A co-owner of a Massachusetts compounding pharmacy whose mold-tainted drugs sparked a deadly fungal meningitis outbreak in 2012 was sentenced on Thursday to one year in prison for deceiving regulators to avoid federal oversight before the tragedy.
Gregory Conigliaro was sentenced by U.S. District Judge Richard Stearns in Boston after a federal appeals court last year revived his conviction for conspiring to defraud the U.S. Food and Drug Administration ahead of the outbreak.
He was among 14 people associated with Framingham, Massachusetts-based NECC who were indicted after mold-tainted steroids it produced sickened 793 people nationally, including more than 100 who died.
The defendants included Barry Cadden, NECC's ex-president, and Glenn Chin, its former supervisory pharmacist, who were convicted of racketeering and fraud and are serving prison sentences of 14-1/2 and 10-1/2 years, respectively.
Conigliaro, Cadden's brother-in-law, was not charged over the tainted drugs. But Assistant U.S. Attorney Amanda Strachan said his lies to regulators in the decade beforehand ensured NECC remained open, allowing the tragedy to unfold.
"He was responsible for keeping that business open until they got caught," Strachan said.
Prosecutors said Conigliaro, 57, conspired with others at NECC to deceive the FDA into believing it was operating like a conventional pharmacy subject to state oversight and not like a drug manufacturer subject to tougher federal oversight.
Prosecutors said Conigliaro in particular misled the FDA into believing it was dispensing drugs pursuant to valid, patient-specific prescriptions like a typical pharmacy when it was actually shipping drugs nationally without them.
A jury in 2018 found Conigliaro guilty, but Stearns threw out his conviction, saying it was legally impossible for Conigliaro to have impeded the FDA's functions. A federal appeals court disagreed and reversed that decision in 2021.
In addition to prison, Conigliaro must pay a $40,000 fine.
He told Stearns that had he known about the "horrible" conduct that occurred in the so-called clean rooms in which NECC's drugs were produced, "I would have done everything and anything possible to stop it, period."
The Supreme Court on Thursday agreed to review theBiden administration’s effort to reinstate its student debt relief plan, but the justices declined to immediately revive the program.
In a brief unsigned order, the court indicated it would hear arguments in the case as early as February.
The move comes after the administration urged the Supreme Court last month to clear one of the legal obstacles blocking the policy.
The administration is currently fending off two separate rulings issued in recent weeks that have effectively halted President Biden’s student loan forgiveness plan, which would give federal borrowers making less than $125,000 a year up to $10,000 debt relief.
The appeal to be heard by the justices arose after the St. Louis-based U.S. Court of Appeals for the 8th Circuit halted the loan relief program.
Separately, the New Orleans-based U.S. Court of Appeals for the 5th Circuit last night denied the administration’s request to revive the policy while it appeals a lower court ruling.
Biden’s policy, which the Congressional Budget Office estimates will cost about $400 billion over 30 years, has drawn numerous legal challenges. Its aim is to forgive up to $10,000 in federal student loan debt for those making under $125,000 annually and up to $20,000 for recipients of Pell Grants, which assist students from lower-income families.
In court papers filed last month, the Department of Justice (DOJ), on behalf of the administration, told the justices the program’s current legal status has left “vulnerable borrowers in untenable limbo.”
“The [8th Circuit’s] injunction thus frustrates the government’s ability to respond to the harmful economic consequences of a devastating pandemic with the policies it has determined are necessary,” U.S. Solicitor General Elizabeth Prelogar told the justices.
The administration’s appeal followed a unanimous ruling by a three-judge panel of the 8th Circuit that halted Biden’s massive debt relief plan.
The ruling was a win for six conservative-led states — Nebraska, Missouri, Arkansas, Iowa, Kansas and South Carolina — that challenged the program on the grounds that they were harmed by a freeze on the collection of student loan payments and interest. Among the challengers’ arguments is the claim that the debt-relief usurped Congress’ authority.
The White House, for its part, maintains that its policy is authorized by a 2003 federal law known as the Higher Education Relief Opportunities for Students Act, which both the Trump and Biden administrations have drawn upon to alleviate student borrowers’ financial strain during the global pandemic.
In a related legal development last month, a Trump-appointed federal judge in Texas invalidated the program, saying the presidential action unlawfully encroached on Congress’s power. The Biden administration is appealing that decision to the 5th Circuit.
Several other similar challenges to Biden’s plan have so far proved unsuccessful. Among them were two cases that eventually sought emergency relief in the Supreme Court but were unilaterally rejected by Justice Amy Coney Barrett.
A coalition of leading physician groups urged a federal judge in Texas to preserve ObamaCare’s coverage of preventive services, arguing that gutting the requirements would be disastrous for patient care.
