Cadiomyopathy and Exercise: The Ball Is in Whose Court?

 Cardiologists are drifting away from blanket restrictions on exercise for people with the most prevalent genetic cardiomyopathy causing sudden cardiac death in the young -- hypertrophic cardiomyopathy (HCM). But how are patients and physicians now expected to make personalized and informed decisions?

Fears of HCM patients triggering a life-threatening arrhythmia during exercise stem from the presumed unstable myocardial substrate in these individuals. In the past, expert opinion on this resulted in patients being barred from vigorous exercise and most competitive sports, despite the known benefits of regular physical activity.

Now, evidence continues to mount that exercise poses a lower risk for sudden death in HCM than previously thought. Recent data suggest that the largest proportion of sudden death in athletes, as well as young people in general, occurs in people with normal hearts, with HCM accounting for less than 10% of cases. Reporting biases keep the exact number of HCM-related deaths unknown, however.

Also muddying the water are observations that athlete sudden deaths, even when HCM is involved, commonly occur outside exercise.

Rachel Lampert, MD, an electrophysiologist at Yale School of Medicine in New Haven, Connecticut, said that we simply don't have data yet on continuing sports for patients who do not have defibrillators.

Data suggest that once an implantable cardioverter-defibrillator (ICD) is placed, the patient's risk from exercise is very low. Lampert's group found in a registry study that athletes fitted with ICDs had no instances of physical injury or failure to terminate the arrhythmia over 2 years.

The LIVE-HCM prospective observational study comparing outcomes of HCM patients who exercise moderately or vigorously versus staying sedentary has finished enrolling and hopefully will be analyzed by Lampert's group by the end of this year, she said.

Acknowledging the gaps in the literature on HCM patients without ICDs, the latest guidelines have become more relaxed in keeping moderate- to high-intensity sports participation an option for patients. In particular, guidelines stressed weighing different risks and benefits in discussions between patient and clinician.

"The prior approach, in my opinion, was more paternalistic, that 'in the absence of data, we need to be cautious, so we should restrict patients from doing sports.' Now the current approach is more based on shared decision-making, which means that our role is to help patients and give them the information they need to make the decision," said Lampert in an interview.

For a patient who doesn't have any risk factors suggesting elevated risk, the cardiologist needs to share the data available and help the patient consider their own approach to risk, she added. "Some say, 'If you can't say it's risk-free, I'm not doing it' ... There are other people that say, 'Risk is a part of life. I'm going to live my life, not let potential small risks put a limit to what I do.'"

Indeed, a comprehensive risk assessment is key to shared decision-making, according to preventive and sports cardiologist Elizabeth Dineen, DO, of the University of California Irvine.

"We start with a history and physical, especially focusing on any exercise-related symptoms past or present and family history, and ensure we have echocardiogram, Holter monitor, stress test, and cardiac MRI data to guide the assessment and next steps," she told MedPage Today.

Factors that point to greater risk include young age, a history of unexplained syncope or nonsustained ventricular tachycardia, late gadolinium enhancement on cardiac MRI, a thicker left ventricular wall, and a family history of sudden cardiac death.

"For those asymptomatic and deemed low risk for sudden cardiac death from a cardiovascular standpoint, the data is moving in the direction of supporting their participation if it is deemed an acceptable risk from the athlete, based on their individual risk and the intensity of exercise they wish to engage in," Dineen said.

There is an understanding that some risk does exist, she said. The level and intensity of competition could indicate an emergency action plan and/or additional support.

But some say there are downsides to this new way of doing things. Case in point: a situation where athlete, cardiologist, and trainer disagree on the level of acceptable risk.

"Undoubtedly, balancing patient autonomy with respect for the common good in order to prevent catastrophic events in sport is a massive challenge," wrote sports medicine physician Jonathan Drezner, MD, of the University of Washington in Seattle, and colleagues, in a review article from 2020.

