Brazil health regulator lacks data needed to evaluate Sputnik V

 Brazil's health regulator Anvisa lacks the information necessary to evaluate the safety and efficacy of Russia's Sputnik V vaccine, the agency said in legal documents seen by Reuters on Friday.

The documents were sent to the nation's Supreme Court as part of an emergency request by the northeastern state of Maranhao to import the vaccine.

In the documents, Anvisa lists various types of data that it lacks, including mass trial results and quality assurances, saying that it does not have sufficient information to carry out a "positive benefit-versus-risk analysis of the vaccine."

The documents are enclosed in a court case being overseen by Justice Ricardo Lewandowski, who on Tuesday gave Anvisa 30 days to make a decision on an emergency import request.

Brazil is currently suffering through its worst period of the coronavirus pandemic, with more daily deaths than anywhere else in the world.

While the country's vaccination effort has been faster than some countries in Latin America, it is well behind many developed countries and continues to miss its own inoculation targets due to a shortage of doses.

As a result, the governors of several northeastern states have pushed for the import of the Sputnik V vaccine, developed by Moscow's Gamaleya Institute.

The vaccine's representatives in Brazil did not immediately respond to a request for comment on Friday.

https://www.reuters.com/business/healthcare-pharmaceuticals/brazil-health-regulator-lacks-data-needed-evaluate-sputnik-v-2021-04-16/

J&J scientists refute ‘class effect’ for clots in those who got its COVID vax

 Scientists at Johnson & Johnson (JNJ.N) on Friday refuted an assertion in a major medical journal that the design of their COVID-19 vaccine, which is similar AstraZeneca's (AZN.L), may explain why both have been linked to very rare brain blood clots in some vaccine recipients.

The United States earlier this week paused distribution of the J&J vaccine to investigate six cases of a rare brain blood clot known as cerebral venous sinus thrombosis (CVST), accompanied by a low blood platelet count, in U.S. women under age 50, out of about 7 million people who got the shot.

The blood clots in patients who received the J&J vaccine bear close resemblance to 169 cases in Europe reported with the AstraZeneca vaccine, out of 34 million doses administered there.

Both vaccines are based on a new technology that uses a modified version of adenoviruses, which cause the common cold, as vectors to ferry instructions to human cells.

The U.S. Food and Drug Administration is scrutinizing this design behind both vaccines to see if it is contributing to the risk. 

In a letter on Friday in the New England Journal of Medicine, J&J scientists refuted a case report published earlier this week by Kate Lynn-Muir and colleagues at the University of Nebraska, who asserted that the rare blood clots "could be related to adenoviral vector vaccines."

In an interview with Reuters on Thursday, Dr. Anthony Fauci, the top U.S. infectious disease expert and an adviser to the White House, said the fact that they are both adenovirus vector vaccines is a "pretty obvious clue" that the cases could be linked to the vector. read more

"Whether that is the reason, I can't say for sure, but it certainly is something that raises suspicion," Fauci said.

In the correspondence on Friday, Macaya Douoguih, a scientist with J&J's Janssen vaccines division, and colleagues pointed out that the vectors used in its vaccine and the AstraZeneca shot are "substantially different" and that those differences could lead to "quite different biological effects."

Specifically, they noted that the J&J vaccine uses a human adenovirus while the AstraZeneca vaccine uses a chimpanzee adenovirus. The vectors are also from different virologic families or species, and use different cell receptors to enter cells.

The J&J shot also includes mutations to stabilize the so-called spike protein portion of the coronavirus that the vaccine uses to produce an immune response, while the AstraZeneca vaccine does not.

"The vectors are very different," said Dr. Dan Barouch of the Center for Virology and Vaccine Research at Harvard’s Beth Israel Deaconness Medical Center in Boston, who helped design the J&J vaccine.

"The implications of issues with one vector for the other one are not clear at this point," he said in an interview earlier this week.

The J&J scientists said in the letter there was not enough evidence to say their vaccine caused the blood clots and they continue to work with health authorities to assess the data.

