America Loosens Grip on Glycemic Control

 Glycemic control among Americans still isn't quite as good as it used to be, a new study indicated.

In a cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) data, the number of adults with diabetes achieving glycemic control -- a glycated hemoglobin (HbA1c) under 7% -- dropped in recent years, reported Elizabeth Selvin, PhD, MPH, of Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues.

About 57% of adults were able to achieve glycemic control from 2007-2010, reaching peak levels, but this proportion dropped down to 50.5% by 2015-2018, the group wrote in the New England Journal of Medicine.

In 1999-2002, only 44% of adults had an HbA1c under 7%. This later rose to 56.7% in 2003-2006. After the peak in 2007-2010, the proportion of patients achieving an HbA1c under 7% slowly declined, dropping off to 51.8% in 2011-2014, and then further down in 2015-2018.

"These are concerning findings. There has been a real decline in glycemic control from a decade ago, and overall, only a small proportion of people with diabetes are simultaneously meeting the key goals of glycemic control, blood pressure control, and control of high cholesterol," Selvin explained in a statement.

"These trends are a wake-up call, since they mean that millions of Americans with diabetes are at higher risk for major complications," added co-author Michael Fang, PhD, also of Johns Hopkins Bloomberg School of Public Health. "Our study suggests that worsening control of diabetes may already be having a detrimental effect at the national level."

In addition, adults with diabetes saw an improvement in blood pressure in early years, which has since begun to decline again.

The earliest study time frame, from 1999-2002, saw the fewest number of adults achieving a blood pressure measurement under 130/80 mm HG -- only 38.8%. Things started to improve, as 45% of adults with diabetes achieved blood pressure control by 2003-2006, similarly peaking in 2007-2010 as 51.2% achieved control. As seen with the glycemic control trends, this number started to taper off by 2011-2014, with only 48.1% achieving blood pressure control, further dropping to 47.7% from the years 2015-2018.

On the other hand, lipid control has only improved since 1999 for adults with diabetes, as the prevalence of those achieving a non-HDL cholesterol under 130 mg/dL more than doubled over the past 20 years:

• 1999-2002: 25.3%
• 2003-2006: 42.9%
• 2007-2010: 52.3%
• 2011-2014: 53.4%
• 2015-2018: 55.7%

When combining all these factors together -- glycemic, blood pressure, and lipid control -- few were able to achieve this trifecta during any time point in recent history.

Specifically, just 9% of adults with diabetes had all these risk factors under control from 1999-2002. This nearly doubled to 17.5% achieving full risk factor control by the next survey time frame, again peaking in 2007-2010 with a quarter of people with diabetes achieving full control. Again, this tapered off in recent years, with 22.2% of adults having full control during the last survey time frame.

There are some obvious explanations for these diabetes-related trends, as there was a stark increase by 8.6% in the use of any glucose-lowering agent from 1999-2002 through 2007-2010, tapering off thereafter. In particular, more adults with diabetes added metformin, insulin, and newer classes of agents like SGLT-2 inhibitors to their regimen, offset by a decrease in the use of older agents like sulfonylureas and thiazolidinediones.

In a similar vein, there was also a sharp uptick by nearly 16% in the use of any type of blood pressure-lowering medication, peaking in 2007-2010 and plateauing thereafter. Specifically, more adults were being prescribed beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, while the uses of diuretics and calcium channel blockers were stable. Most notably, statin use saw a huge uptick in use, increasing by nearly 28% from 1999-2002 through 2011-2014 before plateauing.

Looking even closer at medication use, there were some significant demographic differences, as younger adults with diabetes, Mexican Americans, and those without health insurance were less likely to receive any sort of diabetes, blood pressure, or lipid control treatment. This included monotherapy and combination therapies. Additionally, Black patients were also less likely than white patients to be put on combination therapies for glycemic control, but were more likely to be prescribed blood pressure-lowering agents when they had a number over 130/80 mm Hg.

Underlying these trend changes in medication use may be the findings of some large clinical trials, Selvin's group suggested. They pointed out that three clinical trials in particular -- ADVANCE, ACCORD, and a study in veterans -- found that intensive glycemic control (HbA1c <6% or <6.5%) had no significant cardiovascular benefit in patients with type 2 diabetes. In fact, some patients in the trials experienced hypoglycemia as a result of trying to achieve very tight glycemic control.

