Amylyx Augments Case for ALS Drug Ahead of PDUFA Date

 Shares of Amylyx Pharmaceuticals are falling again, despite the company announcing positive long-term survival analysis data for AMX0035, its experimental amyotrophic lateral sclerosis (ALS) therapy that is up for potential approval from the U.S. Food and Drug Administration next month.

A post hoc analysis of data from the Phase II CENTAUR study that uses the rank-preserving structural failure time model, often used in oncology studies to account for placebo crossover, showed a 10.6-month longer median survival duration for AMX0035 participants, Amylyx announced Thursday.

Additionally, trial participants who received the Amylyx drug and who continued into an open-label extension phase demonstrated an 18.8-month longer median survival duration than participants who never received AMX0035 in a subgroup analysis, the company said. All told, the latest CENTAUR analysis suggested a larger survival benefit for AMX0035 when making that placebo crossover adjustment. Amylyx reported that this latest data shows a median survival duration of 10.6 to 18.8 months compared with the 6.9 months seen in the original prespecified intent-to-treat analysis in ALS patients.

Amylyx also noted that, as of the March 2021 cutoff date, there was a lower hazard of death and longer median survival duration of 4.8 months in those originally randomized to AMX0035 compared to those originally randomized to placebo.

How this will impact the FDA’s decision next month is unknown. At the end of March, the regulatory agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted 6 to 4 against recommending approval of the experimental drug. As BioSpace previously reported, the committee members who opposed approval did so primarily on the Phase II CENTAUR trial design. The committee also questioned the 6.9-month survival benefit initially posted, and suggested the difference in decline measured on the ALSFRS-R scale between the placebo and treatment groups was not great enough.   

Justin Klee and Joshua Cohen, co-chief executive officers at Amylyx, expressed excitement about the post hoc analysis and said they hope the FDA takes this data into consideration before making a decision on AMX0035 next month.

“The thing we think is important is that this data highlights a treatment that can slow disease progression and increase life span. This is an important thing for the FDA and other agencies to consider,” Klee told BioSpace.

The latest survival data provides additional hope for an ALS community that currently only faces a grim future. Cohen said that most ALS patients who participate in a clinical trial typically only get one shot at possibly receiving an experimental medication that could slow their disease and prolong their life. He noted that the company wanted to use the trial structure it chose for the CENTAUR study because they believed it was unethical to run a survival study in ALS where some patients are kept on placebo the entire time. They wanted to ensure that placebo patients would have an opportunity to cross over and receive the active treatment of AMX0035.

“We have a very clear clinical benefit. If you can see that it has a functional benefit, it feels cruel for that to be denied to patients,” he said.

Amylyx’s AMX0035 is a fixed-dose combination of two small molecules, sodium phenylbutyrate and taurursodiol. It is designed to target the endoplasmic reticulum and mitochondrial-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases.

If the FDA does opt to give AMX0035 the green light in June, Cohen said Amylyx will be in a position to manufacture the medication for commercialization.

While the updated CENTAUR data may not move the needle for the FDA regarding potential approval, it adds to the depth of understanding of how AMX0035 can impact the devastating disease as the company pushes forward with its ongoing Phase III PHOENIX study. The primary endpoint of the PHOENIX trial will include safety and efficacy, as well as the potential impact of AMX0035 on disease progression over 38 weeks. That will be determined following baseline readings of ALSFRS-R and survival. Amylyx noted that additional measures critical to ALS patients including slow vital capacity (SVC), serial assessments of patient-reported outcomes and ventilation-free survival rates, will also be assessed in the study.

The PHOENIX trial is expected to include 600 patients who have definite or clinically probable ALS within 24 months of symptom onset. The PHOENIX trial will have broader inclusion criteria than CENTAUR.

ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that negatively affects neurons in the brain and the spinal cord. Patients with ALS lose the ability to control muscle movement. That eventually leads to total paralysis and then death. It is estimated that approximately 12,000 to 15,000 Americans have ALS, with about 5,000 to 6,000 new cases diagnosed annually. 

Currently, the standard of care treatment is Riluzole, a glutamate blocker. In addition to Riluzole, which was approved in 1995, is the more recently approved Radicava, developed by Mitsubishi Tanabe. Other drugs in development for ALS include NeuroSense Therapeutics’ PrimeC, an extended-release formulation of two FDA-approved drugs, ciprofloxacin and celecoxib, as well as Clene Inc.’s add-on therapy, CLN-Au8, an investigational gold bioenergetic nanocatalyst that has shown positive data in a mid-stage ALS study. WAVE Life Sciences is developing WVE-004 for ALS. Last month, WAVE posted positive data from a Phase Ib/IIa study.

If Amylyx proves to be successful with AMX0035, the company intends to begin assessing the therapeutic in other indications “where the science makes sense,” Cohen said. “If we’re lucky enough to be successful, we see it as our responsibility to triple our efforts in this area."  

The PDUFA date for AMX0035 is June 29. 

https://www.biospace.com/article/amylyx-adds-to-case-for-als-drug-ahead-of-pdufa-d-ate-/

FDA limits J&J COVID-19 vaccine due to rare blood clot risk

 The announcement follows a recommendation from the Centers for Disease Control and Prevention late last year to opt for either Pfizer or Moderna, over the single-shot J&J vaccine after a review of new CDC data on rare blood clots linked to J&J.

https://abcnews.go.com/Health/fda-limits-jj-covid-19-vaccine-due-rare/story

Online Adderall prescriptions raise new questions about telehealth

 Online pharmacy startups have pledged to make it faster and easier than ever to get needed medications. But a high-profile series of setbacks is calling into question whether the realities of drug prescribing are clashing with those promises.

In recent weeks, major brick-and-mortar pharmacy chains have stopped filling prescriptions for Adderall and other controlled stimulants sent in by some telehealth providers including from Cerebral, an online mental health company that has come under fire for its prescribing practices and its online advertisements touting an easy way to get treated for ADHD. On Monday, the Wall Street Journal reported that Truepill — Cerebral’s “preferred pharmacy partner,” which completes online orders for drugs prescribed by Cerebral’s clinicians — would also stop filling those stimulant prescriptions out of an “abundance of caution.”

Experts say the unfolding debate about online prescribing of ADHD drugs points to the broader, unanswered questions about how to best balance the best of what telehealth can offer — easier access to necessary care for more people — with its risks and the rapidly changing regulations that govern how patients are diagnosed and treated virtually.

“There’s a real problem. There are people who have chronic medical conditions who we know need access to prescription medications, and there’s an important problem to be solved,” said Aaron Neinstein, vice president of digital health at UCSF Health and associate professor in the University of California, San Francisco’s endocrinology department. But newer companies that bill themselves as sources for speedy medication delivery are “completely losing the nuance of a health care interaction and the relationship between a doctor and a patient,” he said. “It’s about so much more than the prescription.”

The pauses, even if temporary, could have ripple effects on the fledgling digital pharmacy industry, which partners with telehealth companies and other providers to fulfill prescriptions that patients receive online and often just after a video consultation, including for controlled substances.

Prescription medications have become easier to obtain online during the pandemic, when regulatory officials waived requirements for in-person examination before certain types of drugs are prescribed. Truepill is still fulfilling Schedule III and V drug prescriptions from licensed clinicians. But the company is suspending delivery for Schedule II drugs like Adderall, which the Drug Enforcement Administration classifies as having a high level of potential abuse. In the case of stimulants, misuse has been linked to adverse effects, like heart failure or paranoia.

A Truepill spokesperson told STAT said it would use the pause to “evaluate next steps” for fulfillment of Schedule II substances, which account for less than 1% of its total prescription volume. But it could also give the company time to establish more rigorous guidelines around filling orders and flagging potentially suspicious prescriptions, University of Michigan clinical assistant professor Erik Gordon said.

