Merck's Cancer Blockbuster Keytruda Might Treat HIV Too

 Merck’s Keytruda (pembrolizumab) is the company’s blockbuster checkpoint inhibitor used to treat numerous cancers. And now, a study published in Science Translational Medicine suggests it might help treat HIV.

Keytruda is an anti-PD-1 antibody. PD-1 stands for programmed cell death protein and is a protein found expressed by T cells during activation. It has a role in regulating the immune system’s response. Cancer cells often trigger PD-1 in order to hide from the immune system. Drugs like Keytruda block that interaction, allowing the immune system to work better against tumors. 

HIV attacks and “lives” in CD4+ T cells, which express PD-1. The research evaluated the effect of Keytruda on the HIV reservoir — HIV levels in the T cells — in 32 people living with HIV who were on suppressive antiretroviral therapy and also diagnosed with cancer. The authors wrote, “They observed evidence of increased unspliced HIV RNA and the unspliced RNA: DNA ratio, consistent with anti-PD-1 treatment having the potential to reverse HIV latency.”

In a statement, Adeeba Kamarulzaman, President of the International AIDS Society, said, “This is an exciting advance. Being able to stop HIV from hiding is an important part of finding an HIV cure.”

Antiretroviral drugs are pretty good at suppressing HIV. Without those drugs, HIV proliferates, overwhelming the immune system. But the virus still hides out in reservoirs in the body, staying latent.

“But treatment can’t clear latent virus,” said Sharon Lewin, an HIV researcher at the University of Melbourne and senior author of the study. “And you always end up with exhausted T cells.”

Exhausted T cells generate PD-1. But PD-1 also can cause HIV to become senescent. Lewin said, “PD-1 causes a bit of trouble in HIV. It means you have an exhausted immune system that can’t clear [infected] cells, but you basically also silence the virus and put it in a latent form. So, you find a lot of these latent viruses inside cells that express PD-1.”

The researchers believe Keytruda and possibly other anti-PD-1 checkpoint inhibitors might help the immune system track the last signs of HIV while also preventing HIV’s ability to hide. “It has the potential to be a double whammy,” Levin said.

It’s not quite as easy as it sounds, however. Checkpoint inhibitors have potential side effects, including cytokine storms and neuroinflammation. Lewin notes that it’s challenging to use checkpoint inhibitors in people without cancer, and the studies that have been conducted were halted because of the side effects.

Lewin partnered with researchers at the Fred Hutchinson Cancer Research Center to find patients who were receiving Keytruda for cancer but were also receiving antiretroviral therapy for HIV. They received Keytruda, which is dosed via infusion, every three weeks for up to 105 weeks. They collected blood samples regularly and analyzed it for genetic signs of HIV. 

Right after the first infusion, they found HIV genetic evidence in the blood, which suggested it was pushing the virus out of hiding and making it more vulnerable to the antiretroviral drugs as well as the body’s immune system. But it didn’t completely remove the HIV from the first five patient’s blood.

“It released the brakes on the virus, and now they’re visible to the immune system,” Lewin said. “But this is just a proof of concept. Anti-PD1 on its own repeatedly didn’t get rid of the reservoir.”

Much more research will be needed to see if this is practical.

Dr. Shyam Kottilil, an infectious disease doctor and Professor at the Institute of Human Virology at the University of Maryland School of Medicine, who was not involved in the research, told STAT, “It makes us more enthusiastic about cure efforts, but I would not say we are close.” He added the “major concern is safety of these agents in people with HIV without cancer.”

https://www.biospace.com/article/merck-s-blockbuster-checkpoint-inhibitor-keytruda-might-treat-hiv/

Lithium-Sparing Alzheimer’s Therapy has Strong Benefit-to-Risk Profile

 On the strength of data from its Phase I study of lead compound, AL001, being developed for the treatment of Alzheimer’s disease, Alzamend Neuro is looking to commence a Phase II multiple ascending dose study for that indication during the second quarter of this year.

AL001, also known as LiProSal™, is a patented new formulation that delivers lithium orally through a crystal-engineered combination of lithium, L-proline and salicylate and was shown to be bioequivalent to the 300mg marketed lithium carbonate product.

