Snakebites kill nearly 140,000 people a year, overwhelmingly in impoverished rural areas of Asia and Africa without adequate medical infrastructure and knowledge to administer anti-venom.

This article was published on Monday, November 9, 2020 in Kaiser Health News.

By Jim Robbins

Dr. Matthew Lewin, founder of the Center for Exploration and Travel Health at the California Academy of Sciences, was researching snakebite treatments in rural locations in preparation for an expedition to the Philippines in 2011.

The story of a renowned herpetologist from the academy, Joseph Slowinski, who was bitten by a highly venomous krait in Myanmar and couldn't get to a hospital in time to save his life a decade earlier, weighed on the emergency room doctor.

"I concluded that I needed something small and compact and that doesn't care what kind of snake," Lewin said.

It didn't exist. That set Lewin in pursuit of a modern snakebite drug, a journey that finds his Corte Madera, California, company, Ophirex, nearing a promising oral treatment that fits in a pocket; is stable, easy to use and affordable; and treats the venom from many species. "That's the holy grail of snakebite treatment," he said.

His work has gotten a boost with multimillion-dollar grants from a British charity and the U.S. Army. If it works — and it has been shown to work extremely well in mice and pigs — it could save tens of thousands of lives a year.

Lewin and Ophirex are not alone in their quest. Snakebites kill nearly 140,000 people a year, overwhelmingly in impoverished rural areas of Asia and Africa without adequate medical infrastructure and knowledge to administer anti-venom. Though just a few people die each year in the U.S. from snakebites, the problem has risen to the top of the list of global health concerns in recent years. Funding has soared, and other research groups have also done promising work on new treatments. Herpetologists say deforestation and climate change are increasing human-snake encounters by forcing snakes to move to new habitats.

Lewin's research is centered on a drug called varespladib. The enzyme inhibitor has proven itself in in-vitro lab studies and has effectively saved mice and pigs dosed with venom.

Along the way, Lewin and his team have come across another potential use for the drug. Varespladib has a positive effect on acute respiratory distress syndrome, associated with COVID-19. Next year, Ophirex will conduct human trials for the possible treatment of the condition funded with $9.9 million from the Army.

The link to a snakebite? The inflammation of the lungs caused by the coronavirus produces the sPLA2 enzyme. A more deadly version of the same enzyme is produced by snake venom.

The other companies that have come up with promising approaches to snakebite aren't as far along as Ophirex. At the University of California-Irvine, chemist Ken Shea and his team created a nanogel — a kind of polymer used in medical applications — that blocks key proteins in the venom that cause cell destruction. At the Technical University of Denmark, Andreas Laustsen is looking at engineering bacteria to manufacture anti-venom in fermentation tanks.

The days of incising a snakebite and sucking out the poison are long over, but the current treatment for venomous snakebites remains archaic.

Since the early 1900s, anti-venom has been made by injecting horses or other animals with venom milked from snakes and diluted. The animals' immune systems generate antibodies over several months, and blood plasma is taken from the animals and antibodies extracted from it.

It's extremely expensive. Hospitals in the U.S. can charge as much as $15,000 a vial — and a single snakebite might require anywhere from four to 50 vials. Moreover, anti-venom exists for little more than half the world's species of venomous snakes.

A major problem is the roughly two hours it takes on average for a snakebite victim to reach a hospital and begin treatment. The chemical weapon that is venom starts immediately to destroy cells as it digests its next meal, making fast treatment essential to saving lives and preventing tissue loss.

"The two-hour window between fang and needle is where the most damage occurs," said Leslie Boyer, director of the University of Arizona's Venom Immunochemistry, Pharmacology and Emergency Response — VIPER — Institute. "We have a saying, 'Time is tissue.'"

That's why the search for a new snakebite drug has focused on an inexpensive treatment that can be taken into the field. Lewin's drug wouldn't replace anti-venom. Instead, he thinks of it as the first line of defense until the victim can reach a hospital for anti-venom treatment.

Lewin said he expects the drug to be inexpensive, so people in regions where snakebites are common can afford it.

Venom is extremely complicated chemically, and Lewin began his search by sussing out which of its myriad components to block. He zeroed in on the sPLA2 enzyme.

