Last week, the Food and Drug Administration (FDA) approved two gene therapy treatments for sickle cell disease, Casgevy and Lyfgenia.
Casgevy, jointly developed by Boston, MA-based Vertex Pharmaceuticals and Switzerland-based CRISPR Therapeutics, is the first approved treatment of any kind available to US patients that uses CRISPR’s gene-editing capabilities.
Lyfgenia, made by Somerville, MA-based Bluebird Bio, uses a more common retrovirus technique for genetic modification. The FDA estimates that about 20K Americans with sickle cell disease will be eligible for the therapies, limited to those patients 12 and older who have had episodes of debilitating pain.
Both treatments will only be available at a small number of facilities nationwide, priced between $2-3M, and require a patient to endure months of hospitalization as well as intensive chemotherapy. Around 100K mostly Black Americans suffer from sickle cell disease, which causes intense pain, organ damage, and reduced life expectancy. Previously, the only curative treatment was a bone marrow transplant.
The Gist: The approval of these drugs represents a milestone moment for those suffering from sickle cell disease, while Casgevy also fulfills the revolutionary promise scientists have seen in CRISPR since it first received broad attention in 2005.
However, now that gene-editing therapies have graduated from the domain of scientific possibility into the realities of our healthcare delivery system, the new challenge becomes ensuring accessibility and equity, as many Americans who most stand to benefit from it also experience barriers in access to care and insurance coverage. (We’d expect insurer pushback similar to that seen when the first highly effective, but extremely costly, hepatitis C treatments like Solvaldi hit the market a decade ago this month.)
While the clinical trial patients who received Casgevy reporthaving “a new lease on life”, sky–high costs, questions of insurance coverage, and the arduous, time-intensive nature of the procedure stand in the way of a population-wide cure for sickle cell disease.
On Wednesday, CVS revealed plans to phase out its clinical trials unit by December 2024. The company launched the business line in 2021, building off its successful participation engaging CVS patrons in COVID vaccine and treatment studies.
With 40 percent of Americans living near a CVS pharmacy, the company had hoped to facilitate the decentralization of the clinical trials business, recruiting patients who lived in markets without academic medical centers, with goals to engage 10M patients across 150 research sites. However, to date it has only enrolled 33K participants, just over 10 percent of its COVID vaccine volunteer patient cohort.
The Gist: While CVS appears to be focusing on its faster-growing Medicare Advantage and provider businesses, following its expensive acquisitions of Oak Street Health and Signify Health, the promise for decentralized clinical research remains.
Traditional clinical trials often suffer from low participation; recruiting from more diverse populations would improve enrollment and could enhance the quality of research conducted.
Decentralization is also a win for patients, providing access to clinical trials for lower-income patients who may have difficulty regularly traveling to academic centers. Other players, ranging from startups to retail giants like Walmart and Walgreens, remain active in this space. While we hope they may bring new models to market, they will likely evaluate their programs against similar business decisions and profit objectives.
The company plans to leverage its expansive retail footprint of 9,000 stores, as well as its pharmacy business and other care delivery assets, to connect patients with late-stage pharmaceutical trials either at retail clinics, at home, or virtually. To match patients with trials, Walgreens is partnering with health data company Pluto Health, which aggregates information across medical records, insurance claims, and other sources.
The Gist: The decentralized clinical trial business has been growing since the pandemic spurred a rapid switch to remote trial participation. This announcement comes roughly a year after competitor CVS announced its entry into the clinical trial space.
Most clinical research is centered in academic medical centers, which are disproportionally located in large urban areas, forcing many patients to travel long distances to participate. With large amounts of patient data and footprint spanning all fifty states, retail pharmacies are well-positioned to partner with investigators to reach patients who lack access to clinical trials today, given lack of financial resources or ability to travel.
CVS Health announced it has struck a deal with Medable, a decentralized clinical trial software company, incorporating its offerings into MinuteClinics to help reach more patients for late-stage clinical trials. With over 40 percent of Americans living near a CVS pharmacy, CVS says it can help gather data and manage patients at MinuteClinic locations, and through its home infusion service, Coram. CVS has already cut its teeth in the clinical research space by conducting COVID-19 vaccine and treatment trials and testing home dialysis machines, and said it plans to engage 10M patients and open up to 150 community research sites this year.
