After $10B in market value lost, China's WuXi Biologics removed from US unverified list

 WuXi Biologics has cause to celebrate as it finds itself removed from the US Department of Commerce’s unverified list.

The China-based contract research and manufacturing giant was initially placed on the list in February of this year after delays in verifications for certain products that were being exported to the US. At the time, the company had been importing items that were subject to US export control, but with the commerce department’s verification process not being able to take place due to Covid-19, it was enough for the company to find its way onto the unverified list. However, WuXi Biologics stressed that it was not blacklisted.

Still, the move managed to knock the company’s market value down almost $10 billion, and drive its stock price down 26%. On the news of the removal, the price did see a slight increase before evening out. The price is still down 58% since last year.

WuXi Biologics was on the correct path to getting off the list this summer as a US export control officer was able to inspect facilities in the city of Wuxi. According to the company, this onsite inspection was in coordination with China’s Ministry of Commerce. The company is also working to ensure that its other facilities and subsidiaries are up to standard as well.

“The company is also working closely with relevant government authorities to schedule the on-site end-use check of its other subsidiary, WuXi Biologics (Shanghai) Co., Ltd., and will commence the UVL delisting process for the such entity as soon as the check is completed,” said a statement from WuXi Biologics.

This comes as the company has been investing heavily in infrastructure expansion. In June, the company announced it would spend over $1.4 billion over 10 years expanding its facility in Singapore. The expansion will add around 120,000L of biomanufacturing capacity to its global network by 2026 and is expected to employ around 1,500 staff.

https://endpts.com/after-10b-in-market-value-lost-chinas-wuxi-biologics-removed-from-us-unverified-list/

FDA settles drug compounding suit, agrees to 'speed its review of bulk ingredients'

 Back in 2014, the FDA made very clear to the growing but under-regulated pharma compounding world that it would begin implementing a new law from Congress requiring the agency to develop a list of bulk drug substances (or active ingredients) that companies may use to compound drugs.

But the nomination process for these bulk ingredients ran into a wide variety of submissions, with the FDA noting at the time that many of the nominations were not even for bulk drug substances used in compounding as active ingredients, “and none included sufficient information to justify inclusion.”

Fast forward eight years later, and the trade association for drug compounders today announced that it reached a settlement with the FDA that will spur the agency to more promptly review these long-pending nominations for active ingredients.

In 2013, Congress created what are known as 503B outsourcing facilities as part of an attempt to better safeguard these compounded drugs that didn’t have to meet the same requirements as generic or brand name drug manufacturers. The world of drug compounding at the time had ballooned with little state and federal oversight, and there was a major meningitis outbreak in 2012 in the Northeast that resulted in the deaths of more than 100 people due to contaminated steroids.

And while the Outsourcing Facility Association (OFA), the trade group announcing today’s settlement, explains on its website that outsourcing facilities “are subject to MORE QUALITY STANDARDS than other compounders and supply drugs in shortage,” the FDA has its own webpage dedicated to warning compounders about knowing their bulk suppliers, as several have received warning letters over the past several years.

OFA member and FDA-registered 503B outsourcing facility Fagron, which has its headquarters in the Netherlands, received a warning letter in 2018 for, among other violations, “basic failure in your quality system.”

Last June, OFA sued the FDA over its delays in signing off on new ingredients for the 503B list, noting that after eight years,

“FDA has added only four substances to the 503B Bulks List, all of which are for compounding topical dosage forms, not sterile drugs. Defendants’ unreasonable delay in identifying the bulk drug substances for which there is a clinical need is thwarting Congress’ purpose in creating 503B facilities and hurting public health by denying healthcare providers’ access to the safely compounded sterile drugs their patients need.”

According to the settlement, within one year, the FDA will categorize bulk drug substances that were nominated to its 503B list prior to the filing of the lawsuit, but the FDA said it only expects to categorize 25% of those ingredients that were nominated but not yet categorized every twelve weeks.

Within twelve weeks of the completion of this categorizing, the FDA also committed to reviewing for possible recategorization of all substances that were in Category 3 of the 503B list (i.e. may be eligible for inclusion on the list, but were nominated with insufficient supporting information). But the FDA didn’t make any guarantees, with the settlement noting that, “Depending on the content of the additional supporting information submitted with respect to a particular substance, FDA may move the substance to a new category or leave the substance’s categorization unchanged.”