"As a result of these trials, what we may be seeing is that doctors of people with diabetes may have backed off a bit on glycemic control, with potentially damaging results," Selvin added.

In order to address the rising rates of those missing glycemic targets -- possibly leading to a mushroom in subsequent problems such as amputation, nephropathies, and vascular complications -- the group suggested greater adoption of new second-line glucose agents, like SGLT-2 inhibitors and GLP-1 receptor agonists.

While the root of the low-prescribing problem of these medication classes likely stems from their high costs, the group provided some hope for the future: "Many of these drugs will become generic during the next several years, which could translate into expanded access and population-level changes in glycemic control."

Disclosures

The study was supported by grants from the National Heart, Lung, and Blood Institute, National Institutes of Health.

Selvin reported fees from Novo Nordisk, and a co-author reported owning stock options in Healthy.io. No other disclosures were reported.

Primary Source

New England Journal of Medicine

Source Reference: Fang M, et al "Trends in diabetes treatment and control in U.S. adults, 1999-2018" N Engl J Med 2021; DOI: 10.1056/NEJMsa2032271.

https://www.medpagetoday.com/primarycare/diabetes/93013

Myocarditis and COVID Vaccines: Where Do We Stand?

 Neither U.S. nor European health regulators have yet confirmed a causal link between COVID-19 mRNA vaccines and myocarditis, but they continue to investigate reports of a potential relationship.

In early June, the CDC issued a note to healthcare providers raising awareness of myocarditis and pericarditis after vaccination, particularly in younger males. That guidance stated that, since April, there's been an increase in reports of myocarditis and pericarditis after getting the Pfizer or Moderna vaccines, but that there hasn't been a similar reporting pattern following the Johnson & Johnson vaccine.

The CDC's "clinical considerations" update followed a May 24 report from Advisory Committee on Immunization Practices (ACIP)'s COVID-19 Vaccine Safety Technical (VaST) Work Group, which found "a higher number of observed than expected myocarditis/pericarditis cases in 16- to 24-year-olds" in Vaccine Adverse Event Reporting System (VAERS) data within 30 days of dose 2, though it didn't see the same pattern in data from Vaccine Safety Datalink. Nonetheless, "analyses suggest that these data need to be carefully followed as more persons in younger age groups are vaccinated," the work group wrote.

ACIP has scheduled a meeting for June 18 to present updated data on myocarditis and assess vaccine risks and benefits in adolescents and young adults.

Israeli health regulators said last week that the small number of myocarditis cases seen mainly among men ages 16 to 30 were likely linked to Pfizer's vaccine.

The country saw 275 cases of myocarditis from December 2020 to May 2021 among more than 5 million vaccinated people, according to Reuters. Most of these patients spent no more than 4 days in the hospital, and 95% of cases were classified as mild. The association appeared strongest among men ages 16 to 19 and was more common after the second dose, regulators said.

Pfizer said in a statement to Reuters that no causal link between myocarditis and its vaccine has yet been established.

Israel still went ahead with authorizing the vaccine for 12- to 15-year-olds as soon as the myocarditis reports were made public.

In early May, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) said it was investigating reports of myocarditis and pericarditis among people who received Pfizer's vaccine. It requested data from both Pfizer and Moderna, but has not yet provided an update on its review.

CDC's healthcare professional guidance notes that cases have occurred mainly in males ages 16 and up, and onset came within the first several days following vaccination, more often after the second dose.

Symptoms of myocarditis and pericarditis include chest pain, shortness of breath, or palpitations. In most cases, patients responded well to medications and rest, and their symptoms improved quickly, CDC said.

The agency has recommended an initial evaluation "considering an ECG, troponin level, and inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate."

It also said that for suspected cases, physicians should consider consulting with cardiology for help with evaluation and management.

CDC has asked physicians to report all potential vaccine-related cases of myocarditis or pericarditis to VAERS. It continues to recommend vaccination for everyone age 12 and older, given the risk of severe illness and complications from infection with SARS-CoV-2.

The American Academy of Pediatrics has also published in its journal Pediatrics a "prepublication review" series of seven male patients ages 14 to 19 who developed symptomatic myocarditis 2 to 4 days after the second dose of the Pfizer vaccine. All had rapid resolution of their symptoms.

In an accompanying commentary, Sean O'Leary, MD, MPH, of the University of Colorado in Aurora, and Yvonne Maldonado, MD, of Stanford University, wrote that while the authors "are quick to point out that a causal relationship between vaccination and myocarditis has not been established, the temporal association of these cases with vaccination as well as the striking similarity in the clinical and laboratory presentations raise the possibility for such a relationship."