In a friend-of-the-court brief led by the American Medical Association, the groups asked Judge Reed O’Connor to exercise discretion and refrain from issuing a nationwide injunction that would invalidate every significant recommendation from the U.S. Preventive Services Task Force ( USPSTF).
“If the Court were to vacate and/or enjoin the Task Force’s recommendations and any efforts to implement them on a nationwide basis, preventive care would be in grave jeopardy for tens of millions of Americans,” the groups wrote.
They urged him to only restrain the provision’s enforcement against a single employer challenging the mandate.
O’Connor in September ruled that ObamaCare’s process for determining what kinds of preventive care must be fully covered by private health insurance is unconstitutional. The ruling puts at risk free screenings for colorectal and other cancers, depression screenings and hypertension screenings, among many others.
O’Connor — who previously struck down the entire ObamaCare law before it was upheld by the Supreme Court — said the USPSTF violated the Constitution because its members are not appointed by the president or confirmed by the Senate, yet its recommendations are binding.
Additional organizations that signed the brief include the American Academy of Family Physicians, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, the American Medical Women’s Association, the Infectious Diseases Society of America, the National Medical Association, and the Society for Maternal-Fetal Medicine.
The Affordable Care Act requires insurers and group health plans to cover more than 100 preventive health services recommended by the task force, with no cost to patients. The groups in the brief said if the requirement is overturned, health plans would likely impose deductibles and co-pays.
Cost sharing will deter patients — particularly those of limited means — from scheduling mammograms, colonoscopies, and other potentially life-saving screening tests, the groups said.
An analysis by the Robert Wood Johnson Foundation in July found that overturning the preventive services requirement could threaten access to life-saving care for nearly 168 million Americans covered under private employer health plans as well as the ACA’s individual market plans.
While O’Connor found for the plaintiffs, he postponed ruling on the scope of relief or remedy. Additional briefs from both sides are due in January.
As if the Pentagon and US intelligence hadn't already escalated its presence enough inside Ukraine, given there are already literally a small contingent of "boots on the ground" - aswe detailed last month, CNN is now reporting that the Biden administration is considering"dramatically" increasing its training of Ukrainian forces.
The proposal would involve US advisers training "much larger groups of Ukrainian soldiers in more sophisticated battlefield tactics" at American installations in Germany, and perhaps other locations in Europe, according to the new report.
CNN begins by reporting that "The Biden administration is considering a dramatic expansion in the training the US military provides to Ukrainian forces, including instructing as many as 2,500 Ukrainian soldiers a month at a US base in Germany, according to multiple US officials."
US advisers training Ukrainians in 2015, via NPR.
"If adopted, the proposal would mark a significant increase not just in the number of Ukrainians the US trains but also in the type of training they receive," the report continues, also noting that this far "only a few thousand" Ukrainian soldiers have been trained on specific US-provided weapons systems.
Under the new program, the US would begin training much larger groups of Ukrainian soldiers in more sophisticated battlefield tactics, including how to coordinate infantry maneuvers with artillery support –"much more intense and comprehensive" training than Ukraine has been receiving in Poland or the UK, according to one source briefed on the proposal.
This is a significant statement given the ongoing British program at multiple UK bases is large in size. However what's being mulled by the Pentagon would see some 15,000 Ukrainians trained by the United States every six months. Multiple US officials have meanwhile projected they expect the war could take years before there's a final ceasefire and resolution.
The UK's own infantry training program for Ukraine forces has a stated goal of trainingat least 10,000 Ukrainian troops.
The Kremlin for its part has warned repeatedly of such deepening Western involvement which clearly is now going far beyond just weapons shipments. Russia this week walked away from New START nuclear arms reduction treaty negotiations with the US while citing its growing involvement in backing Kiev as a major reason for halting resumption of talks.
Earlier in the conflict, Russia's military vowed to attack any inbound foreign weapons shipments or training grounds inside Ukraine...
Prior to Russia's February invasion, the Pentagon as well as US intelligence had been deeply involved in advisory training for Ukraine forces. US advisors however withdrew (in an official capacity at least) just prior to the Feb.24 assault.
With a deadly crisis of fentanyl-related overdose deaths fast becoming a scourge in the US, New York Gov. Kathy Hochul has vetoed a bipartisan bill aimed at fighting the problem.
The measure, unanimously approved by both the state Assembly and Senate in the spring — but left in the Democratic governor’s drawer as she ran for election — would create a 16-member fentanyl abuse and overdose prevention task force to consult with experts and issue a report within a year to bolster New York’s efforts to address the addictive scourge, both in terms of enforcement and treatment.
Staten Island District Attorney Mike McMahon and lawmakers ripped Hochul on Wednesday for spiking the legislation.
“Frustrated & confused why Governor Hochul vetoed this bill. More NY’ers are dying from overdose than ever + this bill would have brought stakeholders together to implement real solutions,” tweeted McMahon, a Democrat who is first vice president of the NYS District Attorneys Association.