“The FDA’s commitment to prioritize the nomination process is a welcome step toward identifying all API for which there is a clinical need,” Lee Rosebush, partner at the BakerHostetler law firm and chairman and general counsel of OFA, said in a statement.

https://endpts.com/fda-settles-drug-compounding-suit-agrees-to-speed-its-review-of-bulk-ingredients/

Fed’s Bullard Leaves Open Possibility of Larger December Hike

 Federal Reserve Bank of St. Louis President James Bullard left open the possibility that the central bank would raise interest rates by 75 basis points at each of its next two meetings in November and December, while saying it was too soon to make that call.

The Fed hiked rates by 75 basis points for the third straight meeting last month, to a target range of 3% to 3.25%. Officials projected 125 basis points of tightening for the rest of the year, suggesting a 75 basis-point move in November and 50 basis points in December. A further 25 basis points of tightening was penciled in for 2023, according to their median estimate.

“Whether the committee would want to pull some proposed or thought-of policy-rate increases from 2023 into the December meeting, I think that’s a judgment that is premature to make,” he said Saturday in Washington during an event on the sidelines of the annual meeting of the International Monetary Fund and World Bank.

The US central bank is raising interest rates at the most rapid pace since the 1980s to curb inflation at 40-year highs. Investors now see a solid chance the Fed will raise rates 75 basis points in both November and December after data Thursday showed core consumer prices rising more than anticipated in September.

Projections released Sept. 21 by the Fed showed officials expecting rates to rise to 4.4% this year and 4.6% next, according to their median estimate.

Bullard said it probably didn’t make much difference from a macroeconomic perspective if that additional tightening happened later this year or in the first quarter of 2023. But he reminded the audience that he has been a fan of “frontloading” rate increases by rapidly moving policy to a level that restrains inflation, at which point officials can pause and take stock.

“You want to get where you need to be and then after you can react to data,” he said, adding that there was a “bullish case” for next year if declines in inflation forecast by both the central bank and private sector economists are proved correct.

“If that dynamic comes in it’s going to look very good, and we’ll be able to basically stay where we are and watch the inflation come down,” he said. “But there is a lot of risk also that inflation goes still higher and then we have to react to that.”

Bullard also backed continuing to shrink the central bank’s balance sheet at the current pace for some time.

“It is way too early to say that we would change this policy any time soon,” Bullard said during a panel discussion, in response to a question about whether the Fed would alter its balance-sheet runoff, currently at a pace of a maximum $95 billion a month.

Bullard votes on monetary policy this year and has been one of the more hawkish officials on its 19-member policy committee.

He said he’s glad that the Fed’s 75 basis-point rate increases hadn’t caused any significant market turmoil. “We’ve managed to get this far with relatively low financial stress,” Bullard said.

Responding to questions, he said moves in the dollar in response to Fed rate hikes were “not surprising.” The greenback has surged 16.4% in the 12 months, according to the Bloomberg Dollar Spot Index.

“It will not always be this way,” Bullard said. “If the Fed can get to a place where the committee thinks that we’re putting meaningful downward pressure on inflation with the level of the policy rate that we have,” and other central banks change their policies and perhaps become more aggressive, “you might see other movements in the dollar.”

https://www.yahoo.com/now/bullard-says-fed-hikes-caused-175434086.html

Why I Voted 'No' on the New ALS Drug

 In March and September 2022, I served on an FDA Advisory Committee reviewing the application of Amylyx Pharmaceuticals for the novel drug AMX0035 for patients with amyotrophic lateral sclerosis (ALS).

I voted against approval of this drug at both meetings, first as part of a 6-4 majority and then with the minority in a 7-2 vote.

On September 29, the FDA announced approval of the drug, which now has the brand name Relyvrio. I still believe that approval should have been deferred, pending the results of a large phase III study currently underway in Europe.

Past Experience With ALS and Other Diseases

I am a neurologist and clinician-investigator who has worked on ALS and other neuromuscular diseases for many years, first at the University of Pennsylvania and now in the National Institute of Neurological Disorders and Stroke at NIH. We have long sought to reduce the burden of this horrible disease.