“We want to avoid an opioid crisis part two,” Gordon said. Widespread overprescribing of painkillers fueled early stages of the opioid epidemic. “Fulfilling prescriptions remotely has obvious benefits, and obvious potential for abuse. The trick is going to be to keep as many of the benefits as we can.”

Gordon said the risk of inappropriate prescriptions was likely minimal, given a lack of data suggesting that virtual prescribing meaningfully drives up deaths. He added that online prescription and delivery could help patients avoid having to wait months for an in-person appointment or brick-and-mortar supply chain issues, Gordon said. Some patients are also forced to visit multiple pharmacies before pharmacists will fill prescriptions, especially if they have multiple providers — a factor that some prescription drug monitoring systems flag as an indicator of potential misuse.

“The health care system is truly failing to meet so many people out there who don’t have easy access to high quality, affordable care,” said Neinstein. Despite what he sees as temporary setbacks for digital prescribing, Neinstein said he’s “still optimistic that telehealth is one of the potential solutions.”

In-person prescribing comes with its own share of risk, said Neinstein. “There are clinics and doctors who will perpetrate fraud everywhere. Is it possible that telehealth allows those types of people to do so on a larger scale? Probably, but is that reason to not make it an option for more affordable, more convenient access to care for the 99%-plus of doctors and patients for whom it’s used properly,” he said, adding that large pharmacy companies are investing in analytics that could pick up aberrations in prescribing.

Craig Surman, an associate professor of psychiatry at Harvard Medical School, said that while online prescribing platforms could help patients with ADHD, particularly those who live in areas with a dearth of providers, he also warned that we know relatively little so far about telehealth’s impacts on ADHD drug prescribing, dose maintenance, or patient outcomes.

In behavioral health, particularly, there are concerns that providers examining patients for the first time in short, video-based appointments may not be able to detect important diagnostic cues like body language, given the range of symptoms certain conditions can present with. Some experts have also said they’re worried about whether such quick appointments let providers get in-depth enough to decide on the best course of treatment, including non-drug options.

“There’s a lot of concern among my colleagues that a new paradigm, a new way of doing evaluations and treatments, may not be grounded in the established sort of methods that people have basically developed over years of practice,” said Surman, who is also the co-chair of the Professional Advisory Board of Children and Adults with ADHD.

There are also concerns about the continuity of care at telehealth startups that patients don’t necessarily see as a source of long-term care. ADHD drug doses often need to be adjusted due to side effects or patient response. Again, that issue also arises in in-person care — but if a patient’s telehealth visits and prescriptions aren’t connected to their health care more broadly, it makes follow-up much more difficult.

In the meantime, patients who rely on online pharmacies for faster access to medication may find their care disrupted. While Truepill said it was working with Cerebral to ensure that prescriptions didn’t fall through the cracks, a spokesperson did not clarify for STAT what exactly what that process entailed.

That disruption, too, could carry risks. As Surman warned, “unpredictability is not something you want to add to the life of a person with ADHD.”

https://www.statnews.com/2022/05/04/cerebral-truepill-adhd-prescriptions/

Rise noted in uterine cancer death rates

 A rare but aggressive kind of uterine cancer appears to be driving an increase in U.S. deaths from the disease, particularly among Black women, researchers reported Thursday.

Over eight years, deaths from the aggressive type rose by 2.7% per year, while deaths were stable for the less aggressive kind, their study found. Black women had more than twice the rate of deaths from uterine cancer overall, and of the more aggressive type, when compared to other racial and ethnic groups.

The aggressive kind — called type 2 endometrial cancer — is more difficult to treat. By the end of the study period, it accounted for about 20% of cases and 45% of deaths.