A panel of advisers to the U.S. Centers for Disease Control and Prevention are expected to meet on April 23 to determine whether the pause on use of the J&J vaccine can be lifted.

https://www.reuters.com/business/healthcare-pharmaceuticals/jj-scientists-refute-class-effect-blame-clots-those-who-got-its-covid-19-vaccine-2021-04-16/

Med-Aided Treatment Not an Option for Opioid Users in Justice System

 Criminal justice populations were significantly less likely to receive medication-assisted treatment (MAT) for opioid use disorder (OUD) -- such as methadone and buprenorphine -- even with the increased access brought about by Medicaid expansion in certain states, a recent study found.

When compared to individuals referred to treatment by all other sources, those referred to treatment by the criminal justice system were far less likely to receive MAT in the years before (2008-2013) and after (2015-2017) enactment of the Affordable Care Act (pre-ACA, adjusted risk ratio 0.15, 95% CI 0.15-0.16; post-ACA, ARR 0.28, 95% CI 0.28-0.28), Utsha Khatri, MD, of the University of Pennsylvania's Perelman School of Medicine, and colleagues reported in Health Affairs.

Those risk ratios also differed significantly between the two periods. (P<0.001).

In Medicaid expansion states, criminal justice populations saw higher rates of receiving medications for OUD than did those in states without this expansion (ARR 2.07, 95% CI 2.00-2.13) over the course of the entire study period, 2008-2017. The trend was similar when researchers looked at those who received MAT through other referrals in Medicaid expansion states (ARR 1.60, 95% CI 1.59-1.61).

Khatri and her team used 10 years of data from the Treatment Episode Data Set-Admissions (TEDS-A), a national database of substance treatment facility admissions organized by the Substance Abuse and Mental Health Services Administration. The sample -- which lists the primary, secondary, and tertiary substances that led to an individual's admission to treatment -- was limited to those over the age of 18 whose primary reason for seeking treatment was opioid-related.

Those who were referred to evidence-based treatments through the criminal justice system tended to be younger than those from other referral sources (ages 18-24, 23.4% vs 17.9% respectively) and somewhat more likely to be white (64.6% vs 60.7%).

"It's important to note that this disparity existed before the implementation of the Affordable Care Act, but then also continues beyond that," Khatri told MedPage Today. Medicaid expansion as a policy, she said, was clearly effective in addressing some of that disparity, with those states seeing a 165% increase in individuals referred to evidence-based treatment for OUD from criminal justice agencies. "But even though things got better after Medicaid expansion, the disparity between the people who have criminal justice involvement and people who don't persisted."

Khatri also emphasized that one of the study's major drawbacks is that it can only capture the number of individuals who do get referred to evidence-based treatment. When looking at the general population outside of those involved in the criminal justice system, Black and brown patients were significantly less likely to receive medications like buprenorphine than their white counterparts.

"So when you're adding on the stigma of also having criminal justice involvement on top of the stigma of being a person of color who has an addiction, the disparity is even more pronounced," Khatri said. "We can assume, just knowing what we know about substance use disorder treatment in this country, that all systems are likely under-referring people of color into treatment."

For individuals in the criminal justice system, gaining access to medications for OUD can be life-saving at many different points in the justice process. One study found that formerly incarcerated people were 40 times more likely to die from opioid overdose in the first two weeks after their release from prison; when examining just heroin overdoses, the likelihood of overdose death for the same population increased to 74 times the normal overdose rate within the same two weeks.

"Overdose rates are so high because people have spent a period of time confined and not using, they lose their tolerance," said Christine Grella, PhD, of the University of California Los Angeles's Integrated Substance Abuse Programs. "So they may leave and then resume use at similar levels and their bodies are no longer habituated to that level."

Khatri noted that addicts released from prison, beyond having the increased risk of relapse and overdose, may not put health insurance high on their long list of immediate needs and priorities.

"People are looking for housing, they're trying to reconnect with families, they're trying to find a job," Khatri said. "I think the less burden we put on the individual and the more we can formalize into policy things that we know help folks getting treatment, like having active Medicaid, the more people will be able to prioritize their recovery and their substance use treatment during that vulnerable period."