One experience from early in my career has affected my approach to novel treatments. In the early 1980s I saw an ALS patient and his family who sold their home in Philadelphia to pay $45,000 (over $130,000 in today's dollars) for a snake venom extract from Florida. The person selling this extract had been featured in a positive story on "60 Minutes." I cannot think of anything worse than taking advantage of patients and families suffering from ALS. Unfortunately, ALS patients are often drawn into trying treatments that have little-to-no proof of efficacy.

Unsubstantiated claims of efficacy have impeded therapeutics development for other diseases too. Over 30 years ago, the parents of a child with adrenoleukodystrophy, a severe hereditary neurological disease, sought to develop a treatment. The story was featured in the 1992 film "Lorenzo's Oil," which portrayed the treatment as effective. However, randomized, placebo-controlled trials were never done, and all these years later we still don't know whether it is effective.

In another case, Sarepta Therapeutics received FDA approval in 2016 for eteplirsen (Exondys 51), an exon-skipping drug for Duchenne muscular dystrophy, despite a lack of convincing evidence that it had clinical benefit or even a clinically meaningful biological effect. The approval was granted with the understanding that a follow-up study would be conducted to confirm clinical efficacy, but this has not yet happened. Meanwhile, Sarepta has continued to market the drug for $300,000 per year and has now received FDA approval for two other drugs for Duchenne muscular dystrophy with a similar mechanism of action (and similar lack of evidence for clinical efficacy).

FDA's Role

The FDA is charged with assuring drug safety and confirming that new drugs have the benefit they are claimed to have. Recently, it seems the bar for confirming benefit has been lowered, particularly for diseases with a heavy burden of unmet need like ALS.

Traditionally, proof of efficacy has required two phase III studies (i.e., two randomized, placebo-controlled trials adherent to prospective statistical analysis plans and with sufficient power to show clinically meaningful benefit). However, the FDA grants approval where the need is great and a single well-designed and implemented phase II trial and additional data give "substantial evidence" of efficacy.

The Amylyx Story

The Amylyx drug AMX0035 is a combination of two generally available compounds, sodium phenylbutyrate and taurursodiol, which are thought to affect the ALS disease mechanism. The biological rationale for these compounds is relatively weak, in contrast to other drugs currently under development (like tofersen) that specifically target the genetic cause of the disease in patients with familial ALS.

The phase II trial on which the application for FDA approval of AMX0035 was based had a number of shortcomings, including:

1. An error that led to the first 27 participants not being randomized (the first 18 received the active agent, and the next 9 were given placebo to compensate)
2. Gastrointestinal side effects with the active agent that may have led to unblinding (although a survey at the end of the study did not show this)
3. Thirteen participants started treatment with edaravone (Radicava), a recently approved ALS drug, during the course of the trial
4. Historical controls (some dating from the 1990s when standard care for ALS was considerably different) were included in the statistical analysis
5. The primary endpoint, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), does not have a well-established minimal clinically important difference based on patient experience
6. The statistical analysis assumed linearity of ALSFRS-R change, which does not fit the data
7. Post-hoc statistical re-analysis was included in the application for approval

For all these reasons, I feel the AMX0035 phase II trial did not show substantial evidence of efficacy.

A confirmatory phase III trial is currently underway in Europe (where it is required for approval), but the trial was discontinued in the U.S. pending the FDA review.

One factor that may have led members of the FDA Advisory Committee to change their votes at the September meeting was a comment by an Amylyx co-CEO that the company would consider withdrawing the drug if the phase III result is negative. However, it may be difficult to hold the company to this, and to agree on what a negative result would be.

The ALS Patient Perspective

Another factor that may well have led to FDA approval of AMX0035 is the strong support from ALS patients and family members.

I met recently with representatives of I Am ALS, an ALS advocacy group. I was impressed by their plans for reducing the ALS burden and by how passionate and well-informed they are. When I suggested that Amylyx make the drug more readily available for free by extending its expanded access program and restarting the phase III trial in the U.S., they argued that it is difficult for a small company to do this on a larger scale.

Furthermore, people now living with ALS have a limited life span and little time to spare. We agreed about the heavy disease burden and the exorbitance of the price ($158,000 per year) that Amylyx has recently chosen to charge, and we share the hope that the phase III trial will result in a drug we can all agree is safe, effective, and affordable.