The Gist: With this deal, CVS Health joins companies like Verily, Alphabet’s life sciences subsidiary, in taking advantage of patient appetite for clinical trials without regularly traveling to a research center, which became difficult during the pandemic.
Clinical research is a $50B market that has largely revolved around academic medical centers in large urban areas, which could see their dominance of the research business challenged. CVS’s entry into this space could lower the barriers to entry for community health systems to expand into clinical research.
Ultimately, the decentralization of the clinical trials business is a win for patients, especially groups that have historically been under-represented in medical research, including rural and lower-income individuals. They may find participation through a local pharmacy—or even completely virtually from the comfort of their own home—much more accessible, affordable, and convenient.
Even as daily new COVID cases set all-time records and hospitals fill up, epidemiologists have arrived at a perhaps surprising consensus. Yes, the latest Omicron variant of the novel coronavirus is bad. But it could have been a lot worse.
Even as cases have surged, deaths haven’t—at least not to the same degree. Omicron is highly transmissible but generally not as severe as some older variants—“lineages” is the scientific term.
We got lucky. But that luck might not hold. Many of the same epidemiologists who have breathed a sigh of relief over Omicron’s relatively low death rate are anticipating that the next lineage might be much worse.
Fretting over a possible future lineage that combines Omicron’s extreme transmissibility with the severity of, say, the previous Delta lineage, experts are beginning to embrace a new public health strategy that’s getting an early test run in Israel: a four-shot regimen of messenger-RNA vaccine.
“I think this will be the strategy going forward,” Edwin Michael, an epidemiologist at the Center for Global Health Infectious Disease Research at the University of South Florida, told The Daily Beast.
Omicron raised alarms in health agencies all over the world in late November after officials in South Africa reported the first cases. Compared to older lineages, Omicron features around 50 key mutations, some 30 of which are on the spike protein that helps the virus to grab onto our cells.
Some of the mutations are associated with a virus’s ability to dodge antibodies and thus partially evade vaccines. Others are associated with higher transmissibility. The lineage’s genetic makeup pointed to a huge spike in infections in the unvaccinated as well as an increase in milder “breakthrough” infections in the vaccinated.
That’s exactly what happened. Health officials registered more than 10 million new COVID cases the first week of January. That’s nearly double the previous worst week for new infections, back in May. Around 3 million of those infections were in the United States, where Omicron coincided with the Thanksgiving, Christmas, and New Year holidays and associated traveling and family gatherings.
But mercifully, deaths haven’t increased as much as cases have. Worldwide, there were 43,000 COVID deaths the first week of January—fewer than 10,000 of them in the U.S. While deaths tend to lag infections by a couple weeks, Omicron has been dominant long enough that it’s increasingly evident there’s been what statisticians call a “decoupling” of cases and fatalities.
“We can say we dodged a bullet in that Omicron does not appear to cause as serious of a disease,” Stephanie James, the head of a COVID testing lab at Regis University in Colorado, told The Daily Beast. She stressed that data is still being gathered, so we can’t be certain yet that the apparent decoupling is real.
Assuming the decoupling is happening, experts attribute it to two factors. First, Omicron tends to infect the throat without necessarily descending to the lungs, where the potential for lasting or fatal damage is much, much higher. Second, by now, countries have administered nearly 9.3 billion doses of vaccine—enough for a majority of the world’s population to have received at least one dose.
In the United States, 73 percent of people have gotten at least one dose. Sixty-two percent have gotten two doses of the best mRNA vaccines. A third have received a booster dose.
Yes, Omicron has some ability to evade antibodies, meaning the vaccines are somewhat less effective against this lineage than they are against Delta and other older lineages. But even when a vaccine doesn’t prevent an infection, it usually greatly reduces its severity.
For many vaccinated people who’ve caught Omicron, the resulting COVID infection is mild. “A common cold or some sniffles in a fully vaxxed and boosted healthy individual,” is how Eric Bortz, a University of Alaska-Anchorage virologist and public health expert, described it to The Daily Beast.
All that is to say, Omicron could have been a lot worse. Viruses evolve to survive. That can mean greater transmissibility, antibody-evasion or more serious infection. Omicron mutated for the former two. There’s a chance some future Sigma or Upsilon lineage could do all three.
When it comes to viral mutations, “extreme events can occur at a non-negligible rate, or probability, and can lead to large consequences,” Michael said. Imagine a lineage that’s as transmissible as Omicron but also attacks the lungs like Delta tends to do. Now imagine that this hypothetical lineage is even more adept than Omicron at evading the vaccines.