The COVID-19 pandemic has prompted efforts to reduce the volume of people in our country's prisons and jails. But Noa Krawczyk, PhD, a population health professor at New York University, said the haste and disorganization of the release process may add more complications to getting formerly incarcerated individuals referred to evidence-based treatment programs.

"There is some concern about people who are being released who might have been receiving treatment while incarcerated or would benefit from treatment when they come out of incarceration, and yet the linkage to services isn't there," Krawczyk told MedPage Today.

The stigma surrounding the use of medications used to treat opioid use disorder seems to be the most everlasting and ubiquitous barrier to treatment, in states both with and without Medicaid expansion.

"There are still a lot of misconceptions that are driving people to receive treatment, but treatment that's not as effective as it could be if it involves medication," Krawczyk said, noting that many still believe methadone and buprenorphine merely replace one addiction for another. "There's a lot of work to do in correctional settings and in the community of people who are criminal-justice-involved to get people up to speed, to make sure that everybody has at least equal access and the knowledge of the effectiveness of these treatments."

Disclosures

Khatri's work is funded by the Department of Veterans Affairs. One co-author reported grants from the National Institute on Drug Abuse.

Primary Source

Health Affairs

Source Reference: Khatri U, et al "Medicaid expansion increased medications for opioid use disorder among adults referred by criminal justice agencies" Health Affairs 2021; DOI: 10.1377/hlthaff.2020.01251.

https://www.medpagetoday.com/special-reports/exclusives/92144

New Side Effect From mRNA COVID Vaccines?

 Herpes zoster reactivation -- a.k.a. shingles -- following COVID-19 vaccination in six patients with comorbid autoimmune/inflammatory diseases may be a new adverse event associated with the Pfizer/BioNTech mRNA vaccine, suggested a new report.

At two centers in Israel, there have been six cases of herpes zoster developing shortly after administration of the Pfizer vaccine in patients with disorders such as rheumatoid arthritis since December 2020, according to Victoria Furer, MD, of Tel Aviv University, and colleagues.

Little has been known about the safety and efficacy of the COVID-19 vaccines among patients with rheumatic diseases, because immunosuppressed individuals were not included in the initial clinical trials, they explained.

Accordingly, an observational study has been conducted at the Tel Aviv Medical Center and the Carmel Medical Center in Haifa, monitoring post-vaccination adverse events in patients with rheumatoid arthritis, spondyloarthropathies, connective tissue diseases, vasculitis, and myositis. This interim analysis included 491 patients and 99 controls, with events reported during the 6-week post-vaccination monitoring period. The prevalence among patients was 1.2% versus none in controls, Furer and colleagues reported in Rheumatology.

"We haven't seen any additional cases so far," Furer told MedPage Today. However, "further surveillance of potential adverse effects following anti-COVID-19 vaccination in patients with rheumatic diseases is warranted," she added.

The Cases

Case 1 was a 44-year-old woman with Sjogren's syndrome who was being treated with hydroxychloroquine. She had a history of varicella and had not received a shingles vaccine. Three days after the first dose of the vaccine, she developed a vesicular skin rash with pruritus, along with low back pain and headache. The symptoms resolved spontaneously within the subsequent 3 weeks without treatment, and she was given the second dose 4 weeks after the first.

Case 2 was a 56-year-old woman with a long history of seropositive rheumatoid arthritis who had received a variety of biologics and had achieved low disease activity with tofacitinib (Xeljanz) beginning in 2014. She had a history of varicella and had not been given the shingles vaccine.

After the first dose of the vaccine, she reported malaise and headache, and 4 days after the shot she developed severe pain in the left eye and forehead, along with a rash along the distribution of the ophthalmic division of the V cranial nerve -- herpes zoster ophthalmicus. Ocular examination revealed hyperemic conjunctivitis sparing the cornea. She was given a 2-week course of acyclovir and analgesics, and symptoms gradually cleared by 6 weeks. Tofacitinib was withdrawn for 2 weeks, but she did not experience an arthritis flare. She declined the second dose.