O'Leary and Maldonado acknowledged that the case series is limited by the potential for reporting bias and the fact that cases "mirror the seasonal prevalence, sex, and age profile of background cases of myocarditis, thereby complicating an assessment of a potential association with SARS-CoV-2 vaccines."

Still, they called for further investigation of a possible causal link, as several factors suggest one, including the consistent timing in development of symptoms, which indicates a uniform biological process; similarities in clinical findings and laboratory characteristics that point to a common etiology; and the fact that these cases occurred when other common respiratory viruses known to be tied to myocarditis weren't circulating widely.

They also emphasized that the benefits of vaccination outweigh risks at this point: "With over 4 million COVID-19 cases diagnosed in children under 18 in the U.S. that resulted in over 15,000 hospitalizations and between 300 and 600 deaths, the benefits of vaccination in this population far exceed the risks of rare adverse events."

https://www.medpagetoday.com/special-reports/exclusives/93040

Think Twice Before Giving the COVID Vax to Healthy Kids

 The case to vaccinate kids is there, but it's not compelling right now. The Delta variant (B.1.617.2) could change the calculus depending on forthcoming data from the U.K., Singapore, and India where the variant may be demonstrating more contagious and virulent properties in younger people. By now we should all know that it is important to have humility in dealing with this virus. An increase in cases in the U.K. over the last few days is concerning and should be something we follow closely.

Returning to the discussion of the COVID-19 risk to kids (ages 0 to 12 years) right now, it's worth aggregating the best available data to date. In reviewing the medical literature and news reports, and in talking to pediatricians across the country, I am not aware of a single healthy child in the U.S. who has died of COVID-19 to date. To investigate further, my research team at Johns Hopkins partnered with FAIR health to study pediatric COVID-19 deaths using approximately half of the nation's health insurance data. We found that 100% of pediatric COVID-19 deaths were in children with a pre-existing condition, solidifying the case to vaccinate any child with a comorbidity.

Given that the risk of a healthy child dying is between zero and infinitesimally rare, it's understandable that many parents are appropriately asking, why vaccinate healthy kids at all?

To those parents, I would say the primary reason to give a healthy child the vaccine may not be to save their life, it's to prevent the multisystem inflammatory syndrome (MIS-C), which can be painful and have long-term health sequelae. According to the CDC, there have been 4,018 cases of MIS-C after COVID-19 with the average age being 9 years old. A total of 36 children died. Cases of MIS-C were heavily skewed toward minority children (62% were Hispanic/Latino or Black), likely due to the disproportionate rates of childhood obesity and chronic conditions in these populations. This finding again supports COVID-19 vaccination in any child with a medical condition, including being overweight.

It's also important to note that the COVID-19 exposure risk in children is not linear over time. Since new COVID-19 case rates began quickly declining in May, the weekly rate of new cases of MIS-C associated with COVID-19 has decreased to zero. And this week, a CDC report on child hospitalizations for COVID-19 in March and April, 2021 found zero deaths in the entire cohort of children studied.

There is an argument for vaccinating children to create a community benefit for kids. Vaccinating healthy kids can help reduce virus transmission to at-risk kids who choose not to get vaccinated or others who cannot get the vaccine. On the other hand, data from Israel suggest that when adult vaccination rates are high, transmission among kids is markedly reduced -- a trend now noted in the U.S. We also know that children are inefficient transmitters of COVID-19 compared to adults. That could potentially change with new information on the recent Delta variant, but so far it hasn't.

The extremely low chance of any benefit for healthy children is exactly why pediatricians like Richard Malley, MD, of Harvard, and Adam Finn, MD, PhD, of the University of Bristol, have passionately written to not "use precious coronavirus vaccines on healthy children." A recent editorial in The BMJ echoed this sentiment -- an argument also eloquently articulated by MedPage's own Vinay Prasad, MD, MPH. From a global perspective, two doses of a globally scarce, life-saving vaccine could be more equitably used to immunize a 65-year-old couple in India or Brazil (one dose for each person) rather than giving both doses to one 5-year-old healthy child. Accordingly, California's announcement to spend $116 million to pay people to get the vaccine when much of the world is begging for it in the midst of raging epidemics is a sad commentary on our country's excess, inequity, and ethnocentrism.