“For most cancers, there have been improvements over the last 20 years. It’s alarming that we haven’t had the same success with uterine cancer,” said Dr. Pamela Soliman of MD Anderson Cancer Center in Houston, who was not involved in the study.

“This allows us to focus our efforts on specific areas that could potentially have a bigger impact on mortality,” Soliman said.

An estimated 65,950 new cases of uterine cancer will be diagnosed in the U.S. this year and 12,550 women are expected to die from it. Irregular bleeding can be a warning sign, but there is no recommended screening test.

Researchers analyzed U.S. cancer data for women 40 and older. They found overall uterine cancer death rates increased by 1.8% per year from 2010 to 2017.

Annual rates increased 3.4% among Asian women, 3.5% among Black women, 6.7% among Hispanic women, and 1.5% among white women. (The researchers adjusted for hysterectomy rates, which vary by race. Women who’ve had their wombs removed cannot get uterine cancer.)

Obesity is a risk factor for the less aggressive uterine cancer, but there’s no clear risk factor for the more aggressive kind, said the National Cancer Institute’s Megan Clarke, who led the study, published in the journal JAMA Oncology.

“We think it is something that is more common in Black women and increasing in the population for all women,” Clarke said. “It’s very puzzling and concerning.”

https://www.statnews.com/2022/05/05/study-uncovers-clues-rise-uterine-cancer-death-rates/

Why are Standards So Lax on Covid Drug Approvals?

 Many scientists made a career fighting for better regulatory standards. Strangely, when it comes to the regulatory policy around COVID-19, they are dead quiet. 

First, consider that EUA ( emergency use authorization ) is like accelerated approval. Both require lower levels of evidence, and are predicated on the fact that we’re dealing with a situation that is dire, with few available options. That’s the justification for lower standards, including acceptance of surrogates.

Next, consider that COVID-19 is a life-threatening illness in an older person, for instance someone over the age of 80. For an older person, it rivals cancer or heart disease.

But also consider that COVID-19 is a flu-like illness for most children, particularly in the era of Omicron. It would be incorrect to say children have ever faced an ’emergency’.

Now think about what regulatory experts have said for years. We should be cautious with accelerated approval. We should use it sparingly, and when appropriate. We can’t use accelerated approval for high blood pressure.

It’s naturally follows from this logic that the use of EUA for kids was unjustified. There was no emergency in those ages. The IFR was always comparable with flu. The appropriate regulatory pathway was biological licensing authorization. However, with the exception of a single article that I co-authored in the BMJ, I’m not aware of any one making this case.

Regulatory experts have told us for year that if outcomes are generally favorable, you need a very large randomized control trial to show a benefit. You can’t use a surrogate endpoint. They say, you have to use a measure of what matters to people. This means we should not accept disease-free survival, as it is an unreliable surrogate for adjuvant breast cancer. 

But now think of boosting a 20-year-old man. Antibody titers are also an unreliable surrogate endpoint. Boosting 20-year-olds should not come under the auspices of an EUA. You should do a very large randomized trial to show it has a benefit. And if you can’t run the trial because the sample size is too large that tells you something about how marginal the effect size is.

Think about what regulatory experts said about aducanumab. They said that only 6% of all Alzheimer’s patients would be eligible for the trial. Therefore, we should be careful about generalizing. 

Similarly, take Paxlovid. The only trials that have been published to support its use are in unvaccinated people. There are zero trial data published for vaccinated people. And yet the majority of the uses in vaccinated people. 

Why are the experts who say you can’t extrapolate aducanumab to all’s Alzheimer’s patients not saying you can’t extrapolate Paxlovid to all vaccinated people?

Why are those who say accelerated approval is abused not saying that EUA authority is abused when you move to children, who face thousandfold less times the risk?

Why are the same people who say we need large randomized trials for clinical outcomes for blood pressure pills dead silent on the question of boosting adolescents?

There are at least 3 possible reasons:

Number one. They have not made the connection between the same principles in their mind. This explanation should be rejected. Because you would have to be quite dense to not see the parallels. 