“It has the potential to reduce the lithium dose needed to achieve efficacy for multiple neurodegenerative and psychiatric medical conditions,” Stephan Jackman, CEO of Alzamend Neuro, an early clinical-stage company, told BioSpace. In this trial, the dose of lithium was half that of the currently marketed lithium-based drugs treating Alzheimer’s disease.

The significantly lower level of lithium per dose is notable and is expected to give this drug a key advantage against competitors. As Jackman explained, other lithium carbonate and currently marketed lithium products are constrained by a very narrow margin between efficacy and toxicity. Therefore, they have a narrow therapeutic index and require therapeutic monitoring via routine blood tests, he said. For example, for currently-marketed lithium salts, “An often-cited reference range for therapeutic blood levels of lithium is 0.8-1.2 mEq/L. Levels above 1.2 mEq/L are often associated with toxicity, so clinicians monitor lithium levels in blood routinely to avoid side effects.”

By halving the usual lithium dose used to treat bipolar disease using lithium salts, the likelihood of detecting lithium concentrations in the blood that exceed 1.2 mEq/L is small. The comparatively low-dose AL001, therefore, reduces potential side effects and eliminates the need for routine blood tests to monitor lithium levels, thus conferring a definite benefit to patients.

Salicylate levels also are well within safety tolerances. In fact, “The amount of salicylate absorbed from AL001 (at the equivalent lithium dose of lithium carbonate 150 mg) is the same as that absorbed from two and a quarter 325 mg aspirin tablets,” Jackman said. “That’s close to the labeled over-the-counter dosage for pain, fever and inflammation.” Consequently, the benefit-to-risk relationship of this formulation (administered by a medical professional) appears favorable, especially when the paucity of available treatments for Alzheimer’s disease is considered.

Topline data from the Alzheimer’s study that Alzamend released in mid-December “confirms AL001’s potential as a replacement for current lithium-based treatments,” Jackman said. “The completed Phase 1 study for AL001-ALZ01 showed that the rate and extent of lithium absorption/persistence in blood (and therefore for most organs in the body) are closely comparable between AL001 and lithium carbonate.

“Such findings may serve as surrogate endpoints,” Jackman added, aided by data already in the public domain. Combined, this body of evidence may “mitigate or obviate some requirements for Phase II and III studies for safety and/or efficacy.” That possibility could come into play in indications for other disorders for which lithium is a treatment, as well as for new indications.

For example, preclinical data in mice suggested AL001 also may prove effective in preventing cognitive deficits, depression and irritability, and that it improved associative learning, memory and irritability when compared to lithium salt treatments. Data suggest this may be related to differences in uptake and persistence in the target organ for efficacy – the brain – between AL001 and lithium carbonate. Therefore, its range of indications may be expanded to include such neurodegenerative and psychiatric conditions as amyotrophic lateral sclerosis (ALS), Parkinson’s disease and bi-polar disorder.

As this drug advances through the clinic, one of the greatest challenges – one shared by all clinical-stage Alzheimer’s researchers – is the timely recruitment of qualifying Alzheimer’s patients for clinical studies. According to the most current analysis, in the U.S. in 2020, the 152 Alzheimer’s trials listed on ClinicalTrials.gov required 38,826 participants and 2,540,014 participant weeks, in addition to clinician time spent screening and managing patients, according to Jeffrey Cummings of the University of Nevada, and colleagues, in “Alzheimer's disease drug development pipeline: 2021”, published in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association.

In nearly all cases, recruitment time exceeds the time required for the treatment portion of the trials and the anticipated completion date. COVID-19 only exacerbated an existing problem. As the previous year’s report, published in 2020, noted, “The mean difference between the actual completion date and the anticipated completion date was 30 weeks for completed trials in Phase 1, 32 weeks for Phase 2 and 72 weeks for Phase 3, respectively.”

Such delays in recruitment are expected to be at least partially offset by a large body of relevant studies in the public domain. As Jackman stressed, “The lithium, salicylate and L-proline components of the engineered crystal are well-characterized and can be repurposed to address new indications and improve treatments for extant indications. Since the data already is extensive…the regulatory burden can be expected to be inherently mitigated.”

