists for glycemic control in type 2 diabetes carried warnings about the risk for acute gallbladder disease, while others did not. To assess the risk in the latter group of agents in the class, staff at the agency conducted an analysis of FAERS to look for cases of acute cholecystitis linked to GLP-1 receptor agonists starting from the time of the first approval in 2005 through 2016.

In total, 36 cases of acute cholecystitis were identified based on pathology reports, diagnosis by a healthcare provider, or compatible signs and symptoms treated with cholecystectomy. Excluded from the analysis were patients with cholelithiasis or cholecystitis prior to use of a GLP-1 receptor agonist, or cases where an alternative cause of cholecystitis was suspected.

Nine patients had weight loss before their diagnosis (mean 7.6 kg [16.8 lb] in cases where the weight loss was recorded). Two patients were also receiving fenofibrate, which comes with a labeled warning of cholelithiasis.

Median patient age was 55, and 53.1% of the cases involved women. Thirty-three of the patients were taking the drugs for type I or II diabetes, with the remaining taking the drug for weight loss. Overall, 21 patients were overweight or obese, 19 had hyperlipidemia, six had non-alcoholic fatty liver disease, and one had periportal fibrosis.

Fourteen of the cases were in patients who received the recommended starting dose of GLP-1 receptor agonist, another 14 were in those on the maximum recommended dose, four were receiving a dose somewhere in between, and the dose was unknown in the other cases.

Time to disease onset was shorter in those on the starting dose compared to patients on the maximum recommended dose (mean 49 days vs 16 months, respectively).

Woronow and co-authors acknowledged limitations to the analysis, including the potential for underreporting in FAERS, along with differences in product marketing times and market shares.

Disclosures

Woronow and coauthors reported no conflicts of interest.

Primary Source

JAMA Internal Medicine

Source Reference: Woronow D, et al "Acute cholecystitis associated with the use of glucagon-like peptide-1 receptor agonists reported to the US Food and Drug Administration" JAMA Intern Med 2022; DOI: 10.1001/jamainternmed.2022.3810.

https://www.medpagetoday.com/primarycare/diabetes/100464

Are EDs Bombarded With Apple Watch Afib Alerts?

 Paul Chernoff was in the middle of a Zoom call this past June when his Apple Watch sent him an alert.

His heart rate had jumped to 142 beats per minute, and he might be in atrial fibrillation, or Afib, the alert said.

He felt fine -- no dizziness, lightheadedness, or shortness of breath. But his brother has Afib that has proven difficult to treat, and a family friend who is a physician said it couldn't hurt to go to the emergency department (ED)

So Chernoff, who's in his early 60s, caught a ride to a nearby hospital in Virginia, where emergency doctors confirmed an episode of Afib. Paired with his low blood pressure, they decided to admit him.

It wasn't until the next day that he saw a cardiologist, who noticed in Chernoff's medical history that low blood pressure was normal for him.

"If he'd seen me [the day before], he would have said not to go to the hospital," Chernoff, the director of information technology at Washingtonian Media, told MedPage Today in a phone interview.

The cardiologist recommended an electrocardiogram (EKG), but there was no reason for Chernoff to stay in the hospital to wait for it. He had no major risk factors for the big worry with Afib -- having a stroke -- and the arrhythmia likely was temporary and would resolve on its own.

More than 100 million people around the world reportedly have an Apple Watch, which touts the ability to detect Afib, and untold more have other wearable devices, like Kardia Mobile, that can alert them to irregular heart rhythms.

So how is the rise of arrhythmia-detecting devices playing out in EDs across the country?

There aren't any hard data on that, but anecdotally, emergency physicians say the technology is becoming a much more common part of their interactions with patients.

"I've been seeing more and more people for whom their watch is an adjunct to their healthcare," said Sean McGann, MD, an emergency physician at Thomas Jefferson University Hospital in Philadelphia and a spokesperson for the American College of Emergency Physicians (ACEP). "I think the trend is that these are going to be more pertinent in peoples' lives and their healthcare."

McGann sees the arrhythmia-detecting technology as "something that can go either way."

"It could cause a lot of anxiety in people," he said. "But if the technology continues to improve, it could be something that's useful for us in the ED and for all of healthcare."

He said the literature is pretty convincing that these devices are good at detecting abnormal heart rhythms, particularly Afib. Surely, they're not as good as telemetry monitors used in the ED, McGann said, but they can help with decision-making in some instances.

"A lot of what we do in the emergency department is making risk-benefit decisions, and it's another piece of data we can use to help us with those decisions," he said.

One of the most frequent complaints he sees in the ED is palpitations, "which could mean anything," he said. If someone who had palpitations earlier now shows a normal EKG in the ED, McGann can go back and look at Apple Watch data.

"If their heart rate was 150 bpm for 10 minutes [when they felt palpitations], that's pretty good evidence that something was going on during that time," he said. "I might be more likely to refer that patient to cardiology, or give them a wearable monitor for a couple of days."