Number two. They think that it is a stronger argumentative position to press the issue in the world of non COVID-19 drugs than COVID-19 drugs. This is the great blunder of their thinking. When you push for the equal application of rational principles, you must push for the equal application of rational principles. If you think you can omit or make sacrosanct some category, then you are irrational. And your opponents can rightly argue that their categories should be exempted. Why should cancer have a higher standard than COVID?

If you want to persuade people on issues, you won’t persuade them if you don’t issue principles. Consistency and clarity hallmarks of clear thinking. 

Number three: They are scared to voice their opinion on COVID-19 issues because they are afraid of the mob. Quite possibly, this is it. And this is likely paired with the fact that it is to there career benefit to not comment on issues outside their perceived scope. And thus they can go to conferences for another 40 years saying the same thing they’ve always said without any progress or advancement. Or, as a friend of mine likes to say, no new ideas. 

I’m fear the right answer is number three. Even though most of these people run large groups or have tenure. They still are thinking of themselves.

And I think it has logical consequences. It’s the reason why people don’t want to be in the academy. You don’t have the freedom, or the incentive to fight when it actually matters. You labor under a curse. You can’t speak of the things that truly matter, when they matter. Your focus is narcissistic, and you will not accomplish any meaningful goals. And we will all fail together. Because regulatory science is just going to get worse and worse.

And the industry is going to take advantage of the crack we have shown in our foundation.

Vinay Prasad MD MPH is a hematologist-oncologist and Associate Professor in the Department of Epidemiology and Biostatistics at the University of California San Francisco. He runs the VKPrasad lab at UCSF, which studies cancer drugs, health policy, clinical trials and better decision making. He is author of over 300 academic articles, and the books Ending Medical Reversal (2015), and Malignant (2020).

https://brownstone.org/articles/why-are-standards-so-lax-on-covid-drug-approvals/

Novartis suspends two cancer therapies over quality concern

 Novartis said on Thursday it had temporarily suspended the production of its Lutathera and Pluvicto cancer therapies at facilities in Italy and New Jersey after potential quality issues were discovered in their manufacturing.

"Novartis is conducting a thorough review of the situation and currently expects to resolve the issues and resume some supply in the next six weeks", the Swiss company said.

The drugmaker added in a statement that some doses of cancer therapy Lutathera would be available in Europe and Asia from a site in Spain, but there might be some delays in supply.

Lutathera and Pluvicto are both so-called radioligand therapies, a type of treatment that uses nuclear medicine to precisely target and treat cancer cells

https://www.marketscreener.com/quote/stock/NOVARTIS-AG-9364983/news/Novartis-suspends-two-cancer-therapies-over-quality-concerns-40286513/

Tandem Diabetes' Q1 Bottom-Line Slide Deeper Into Red Despite Sales Growth

 

• Tandem Diabetes Care Inc 
  TNDM-16.5%+ Free Alerts
   posted Q1 losses of $(0.23) deeper than $(0.08) posted a year ago and missing the consensus of $(0.07).
• Sales increased 25% to $175.91 million, beating the consensus of $168.43 million.
• Worldwide pump shipments increased 11% Y/Y to 28,095.
• The gross margin remained almost unchanged at 52%.
• The company reported an operating loss of $(15.34) million, compared to $(3.24) million.
• Tandem Diabetes ended Q1 with cash and equivalents of $635.4 million.
• Guidance: Tandem expects FY22 revenues of $850 million - $865 million, reflecting Y/Y growth of 21% - 23%, versus the consensus of $846.54 million.
• Earlier, the company estimated sales of $845 million - $860 million.
• It expects gross margin to be 54% and Adjusted EBITDA margin to be 14% - 15%.

https://www.benzinga.com/general/biotech/22/05/27012746/tandem-diabetes-q1-bottom-line-slide-deeper-into-red-despite-sales-growth