Surveying the literature about drugs that had been clinically tested for other conditions, he came across varespladib. It had been developed jointly by Eli Lilly and Shionogi, a Japanese pharmaceutical company, as a possible treatment for sepsis. They had never taken it to market.

If it worked, Lewin could license the right to produce the drug, which had already been thoroughly studied and was shown to be safe.

He placed venom in an array of test tubes. Varespladib and other drugs were added to the venom. He then added a reagent. If the venom was still active, the solution would turn yellow; if it was neutralized, it would remain clear.

The vials with varespladib "came up completely blank," he said. "It was so stunning I said, 'I must have made a mistake.'"

Dr. Matthew Lewin holds up a vial containing varespladib, a drug being tested for snakebite treatment. Varespladib may also help treat a respiratory condition caused by COVID-19. (Daniel Z. Lewin)

With a small grant, he sent the drug to the Yale Center for Molecular Discovery and found that varespladib effectively neutralized the venom of snakes found on six continents. The results were published in the journal Toxins and sent ripples through the small community of snakebite researchers.

Lewin then conducted tests on mice and pigs. Both were successful.

Human clinical trials are next, but they have been delayed by the pandemic. They are scheduled to get underway next spring.

Along the way, Lewin was fortunate enough to make some good connections that led to funding. In 2012, he attended a party at the Mill Valley, California, home of Jerry Harrison, the former guitarist and keyboardist for Talking Heads. Harrison had long been interested in business and startups — he said he was the most careful reader of the '80s band's contracts — and at the party he asked "if anyone had any ideas lying fallow," Harrison said.

"And Matt pipes up and says, 'I have this idea how to prevent people from dying from snakebites,'" Harrison said.

The musician said he was a bit taken aback by such an unusual and dire problem, but "I thought if it can save lives we have to do it," he said. He became an investor and co-founder of Ophirex with Lewin.

Lewin met Lt. Col. Rebecca Carter, a biochemist who was assigned to lead the Medical Modernization Division of Air Force Special Operations Command, in 2016 when she attended a Venom Week conference in Greenville, North Carolina. He was presenting the results of his mouse studies. She told him about her first mission: to find a universal anti-venom for medics on special operations teams in Africa. She persuaded the Special Operations Command Biomedical Research Advisory Group, which specializes in getting critical projects to production, to grant Ophirex $148,000 in 2017. She later retired from the Air Force and now works for Ophirex as vice president.

More multimillion-dollar grants followed, including the Army's COVID grant. Clinical trials are scheduled to begin this winter.

Despite the progress and the sudden cash flow, Lewin tamps down talk of a universal snakebite cure. "There's enough evidence to say the drug deserves to have its day in clinical trials," he said.

Even if Biden moves at breakneck speed to replace outgoing Commissioner Stephen Hahn, it could be weeks after Biden is in the White House before his pick could get to work.

This article was published on Sunday, November 8, 2020 in Kaiser Health News.

By Rachana Pradhan

President-elect Joe Biden made COVID-19 a linchpin of his campaign, criticizing President Donald Trump’s leadership on everything from masks and packed campaign rallies to vaccines.

That was the easy part. Biden now has the urgent job of filling top health care positions in his administration to help restore public trust in science-driven institutions Trump repeatedly undermined, and oversee the rollout of several coronavirus vaccines to a skeptical public who fear they were rushed for political expediency.

At the top of that list is a new commissioner of the Food and Drug Administration, an agency where Biden faces immense pressure to move faster than any other modern president as the pandemic rages and COVID deaths are expected to surge through the winter. That agency and its beleaguered personnel will be relied on to give the green light to vaccines and therapeutics to fight the COVID pandemic.

Biden is expected to swiftly announce his choices to lead the FDA and the Centers for Disease Control and Prevention, given their importance in informing the federal government’s COVID strategy, according to interviews with Biden advisers, former agency officials and Democrats with knowledge of the transition team’s inner workings. But how soon they’ll be able to begin work after Biden’s Jan. 20 inauguration is unclear.