That would be the nightmare lineage. And it’s entirely conceivable it’s in our future. There are enough vaccine holdouts, such as the roughly 50 million Americans who say they’ll never get jabbed, that the SARS-CoV-2 pathogen should have ample opportunities for mutation.
“As long as we have unvaccinated people in this country—and across the globe—there is the potential for new and possibly more concerning viral variants to arise,” Aimee Bernard, a University of Colorado immunologist, told The Daily Beast.
Worse, this ongoing viral evolution is happening against a backdrop of waning immunity. Antibodies, whether vaccine-induced or naturally occurring from past infection, fade over time. It’s not for no reason that health agencies in many countries urge booster doses just three months after initial vaccination. The U.S. Centers for Disease Control and Prevention is an outlier, and recommends people get boosted after five months.
A lineage much worse than Omicron could evolve at the same time that antibodies wane in billions of people all over the world. That’s why many experts believe the COVID vaccines will end up being annual or even semi-annual jabs. You’ll need a fourth jab, a fifth jab, a sixth jab, et cetera, forever.
Israel, a world leader in global health, is already turning that expectation into policy. Citing multiple studies that showed a big boost in antibodies with an additional dose of mRNA and no safety concerns, the country’s health ministry this week began offering a fourth dose to anyone over the age of 60, who tend to be more vulnerable to COVID than younger people.
That should be the standard everywhere, Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, told The Daily Beast. “Scientifically, they’re right,” he said of the Israeli health officials.
If there’s a downside, it’s that there are still a few poorer countries—in Africa, mostly—where many people still struggle to get access to any vaccine, let alone boosters and fourth doses. If and when other richer countries follow Israel’s lead and begin offering additional jabs, there’s some risk of even greater inequity in global vaccine distribution.
“The downside is for the rest of the world,” Mokdad said. “I’m waiting to get my first dose and you guys are getting a fourth?”
The solution isn’t to deprive people of the doses they need to maintain their protection against future—and potentially more dangerous—lineages. The solution, for vaccine-producing countries, is to further boost production and double down on efforts to push vaccines out to the least privileged communities.
A sense of urgency is key. For all its rapid spread, Omicron has actually gone fairly easy on us. Sigma or Upsilon might not.
Scientists at UCL National Amyloidosis Centre at the Royal Free Hospital, London are hoping their gene editing therapy using CRISPR will be a breakthrough for patients suffering from hereditary transthyretin (ATTR) amyloidosis. In a phase 1 clinical trial, the first six patients have shown positive interim results for gene-editing treatment.
The CRISPR breakthrough comes in treating transthyretin amyloidosis, a mutation in the transthyretin (TTR) gene. Those with this mutation produce an abnormal protein, which gradually builds up in the heart and nerves. Symptoms can include numbness in the hands and feet, loss of control of the bowel and bladder, and loss of mobility.
Hereditary transthyretin amyloidosis gets progressively worse and is fatal. Up until this point, most of the treatment options available to patients have included management of the symptoms and prevention of progression.
Those taking part in the trial have received a molecule knows as CRISPR/Cas9 via one-off infusion. The purpose of this is to deactivate the incorrect gene within the liver cell.
“With the gene no longer active in the liver, it is expected that the patient will only produce negligible levels of the harmful transthyretin protein,” UCL stated in a press release.
Scientists saw in the first six patients a reduced production of the harmful transthyretin protein by up to 96 percent, 28 days after the treatment. Additionally, there were no serious adverse effects witnessed. This data was published in the New England Journal of Medicine.
“As the trial progresses, patients will be given higher doses of the gene editing therapy with the hope that will drive the levels of toxic protein even lower,” UCL explained.
CRISPR/Cas9, a Nobel Prize-winning technology, has been used to edit cells outside the body in the past. However, UCL is presenting the first clinical data which CRISPR/Cas9 is being used as medicine itself for a potential therapy.
“This is wonderful news for patients with this condition. If this trial continues to be successful, the treatment may permit patients who are diagnosed early in the course of the disease to lead completely normal lives without the need for ongoing therapy,” Professor Julian Gillmore, the trial lead, of the UCL National Amyloidosis Centre, part of the UCL Centre for Amyloidosis and Acute Phase Proteins said in a press release.