Case 3 was a 59-year-old woman with seropositive rheumatoid arthritis who had not responded to several biologic therapies and baricitinib (Olumiant), but 6 months earlier she initiated treatment with upadacitinib (Rinvoq) plus prednisone 5 mg/day and had a partial response. She had a history of varicella and had been given the live attenuated zoster vaccine in 2019.

Two days after receiving the second dose of the COVID vaccine, she reported pain and had a vesicular skin rash on the lower abdomen, inguinal area, buttock, and thigh, and was given valacyclovir. The antiviral was given for 3 days but was discontinued because of adverse effects, and the skin lesions healed slowly over a course of 6 weeks.

The upadacitinib had been discontinued with the zoster eruption and she experienced a severe rheumatoid arthritis disease flare affecting multiple joints, and her arthritis treatment was subsequently switched to etanercept (Enbrel).

Case 4 was a 36-year-old woman with a long history of seropositive rheumatoid arthritis plus interstitial lung disease. For the previous 2 years she had been treated with rituximab (Rituxan), mycophenolate mofetil (CellCept), and prednisone in doses of 7 mg/day. She had a history of varicella and had not been given the shingles vaccine.

Ten days after receiving the first COVID-19 vaccine dose, she reported pain and a vesicular rash on the abdomen and back along the T10 dermatome, and was given acyclovir for 7 days. The rash resolved within 6 weeks, and she was given the second vaccine dose 4 weeks after the first. She had no further adverse effects to the vaccine and did not experience a rheumatic disease flare.

Case 5 was a 38-year-old woman with undifferentiated connective tissue disease and antiphospholipid syndrome who was being treated with aspirin and hydroxychloroquine. She had prior varicella exposure and had not received the shingles vaccine.

Two weeks after receiving the first dose of the COVID-19 vaccine, she developed an itchy vesicular rash on the right breast, and was given a week's course of acyclovir. Her zoster symptoms resolved within 3 weeks and she received the second vaccine dose on schedule with no further side effects or disease flare.

Case 6 was a 61-year-old woman with a long history of seropositive rheumatoid arthritis, who was being treated with tocilizumab (Actemra) and prednisone 5 mg/day at the time of the first dose of the vaccine. Two weeks later, a rash appeared along the T6 dermatome, and she was given valacyclovir for a week, which resulted in resolution of zoster symptoms within 10 days.

However, she did report a mild flare of arthritis and the prednisone dose was increased to 7.5 mg/day. The second dose was given uneventfully as scheduled.

Patterns and Mechanisms

Furer and colleagues noted that there had been no reports of herpes zoster in the clinical trials of the mRNA COVID-19 vaccines, and that, to their knowledge, this is the first case series of these events among patients with autoimmune/inflammatory diseases.

The pattern of disease was relatively mild, with no patients experiencing disseminated disease or post-herpetic neuralgia. It was notable, the researchers pointed out, that one case was in a patient who had received the shingles vaccine 2 years before the COVID-19 vaccination.

"Cell-mediated immunity plays an important role in the prevention of varicella zoster virus reactivation. Declining cell-mediated immunity with age or disease is associated with a reduction in varicella zoster virus-specific T cells, disrupting immune surveillance and increasing the risk of reactivation, with age being the major risk factor for 90% of cases of herpes zoster," the researchers wrote. Nonetheless, these cases were among relatively young women, whose mean age was 49 and whose rheumatic disease was mild or stable.

Other factors are also likely to have been involved. For instance, the risk of herpes zoster in the rheumatic disease population is higher than healthy individuals, with a pooled incidence rate ratio of 2.9 (95% CI 2.4-3.3). In addition, the risk among patients with rheumatoid arthritis specifically has been estimated to be twofold higher than in the general population.

Further raising risk are increased levels of disease activity and high doses of prednisone. Moreover, double the risk of herpes zoster has been reported for patients being treated with JAK inhibitors such as tofacitinib, as was the case with two patients in this series.

COVID-19 infection itself has been linked with varicella-like rashes, suggesting that the infection can interfere with the activation and function of CD4+ and CD8+ cells, which can influence immunity against viruses.

"Potential mechanisms that might explain the pathogenetic link between mRNA-COVID-19 vaccination and herpes zoster reactivation are related to stimulation of innate immunity through toll-like receptors," the researchers wrote.