“We will continue our fight to hold drug dealers accountable + help those battling addiction.”
To underscore the point, McMahon noted that fentanyl accounts for 80 percent of overdose deaths in the borough.
The bipartisan measure was pushed by state Sen. Diane Savino and Assemblyman Michael Cusick — both Democrats — and co-sponsored by Republican Assemblymen Michael Reilly and Michael Tannousis.
“We are disappointed with the veto of our fentanyl task force bill but are confident that the governor understands the gravity of this issue and that it will be addressed next session,” Savino and Cusick said in a joint statement.
Reilly and Tannousis said in a tweeted statement that Hochul’s veto “is yet another one of her infamous bold-faced dismissals of public opinion when it comes to matters weighed by state lawmakers in Albany.”
Gov. Kathy Hochul has vetoed a bipartisan bill aimed at fighting the fentanyl crisis.Dennis A. Clark
“What we are witnessing in New York right now is a public health emergency unlike any other — yet the only emergencies that Kathy Hochul seems focused on are those that are self-proclaimed and politically expedient.”
Hochul, in a series of veto messages last week, said the fentanyl fighting bill was one of 39 measures that would have created task forces and commissions costing about $40 million that was not accounted for in the state budget. Politicians often use such panels as a dodge when they don’t have immediate fixes to problems, but the lawmakers said the fentanyl task force is an earnest attempt to craft a more comprehensive solution to the crisis.
The Staten Island Advance first reported on Hochul’s veto of the anti-fentanyl bill.
“None of these costs are accounted for in the State Financial Plan,” Hochul wrote. “Without appropriate funding, these unbudgeted costs would create significant staffing and other programmatic burdens on state agencies.”
Most fentanyl overdose deaths are related to opioids mixed with heroin or cocaine, “often without the user’s knowledge.”DEA
Hochul spokesman Avi Small responded, “As one of the millions of Americans who has lost a loved one to the opioid epidemic, Governor Hochul has a deep personal commitment to fighting this crisis and will continue her administration’s ongoing efforts to address overdoses and addiction. The governor recently vetoed dozens of bills that would have cost taxpayers $40 million in unbudgeted costs, and we are committed to working with the legislature on ways to crack down on fentanyl and protect New Yorkers.”
State commissioners of health, mental health, addiction services and reps from the DAs and state police would serve on the panel along with appointees selected by the governor and legislative leaders.
In their bill memo, Savino and Cusick said that while pharmaceutical fentanyl is a synthetic opioid dispensed for treatment of severe pain, most fentanyl overdose deaths are related to opioids mixed with heroin or cocaine, “often without the user’s knowledge.”
They also emphasized that “deadly amounts” of fentanyl are often added to other counterfeit pills being sold as xanax or oxycodone.
“These illegally made drugs are sold on the drug market relatively cheaply, which is why so many individuals with a substance use disorder can afford these drugs. Overdose deaths involving these synthetic opioids has increased at an alarming raze. The pandemic has further exacerbated the situation, and though naloxone, which can overturn an overdose if caught in time, the overdose deaths continue to rise,” the lawmakers said.
Robust, Statistically Significant and Clinically Meaningful Absolute Improvement in Cognitive Function as Measured by ADAS-Cog and ADCS-ADL
Key Secondary Endpoint CDR-SB Also Met, Demonstrating Statistically Significant Results
Plan to Meet with Regulatory Authorities to Determine Next Steps
Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) disorders, today announced positive topline results from its Phase 2b/3 ANAVEX®2-73-AD-004 clinical trial of oral ANAVEX®2-73 (blarcamesine) for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD). ANAVEX®2-73 met the primary endpoints ADAS-Cog1 and ADCS-ADL2 and key secondary endpoint CDR-SB3 with statistically significant results. Next step, in light of this data, is meeting with regulatory authorities to discuss this data in the context of ongoing development with an aim to bring this therapy to patients in Europe, Asia-Pacific, and the U.S.
ANAVEX®2-73 (blarcamesine) is an orally available, small-molecule activator of the sigma-1 receptor (SIGMAR1), which, data suggest, is pivotal to restoring neural cell homeostasis and promoting neuroplasticity.4
ANAVEX®2-73-AD-004 was a randomized, double-blind, multicenter, placebo-controlled 509 patient Phase 2b/3 study (randomized 1:1:1 to mid or high dose of ANAVEX®2-73 or placebo), for the treatment of early Alzheimer’s disease over 48 weeks. Top line data will be presented later today in the late breaking oral communication presentation at the Clinical Trials on Alzheimer’s Disease (CTAD) Congress 2022, December 1, 2022, at 4:30pm PT in San Francisco, CA. Further analysis of the data remains ongoing, and the Company plans to submit the data for publication in a peer-reviewed medical journal. The open-label extension study ATTENTION-AD will continue to follow participants over a 96 week period.