The CDC director does not need Senate confirmation, avoiding a hurdle that could slow that process. That is not the case for the FDA commissioner, who now appears increasingly likely to face a Republican-controlled Senate that may not be as keen as Democrats to swiftly clear Biden’s nominees. As a result, even if Biden moves at breakneck speed to replace outgoing Commissioner Stephen Hahn, it could be weeks after Biden is in the White House before his pick could get to work.

In the meantime, the FDA will face critical decisions about vaccines needed to help put the nation on its path out of the pandemic. Biden will have to rely on a temporary head of the FDA to steer the 17,000-employee agency during one of the most challenging times in its history.

“It’s not ideal timing, for sure,” a former FDA official said. “It’s a huge job.”

The transition of power will occur at one of the most high-profile times for the FDA, as it vets multiple coronavirus vaccine candidates that could reach the public before the inauguration. The Trump administration could oversee emergency authorizations of initial vaccines from two front-runners, Pfizer and Moderna, that would be prioritized for health care workers and other groups at higher risk of severe COVID complications. But other companies’ vaccines that could be available for many more Americans — such as teachers, adults at lower risk of severe health consequences if they get sick, and children — are all but certain to fall under Biden’s FDA for review because the data on safety and efficacy isn’t expected until next year.

FDA’s credibility in vetting the safety and benefits of COVID products has been in question for months, fueled by Hahn’s inaccurate statements about certain treatments for sick patients. Further, infighting between officials there and political appointees at the White House and the Department of Health and Human Services persisted even in the weeks leading up to the election, with HHS Secretary Alex Azar openly plotting Hahn’s removal because of disagreements over vaccine standards, Politico reported in October.

In September, eight senior FDA officials who have served in multiple administrations took the extraordinary step of publishing an op-ed in USA Today stating they would work with agency leadership “to maintain FDA’s steadfast commitment to ensuring our decisions will continue to be guided by the best science.”

“Protecting the FDA’s independence is essential if we are to do the best possible job of protecting public health and saving lives,” the officials wrote.

“Trust has eroded so significantly in these institutions that have undermined public confidence, especially on vaccines,” a Biden adviser said of the FDA and CDC. “Change in leadership is critical.”

Getting new people into the federal government — where Biden is charged with filling roughly 4,000 jobs held by political appointees — is a mammoth slog on its own, let alone while moving to take over the U.S. pandemic response. Former President Barack Obama set the record for presidential appointments in the first 100 days, securing Senate confirmation for 69 appointees. The FDA commissioner wasn’t among them — Dr. Margaret Hamburg was not nominated until March 2009 and became commissioner that May. A similar timeline held for Trump’s first FDA commissioner, Dr. Scott Gottlieb, who began in May 2017.

“It is a difficult period because you’re going to have a lot of folks who need to get into place,” said Max Stier, CEO of the Partnership for Public Service, which advises presidential candidates and their teams installing new administrations. “The track record has not been good on getting people in quickly.”

At the outset of the Biden administration, it’s expected there will be a fair number of “acting” agency heads rather than Senate-confirmed appointees, Stier said. Biden has said he’ll trust the government’s scientists on COVID vaccines. Former FDA officials said in interviews that if there’s an acting official in charge when a specific vaccine is under review, it should not make a difference because the agency’s longtime scientists conduct the necessary scientific evaluations.

Where it could make a difference is in messaging and accountability, not just to the new president but to the public: The traditionally lower profile and temporary nature of an acting FDA commissioner is at odds with the highly visible role the commissioner is expected to play during a public health emergency, particularly in convincing people that vaccines are safe.

“An agency needs a face, and it’s hard for an ‘acting’ to be the face of the agency,” a former senior agency official said. “The work could be done, but the communication is always better if there’s an FDA commissioner who’s willing to take responsibility.”

The messaging role has taken on extraordinary importance since public confidence in a coronavirus vaccine has eroded significantly. A September Pew Research Center poll found that only 51% of U.S. adults would definitely or probably get a vaccine to prevent COVID-19 if it were available, a drop of 21 percentage points since May.

“Things can only be better,” said Michael Carome, director of the health research group at Public Citizen, a left-leaning group that advocates for consumer interests. “I think an acting commissioner under a Biden administration will be far more trusted than the current FDA commissioner, who has been kowtowed by the White House.”