There may also be unique side effects in children from the second COVID-19 vaccine dose. Seven adolescent children were reported to have myocarditis within 4 days after receiving the second Pfizer vaccine dose. All were in boys ages 16 to 19. Both mRNA vaccines have been found to be 100% effective in preventing COVID-19 in kids. But anytime a medication is found to be 100% effective, it should call to question whether the dose is too high, the interval is too short, or if there is a need for the second dose at all. Pfizer is now looking at lower vaccine doses for children, as they mentioned Tuesday in their announcement that they are starting their vaccine trial in kids under age 12.

Importantly, and affirmed 2 weeks ago from a Washington University study, immunity is not just conferred by antibodies, it's also a function of memory B and T cells, which the study researchers suggested may confer long-lasting immunity. Given the near-zero risk of COVID-19 death in healthy children and the recent discovery of rare myocarditis complications immediately after the second dose, this should raise a discussion of whether a single dose is the more appropriate approach for healthy kids.

In my residency training, I was taught an old dictum many of you might be familiar with: "If you give someone blood, always give at least two units." It took decades for the medical community to undo that dogma. We now understand that there are rare but real harms to a second unit of blood. We have matured to recognize that if a second unit is not necessary, one unit is actually safer than two. We should similarly abandon the notion that the vaccine must always be given as two doses. In transplant patients for example, it may be three. In kids with natural immunity from prior infection, it may be none.

What about children who are confirmed to have had COVID-19 infection in the past? I would recommend avoiding COVID-19 vaccination. Looking at natural immunity in adults as a point of comparison, the observational and empirical data are overwhelming: natural immunity is real and it works.

Researchers from the Cleveland Clinic published a study this week that found "Not one of the 1,359 previously infected subjects who remained unvaccinated had a SARS-CoV-2 infection over the duration of the study." This is one of many studies showing that natural immunity is powerful. While the long-term durability of natural immunity is unknown, it's also unknown for vaccinated immunity. We can postulate with strong rationale, but to be true to the science, we have zero data beyond 18 months for either. In fact, there is more follow-up data on natural immunity than there is on vaccinated immunity. Based on accumulating data, children who have had COVID-19 should not get vaccinated, unless they are immunocompromised.

One final and minor consideration should be needle anxiety, which has no or minimal effect on most children but can be traumatic for some. For kids who should receive the vaccine and also have needle anxiety, cold therapy and vibrating devices, such as with the "Buzzy" device, can be applied to the skin injection site prior to injection and result in little to no pain.

In my opinion, the COVID-19 vaccine makes sense for any child who is overweight or has a pre-existing condition. It also may make sense for a teenager given their closer physiologic similarity to adults and the fact that historically, vaccines safe in adults have been safe in kids when dosed appropriately. But given the case-report level rarity of a healthy child dying of COVID-19, I would not recommend a two-dose vaccine regimen for a healthy child ages 0 to 12 years until we have more data. Each parent will have to assess their own child's individual risk, but in my opinion, the case to vaccinate young healthy kids is not compelling right now.

Marty Makary, MD, MPH, is Editor-in-Chief of MedPage Today and a professor at the Johns Hopkins School of Medicine, Bloomberg School of Public Health, and Carey Business School. He is author of The Price We Pay.

https://www.medpagetoday.com/opinion/marty-makary/93029

3rd FDA Advisor Quits After Controversial Alzheimer's Drug Approval

 While the mainstream media focused on the hope-filled headlines that, for the first time since 2003, the FDA approved Biogen's Aduhelm treatment for Alzheimer's Disease; few, if any, were fully aware of the levels of controversy behind the scenes.

Aside from the scientific uncertainty over whether amyloid plaque treatments are an approach worth continuing...

Despite the dominance of the amyloid hypothesis over the past few decades, evidence that links reductions in plaque levels to improvements in cognition is “thin, at best”, says Jason Karlawish, a geriatrician and co-director of the Penn Memory Center in Philadelphia, Pennsylvania.

“Desperation should drive the funding of science, not drive the way we interpret the science,” he says.

It turns out that despite the fact that not one member of the FDA Advisory Committee voted to approve Aduhelm, the FDA recently approved this Alzheimer therapy anyway, relying on an alternative measure of activity.

As Statnews reports, since the FDA's decision, three members of that FDA Advisory Panel have quit.