"Most young athletes do not consider themselves vulnerable to the risks of sport, catastrophic injury, or sudden death. In combination with the lure of fame and/or fortune or family pressure for economic gain, this raises an important ethical question: can young athletes truly make an unbiased and informed decision under duress?" the group asked.

What clinicians can all agree on is that placing an ICD for the sole purpose of a lower-risk HCM patient participating in sports is a bad idea.

"A defibrillator is a great device for people who are at significant risk of dying from cardiac arrest. However, if you don't need one, you don't want one. The risk of implantation is not zero, and there are long-term potential downsides," Lampert said.

Disclosures

Lampert and Dineen disclosed no relevant conflicts of interest.

https://www.medpagetoday.com/clinical-challenges/acc-cardiomyopathy/98094

FDA Panel Mulls COVID Booster Issues Despite 'Insufficient' Data

 All the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) could agree about on Wednesday in terms of a plan for COVID boosters is that they need more data.

The 8-hour meeting, broadcast over YouTube, was riddled with technical glitches early on, and ended with some frustration over the open-ended questions the agency posed.

FDA staff charged VRBPAC members with discussing what considerations should inform strain composition decisions for COVID boosters, how often should these be assessed, what would indicate a need for an updated strain composition, and what considerations should inform timing and populations for COVID boosters.

Members agreed that the focus of boosters should be preventing hospitalization and death, but they didn't feel comfortable with boosters every 8 weeks. They also seemed to settle on 80% protection from severe outcomes as an acceptable threshold for vaccine effectiveness. But questions about which data should inform booster selection, and timing of vaccination were more gray areas.

VRBPAC chair, Arnold Monto, MD, of the University of Michigan, also lamented the lack of a concrete proposal from the agency that the committee could respond to, specifically.

Monto began the discussion by saying evidence was "insufficient right now to give you in any way precise comments for all the discussion questions."

"How often should adequacy of strain composition of available vaccines be assessed? 'As often as you can,'" he said. "We really have to be very flexible in some of the conclusions we come to."

Michael Nelson, MD, PhD, of UVA Health and UVA School of Medicine in Charlottesville, Virginia, said he supported a "unified approach" for vaccine strain composition, but urged adopting "a framework that is more intentional" and involves "making changes only when we feel that the changes will lead to a longer duration" of protection.

"We need to use our predictive models and perhaps pivot to a multi-valent approach," he said, adding that future COVID boosters would perhaps be comprised of "historically based strains" and then "cautiously fold in future variants."

FDA staff, including Doran Fink, MD, PhD, agreed, saying it would also provide better coverage especially for those who might be getting the two-dose primary series for the first time.

"Pivoting towards a mono-valent vaccine runs the risk of narrow ... coverage for people getting the vaccine as a primary series," he said. "It seems at least to me to make a compelling case for any modifying vaccine ensuring breadth of coverage [and] able to handle whatever variant may come."

Ultimately, Monto said, "we would love to see an annual vaccination similar to influenza, but we realize the evolution of the virus will dictate how we respond in terms of additional vaccine doses."

VRBPAC members also lamented the lack of concrete correlates of protection. FDA's Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research, said that the agency is "working with NIH colleagues, trying to work through this."

In the absence of a clear correlate, however, he said they've been using "poor man's correlates," such as antibody levels.

Though VRBPAC members agreed that in an ideal world, they would like to see clinical data to inform decisions on boosters, Eric Rubin, MD, PhD, of Brigham and Women's Hospital in Boston, questioned if the timing for manufacturing would make that feasible.

"If we're going to do this in a timely fashion, we're going to have to use safety and immunogenicity as our endpoints and not clinical data," said Rubin, who is also editor-in-chief of the New England Journal of Medicine. "I just don't think it's going to be practical."

Marks indicated that FDA would need to decide by June if current vaccines were to be updated to target different strains for a fall booster.

Amanda Cohn, MD, of the CDC, addressed the question of protection, saying that CDC is doing multiple studies on vaccine effectiveness, but they're "never going to get the kind of specificity everyone would like to see."