He noted the publication of multiple preclinical and clinical studies that suggest a positive outcome for lithium – and, by extension, AL001 – as a treatment for Alzheimer’s disease. There are also extensive safety data in the public domain relevant to the lithium, salicylate and L-proline components of AL001. To avoid redundant clinical efforts and to avoid subjecting frail subjects unnecessarily to the rigors of clinical trials, referencing this extensive literature for regulatory authorities can serve to reduce the need to reproduce such data and trials de novo.

Going forward, Alzamend is looking toward launching a Phase II study for Alzheimer’s disease in the second quarter of 2022 and also is continuing to refine the formulation. The treatment currently is administered three times each day but, Jackman said, “We are working on a formulation specifically designed to minimize the burden of drug administration for Alzheimer’s patients.”

https://www.biospace.com/article/lithium-sparing-alzheimer-s-therapy-has-strong-benefit-to-risk-profile-/

Hong Kong's Zero-COVID Policy Called Unsustainable

 With thousands of people locked down in tiny apartments, government quarantine centres filling up and many businesses shuttered, Hong Kong is scrambling to sustain a zero-COVID policy that has turned one of the world's most densely packed cities into one of the most isolated.

The economic and psychological tolls from the global financial hub's hardline approach - in line with China's strategy - are rapidly rising, residents say, with measures becoming more draconian than those first implemented in 2020.

Flights out of Hong Kong's international airport are down around 90%, over 8,000 people are locked down in government quarantine facilities and a congested housing block, while 900,000 students have been shut out of schools since the start of this week. Doctors say the restrictions are taking an increasingly heavy toll on residents' mental health.

Once one of the world’s most connected places, Hong Kong is reeling from the closure of its borders, impacting the free flow of people and the availability of food and foreign products the city is so highly dependent on.

Besides schools, authorities in the city of 7.5 million have shut down playgrounds, gyms and most other venues, while tens of thousands of people are required to do daily coronavirus tests.

Restaurants and bars close at 6 p.m. (1000 GMT).

Over 2,000 hamsters and other animals have been culled to stop transmissions as community cases surge.

Siddharth Sridhar, clinical assistant professor at the University of Hong Kong’s Department of Microbiology, said "a very practical adjustment in terms of our containment strategy" was needed.

"This is not sustainable," he said. "Eventually we are going to see a very local protracted outbreak, likely to be worse than previous cases."

While Hong Kong succeeded in keeping the virus under control for much of 2021, there have been over 600 locally transmitted infections in January so far, compared with just two in December, as the highly transmissible Omicron variant spread.

"Essentially it's playing whack-a-mole. It (coronavirus) will simply keep coming back," said Keith Neal, professor at the University of Nottingham in the United Kingdom, referring to the popular amusement arcade game.

UNVACCINATED ELDERLY

Shutting itself off is an "unworkable strategy" for Hong Kong, said Sumit Agarwal, professor at the National University of Singapore’s Business School, as the economic and social costs of the policy continue to soar.

"Only Hong Kong and China are saying they are trying to eradicate the virus," he said. "It would have worked if other countries did the same but the fact they don’t think that way means the virus is always flowing."

Leader Carrie Lam has said Hong Kong cannot live with the virus as many major cities are doing. She says over 80% of the city's elderly are unvaccinated, and a large outbreak of infections will heavily increase the burden on already stretched healthcare services.

Increasing Hong Kong’s vaccination rate is key, she said, with just over 70% of the people double vaccinated and around 10% having received a booster or third shot.

Lam said on Thursday that Hong Kong will shorten its 21-day quarantine requirement to 14 days for incoming travellers starting from Feb. 5, after months of pressure from financial executives and foreign diplomats who said the rule was eroding the city's competitiveness.

Many professionals and expatriates are leaving or planning to leave the former British colony, seeing no end in sight to the restrictions.