FDA staffing policy outlines who should be the agency’s acting head in the event there isn’t a permanent commissioner. The most recent version, from 2016, says the position is delegated to the deputy commissioner for foods and veterinary medicine, a title that has since been recast as deputy commissioner for food policy and response. The job is currently held by Frank Yiannas, a longtime food safety expert who joined the agency in 2018 after the retirement of Stephen Ostroff, a veteran FDA scientist who served as acting commissioner twice. The FDA did not respond to questions about whether it had a new staffing policy.

Some administrations, however, have ignored that policy. The Trump administration, for example, briefly installed senior HHS official Brett Giroir, a political appointee, as acting FDA commissioner, a move criticized by Democrats in Congress.

But critical decisions await the new appointee.

The earliest officials would know whether COVID vaccines from Johnson & Johnson and AstraZeneca work is January or February, said Moncef Slaoui, the top scientific adviser for Operation Warp Speed, which is funding multiple coronavirus vaccines and treatments. Other efficacy trials won’t be completed until spring, he said in October.

Safety will take even longer to assess — Johnson & Johnson’s and AstraZeneca’s late-stage clinical trials were already paused earlier this year for safety reasons —and companies will seek emergency authorization or FDA approval only once both metrics are known.

After four years of politicization of the science agency, a Biden adviser said, most important was having a “trusted, credible voice to restore trust in a vaccine.”

The largely unpublicized effort follows a Department of Defense announcement in September that it has partnered with AstraZeneca to recruit volunteers.

This article was published on Friday, November 6, 2020 in Kaiser Health News.

By Patricia Kime

The Department of Veterans Affairs is recruiting 8,000 volunteers for the Phase 3 clinical trials of at least four COVID-19 vaccine candidates at 20 federal medical facilities across the U.S., according to officials with the VA and Operation Warp Speed, the Trump administration’s initiative to fast-track a coronavirus vaccine.

The largely unpublicized effort follows a Department of Defense announcement in September that it has partnered with AstraZeneca to recruit volunteers at five of its medical facilities, which are separate from the VA system.

DOD is also is in talks with developers of other vaccine candidates, although officials won’t say which ones.

Both federal departments have long experience in medical research and diverse populations — a crucial component of effective clinical trials, said J. Stephen Morrison, senior vice president and director of global health policy at the Center for Strategic and International Studies, a bipartisan think tank in Washington, D.C.

Since active troops are essential to national security, and veterans are extremely vulnerable to COVID-19, both departments have a vested interest in supporting the development of safe, effective vaccines, Morrison said.

“On the DOD active servicemen and -women side, it’s a question of making sure they’re ready, they are protected,” Morrison said. “With VA, their population, all elderly and infirm with underlying conditions, they could really be suffering if we don’t get a vaccine.”

According to a VA website, of its 20 medical centers involved, 17 would be part of the Johnson & Johnson vaccine trial, while the three others are recruiting — or have completed recruitment — for advanced-stage trials for Moderna, AstraZeneca and Pfizer vaccines.

Dr. Matthew Hepburn, head of vaccine development at Operation Warp Speed, said the VA effort lets veterans contribute to the overall well-being of the country.

“This is another way they can continue to serve in this way, fighting the pandemic as a volunteer,” Hepburn said during a discussion of vaccine and therapeutics development hosted by the Heritage Foundation on Oct. 27.

It’s not unusual for the military to participate in multicenter trials for treatments of ailments as diverse as cancer and trauma. Historically, many vaccines have been tested first by the military.

In the general population, clinicians often have difficulty recruiting African Americans and other minorities for medical research, and “the military provides a rich opportunity to find volunteers for those groups,” said retired Rear Adm. Thomas Cullison, a doctor and former deputy surgeon general for the Navy.

Military health facilities are held to the same standards as private research facilities, he said.

No service members will be required to participate in the COVID vaccine trials. All volunteers will be paid by the developer.

Support for routine vaccinations runs high in the military, but some have expressed concerns about new vaccines and mandatory inoculations, especially for anthrax. In a 2002 federal study, 85% of those who received that vaccine reported an adverse reaction, with just under half noticing minor redness at the injection site. But nearly a quarter of the side effects reported were more systemic, including fevers, chills, fatigue and joint pain.