She brought up a point, also hammered early on by Marks, that half of Americans have yet to receive a third dose, and cautioned not to just look at "relative [vaccine] effectiveness" as it can "misstate the overall protection the three-dose series does provide."

Monto backed up his support for an 80% vaccine effectiveness threshold by saying that with the "development of antivirals and therapeutics, you can't prevent everything with an evolving virus."

"The need for revaccination will be dictated by the virus more than by us," he noted.

Marks said that VRBPAC would meet again in early summer to discuss "more specific detail" regarding the composition of future boosters to "stay ahead of future variants and outbreaks" and promised "a fair number of meetings for this committee" in the future.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/98096

Polypill Looks Good for Parkinson's

 Parkinson's disease patients did better taking two drugs than one in a pivotal trial, a researcher said here.

Scores on standard tests improved more among patients taking a fixed-dose combination of 0.6 mg of immediate-release pramipexole and 0.75 mg of rasagiline -- dubbed P2B001 -- than with either agent alone, said C. Warren Olanow, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

P2B001 also outperformed an extended-release version of pramipexole (Mirapex ER) titrated to doses of 1.5-4.5 mg, he told attendees at a late-breaker session during the American Academy of Neurology's annual meeting. The efficacy was similar, but patients receiving the combination had less daytime sleepiness and other dopaminergic side effects typical of higher-dose pramipexole.

The two-drug polypill is also attractive because its one-size-fits-all dosing, supported in multiple studies, means patients and clinicians can skip the dose titration recommended for current therapies. Moreover, said Olanow, it could be suitable as first-line therapy.

If approved, P2B001 would be a "new option for initiating treatment" in Parkinson's disease, he said.

Pramipexole, of course, is a dopamine agonist, while rasagiline is a monoamine oxidase inhibitor. Current treatment guidelines put these drug classes as second- and third-line therapy, respectively, after levodopa, because their better efficacy comes with more side effects. In addition to somnolence, these include gastrointestinal problems, orthostatic hypotension, and psychobehavioral symptoms such as hallucinations and diminished impulse control.

For the phase III study, Olanow and colleagues enrolled 544 previously untreated patients with early Parkinson's disease (<3 years since diagnosis) at 70 centers in multiple countries. Patients were randomized at 2:2:2:1 to receive capsules combining low-dose pramipexole with rasagiline, to each of these alone, and to extended-release pramipexole for 12 weeks.

The primary outcome measure was the total Unified Parkinson's Disease Rating Scale (UPDRS) score (i.e., parts II and III). Patients receiving the combination showed an improvement of about 8 points relative to baseline, versus approximately 5.5 points for both of the components individually.

With respect to pramipexole ER, changes in UPDRS score were virtually identical. But Epworth Sleepiness Score ratings jumped almost immediately in patients receiving pramipexole ER and stayed elevated through the 12-week study. There was no change from baseline in the P2B001 group.

Rates of other adverse effects also favored the combination. For example, orthostatic hypotension was identified in 13% of the pramipexole ER group versus 3% of those on P2B001. Nausea, constipation, and peripheral edema were also more common with pramipexole ER. Overall, the safety profile for P2B001 was as expected given its components (e.g., somnolence was still present at rates similar to those seen with low-dose pramipexole alone).

Israeli drugmaker Pharma Two B had released topline results last December and said it expects to file marketing applications later this year.

Disclosures

The study was funded by Pharma Two B, developer of P2B001. Several co-authors were company employees. Olanow reported a financial relationship with Pharma Two B.

Primary Source

American Academy of Neurology

Source Reference: Olanow CW, et al "Efficacy and safety of P2B001 in the management of early Parkinson's disease: results from a phase 3, randomized, double-blind, double-dummy controlled trial" AAN 2022.

https://www.medpagetoday.com/meetingcoverage/aan/98098

Memory Enhancer Succeeds in Phase II Alzheimer's Trial

 A first-in-class oral compound targeting N-methyl-D-aspartate (NMDA) receptors proved beneficial in a mid-stage clinical trial in Alzheimer's disease, setting the groundwork for a full safety and efficacy study, a researcher said here.