Quarantine rules for those infected as well as close contacts is curbing the city’s desirability and risks an exodus, according to an internal report by the city’s European Chamber of Commerce. Companies are repositioning their staff to Singapore and Seoul, it said.

Hong Kong authorities hold daily briefings, providing details on each infected person, where they live, where they ate and where they went. Credit card statements, transport records, CCTV footage and a government app are some of the methods they use to identify and quarantine close contacts.

"The Omicron variant is so explosive in its spread that it will be the sorest test of Hong Kong's response yet if it keeps up testing, tracing, isolation and quarantine," said Alex Cook, associate professor at the National University of Singapore’s Saw Swee Hock School of Public Health.

"Once the number of cases for contact tracing becomes too high...more secondary cases will slip through and the epidemic growth would be compounded."

https://www.usnews.com/news/world/articles/2022-01-27/whack-a-mole-experts-call-hong-kongs-zero-covid-policy-unsustainable

Oscar Health Guidance for 2022 of More Than $6B in Premiums

 

• Total enrollment for 2022 tops one million members across the Oscar platform

• Provides 2022 guidance, which includes premiums of $6.1 to $6.4 billion, representing more than 80% year-over-year ("YoY") growth at the midpoint

• Announces $305M capital raise, led by Dragoneer Investment Group, to strengthen the balance sheet and fund growth

• Reports preliminary FY21 results, with all key metrics meeting or beating expectations

https://finance.yahoo.com/news/oscar-health-delivers-historic-growth-210500768.html

Biogen tweaks confirmatory trial of Alzheimer’s drug Aduhelm

 Biogen and Eisai have expanded the size of the confirmatory trial of their Alzheimer’s drug Aduhelm in order to “strengthen the data” for the drug.

The decision comes as the Centre for Medicare and Medicaid Services (CMS) is finalising its decision on reimbursement of Aduhelm (aducanumab) which – for the time being– would restrict cover of the drug to patients enrolled in clinical trials.

If the current draft decision remains unchanged, it would slam the brakes on take-up of Aduhelm via federal healthcare schemes, and it’s quite possible private insurers could follow the CMS’ lead as well.

Given the restriction to participants in randomised clinical trials, Biogen and Eisai’s decision to expand the size of ENVISION by 200 subjects to 1,500 might be seen as a way to boost near-term revenues for Aduhelm as they try to convert the FDA’s conditional okay for the drug to a full approval.

However, a spokesperson for the company told Pharmaphorum that it is too soon to speculate how ENVISION might fit into the ‘coverage with evidence development’ (CED) approach adopted by the CMS in its draft.

He also said that there is no cost to the patient and no revenue for Biogen from the trial. Biogen and Eisai are emphasising other reasons for the expansion of the study, which is due to read out in four years time, including increasing the diversity of subjects with a target of 18% black/African American and Latinx populations.

“This goal matches the diversity among Americans diagnosed with early Alzheimer’s disease, while at the same time, the trial will generate substantial data to verify the effectiveness of Aduhelm,” said Biogen’s head of global safety and regulatory sciences Priya Singhal, who is acting head of R&D following the departure of Al Sandrock.

Subjects in the trial will also have to have evidence of amyloid plaques at enrolment as well as mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s disease, something that was required in the CMS’ initial decision but not the approved FDA labelling for Aduhelm.

Another change means that the primary endpoint for the trial will be the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months after treatment starts with the drug – the same endpoint that was used in Biogen and Eisai’s two phase 3 trials – EMERGE and ENGAGE – which generated mixed results.

Referring to the CMS draft, Biogen said that it is “committed to engaging with CMS to avoid unnecessary duplication of clinical trials and work towards finding a path to offer immediate access to patients to the first FDA approved treatment for Alzheimer’s disease since 2003.”

The CMS’ decision to restrict the drug came despite Biogen slashing the cost of Aduhelm in half to $28,200 a year, acknowledging that it had made a mistake in its initial pricing level. A final decision by the agency is expected by 12 April.