On the other hand, if there was no blip in the watch data, that "makes me less likely to suspect there's something dangerous going on."

But what about a completely asymptomatic person, like Chernoff, who gets an alert but probably doesn't need immediate care?

"The downside here is false positives," McGann said. "The downstream effects are cost and time for yourself, resource utilization, overtesting, and things like that."

Gregory Marcus, MD, an electrophysiologist at the University of California San Francisco, warned that an Afib episode itself "is not an indication for an emergency department visit."

"By itself, it's not an emergency, nor does it require emergent, and usually not even urgent, attention or treatment," he said, adding that "going to the ED is almost certainly a waste of valuable healthcare resources and an inappropriate response."

People alerted to an abnormal rhythm should only go to the ED if they would have gone anyway based on their symptoms, Marcus said.

"If someone is having crushing chest pain or they are having difficulty breathing, sure, then an ED visit is likely appropriate," he said.

McGann said symptoms are "more important than the rhythm that pops up on your watch." He said the best course of action if someone gets an Afib alert while asymptomatic would be to call their primary care doctor "and see what next steps would be indicated, such as going into their office to get an EKG."

"That would probably make the most sense, rather than going right to the cardiologist based on what your watch tells you," McGann said.

As for patients who've been previously diagnosed with an arrhythmia, Marcus said, the devices "can be extraordinarily valuable in both detecting and even characterizing clinically important arrhythmias" -- and might even lead to less healthcare utilization.

For instance, Marcus recently performed an ablation for premature ventricular contractions (PVCs) on a symptomatic patient. During a routine follow-up, the patient said she felt better but intermittently felt a bit off. When Marcus reviewed her Apple Watch data during those vague symptoms, there was no evidence that her PVCs had returned.

"She, her insurance, our clinic, and the healthcare system was therefore saved from another wearable [EKG] monitor, interpretation, subsequent communications, and subsequent visits," he said.

But Marcus is far more hesitant about using these devices to screen the general population for Afib. Without professional recommendations on Afib screening in asymptomatic people, private industry has jumped ahead of the science, he said.

Even though the devices have been shown to be accurate for detecting Afib -- notably in the Apple Heart Study, which was published in the New England Journal of Medicine in 2019 -- only about 3 million people in the U.S. are estimated to have the condition.

"Even with highly accurate devices, when the prevalence of any disease is very low in a given population, the number of false positives will be very high just due to simple, inescapable math," Marcus said.

In addition to the unnecessary testing and stress for patients, this surveillance could even lead to inappropriate anticoagulant prescribing, he said -- and that could come with an increased risk of serious bleeding.

"Recognizing there is always a balance between the benefits of possible thromboembolic prevention versus the harms of false positive test results, investigators and clinicians are busy playing catch-up," said Marcus.

Chernoff went to the cardiologist's office for an EKG 2 days after his hospital stay, and his Afib had resolved by then. His Apple Watch alerted him to one more Afib episode that following weekend, but he hasn't had one since, he said.

Overall, he was happy with the way things worked out. He only paid about $150 out-of-pocket for the entire hospital encounter because he had good insurance. And now he has a cardiologist who he'll probably see regularly.

That cardiologist told him that as he gets older, he will most likely have more episodes of Afib; but without serious risk factors for stroke, he's not likely to have an adverse outcome.

"He recommended I turn off Afib detection," Chernoff said. "He says it's useful, but there are many people who are constantly looking at the numbers, and it's not doing them any good. It's probably just creating more stress for them."

https://www.medpagetoday.com/special-reports/exclusives/100522

Reviva Q2 business update

 Second Quarter 2022 and Recent Business Highlights

• Enrollment update reporting over 20% of the approximately 400 patients planned for pivotal Phase 3 trial already enrolled (July 2022)
• Developing Phase 2a trial protocols for studies of brilaroxazine in attention deficit hyperactivity disorder (ADHD) and pulmonary arterial hypertension (PAH) (July 2022)
• Hosted key opinion leader webinar on brilaroxazine for schizophrenia and other neuropsychiatric disorders, featuring presentations by Leslie Citrome, MD (New York Medical College) & Larry Ereshefsky, PharmD (Apex Innovative Sciences) (May 2022)
  

Anticipated Milestones and Events

• Enrollment initiation at sites in Europe and India for RECOVER Phase 3 study expected in Q3 2022
• Topline data for pivotal Phase 3 trial evaluating brilaroxazine for the treatment of schizophrenia anticipated in mid-2023
• May initiate Phase 2a studies in bipolar disorder, major depressive disorder (MDD), attention deficit hyperactive disorder (ADHD), pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF) subject to the receipt of non-dilutive financing
• Pursue strategic partnership opportunities for the development of our pipeline
• Evaluate grant and other non-dilutive financing opportunities for product candidates from Federal and State Healthcare Agencies and Foundations

https://www.globenewswire.com/news-release/2022/08/15/2498581/0/en/Reviva-Pharmaceuticals-Holdings-Inc-Reports-Second-Quarter-2022-Financial-Results-and-Recent-Business-Highlights.html

Look for an end-of-year boost to drug approvals

 An apparent slowdown at the FDA has biopharma fretting. With the sector struggling to beat off a bear market, the last thing downtrodden developers need are regulatory worries.