Kenneth Fischbeck, MD, is an NIH Distinguished Investigator at the National Institute of Neurological Disorders and Stroke (NINDS). The opinions expressed are the author's own and do not necessarily reflect the views of the NIH or FDA.

https://www.medpagetoday.com/opinion/second-opinions/101206

Repurposing rheumatoid arthritis drug auranofin for diabetes

 Researchers at Baylor College of Medicine and collaborating institutions discovered that the rheumatoid arthritis drug auranofin can potentially be repurposed to improve diabetes-associated symptoms. The study, which was conducted in mice, appeared today in the journal Cell Metabolism.

Although scientists have identified definitive associations between inflammation in white adipose tissue and insulin resistance in humans and rodents, broad anti-inflammatory treatments lack durable clinical efficacy on diabetes. In the current study, the researchers explored in more detail this association between inflammation and diabetes by looking for existing drugs that might affect both conditions.

"We computationally screened a small-molecule dataset and identified auranofin, an FDA-approved drug that has been used to treat rheumatoid arthritis, a condition involving inflammation," said first and co-corresponding author Dr. Aaron R. Cox, instructor of medicine-endocrinology, diabetes and metabolism at Baylor. "Auranofin exerts anti-inflammatory properties, which many people suspected would be beneficial in obesity and diabetes; however, nothing was really known about how it might affect metabolism."

The team evaluated the metabolic effects of auranofin in a mouse model of diabetes in which the animals consume a high-fat diet.

"We discovered that auranofin has anti-inflammatory and anti-diabetic effects that are independent from each other," said co-corresponding author Dr. Sean Hartig, associate professor of medicine-endocrinology, diabetes and metabolism and molecular and cellular biology at Baylor. Hartig also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center.

"Auranofin improved insulin sensitivity, or the body's ability to respond to insulin to keep blood sugar at healthy levels. The drug also normalized obesity-associated changes such as hyperinsulinemia—blood insulin levels that are higher than normal—in the mouse model. In addition, we found that auranofin accumulation in white adipose tissue reduced inflammatory responses without altering body composition in obese mice."

Looking into the mechanism of these metabolic changes, the team discovered that the anti-diabetic effects of auranofin involved reduction of leptin levels. Leptin is a hormone whose levels markedly increase in obesity, contributing to insulin resistance and diabetes. In addition, auranofin restored white adipose tissue's ability to respond to catecholamines, which are signals that increase metabolic activities in adipose tissue, triggering the burning of lipids at a higher rate.

"These changes coupled together contribute to the overall improvement in insulin sensitivity of the mice, leading to blood glucose control, which is the ultimate goal of diabetes treatments," Cox said. "High levels of glucose in the blood are detrimental to many tissues in the body. Uncontrolled, diabetes can lead to organ failure."

"We are very excited about these findings; however, more research will be needed to determine an effective strategy to translate them to the clinic," said Hartig.

More information: Sean M. Hartig, The rheumatoid arthritis drug auranofin lowers leptin levels and exerts anti-diabetic effects in obese mice, Cell Metabolism (2022). DOI: 10.1016/j.cmet.2022.09.019. www.cell.com/cell-metabolism/f … 1550-4131(22)00409-0

https://medicalxpress.com/news/2022-10-repurposing-rheumatoid-arthritis-drug-auranofin.html

Unique danger of postpartum breast cancers

 Breast cancers that emerge within five years of giving birth are more likely to spread and become deadly. Additionally, a new study shows that recent childbirth alone is an independent risk factor for breast cancer progression.

The findings suggest that current clinical guidelines, which don't factor in postpartum status, are less able to accurately predict the risk of cancer recurrence and guide optimal treatment strategies in young patients.

"This has profound implications for prognosis," said senior author Pepper Schedin, Ph.D., professor of cell, developmental and cancer biology in the OHSU School of Medicine and OHSU Knight Cancer Institute. "A postpartum diagnosis can move women who appear to have good prognosis into a high-risk category."

A paper describing the research published today in JAMA Network Open. OHSU Knight Cancer Institute scientists Zhenzhen Zhang, Ph.D., M.P.H., and Solange Bassale, M.S., are co-first authors.