ENVISION is due to get underway in May. Meanwhile, Biogen and Eisai are also running a real-world study called ICARE AD that aims to provide information on the long-term effectiveness and safety of Aduhelm as used in clinical practice in around 6,000 patients.

https://pharmaphorum.com/news/biogen-tweaks-confirmatory-trial-of-alzheimers-drug-aduhelm/

Wife of COVID patient suing to force NYC hospital to treat husband with Ivermectin

 The wife of a COVID-stricken man “on death’s doorstep” wants a judge to force a Manhattan hospital to give her husband Ivermectin — a derided treatment not approved by the Food and Drug Administration to combat the virus.

Erika Quintero-Sherry, 48, filed suit against Mount Sinai West claiming that despite her rabbi husband Benjamin Chernyavsky’s doctor recommending the drug, other doctors in the intensive care unit of the 10th Avenue hospital have refused, according to a suit filed Wednesday.

The 60-year-old father of five contracted the virus on Jan. 8 and is now on a ventilator in a medically induced coma. The suit claims he has less than a 20 percent chance of surviving.

“Once my husband went onto the ventilator, I felt like, what do we do now?” Quintero-Sherry told The Post. “Are we going to try something else or are we continuing with the same protocol that isn’t working and just keep him on oxygen?”

“Every day I go to the hospital and it’s just nerve wracking,” the wife said.

Chernyavsky’s mother, Margaret Franco, 78, told The Post the situation is a “nightmare.”

“It’s a nightmare to see … your son laying there and nothing is being done for him,” Franco said.

“He is having excellent care from the hospital for the rest of his body but not for COVID — which is going to kill him,” Franco said. “And he’s been on the ventilator for 11 days now, and how much longer can he live on the ventilator?”

“To see him suffering and we can’t do anything — it’s absurd,” she said.

Chernyavsky’s daughter, Diane Sherry, 31, said, they “are wiling to try” Ivermectin because “the most important thing for us is to do anything to save his life.”

Quintero-Sherry said their 8-year-old son, Daniel, who is extremely close to his father, “is in tremendous distress about this situation.”

Chernyavsky’s treatment under the hospital’s health care protocol has included “steroids, antibiotics, high-flow oxygen and BiPAP,” the court papers say.

The FDA says Ivermectin is only approved to treat certain parasites in animals and humans — and only at “very specific dosages” for humans — as data shows it’s not effective against COVID-19, according to its website.

Doctors are taking a “wait and see” approach, the suit claims. But, Quintero-Sherry claims they have nothing to lose by treating her husband with the drug, the filing says.

“I cannot give up on him, even if the defendants have,” the court papers say. “There is no reason why the defendants cannot approve or authorize other forms of treatment so long as the benefits outweigh the risks.”

“Mr. Chernyavsky is on death’s doorstep; there is no further COVID-19 treatment protocol for defendants to administer to Mr. Chernyavsky; his family does not want to see him die, and they are doing everything they can to give him a chance,” the court documents claims.

“It’s unfortunate that in our country families have to resort to litigation to get the treatment that could potentially save their loved one’s life,” family lawyer, Beth Parlato, told The Post.

–– ADVERTISEMENT ––

Mount Sinai did not immediately return a request for comment.

https://nypost.com/2022/01/27/wife-of-covid-patient-suing-to-force-nyc-hospital-to-treat-husband-with-ivermectin/

COVID-19 Can Be Stopped Without Massive Vaccination: Dr. Peter McCullough

 by Harry Lee and Steve Lance via The Epoch Times (emphasis ours),

COVID-19 can be stopped without massive vaccination, renowned cardiologist and epidemiologist Dr. Peter McCullough told NTD’s “Capitol Report” program during the “Defeat the Mandates” march in Washington D.C., on Jan. 23.

According to McCullough, early treatment and natural immunity are safe and effective against COVID-19, but federal health agencies have ignored these in a push for vaccines, the broad use of which is not needed.

“The government has certainly been in an oblivion in terms of early treatment,” he said.

Thousands of people turned out to march in protest against COVID-19 vaccine mandates—one of the largest U.S. events against the mandates since the start of the pandemic.

“Our CDC, FDA, and NIH have had no effective messaging on early treatment, even the emergency use authorized monoclonal antibodies, which are safe and effective,” McCullough said. “And even on the new Merck and Pfizer drugs, which they’re basically absent in terms of the media, despite being recently distributed across the United States.”