ANAVEX®2-73 treatment met the primary endpoints and reduced clinical decline on the global cognitive and functional scales over 48 weeks in the analysis of the Intent-to-treat (ITT) population.
ANAVEX®2-73 demonstrated visible improvement in patients with Alzheimer’s disease. Patients treated with ANAVEX®2-73 were 84% more likely, to have improved cognition by ADAS-Cog score change of -0.50 points or better from baseline to end of treatment than patients on placebo, Odds Ratio = 1.84 (p = 0.015). On average, patients, who improved cognitively with ANAVEX®2-73 treatment, improved by ADAS-Cog cognition score of -4.03 points. ANAVEX®2-73 treatment was 167% more likely to improve function compared with placebo, at a clinically meaningful improvement of ADCS-ADL score change of +3.5 points or better, Odds Ratio = 2.67 (p=0.0255). This reflects a robust improved and clinically meaningful outcome in cognition and function from baseline. Additionally, treatment with ANAVEX®2-73 statistically significantly reduced cognitive decline, measured with ADAS-Cog, compared to placebo at end of treatment by 45%, representing a treatment difference in mean score change of -1.85 points (p=0.033).
ANAVEX®2-73 treatment also met the secondary endpoint of reduction in clinical decline of cognition and function assessed by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo, by a treatment difference in mean score change of -0.42 points (p=0.040), representing 27% reduction in the ITT population.
ANAVEX®2-73 (blarcamesine) was generally safe and well tolerated. The incidence of treatment emergent adverse events (TEAEs) was similar in the active and placebo arms with dizziness being the most common TEAE. TEAEs ≥7.5% threshold were predominantly mild or moderate. No clinically significant changes in vital signs, laboratory values and ECG parameters in active and placebo arms were observed. Safety findings in the study were consistent with the known safety profile of ANAVEX®2-73.
In addition to safety and efficacy demonstrated on the primary and key secondary endpoints, a pre-specified analysis of patients without SIGMAR1 gene mutation provides further confidence of the robustness of the SIGMAR1 activation in the treatment of neurodegenerative diseases. Approximately 80% of the total worldwide population lack a SIGMAR1 gene mutation.5 ANAVEX®2-73 was more efficacious in this pre-specified population. This effect is consistent with prior clinical trials of ANAVEX®2-73.6
Sodium may hold the key for scientists to develop opioids or other drugs with far fewer side effects.
In a study published Wednesday byNature, scientists from USC, Washington University in St. Louis and Stanford University have demonstrated that by chemically linking fentanyl to thesodiumpockets that exist within nerve cell receptors, they could block the drug's harmful side effects and still reduce pain.
Further study is needed, but the results hold promise—not just for drug development but for addressing the nation's crisis of addiction and overdose. Nearly 70,000 Americans died in 2020 of an opioid overdose—most of them from the synthetic opioid fentanyl, according to the National Institute on Drug Abuse. In 1990s, the Food and Drug Administration approved the use of fentanyl to ease severe pain in cancer patients, but it has since made its way into the streets, worsening the national crisis of opioid abuse.
"In its current form, fentanyl is like a weapon of mass destruction," said Vsevolod Katritch, a computational scientist at the Bridge Institute at USC Michelson Center for Convergent Bioscience and a corresponding author of the study. "Our new collaborative work suggests that we could redesign the drug in such a way that we convert this frequent overdose killer to a much more benign but still effective analgesic."
Drugs of all kinds are designed to target certain receptors on nerve cells known as GCPRs, or G-coupled protein receptors, which act as signal transmitters. These receptors are like switches that mediate a drug's intended effect on the brain and body, but also the unintended side effects. In the case of fentanyl, the most potent painkiller of all opioids, patients may suffer addiction and may die from respiratory arrest.
Katritch noted that he and his fellow scientists Ray Stevens and Vadim Cherezov at the Bridge Institute and the USC Dornsife College of Letters, Arts and Sciences have been looking at the potential of the sodium mechanism since they first identified it within adenosine and opioid receptors about a decade ago.
Katritch and his collaborators said that although further study is needed to prove that their less harmful version of fentanyl will work in humans, the results have opened a new door for scientists to potentially improve the safety of painkillers.
"We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death," said corresponding author Susruta Majumdar of Washington University in St. Louis. "Our research is still in its early stages, but we're excited about its potential for leading to safer pain-relieving drugs."
Beyond opioid receptors, noted Katritch, this work opens a new molecular design concept for dozens of other GPCRs where such functional conversion in existing drugs would be desirable.
More information: Abdelfattah Faouzi et al, Structure-based design of bitopic ligands for the ยต-opioid receptor, Nature (2022). DOI: 10.1038/s41586-022-05588-y
