Adial is Leveraging Genomics to Treat 'Pervasive' Alcohol Use Disorder

 Alcohol Use Disorder (AUD) affects 6.7% of drinking adults. Some of the symptoms of AUD, as listed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), include being unable to reduce alcohol use despite a desire to do so, a need to drink that has become distracting, continuing to drink despite harm caused and experiencing symptoms of withdrawal without alcohol.

Current treatments for AUD include talk therapy or programs such as Alcoholics Anonymous (A.A.). Though three medications for AUD are approved by the U.S. Food and Drug Administration, some cause unpleasant side effects when the patient drinks, and others require painful injections.

Adial Pharmaceuticals is working to address this issue, offering a novel treatment for AUD. “We handle addiction as a disease rather than the disorder or weakness that some people consider it to be,” CEO Bill Stilley told BioSpace.

The company is currently evaluating the use of AD04 as a therapeutic agent for the treatment of AUD. “In certain patients, there’s a genetic defect that allows them to process serotonin differently than others. By blocking one of the known serotonin detectors, we can inhibit someone from the drive or craving that alcohol creates,” Stilley said.

The Phase IIb clinical trial involved a genetically-targeted patient group. “We saw a 50% reduction in the frequency of drinking in the drug versus placebo group, and an almost 60% reduction in how much people drank overall. Patients drank almost half as often, and when they did, they drank less. This shows a reduction in drinking habits.”

Adial is currently in Phase III of development and expects to run analysis on gathered data in the coming months. “It’s a really exciting time for the company. This trial was pivotal and will be used as a basis for approval. Once the trial is done, we will freeze the data and hand it over to statisticians who will run analyses,” Stilley said.

The basis of the product’s mechanism of action is through serotonin. Adial hopes to treat other disorders that affect the brain similarly. “There’s a huge amount of comorbidity between Opioid Use Disorder and AUD. We hope that we can treat opioid use in the future. There are a couple of others beyond that, such as gambling addiction, that are also driven by the serotonin system.” An example of an addiction that the product won’t address would be smoking, Stilley noted, as it’s driven by nicotine receptors rather than serotonin receptors.

The company is also working on a non-opioid pain program involving adenosine analogs. “Our non-opioid pain drug will address the supply side of addiction. Dr. Robert Thompson had a breakthrough in 2019 which was brought in-house through a relationship. We’ve shown that the drug worked in animals, and we’re hoping to test it in humans this year.”

AUD is important to treat because “it’s a massive problem. It’s a problem so large that the U.S. amended the Constitution to try and address it. Prohibition didn’t work, but they still wanted to solve the problem,” Stilley said. “There have been a lot of efforts, such as the few treatments that exist, and self-help groups such as Alcoholics Anonymous. A.A. says that treatment is so difficult that you most likely won’t be successful until you’ve hit rock bottom. Until your life has been destroyed, you will not succeed. This is why this disease needs attention.”

The Lancet analyzed alcohol use across 195 countries from 1990 through 2016. Alcohol use was determined to be the leading global risk factor in 2016 for people aged 15 to 49, with 12.2% of male deaths and 3.8% of female deaths being attributed to it. Deaths involving alcohol rose significantly in the first year of the pandemic, increasing by 25.5% from 2019 to 2020. In comparison, the average annual increase from 1999 to 2017 was only 2.2%.

“The effect the pandemic had on alcohol use is heart-wrenching,” Stilley shared. “We’re seeing alcohol sales going up since people are drinking at home. We’re seeing more harmful levels of drinking, which is not surprising. Alcohol deaths are up, and so is binge drinking. What we’re seeing is devastating. Mental health disorders contribute to this, as well; there’s a huge comorbidity between drinking and mental health disorders. This has been traumatic.”

The line between casual and heavy drinking has been defined in multiple ways, but the NIAAA defines heavy drinking, or heavy alcohol use, as four or more drinks on any day for a man, or three or more drinks for a woman. Binge drinking is categorized by a blood alcohol concentration of 0.08 percent or higher. On average, this equates to five or more drinks for a male or four or more drinks for a female in a period of approximately two hours.

“All damage due to alcohol is occurring on these heavy drinking days,” Stilley said. “The number of drinks is different for different people, but around this point, behaviorally and physically, things start to go south. If these heavy drinking days can be reduced or eliminated, it would be clinically beneficial.”

Adial’s product works to reduce the craving for alcohol. “By reducing the craving, you can eliminate heavy drinking days or potentially get to abstinence. We believe that our product may help reduce the craving. Our trial is designed to reduce heavy drinking days from where the patient started to where they end. We hope to demonstrate that.” The trial will measure reductions in heavy drinking as well as reductions in drinking overall.