They also noted that the vaccine can stimulate type I interferons and cytokines that can interfere with antigen expression.

A limitation of this analysis was that the diagnosis of herpes zoster was made solely on clinical grounds. Also, with only a small number of cases, causality cannot be assumed.

Disclosures

No specific funding was provided for this study.

The authors reported no conflicts of interest.

Primary Source

Rheumatology

Source Reference: Furer V, et al "Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series" Rheumatology 2021; DOI: 10.1093/rheumatology/keab345.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/92106

Moderna CEO: Regulators should handle COVID-19 vaccine safety, review

 Moderna CEO Stephane Bancel said on Friday he believes it’s the regulators' responsibility to collect and compare safety data regarding COVID-19 vaccines after a report revealed that Johnson & Johnson had approached its competitors to collaborate on an investigation. 

Bancel, whose company’s mRNA vaccine saw emergency use approval granted in December, said he doesn’t think a safety review "is something the industry should be doing."  

"We believe it’s the regulators who have to coordinate and gather and collect all of the data and compare the data," Bancel told FOX Business’ Maria Bartiromo. "I don’t think it’s something the industry should be doing." 

In a report published Friday, the Wall Street Journal revealed that Johnson & Johnson had approached its competitors to collaborate on an investigation into blood clot risks, and while AstraZeneca had signaled interest, Moderna and Pfizer-BioNTech declined. 

Federal officials recommended a pause in Johnson & Johnson’s COVID-19 vaccine rollout earlier this week after six instances of a rare, severe blood clot were reported. AstraZeneca, which has yet to see U.S. approval, faced similar stoppages in the European Union. 

Both AstraZeneca and Johnson & Johnson were developed using a viral vector, while Moderna and Pfizer-BioNTech opted for mRNA technology. Neither Moderna nor Pfizer-BioNTech has reported clotting concerns.

"We are of course monitoring safety very carefully and we have been since the vaccine was authorized in December," Bancel told FOX Business. "We are talking of course to the FDA and the CDC on a very regular basis. I think the good news if there is a silver lining to what’s happening today, is the American people should feel great about the CDC and the FDA and how it takes safety of American citizens very seriously and that any signals need to be investigated to make sure that the vaccines can be used safely." 

Bancel said that he’s not involved in the investigations because "it is not our product," but that he does "believe and trust the FDA and CDC and the scientists and the advisors to do the right thing for the American people." 

The chief executive confirmed the company is "on track" to fulfill commitments to the U.S. government, with another 100 million doses by the end of May and another 100 million doses come the end of July.

https://www.foxbusiness.com/economy/moderna-bancel-regulators-should-handle-covid-19-vaccine-safety-review

Rigel eyes emergency green light from FDA on Phase 2 Covid med

 Shares of Rigel Pharmaceuticals (NASDAQ:RIGL) shot higher on Tuesday after the biotech announced positive topline data from a phase 2 clinical trial for fostamatinib as a treatment for hospitalized COVID-19 patients. The stock closed the trading day up by 16.8%, after having been up by as much as 18.8% late in the session. 

Fostamatinib is already approved in the U.S. and elsewhere as a treatment for adult chronic immune thrombocytopenia. Rigel Pharmaceuticals is currently running a phase 2 study for the medicine in COVID-19 patients in collaboration with the National Institutes of Health (NIH) and Inova Health System, a nonprofit healthcare provider headquartered in Virginia. The trial enrolled 59 hospitalized COVID-19 patients, each of whom received either fostamatinib plus standard of care or a placebo plus standard of care twice a day for 14 days.

First, fostamatinib met its primary safety endpoint during the trial. Also, the group of patients who received the medicine had recorded zero deaths at day 29, compared to three deaths in the placebo group.

"Taken altogether, the results of this trial suggest fostamatinib may be a useful addition to improve the outcome of severe and critically ill COVID-19 patients who are at the highest risk of death despite treatment with the best conventional therapies under the current standard of care (including remdesivir and steroids)," said Rigel Pharmaceuticals Chief Medical Officer Wolfgang Dummer.