1. Neurologist J.Perlmutter, a member of the FDA’s expert panel said he quit the committee “due to this ruling by FDA without further discuss with our advisory committee.”

2. Neurologist David Knopman of the Mayo Clinic.

3. Dr. Aaron Kesselheim, director of Brigham and Women’s Hospital’s Program on Regulation, Therapeutics, and Law, said Aduhelm’s approval didn’t just set “a dangerous precedent” for what kind of evidence an Alzheimer’s therapy would need to show to get the green light, “but even more broadly for the idea that a company can turn around and at the last minute seek [accelerated approval] when their primary clinical endpoints in their trials don’t reach the level needed for FDA approval,” he told STAT in an email.

In his letter of resignation to the FDA, Kesselheim said Biogen’s Aduhelm “was probably the worst drug approval decision in recent U.S. history.”

Both Perlmutter and Kesselheim voted against the drug, while Knopman was recused from the November hearing as he had already staked out a public position critical of the drug’s trial results.

Earlier this year, Kesselheim, and two other panelists published a paper in JAMA outlining what they saw as the flaws of the therapy.

As Nature.com reports, others worry that drug developers might abandon other targets. If demonstrating that amyloid-lowering activity is enough to win regulatory approval, it might discourage developers from focusing on treatments with the big cognitive benefits that patients need, say some scientists.

“This is going to set the research community back 10–20 years,” says George Perry, a neurobiologist at the University of Texas at San Antonio and a sceptic of the amyloid hypothesis.

But hey, if there's $56,000 per year per customer patient to be made, the "science" can always be adjusted.

So much for science... again!

https://www.zerohedge.com/medical/dangerous-precedent-3rd-fda-advisor-quits-after-controversial-alzheimers-drug-approval

Public Health Officials Stumped As Southern States' Vaccination Rate Continues To Drag

 Less than a week ago, we reported that the US COVID-19 vaccination scheme had fallen dramatically in recent weeks, likely a factor of a drop in new cases combined with an easing of facemask requirements.

And as President Biden scrambles to hit his July 4 target to vaccinate more than 70% of adults, a goal that's looking increasingly remote every day, the NYT reported Thursday morning that there's one region of the country that's seeing vaccination demand fall more sharply than the others: And that's the deep south. It shouldn't come as a surprise. But what's even more surprising according to the NYT's latest reporting, is that public health departments across the region have tried everything they can think of - public health meetings, church clinics, going door-to-door. In the spirit of offering raffle prizes to those who get vaccinated, one state even offered winners of one a spin around a NASCAR track.

But doctors who spoke to the NYT from states like Alabama, Louisiana and Mississippi (all states where fewer than half of adults have gotten even their first jab), warned that the sense of victory that's settled in across the region is premature.

“A lot of people have the sense, ‘Oh, dodged that bullet,’” said Dr. Jeanne Marrazzo, the director of the Division of Infectious Diseases at the University of Alabama at Birmingham. She added, "I don’t think people appreciate that if we let up on the vaccine efforts, we could be right back where we started."

As of last night, the South is home to 8 of the 10 states with the lowest vaccination rates. Several theories have emerged to try and explain this: hesitancy from conservative white people, concerns among some Black residents, longstanding challenges when it comes to health care access and transportation.

"It’s kind of a complex brew, and we’re teasing apart the individual pieces," said Dr. W. Mark Horne, president of the Mississippi State Medical Association. He added: "There’s no magic bullet. There's no perfect solution. There’s no pixie dust we can sprinkle on it."

Currently in the US, everyone over the age of 12 is eligible to be vaccinated. Daily, vaccinations are down to about 1.1MM doses from a peak of more than 3.3MM doses a day in mid-April. Unless the US see a sharp uptick in jabs, Biden is on track to miss his July 4 goal of getting 70% of Americans vaccinated by July 4.

In some parts of the south, it's unclear if that threshold will ever be attainable.

“I certainly don’t expect us to get to 70 percent by Fourth of July. I don’t know that we’ll get to 70 percent in Alabama,” said Dr. Karen Landers, Alabama’s assistant state health officer. “We just have a certain group of people, of all walks of life, that just aren’t going to get vaccinated.”

Unfortunately for countries that are desperate for more jabs, vaccines have a short shelf-life, with a three-month shelf life at refrigeration temperatures, millions of doses of the Johnson & Johnson vaccine are set to expire nationwide this month, prompting some governors to urgently plead that health providers use them soon.