That survey of a small group of National Guard and Reserve members found that, while 73% said they believe immunizations are effective, two-thirds said they did not support the mandatory anthrax program and 6 in 10 said they were not satisfied with the information they were given on the vaccines.

To quell concerns over the military’s role in supporting COVID vaccine development, the Pentagon has reiterated that troops or their dependents interested in participating in the research must provide voluntary written consent, and they will be allowed to take part only if they will be in the same location for the length of the research, expected to last at least two years.

In addition, active-duty members such as new recruits and boot camp participants will not be allowed to volunteer because they are “considered vulnerable from an ethical and regulatory standpoint,” an official said.

At the VA, officials are seeking to recruit healthy veterans from 18 to 65 years old who are not pregnant and may be at risk for exposure. As with trials conducted in civilian facilities, participants will be paid by the developer, VA spokesperson Christina Noel said.

Also, VA nurses and caseworkers also are being asked to identify their sickest, highest-risk patients to determine who should be at the top of the list once a vaccine is approved, according to a VA nurse and other health officials who asked not to be identified because they were not authorized to speak with the press.

The U.S. military has a long history of contributing to research on vaccines, including a key role in developing inoculations against yellow fever and adenovirus, and the Walter Reed Army Institute of Research is developing its own vaccine against the coronavirus.

Some segments of the population remain skeptical of federal medical experiments. A survey by AP-NORC in May found that Black people are particularly reluctant to get the coronavirus vaccine. Many have concerns about federal research in part because of associations with the infamous Tuskegee Institute syphilis experiments, in which U.S. Public Health Service officials intentionally withheld a cure from Black men infected with the disease.

But Morrison, of the Center for Strategic and International Studies, said the Defense Department and VA are a “natural fit” for the COVID vaccine trials.

“DOD has lots of expertise. They know how to vaccinate; they know how to reach communities. They have a whole science infrastructure and research-and-development infrastructure. And when you are thinking what the mission of VA is, [VA] sees this is part of their mission,” Morrison said.

The Defense Department announced its agreement with AstraZeneca in September, shortly before the drugmaker’s vaccine trial was put on hold to study a serious medical condition that one participant reported. That research was approved by the Food and Drug Administration to begin again Oct. 23. The military plans to restart its efforts to recruit 3,000 volunteers.

The Pentagon has also signed an agreement with another vaccine developer, the head of the Defense Health Agency, Army Lt. Gen. Ronald Place, told reporters Oct. 8. He wouldn’t provide the company’s name.

Democratic Sens. Elizabeth Warren of Massachusetts and Mazie Hirono of Hawaii have called, unsuccessfully, for the Senate Armed Services Committee to investigate what they say is a lack of Pentagon transparency on its role in vaccine development and distribution.

The Defense Department has awarded more than $6 billion in Operation Warp Speed contracts through an intermediary, Advanced Technology International, and the two senators want more information about those contracts.

“There may well be a valuable role for DoD officials in [Operation Warp Speed] — particularly given the department’s logistical capacity,” they wrote to the committee chair and ranking member. “But it is important that Congress conduct appropriate oversight of, and understand, DoD’s activities in this area.”

Neither department has disclosed the financial arrangements they have made with developers to support the vaccine research.

Justice Amy Coney Barrett is considered likely to vote not only to uphold restrictions on abortion, but also, possibly, even to overturn the existing national right to abortion under the Supreme Court’s landmark rulings.

This article was published on Thursday, November 5, 2020 in Kaiser Health News.

By Julie Rovner

Abortion opponents were among those most excited by the addition of Justice Amy Coney Barrett to the Supreme Court. And they had good reason to be.

As a law professor and circuit court judge, Barrett made it clear she is no fan of abortion rights. She is considered likely to vote not only to uphold restrictions on the procedure, but also, possibly, even to overturn the existing national right to abortion under the Supreme Court’s landmark rulings in Roe v. Wade and Planned Parenthood of Southeastern Pennsylvania v. Casey.