SAGE-718, a positive allosteric modulator (PAM) of NMDA receptor activity, improved mean scores on five standard memory tests in 26 Alzheimer's patients with mild cognitive deficits, reported Aaron Koenig, MD, of drugmaker Sage Therapeutics in Cambridge, Massachusetts.

These included a 2.3-point gain in Montreal Cognitive Assessment (MoCA) score over the 28-day study, a 50% improvement in digit symbol substitution, an average 6.9 fewer errors relative to baseline performance on a multitasking test, and a 1.1-point increase on a 5-point verbal recognition test scale, Koenig told attendees at a late-breaking abstract session during the American Academy of Neurology annual meeting.

Moreover, these improvements came without a change in psychomotor performance, meaning that participants were not simply hitting buttons faster during the cognitive tests, he noted.

Sage is developing the agent for several types of cognitive deficits, including those related to Huntington's and Parkinson's diseases, as well as Alzheimer's. A placebo-controlled phase II study is now underway in patients with Huntington's disease, and Sage said it plans to open similar trials for other indications this year.

For the current open-label study, Koenig and colleagues enrolled patients with mild cognitive impairment or mild dementia (Clinical Dementia Rating [CDR] of 0.5-1.0) believed to stem from Alzheimer's disease, and MoCA scores of 15 to 24 at baseline. Patients initially completed the battery of five cognitive tests and the psychomotor evaluation, then received SAGE-718 (no generic name has been officially assigned yet) at 3 mg each morning for 2 weeks. The drug was stopped for 2 weeks, and patients repeated the test suite on day 28.

Mean patient age was 67. About 70% were women, and 80% were white. MoCA scores at baseline averaged 20.7, and about 90% of the group had a CDR score of 0.5.

Seven of the 26 participants had adverse events during the study, with six of the events considered drug-related. Koenig did not give specifics, but he noted that none were considered serious and no one discontinued the treatment because of them. Lab values were all normal, and there were no signs of suicidal ideation or behavioral changes.

"These results support further clinical evaluation of SAGE-718" for memory deficits related to neurodegenerative diseases, Koenig said.

It's certainly a fertile territory for drug development. Attention and research money in recent years has been heavily weighted toward disease-modifying therapies, such as those targeting beta-amyloid for Alzheimer's disease. Payoffs have been slow in coming, however. Meanwhile, currently available drugs that aim to boost memory are only moderately effective and not for very long.

Among the latter is memantine (Namenda), which is a broad NMDA receptor antagonist. Because it is not highly effective, memantine is usually paired with an acetylcholinesterase inhibitor, bringing the risks that come with polypharmacy. Researchers have more recently come to believe that PAMs are a better way to modify receptor activity and may prove more effective. That, however, will only be known when randomized placebo-controlled studies are completed.

Disclosures

The study was funded by Sage Therapeutics.

Koenig and most other authors were Sage employees.

Primary Source

American Academy of Neurology

Source Reference: Koenig A, et al "SAGE-718 in patients with mild cognitive impairment or mild dementia due to Alzheimer's disease: results from the phase 2 LUMINARY study" AAN 2022.

https://www.medpagetoday.com/meetingcoverage/aan/98099

Ikena moves to next stage in urothelial carcinoma trial

 

Item 8.01

Other Events.