Adial hopes that this treatment will be a game-changer for many. “Right now, 93% of patients are not seeking treatment. Of the 7.5% of patients who are seeking treatment, many are not successful. We hope we can get a percentage of these people to be more successful in what they’re trying to achieve.”

He pointed out that eliminating alcohol altogether may not be the solitary goal for a person with AUD. “The real goal is to stop the harmful effects of alcohol in their lives. If the only way available to them today is to stop drinking, it’s great for them if they can do it. It’s courageous, and they worked hard. But the other 90%-plus are not doing that. They’re just living with the harm. We all know people who have lived with the harm to the extreme. It’s so pervasive.”

Stilley wants those suffering from AUD to know that “there’s hope. People like us and others are working. We’re moving into the age of the brain. Our drug couldn’t have been developed until genomics and imaging came along.”

He also noted that a reduction in addiction is a worthwhile goal. “If you can reduce your addiction, that is better. It doesn’t mean that stopping it isn’t best, but reducing harm is also a step. A lot of times, people think that if they weren’t successful at hitting their end goal, they should stop. If you can reduce it, though, that’s still good! Just because you haven’t achieved your optimal goal doesn't mean you should quit.”

https://www.biospace.com/article/adial-is-leveraging-genomics-to-treat-pervasive-alcohol-use-disorder/

Accelerated Approval Integrity Act Could Remove Therapies Before They Prove Merit

 The Accelerated Approval Integrity Act of 2022 (H.R. 6963) aims to remove loopholes in the Food and Drug Administration's accelerated approval pathway. The bill, however, fails to adequately consider the whole picture, and may inadvertently remove medications that simply can’t complete confirmatory trials within the narrow timeframe allowed.

“Patients deserve to know that the drugs they are taking are safe and effective,” Rep. Frank Pallone, Jr. (D-NJ), sponsor of H.R. 6963 and chairman of the Committee on Energy and Commerce, said during the recent hearing titled, “The Future of Medicine: Legislation to Encourage Innovation and Improve Oversight."

To illustrate the problem, he said, “Aduhelm…was approved (for Alzheimer’s disease) last June…and nine months later the sponsor has not screened a single patient for its required confirmatory trial. Other drugs have stayed on the market for eight or nine years without proving a clinical benefit. Removing these drugs from the market is cumbersome and can take months or even years.”

H.R. 6963 proposes to require the FDA and trial sponsors to develop a clinical trial plan before the drug is approved under an accelerated pathway, to enact a one-year timeframe to conclude confirmatory trials (with certain exceptions) and to streamline the process for withdrawing approval when no clinical benefit is shown or when the trials are not conducted with due diligence. Rep. Pallone was unavailable to discuss the rationale behind the shortened timeline.

As Jeff Allen, Ph.D., president & CEO of Friends of Cancer Research, pointed out in testimony before the Committee, “In the past 10 years (2010- June 2021), 80% of FDA’s accelerated approvals were granted for oncology indications.” He also noted, “One assessment of oncology treatments concluded that therapies receiving accelerated approval were made available a median of 3.4 years earlier than if approval had been based on a full clinical endpoint, such as overall survival.”

Furthermore, he noted that nearly half of all drugs approved in the program were converted to full approval. Less than 10% of all accelerated approvals were withdrawn. This left 43% of treatments in this program that have neither been approved nor withdrawn. These are not dangling applications, however.

Allen told the committee that a look at the approval timeline showed that “for oncology indications, conversions to full approval took a median time of 3.1 years, while withdrawals took 3.8 years to generate the evidence necessary for action.” The drugs in the pathway that have not yet gained full approval have held accelerated approval status for 1.8 years. “Therefore, it is unrealistic to expect their post-approval studies to be complete already."  

In written testimony, however, Reshma Ramachandran, M.D., M.P.P. of Yale University School Of Medicine and head of the Doctors for America FDA Task Force, pointed to a study in the British Medical Journal that indicated that 112 of the 253 drugs approved using this accelerated pathway between 1992 and 2020 had not been confirmed as clinically effective. “Of these, 24 have been on the market for more than five years. Only 16 were withdrawn.”

Rep. Pallone’s bill sets automatic expiration at one year after a study is completed, and in no case longer than five years, unless the predicted benefit has occurred or adequate progress has been made.