Her first opportunity to weigh in could come soon. A Mississippi ban on abortions after 15 weeks — impermissible under existing court precedents — is awaiting review by the justices, who could decide as early as this week to take up the case.

That’s the headline. But many overlook other things that could flow from a new abortion jurisprudence — such as erasing the right to birth control that the court recognized in a 1965 case, Griswold v. Connecticut. During her confirmation hearings, Barrett specifically refused to say whether she felt Griswold was correctly decided.

That was a flashing red warning light for Nancy Northup, president of the Center for Reproductive Rights, a legal advocacy group that argues cases on abortion and contraception. Roe, said Northup, is part of a century of jurisprudence based on the idea that the Constitution protects the liberty of individuals. “It began with cases about how one educates one’s children, and includes same-sex marriage, contraception and abortion,” she said. “You can’t just take Roe out and not unravel the whole fabric.”

Yet from what Barrett has said and written about the Constitution, continued Northup, “it’s clear she doesn’t believe it protects the right to personal liberty.”

Abortion rights advocates worry that the court could go beyond overturning Roe and Casey. If those precedents are overturned, abortion decisions would return to the states. But the court could go a step further and recognize “fetal personhood,” the idea that a fetus is a person with full constitutional rights from the moment of fertilization. That would create a constitutional bar to abortion, among other things, meaning even the most liberal states could not allow the procedure.

Personhood amendments were on the ballot in several states about a decade ago. They were rejected by voters even in conservative states like Mississippi after opponents argued that recognizing life at fertilization would outlaw not just abortion, without exceptions, but also things like in vitro fertilization and many forms of contraception, including some birth control pills, “morning after” pills, and intrauterine devices (IUDs) that some think could cause very early abortions by preventing a fertilized egg from implanting in the uterus. (More recent scientific evidence suggests nearly all those methods actually prevent ovulation, not  implantation.)

But an abortion law passed in Georgia in 2019 not only includes a ban on abortion at the point a heartbeat can be detected — often before a woman is aware she is pregnant — but also has a fetal personhood provision. Georgia is appealing a federal district court ruling that struck down the law as a violation of Roe.

Proponents of these personhood provisions are cautiously optimistic. “It looks like there will be a court more friendly to a challenge to Roe,” said Les Riley, interim president of the Personhood Alliance, the group pushing the concept. “But to some extent we’ve been down this road before.”

Previous courts since the early 1990s that were thought poised to overturn Roe did not.

And even if the court were to uphold a law like the Mississippi ban it is considering now, he said, “all that’s saying is they agree that states can regulate or ban abortion at 15 weeks. What we want to do is have the factual reality that life begins at conception recognized in law.”

Mary Ziegler, a law professor at Florida State University who has written two books on the abortion battle, said the court wouldn’t have to recognize fetal personhood to threaten many forms of contraception.

States could effectively ban contraception by arguing that some contraceptives act as abortifacients, she said. The court has already opened the door to this argument. In the 2014 Hobby Lobby case, it allowed some companies to decline to offer birth control coverage otherwise required by the Affordable Care Act to their employees. The owners of the companies that brought the suit said they believe some contraceptives are a form of abortion, and the court said the requirement violated their religious freedom. The court used a similar reasoning in a 2020 case exempting the Roman Catholic order Little Sisters of the Poor from even having to sign a paper that would officially exempt them from the ACA contraceptive mandate.

Medical groups and the federal government don’t consider any form of contraception approved by the Food and Drug Administration an abortion equivalent, because the standard medical definition of the start of pregnancy is when a fertilized egg implants in the uterus, not when sperm and egg first unite. Yet the court has not always followed science on the issue.

Still, Ziegler said, “personhood has always been the endgame” for abortion foes, not simply overturning Roe, which would let each state decide whether to outlaw abortion. “Allowing states to leave abortion legal has never been the endgame,” she said.

Interestingly, however, Riley of the Personhood Alliance said that while he hopes his side will win eventually, he is not necessarily hoping that win will come from the Supreme Court.

“We think the strategy has been misguided for years,” he said. “Right now, five justices can overturn anything. That’s not the system of government our founders had in mind.”

Rather, he said, his organization is working more at the state and local level “to lay the groundwork of people’s hearts being changed.”