Extreme concern is probably a bit premature, at least according to Evaluate Vantage’s look at what remains on the cards for 2022. Several important verdicts are due in the final months of the year, with November looking particularly busy.

But the data do point downwards. The FDA’s CDER and CBER divisions greenlit 19 novel medicines in the first half of the year, the slowest six-month period since 2019. For this analysis imaging agents and reagents are removed from the agency’s official lists of new drug approvals, to construct a tally of solely therapeutic agents. 

A number of reasons have been suggested for the apparent pullback. These range from staff shortages at the agency to a tightening of standards post-Aduhelm and the arrival of a new FDA commissioner. It could also just be a blip, of course, like 2016's, when the annual tally dropped below 30.

Evaluate Vantage also identified 22 remaining approval decisions this year for listed developers being tracked by sellside analysts. This list will be far from exhaustive, as many companies keep regulatory progress under wraps, and there are always below-the-radar projects in the works.

If all 22 get a green light there will be 41 novel approvals in 2022. That would represent a slowdown on the last five years, and would also sit below the 10-year average of 48.

 Approval count: 33

It is probably too early to know whether the FDA really is tightening up. Some believe that more complete response letters are being issued, but this is hard to track because the agency leaves disclosure up to developers. Ongoing pandemic travel restrictions have certainly delayed some decisions – the second half of 2021 also saw a drop on the previous six-month periods.

A separate consideration is whether new drug applications have fallen, but the agency only reveals that number sporadically. Numbers disclosed to 2019 suggest that this is unlikely. 

Whatever the reason, should investors be concerned if this slowdown is confirmed at year end? It is certainly a trend that no one would want to see worsening, given wider pressures on developers right now. 

On the cards

As for the big decisions still pending, next month’s verdict on Bristol Myers Squibb’s deucravacitinib has long been one of this year’s biggest. Whether chunky expectations can be met will depend on the label.

November holds at least seven key Pdufa dates, including those for Apellis’s pegcetacoplan and Travere’s sparsentan. Some in the sellside reckons both could go on to become blockbusters. The first gene therapy for haemophilia B, from Uniqure and its partner CSL, could also get the nod in November.

December could be similarly busy, with decisions due on Mirati’s adagrasib and TG Therapeutics’ ublituximab, with a positive outcome far from guaranteed for either. By the end of the year a couple of followers in the anti-PD-(L)1 space are also hoping to arrive in the US: Novartis and Beigene with tislelizumab and Coherus and Shanghai Junshi with toripalimab.

Six of 2022’s 10 biggest potential launches, as things stood back in February, have crossed the finish line. The remaining four are still in with a chance, with deucravacitinib and lenacapivir featuring among the most important still outstanding.

But several of the contenders in the list are looking shaky. TG's ublituximab, Provention Bio's PRV-031 and Mirati's adagrasib all have questions marks hanging over them. If the year does end with a whimper, it might start to feel like biopharma’s years of excess really are ending, and not just on the stock market.

2022's biggest approvals still to come...
Product	Company	Status	2028e sales ($bn)
Intravitreal pegcetacoplan	Apellis	Nov 25 Pdufa for geographic atrophy	2.6
Adagrasib	Mirati	Dec 14 Pdufa for KrasG12C driven NSCLC; EU decision due H1 2023	2.0
Deucravacitinib	Bristol Myers Squibb	Sep 10 Pdufa for psoriasis; EU decision due Q4 2022	1.6
Sunlenca (lenacapivir)	Gilead	Dec 27 Pdufa for resistant HIV (resubmission); EU approved in Aug	1.6
Sparsentan	Travere Therapeutics	Nov 17 Pdufa for IgA nephropathy	0.9
...and those already across the finish line
Mounjaro	Lilly	FDA approved for type 2 diabetes in May; CHMP positive opinion in Jul	7.4
Spikevax	Moderna	Full approvals in US & EU in Jan, to prevent Covid	4.1
Amvuttra	Alnylam	FDA approved for amyloidosis in Jun; CHMP positive opinion in Jul	2.4
Camzyos	Bristol Myers Squibb	FDA approved for cardiomyopathy in Apr; EU decision due Q4 2022	2.3
Vabysmo	Roche	FDA approved for AMD and DME in Jan; CHMP positive opinions in Jul	1.8
Source: Evaluate Pharma. https://www.evaluate.com/vantage/articles/news/policy-and-regulation-nme-approvals/brace-end-year-boost-drug-approvals