While agreeing that dangling approvals are of concern, this legislation may not be the best recourse, Coleen Klasmeier, a partner in Sidley Austin LLP's Food, Drug and Medical Device Regulatory group, told BioSpace. She formerly served in the FDA Office of the Chief Counsel.

The existing code has accountability that includes consequences for delays, she said, but the FDA is concerned when the confirmatory trial fails to show clinical benefit.

Rep. Pallone’s concern is broader, however. “It covers accelerated approvals when the study hasn’t been completed. It seems to say that if a company hasn’t done the confirmatory trials, regardless of the reasons, it is susceptible to the FDA taking the product off the market,” Klasmeier said.

Consequently, it appears that effective products could be removed, too. “To me, that doesn’t compute. The rationale for accelerated approval is that you want patients to have access based on the reasonable likelihood of clinical benefit, so the timeframe to do the study should not matter in that case.”

There are valid reasons why some confirmatory trials may be slow. “There often is a lot of competition for a finite number of eligible subjects,” Klasmeier pointed out. “Especially during COVID, it is hard to get patients to participate. And, from a patient’s perspective, if you can already get the therapy, there’s no reason to sign up for a trial.”

The confirmatory data can’t be gathered through retrospective studies that mine patients’ medical records. That isn’t the same thing as a randomized clinical trial, she explained. “You have to conduct a particular type of study to confirm clinical benefit. It’s spelled out in the law.”

The use of surrogate – rather than clinical – endpoints as a confirming benefit is a concern mentioned in the proposed legislation. Ramachandran noted that 40% of the drugs in the accelerated pathway program used such endpoints and called for legislation to “explicitly state that post-approval studies should use clinical endpoints, not surrogate endpoints.” His goal is to ensure that trials are scientifically robust.

Klasmeier pointed out a problem with such a blanket approach. Validated surrogate endpoints are meaningful in many diseases, such as measuring cholesterol levels in heart disease. “It’s the more speculative surrogate endpoints that are the issue. The worry is that product development is occurring without adequate scientific validation. In oncology, there’s a certain comfort level around using surrogate markers to predict an outcome, but in rare diseases, more scientific work is needed to achieve consensus around a surrogate,” she said.

Using only clinical endpoints, however, could delay trials significantly. In cancer, improved survival is one common endpoint, but “the design would have to follow subjects until they die,” Klasmeier said. As treatments become more effective, survival times are extended, sometimes for years. This could ultimately push a study’s conclusion beyond the timeframe allowed by H.R. 6963 for accelerated approval. This would make many innovative treatments unavailable outside clinical trials.

“The legislation seems crafted to turn an existing regulatory program into something more punitive in nature and doesn’t seem to account for the impact on patients,” Klasmeier concluded.

https://www.biospace.com/article/accelerated-approval-integrity-act-could-remove-therapies-before-they-prove-merit/

Pharma industry-backed fund invests in two biotech companies to treat 'superbugs'

 A $1 billion fund backed by over 20 drugmakers made its first set of investments on Monday in two biotechnology startups, nearly two years after it was launched to help struggling antibiotic makers tackle the threat of antibiotic-resistant bacteria.

The AMR Action fund invested $20 million in Adaptive Phage Therapeutics as part of an ongoing series B round and spent an undisclosed amount in a series C round for Venatorx Pharmaceuticals. The fund plans to invest over $100 million by the end of the year.

Public health authorities such as the World Health Organization and industry experts have raised an alarm over the "thin" pipeline of new treatments to tackle antibiotic-resistant bacteria, which they say is not enough to combat the so-called superbugs.

"The space (antibiotic) tends to go in these cycles of heavy resistance, and need for new products. Then the new products become generic, and then they're cheap, and the revenue falls down," said Chris Burns, Chief Executive Officer of Venatorx.

Adaptive Phage is not working on antibiotics but instead uses bacteriophages, which are naturally-occurring viruses that infect and kill bacteria

Venatorx is developing antibiotics to treat certain types of pneumonia and urinary tract infections. The company said the funding should help in efforts to seek approval of its treatment cefepime-taniborbactam later this year, and advance the development of its other experimental drugs.

Investors in the fund include Eli Lilly and Co, Amgen Inc and Bayer.

https://www.zawya.com/en/business/healthcare/pharma-industry-backed-fund-invests-in-two-biotech-companies-to-treat-superbugs-wx4bbctl

Gilead’s remdesivir fails to show benefit in European trial

 Two promising drugs for COVID-19 fail to deliver

Two drugs that looked like promising treatments for COVID-19 in preliminary studies – remdesivir for hospitalized patients and camostat for patients who are not seriously ill – failed to show a benefit in those groups in randomized controlled trials, researchers reported in two separate papers.