Early effective treatment of any disease can help avert progression to more serious illness, with an additional benefit of reducing the burden on health care systems, and in a seperate interview, McCullough claimed that 95% of the COVID deaths could have been prevented by early treatment...

The Centers for Disease Control and Prevention (CDC) stated on its website that according to the COVID-19 Treatment Guidelines published by the National Institutes of Health (NIH), “current clinical management of COVID-19 consists of infection prevention and control measures and supportive care, including supplemental oxygen and mechanical ventilatory support when indicated.”

The Food and Drug Administration (FDA) has approved one drug, remdesivir (Veklury), to treat COVID-19 in hospitalized patients, the CDC continued.

On Monday, the FDA announced that it is restricting the use of two monoclonal antibody treatments for COVID-19, saying data show such treatments are “highly unlikely” to be active against the Omicron variant.

A crowd gathers at Lincoln Memorial for the “Defeat the Mandates” rally in Washington on Jan. 23, 2022. (Lynn Lin/NTD)

McCullough said that highly qualified doctors have done the research and have shown that “early treatment can end this pandemic by reducing the intensity and severity of disease and reducing the chances of hospitalization and death in our highest risk seniors.”

“This basically means that the vaccines broadly used aren’t needed. And in fact, we have seen far too many vaccine injuries and now vaccine failures. With the Omicron variant, there’s effectively no coverage of these vaccines against the newest form of the virus,” McCullough said, adding 22 studies showed vaccines ran out of efficacy after six months.

McCullough gave the example of how ivermectin, a Nobel prize-winning, FDA-approved drug that many studies and doctors claim is effective in treating COVID-19 patients, was dismissed by federal health agencies.

Dr. Peter McCullough in an interview with NTD's Capitol Reports program during "Defeat The Mandate" rally in Washington D.C., on Jan. 23, 2022. (Screenshot via The Epoch Times)

The FDA has been saying the drug was approved to treat internal and external parasites, and currently no data shows its effectiveness against COVID-19.

McCullough also claimed that the federal health agencies have ignored natural immunity, which is “robust, complete, and durable in terms of the lethal strains of the virus.”

“It was only until it got to the Omicron variant, which there was a breakthrough, and individuals who are previously immune could get a mild Omicron syndrome. But natural immunity is the end of the pandemic,” McCullough continued. “Remember, as we all become naturally immune, COVID-19 is no longer a threat to our lives.

“And the failure of our governmental agencies to recognize natural immunity has basically created unnecessary suffering, unnecessary testing, unnecessary masking and social distancing. Unnecessary compliance with all kinds of measures that are designed for the susceptible. Those who are naturally immune are no longer susceptible to fatal disease.”

McCullough expressed doubt about the claim that COVID-19 vaccines could reduce hospitalization and deaths.

“All we have at this point of time is bias-confounded, and I think invalid hospitalization data. The U.S. agencies still make the claim that the vaccines protect against hospitalization, whereas we see no evidence of that in the UK, Germany, South Africa, and the rest of the world,” McCullough said. “And I can tell you, the United States is not that different than the rest of these countries. Something is wrong. And I can tell you something is wrong with an incorrect, invalid claim that the vaccines reduce hospitalization. I don’t think it’s supportable.”

On Jan. 19, the CDC published a study showing that people who had not gotten a vaccine but did have a prior infection, also known as natural immunity, were less likely to land in a hospital than the vaccinated without natural immunity.

The Epoch Times has contacted CDC for additional comment.

Last month, President Joe Biden announced new measures to battle COVID-19, the top three of which are boosters for all adults, vaccinations to protect kids, and expanding free at-home testing. Biden did talk about the new treatment, saying that “if and when any new COVID-19 treatment pills have been found to meet FDA’s scientific standards, they are equitably accessible to all Americans.”

Zachary Stieber contributed to this report.

https://www.zerohedge.com/covid-19/covid-19-can-be-stopped-without-massive-vaccination-dr-peter-mccullough