The researchers were able to confirm the link between pregnancy and breast cancer outcomes using the extensive Utah Population Database, in collaboration with Ken Smith, Ph.D., co-senior author of the paper and a distinguished professor of family studies and population science at the University of Utah's Huntsman Cancer Institute. The database combines statewide birth and death records, Utah Cancer Registry data, and patient records from statewide inpatient and ambulatory records.

The final study included 2,970 subjects with breast cancer diagnosed at age 45 or younger, including 860 who never experienced childbirth. Those who had given birth were categorized based on time from most recent delivery: diagnosed within less than five years, five to less than 10 years, or 10 years or longer from childbirth.

The risk of metastasis—cancer spreading to other organs—was 50% higher among those diagnosed within five years of giving birth, as was the risk of breast cancer-specific death, compared with those who had not given birth. And these increased risks of metastasis and death were independent of tumor stage or estrogen receptor status—factors used now to judge how aggressive a cancer is likely to be, and to decide which treatments are appropriate.

Breast cancers that don't have estrogen receptors, known as ER-negative tumors, are generally considered more dangerous than ER-positive tumors. But in the study population, the proportion of women who progressed was the same in ER-negative and ER-positive tumors. The primary risk factor for progression to metastasis was not ER status, but rather a breast cancer diagnosis within five years of childbirth.

"That does not fit with everything we thought we knew about ER-negative disease," Schedin said.

In earlier research, Schedin and colleagues discovered how changes in the breast after childbirth can alter the development of breast cancer. At the end of lactation, most of the milk-secreting cells undergo programmed cell death in a process called involution. It is an inflammatory process that resembles wound healing, and in studies using mouse models, Schedin's lab revealed how involution creates a tumor-promoting environment. Using samples from breast cancer patients, the researchers found evidence that involution leaves a lasting imprint in the pattern of gene activity in breast tissue that could help tumors metastasize.

Schedin's team has also shown in mouse studies that as the liver recovers from the demands of pregnancy and lactation, it becomes an inviting landing spot for escaping cancer cells to take root and grow. Similar processes appear to occur in women's livers after childbirth. The new study found high rates of metastasis to the liver among those diagnosed within five years of childbirth.

"It's a two-hit problem," Schedin said. "Involution causes early tumor cells to get out of the breast. And those cancer cells find the liver to be a great host to establish metastatic tumors."

Factoring in postpartum status should help clinicians make more accurate predictions about breast cancer aggressiveness and guide treatment decisions, such as the need for chemotherapy after surgery to remove tumors. The knowledge might even enable new and more effective treatment strategies, Schedin said.

Knowing that postpartum cases show a distinct signature of gene expression, it may be possible to develop treatments that specifically target signaling pathways active in postpartum cancers.

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Breast cancer up to five times more likely to metastasize even 10 years after childbirth

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More information: Zhenzhen Zhang et al, Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah, JAMA Network Open (2022). DOI: 10.1001/jamanetworkopen.2022.36763

https://medicalxpress.com/news/2022-10-unique-danger-postpartum-breast-cancers.html

Reappraising role of 'zombie' cells that anti-aging medicine has sought to eliminate

 Not all senescent cells are harmful "zombies" that should be wiped out to prevent age-related disease, according to new research from UC San Francisco, which found that some of them are embedded in young, healthy tissues and promote normal repair from damage.

Scientists have now seen these cells in action in lung tissue, as well as other organs that serve as barriers in the body, such as the small intestine, colon and skin. When they used drugs called senolytics to kill these cells, injuries to lung tissues healed more slowly.

"Senescent cells can occupy niches with privileged positions as 'sentinels' that monitor tissue for injury and respond by stimulating nearby stem cells to grow and initiate repair," said Tien Peng, MD, associate professor of pulmonary, critical care, allergy and sleep medicine, and senior author of the study, which appears in Science on October 13, 2022.

Aging cells can both damage and heal

Peng said it was understandable that scientists at first viewed senescent cells as purely detrimental. As people age, senescent cells accumulate that have characteristics of old, worn-out cells, including the inability to make new cells. Instead of dying like normal aged cells, they to live on, spewing a cocktail of inflammatory compounds that form the senescence associated secretory phenotype (SASP). These factors are linked to Alzheimer's disease, arthritis, and other age-related maladies including cancer. The catchy name "zombie cells" was coined for them.