In five European countries, researchers studied 843 COVID-19 patients who were hospitalized between March 2020 and January 2021 and who needed oxygen or machines to help with breathing. Two week after patients had received either Gilead Sciences’ antiviral remdesivir – sold as Veklury – plus standard of care or standard of care alone for up to 10 days, there was no difference between the groups in signs of improvement, investigators reported on Thursday https://www.medrxiv.org/content/10.1101/2022.03.30.22273206v1.

In Japan between November 2020 and March 2021, researchers randomly assigned 155 patients with mild or moderate COVID-19 to receive the pancreatitis drug camostat mesylate from Ono Pharmaceutical Co or a placebo for up to 14 days. Camostat blocks an enzyme that helps some versions of the coronavirus infect cells – including the variants circulating at the time of the study – but did not help patients get rid of the virus in their airways any faster than placebo, the Japanese researchers reported on Saturday https://www.medrxiv.org/content/10.1101/2022.03.27.22271988v1. They said the results “highlight… the necessity of conducting well-designed studies to confirm whether preclinical findings translate into meaningful clinical efficacy.” Both studies were posted on medRxiv ahead of peer review.

https://wtvbam.com/2022/04/04/gileads-remdesivir-fails-to-show-benefit-in-european-trial-no-fetus-risk-seen-with-first-trimester-vaccination/

Introducing 'COVID XE': New Mutant In UK WHO Warns Is More Contagious Than Omicron

 As China and Hong Kong continue to struggle with the worst COVID outbreak since Wuhan, the West has mentally moved on from COVID. That being said, COVID still isn't quite done with the West. Or at least that's what the 'experts' are saying.

The new mutant, called XE, may be more transmissible than any strain of COVID so far, according to the WHO and local health authorities in the UK.

XE is a "recombinant" strain - that is, a mutation that combines features of the BA.1 and BA.2 omicron sub-strans. Recombinant mutations emerge when a patient is infected by multiple variants of COVID at the same time. The variants interbreed and combine their genetic material during replication, forming an entirely new mutated strain. A team of researchers from the UK said as much in a paper released this week.

The UK's health agency said that XE was first detected on Jan. 19. Since then, 637 cases of the new variant have been reported.

Authorities said 4.9 million people in the UK are believed to have contracted COVID in the week ending March 26 - that's 600,000 more than the previous week.

Despite the increasingly widespread use of home COVID tests, which make it increasingly difficult for authorities to track the true number o infections, global COVID cases on Sunday topped 490 million, according to the John Hopkins University data. Meanwhile, the world has confirmed over 6.15 million deaths attributed to the virus (although in many cases patients were counted as 'COVID deaths' even if they died from something unrelated - just because they tested positive for the virus).

Instead of rushing to label XE as a 'variant of concern' (which would entail bestowing the strain with its own Greek letter name), the WHO says the new strain will be counted as omicron until further notice.

In the US, states like New York and California have seen an increase in new cases, but the degree to which XE is contributing to this is unclear (if it's contributing at all). At least one case of the new strain has been confirmed in Thailand. But one Asian viral expert told Bloomberg that there's no need to panic about the new variant - at least not yet.

"We should monitor the new recombinants closely, but we should not panic at the moment," said Leo Poon, a virologist and University of Hong Kong professor who has tracked and written reports on the emergence of new strains.

It’s not unexpected to see Covid recombinant variants, or a mix of two previous strains, particularly since the delta and omicron strains have been circulating widely, he said. It’s likely that some people would be infected by both strains. If a variant were to be detected in multiple regions and was spreading in the community, then that would be of concern, he said.

Finally, an epidemiological update published March 29 by the WHO estimated that XE could be as much as 10% more transmissible than BA.2. However, these findings require further confirmation.

https://www.zerohedge.com/covid-19/introducing-covid-xe-new-mutant-strain-found-uk-who-warns-its-more-contagious-omicron

CDC to ‘revamp’ department as it faces eroding public trust over COVID

 The Centers for Disease Control and Prevention announced Monday it plans to undergo a month-long “revamp” as it faces a credibility crisis more than two years after the onset of the COVID-19 pandemic, according to a report.

CDC Director Rochelle Walensky told her staff in an email reviewed by the Washington Post that “it is time to step back and strategically position CDC to support the future of public health.”