With these positive results to show off, Rigel Pharmaceuticals plans on discussing a potential emergency use authorization with the Food and Drug Administration for fostamatinib as a treatment for COVID-19. Although the rollout of vaccines continues, the need for effective treatments for the disease won't dissipate anytime soon. If the healthcare company can earn a conditional green light from regulators for its potential coronavirus medicine, that will likely have a meaningful impact on its financial results. 

https://www.fool.com/investing/2021/04/13/why-rigel-pharmaceuticals-stock-jumped-today/

No Causal Link Found So Far Between Covid-19 Vaccine and Blood-Clot Cases: J&J

 Johnson & Johnson said Friday there wasn't enough evidence to establish that the company's Covid-19 vaccine causes the rare blood-clotting condition that prompted U.S. health officials this week to recommend a pause in its use.

The New England Journal of Medicine published online a letter from three J&J employees involved in vaccine development and epidemiology saying, "At this time, evidence is insufficient to establish a causal relationship between these events" and J&J's vaccine.

U.S. health authorities this week recommended a pause in vaccinations using J&J's single-dose vaccine while they investigated six cases of a rare blood clot, combined with low blood-platelet counts, in women who had received the J&J vaccine. One of the women died.

The pause is expected to remain in place at least until a federal vaccine-advisory committee meets April 23 to review the matter.

After U.S. health officials recommended the pause, J&J said it was aware of the events and working with health authorities investigating them. A J&J executive said at a U.S. vaccine-advisory panel meeting this week that causality hadn't been fully established between the clot events and its vaccine, but the company recognized they could be a potential risk with the vaccine.

Health authorities in several countries have restricted use recently of J&J's vaccine, and a shot from AstraZeneca PLC and the University of Oxford that uses a similar technology, after receiving reports of people getting blood clots following their vaccinations.

The authorities said they were acting out of caution, while they probe the rare adverse events further.

It isn't clear whether the two vaccines caused the rare cases of blood clots and low counts of platelets, which play a role in clotting.

Researchers in Germany and Norway said last month they found the AstraZeneca-Oxford vaccine could trigger an autoimmune reaction causing blood clots. European health authorities said they had found possible links between the events and the AstraZeneca-Oxford vaccine, though the shot's benefits exceed its potential risks.

AstraZeneca has said it agreed with the assessment of European and other health authorities that its vaccine's benefits outweighed its risks. The company hasn't said whether it agreed there was evidence of a link between its vaccine and severe blood clotting.

"The safety of all patients is paramount and we are working with regulators to understand the individual cases, epidemiology and possible mechanisms that could explain these extremely rare events," AstraZeneca said through a spokesman.

The J&J researchers wrote to the medical journal in response to a case report the journal published earlier this week, describing the clotting condition in a 48-year-old woman in Nebraska, which developed two weeks after she received the J&J vaccine. She was critically ill at the time of the case report.

The doctors who wrote the case report about the woman in Nebraska suggested that the rare clotting events, coupled with low platelets, could be related to the type of vaccine technology in the J&J vaccine, known as viral vector.

They noted that similar cases had been seen in recipients of the AstraZeneca's vaccine, which is also a viral-vector vaccine.

The J&J researchers said in their letter the six cases were among more than 7.2 million people vaccinated with J&J's shot. The researchers also said there were differences between the designs of J&J's vaccine and the AstraZeneca-Oxford shot, and therefore the vaccines may have different biologic effects.

"We continue to work closely with experts and regulators to assess the data, and we support the open communication of this information to health care professionals and the public," the J&J researchers said.

The letter was written by Jerald Sadoff, senior adviser with J&J's vaccine division; Kourtney Davis, senior director and head of global epidemiology at J&J's pharmaceutical division; and Macaya Douoguih, head of clinical development and medical affairs with J&J's pharmaceutical unit.

https://www.marketscreener.com/quote/stock/JOHNSON-JOHNSON-4832/news/No-Causal-Link-Found-So-Far-Between-J-J-s-Covid-19-Vaccine-and-Blood-Clot-Cases-Company-Researchers-32989529/