Using senolytics that target and kill "zombie cells," researchers made the exciting discovery that clearing senescent cells from animals thwarted or diminished age-related disease and extended the lifespan of the animals. Thereafter, a boom of activity ensued in research labs and pharmaceutical companies focused on discovering and refining more powerful versions of these drugs.

But killing off senescent cells has dangers, Peng said. For one thing, this current study showed that senescent cells also possess the ability to promote normal healing through activation of stem cell repair. "Our study suggests that senolytics could adversely affect normal repair, but they also have the potential to target diseases where senescent cells drive pathologic stem cell behavior," said Peng.

Lighting up senescent cells

One major challenge to studying senescent cells is that biomarkers of senescence (such as the gene p16) are often quite sparse, making it difficult to detect the cells. In early experiments, researchers extracted cells called fibroblasts into culture dishes, allowing them to grow and produce enough cells to experiment with, and then stressed the cells with chemicals that induced them to become senescent. But in living organisms, cells interact with tissues around them, strongly affecting the cells' gene activity. This means that the characteristics of cells growing isolated in a glass dish could be quite different from that of cells in their natural environment.

To create a more powerful tool for their studies, postdoctoral scholar Nabora Reyes de Barboza, Ph.D. and colleagues improved on a common technique of fusing a relevant gene—in this case, the p16 gene, which is overly active in senescent cells—with green fluorescent protein (GFP) as a marker that can reveal the location of the cells under ultraviolet light. By enhancing the quantity and stability of green fluorescent protein in these senescent cells, Reyes greatly amplified the fluorescent signal, finally enabling the researchers to see senescent cells in their natural habitat of living tissues.

"Zombies" stimulate stem cells shortly after birth

Using this highly sensitive tool, the researchers found that senescent cells exist in young and healthy tissues to a greater extent than previously thought, and actually begin appearing shortly after birth. The scientists also identified specific growth factors that senescent cells secrete to stimulate stem cells to grow and repair tissues. Relevant to aging and tissue injury is the discovery that cells of the immune system such as macrophages and monocytes can activate senescent cells, suggesting that inflammation seen in aged or damaged tissue is a critical modifier of senescent cell activity and regeneration.

In their studies of lung tissue, Peng's team observed green glowing senescent cells lying next to stem cells on the basement membrane that serves as a barrier preventing foreign cells and harmful chemicals from entering the body and also allows oxygen to diffuse from air in the lungs into underlying tissues. Damage can occur at this dynamic interface. The team saw senescent cells in similar positions in other barrier organs such as small intestine, colon, and skin, and their experiments confirmed that if senescent cells were killed with senolytics, lung stem cells were not able to properly repair the barrier surface. Leanne Jones, Ph.D., director of the UCSF Bakar Aging Research Institute and Stuart Lindsay Endowed Professor in Experimental Pathology, said Peng's study is truly significant for the field of aging research, where the goal is to help individuals live longer and more healthy lives.

"The studies suggest that senolytics research should focus on recognizing and precisely targeting harmful senescent cells, perhaps at the earliest signs of disease, while leaving helpful ones intact," she said. "These findings emphasize the need to develop better drugs and small molecules that will target specific subsets of senescent cells that are implicated in disease rather than in regeneration."

Additional authors include Nabora Reyes, Maria Krasilnikov, Nancy C. Allen, Jinyoung Lee, Ben Hyams, Minqi Zhou, Supriya Ravishankar, Monica Cassandras, Chaoqun Wang, Imran Khan, Michael Matthay, and Dean Shappard from the Department of Medicine, Pulmonary and Critical Care Division, Peri Matatia and Ari Molofsky from the Department of Laboratory Medicine, Makato Nakanishi of University of Tokyo, and Judith Campisi of the Buck Institute.

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Researchers identify target for senolytic drugs

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More information: Nabora Reyes de Mochel et al, Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung, Science (2022). DOI: 10.1126/science.abf3326. www.science.org/doi/10.1126/science.abf3326

https://medicalxpress.com/news/2022-10-scientists-reappraise-role-zombie-cells.html