“Over the past year, I have heard from many of you that you would like to see CDC build on its rich history and modernize for the world around us,” Walensky wrote. “I am grateful for your efforts to lean into the hard work of transforming CDC for the better. I look forward to our collective efforts to position CDC, and the public health community, for greatest success in the future.”

Walensky added that she had hired an outside leader for the review who will look at the CDC’s “structure, systems, and processes.” 

During the pandemic, the agency meant to be a valuable resource for Americans during a time of global crisis was widely mocked and dismissed as it released convoluted and occasionally contradictory guidance.

Americans were confused earlier this year, for example, when CDC said they could go mask-free in public indoor spaces but still required the face coverings in schools.

Walensky and the CDC were criticized over the rollout of the Pfizer COVID-19 booster shot.

EPA/CAROLINE BREHMAN

This past winter it faced scrutiny over its rollout of vaccine boosters, and Walensky herself overruled an advisory panel that declined to recommend booster shots of Pfizer’s COVID-19 vaccine for frontline workers — including health care workers and teachers. The CDC then claimed it didn’t release booster shot data because it feared the information would be misinterpreted.

Throughout the pandemic, the CDC has been repeatedly criticized for failing to quickly and effectively get tests to the American people. 

According to a January 2022 poll from NBC News, only 44% of Americans said they trusted the CDC, down from 69% at the beginning of the pandemic. 

“Never in its 75-year history has CDC had to make decisions so quickly, based on often limited, real-time, and evolving science,” Walensky said in a statement to the Washington Post. “As we’ve challenged our state and local partners, we know that now is the time for CDC to integrate the lessons learned into a strategy for the future.”

https://nypost.com/2022/04/04/cdc-to-revamp-amid-eroding-public-trust/

Beijing Dispatches Military To Shanghai As Expanded Lockdown Triggers More Unrest

 As local authorities expand what was supposed to be a staggered, nine-day lockdown in Shanghai (China's most populous city and also its financial hub), the CCP has decided to send in the military as the backlash worsens in a city that has become a critical battleground in the government's fight to legitimize its "Zero COVID" policy.

After the city reported a record 9,000 COVID cases, the CCP announced the deployment of thousands of soldiers and military personnel to Shanghai in order for them to assist in the mandatory screening of all 25 million inhabitants (the latest in a seemingly interminable policy of mandatory testing). The next round of nucleic acid tests will begin Monday. The reinforcements include more than 2,000 military personnel and another 30,000 "medical workers", per CNN.

The BBC pointed out that the latest lockdown will be "particularly costly" for China's economy - and for western companies like Tesla and Disney which have major bases of operations in the city (including Tesla's Shanghai gigafactory).

On top of this, Shanghai is a hub for semiconductor, electronics, car manufacturing and China's financial services industry. It is also the world's busiest shipping port.

The CCP has struggled to meet the needs of the local population, which has grown restive in the face of shortages of essential goods like food and medicine. Cases of locals dying after being turned away from local hospitals for non-COVID-related illnesses have also rattled them.

Xu Tianchen, China economist for the Economist Intelligence Unit, warned that short-term supply chain disruptions tied to the city's lockdown could have a serious impact on China's economy.

"There will also be ripple effects elsewhere because of the interconnectedness between Shanghai and other regions of China, especially the manufacturing hub of the Yangtze River Delta," he said.

What's more, consumer spending in a city known for its luxury storefronts has also fallen precipitously. Lost business at retailers, hotels, and restaurants could directly cost Shanghai 3.7% of its annual GDP.

All of this threatens to undermine China's target for the country's GDP: the CCP has promised growth of 5.5% this year, but a growing number of analysts doubt that the government will achieve this goal (unless its resorts to even larger-than-normal distortions in its official economic data).

Shanghai isn't the only Chinese city to face mass lockdowns. Shenzhen, known as China's technology hub, and the Province of Jilin, situated in China's industrial heartland, have also faced lockdowns earlier in the year.

But as President Xi has called for increasingly "targeted" COVID restrictions to minimize the blowback for residents, some have taken to the country's heavily censored social media platforms to address the growing chorus of concerns, and to accuse the CCP of breaking its 'social compact' to take care of the population. Locals have been particularly incensed by the CCP's decision to separate COVID positive children from their parents, triggering a wave of outrage that swept across China's social media.

Political pressure has been mounting on Shanghai authorities to both quell the outbreak and address the growing chorus of concerns from residents grappling with the costs and inconveniences of the stringent measures.

https://www.zerohedge.com/covid-19/beijing-dispatches-military-shanghai-expanded-lockdown-triggers-more-unrest