“Until very recently, the majority of treatments we have been able to offer patients with this condition have had limited success. If this trial continues to go well, it will mean we can offer real hope and the prospect of meaningful clinical improvement to patients who suffer from this condition,” Gillmore continued.
The global trial includes patients from the Royal Free London and a hospital located in Auckland, New Zealand. The investigational therapy, designated NTLA-2001, is being developed by Intellia Therapeutics; a biotechnology company based in the United States.
This could be a big step forward in using CRISPR as gene therapy. Typically, the therapy is injected into the site of illness. However, this newest approach injects CRISPR directly into the bloodstream, which could revolutionize how clinicians treat certain illnesses.
There’s a lot of anxiety about the AstraZeneca vaccine thanks to recent reports of incomplete data, as well as reports on blood clot risks. Let’s take a look at both issues in context, understanding the efficacy data before and after numbers were updated, and understanding blood clot risk in relation to other common situations where blood clots are a potential concern.
In this last episode of our six-part series on vaccinations, supported by the National Institute for Health Care Management Foundation, we cover vaccine development – particularly in the context of the current global pandemic. We discuss the timeline of Covid-19 vaccine development and the mRNA vaccine approach.
A new piece in the Atlantic sparked debate this week about the risk of ongoing COVID exposure to children as the country navigates toward the end of the pandemic. Brown University economist Emily Oster equated a child’s risk of serious illness from the coronavirus to that of their vaccinated grandmother. If grandma receives the Pfizer vaccine, her risk of serious illness is decreased by 95 percent. According to Oster, the condition of “being a child” aged 0-17 is 98 percent protective against hospitalization—so go ahead, plan that family summer vacation!
Oster cites no clinical or scientific experts in her piece, but some doctors were quick to respond that the comparisons are not equivalent (and also provide ready-made scripting for the “anti-vaxx” movement, which could claim that kids are already “basically vaccinated”).
But the article does bring up a real question that millions of families will soon face: what can we do when grandma and grandpa (and hopefully mom and dad) are vaccinated, but the kids are not? Given the pace of clinical trials, teens could be eligible for vaccination as soon as late summer, but COVID vaccines might not be approved for younger children until months later—and this generational vaccine divide will likely linger into 2022.
Undoubtedly children are at lower risk from COVID than adults, and likely transmit the disease less frequently (although much of the data supporting the latter comes from studies in schools, where social distancing and masking are enforced). And we’re not out of the woods yet: as COVID cases surge again in Michigan, schools there have seen a spike in outbreaks as well.
As families look at conflicting data and messages in the media, they need clear, coordinated guidance from state and federal officials to help them gauge safety as they navigate their second “pandemic summer”.
The national COVID indicators all continued to move in the right direction this week, with new cases down 16 percent, hospitalizations down 26 percent, and deaths (while still alarmingly high at more than 3,000 per day) down 6 percent from the week prior.
More good news: both nationally and globally, the number of people vaccinated against COVID now exceeds the total number of people infected with the virus, at least according to official statistics—the actual number of coronavirus infections is likely several times higher.
On the vaccine front, Johnson & Johnson filed with the Food and Drug Administration (FDA) for an Emergency Use Authorization for its single-dose COVID vaccine, which could become the third vaccine approved for use in the US following government review later this month. The J&J vaccine is reportedly 85 percent effective at preventing severe COVID disease, although it is less effective at preventing infection than the Pfizer and Moderna shots.
Elsewhere, TheLancet reported interim Phase III results for Russia’s Sputnik V vaccine trials, showing it to be 91 percent effective at preventing infection, and a new study found the Oxford-AstraZeneca vaccine to be 75 percent effective against the more-contagious UK virus variant.
Amid the positive vaccine news, the Biden administration moved to accelerate the vaccination campaign, invoking the Defense Production Act to boost production and initiating shipments directly to retail pharmacies. With the House and Senate starting the budget reconciliation process that could eventually lead to as much as $1.9T in stimulus funding, including billions more for vaccines and testing, it feels as though the tide may be finally turning in the battle against coronavirus.
While the key indicators are still worrisome—we’re only back to Thanksgiving-week levels of new cases—and emerging variants are cause for concern, it’s worth celebrating a week that brought more good news than bad.
Best to follow Dr. Fauci’s advice for this Super Bowl weekend, however: “Just lay low and cool it.”
HENRY KOTULA 