In April 2022, Ikena Oncology, Inc. (the “Company”) advanced to stage two of the nivolumab combination expansion cohort in the Phase 1b clinical trial of IK-175 (NCT04200963). The study is currently evaluating IK-175 in patients with advanced or metastatic urothelial carcinoma who have progressed on multiple prior lines of therapy, including checkpoint inhibitors. The expansion cohorts of the trial follow a Simon two stage statistical design that requires that a predefined threshold of antitumor activity measured by the RECIST 1.1 overall response rate (ORR) be reached in stage one before advancing to stage two. As previously disclosed, the monotherapy expansion cohort advanced to stage two in September 2021. The Company plans to submit the initial clinical data from this trial to an oncology conference in the second half of 2022.

https://www.streetinsider.com/SEC+Filings/Form+8-K+Ikena+Oncology%2C+Inc.+For%3A+Apr+06/19881286.html

German Lawmakers Reject Mandatory Vaccination Bill In Latest Blow To Chancellor Scholz

 Update (0900ET): In what appears to be a major blow for German Chancellor Olaf Scholz, the Bundestag has rejected a bill that would have made COVID vaccination mandatory for all Germans over the age of 60.

Scholz had managed to build broad support for the bill among members of his 'stop sign' coalition, but when it came time to vote, 378 out of 683 parliamentarians voted against the bill, while only 296 voted in favor. The failure of the vote elicited cheers from AfD lawmakers, Reuters reported. It was a free vote, with lawmakers instructed not to follow party lines.

The Chancellor pulled out all the stops for the vote, even summoning his foreign minister, Annalena Baerbock, to leave a NATO meeting in Brussels to return for the vote.

Should the bill have passed, it's pretty clear what Scholz next step would have been. The Chancellor has been pushing for mandatory vaccination for all adults.

* * *

The COVID pandemic has largely subsided in Europe (although health authorities have warned about an uptick in cases caused by subvariants and hybrid variants of the omicron strain). But this hasn't stopped German lawmakers from pushing for a new law that would legally require people age 60 and older to be vaccinated.

But that's not all. The deal struck by members of Germany's ruling "stop sign" coalition, which includes Chancellor Olaf Scholz's Social Democratic Party, the Greens and the 'classical liberal' Free Democrats, also includes an option for making COVID shots mandatory for everybody age 18 and older.

That second provision will depend on how the next wave of the pandemic develops during the fall, according to Bloomberg, which cited a local report.

According to other provisions in the proposed law, the government would initially try to "encourage" the unvaccinated to voluntary submit to inoculation (Germany still has millions of unvaccinated citizens, not unlike the US). Fortunately, even if the proposal becomes a law (it's due for a vote on Thursday), it will also include provisions that would reverse the situation if enough people receive their COVID shots voluntarily before the summer.

Lawmakers told Bloomberg that the goal of the proposal is "effective prevention."

"We are united by the goal of effective prevention through the highest possible level of basic immunity for all adults for the fall, because in this way we can prevent the health system from being overwhelmed," they added.

Germany is still recording more than 200,000 cases and more than 300 deaths from the virus on most days. But with more than 75% of its population vaccinated, the pressure on the country's health-care system has significantly lessened since the depths of the pandemic.

Most western countries have strongly opposed mandatory vaccination requirements (although the Biden Administration in the US has attempted to force millions of workers to either get vaccinated or risk losing their jobs before the Supreme Court to declare Biden's executive orders unconstitutional). But Chancellor Scholz has decided that mandatory vaccination is permissible, so long as the Bundestag grants its blessing.

Another lawmaker said compulsory vaccination for all Germans over 60 will help the German economy remain "free" during the fall wave. Whether that's true or not remains to be seen.

https://www.zerohedge.com/covid-19/bill-introducing-mandatory-vaccination-all-germans-over-60-expected-pass

Biophytis Updates on Clinical Development

 

• Sarcopenia (SARA) : discussions engaged with FDA for the preparation of a Phase 2-3 program in sarcopenia, with the objective of having a First Patient In by end of H2 2022

• COVID-19 (COVA): 237 patients enrolled - early termination of recruitment due to global drop of COVID-19 hospitalizations - results for the phase 2-3 study will be reported in Q3 2022

https://finance.yahoo.com/news/biophytis-provides-updates-sarconeos-bio101-062500516.html