In Alabama, Nick Saban, the championship-winning football coach, urged fans to get vaccinated so they could attend games safely this fa

Across much of the South, vaccine skepticism is pervasive. In Jackson, Miss., Felix Bell Sr., a warehouse supervisor, expressed concern about how quickly the vaccines were developed. He did not plan to get a shot. “At first they said it’s going to take several years,” said Mr. Bell, who said he had previously recovered from Covid-19. “And then all of a sudden, it was ‘Boom.’” He added, “They’ve got to get more information about what happens down the line.”

The big worry right now is that mutant COVID-19 strain's like the fearsome "Delta" mutant first discovered in India could spark another vaccine-resistant strain to take hold and essentially restart thee outbreak.

“If we don’t get our numbers up, we could be where we were last year, sheltering in place,” said William Parker, the president of the Birmingham City Council, who has proposed spending millions of dollars on vaccine incentives and who answered questions about vaccines on Monday as part of an online forum for residents.

Doctors have warned that the low vaccination numbers could make the South vulnerable to another wave of infections. Some polls have suggested that reluctance to accept the vaccine is linked to political affiliation, as Republican voters are more personally resistant to the jab than Democrats. But the big "unknown" right now is whether all this worrying might be for naught. Because as disagreements among doctors have shown, some believe that  antibodies produced by those who have already been infected (which have been found to last longer than earlier studies had suggested) might mean the US has already passed its "herd immunity" threshold.

But there's no way to know for certain until the fall arrives.

https://www.zerohedge.com/covid-19/public-health-officials-stumped-southern-states-vaccination-rate-continues-drag

Orphazyme stock’s rocket ride leads to 20 volatility halts, Galecto stock halted 7 time

 Shares of Orphazyme A/S

ORPH,
+301.53%
blasted 383.8% higher, enough to make the Denmark-based biopharmaceutical company’s stock by far the biggest gainer listed on major U.S. exchanges, prior to a trading halt. The stock, which was up as much as 1,387% at its intraday high of $77.77, was halted for volatility for the 20th time Thursday at 3:24 p.m. Eastern with the last trade at $25.30, and remains halted. The stock’s rally gave the company a market capitalization of $884.3 million. The company confirmed that there was no news released Thursday. The last announcement was May 7, when the company said a pivotal trial of its treatment for Lou Gehrig’s disease failed to meet primary and secondary endpoints, sending the stock plunging 32.8% that day. After Orphazyme, the next biggest gainer Thursday was Boston-based biotech Galecto Inc.’s stock
GLTO,
+60.00%,

https://sportsgrindentertainment.com/orphazyme-stocks-rocket-ride-leads-to-20-volatility-halts-galecto-stock-halted-7-times/

Vertex stops work on second rare disease drug after study results disappoint

 Vertex, one of the world's largest biotechnology companies, has been trying to prove it can succeed outside of cystic fibrosis, a disease that's become treatable thanks to four approved drugs it has developed.

So far, though, the Boston-based company has run into setbacks, with the latest coming Thursday in the form of fresh data from a highly anticipated clinical trial. Technically, the trial was positive, as it found Vertex's experimental drug, VX-864, was able to significantly boost a protein vital to liver and lung health in patients with a rare, genetic disease that leaves them without much of it. Vertex said the results validate the company's underlying theory on how to treat the disease, known as alpha-1 antitrypsin deficiency.

However, the company also said the data, while positive, suggest its drug isn't potent enough to substantially benefit patients. Vertex has therefore decided not to move it forward, and instead focus on getting more potential treatments for AAT deficiency into clinical testing next year.

"We believe we know why the magnitude of response wasn't where we thought it would be, so now we need to find the more potent and efficacious molecule that drives transformative therapeutic benefit," a Vertex spokesperson wrote in an email to BioPharma Dive.

An estimated 100,000 people in the U.S. have AAT deficiency. No treatments have been approved specifically for the disease, but a few companies are working to change that. Aside from Vertex, U.K.-based Mereo BioPharma expects to have data from a mid-stage clinical trial of its AAT drug later this year. And at Arrowhead Pharmaceuticals, executives are hoping regulators can give a speedy review to ARO-AAT, an experimental drug also in mid-stage development.

For Mereo and Arrowhead, more positive data could propel the companies closer toward their first approved products. But for Vertex, a victory in AAT deficiency would be symbolic.

Vertex is a proven powerhouse in cystic fibrosis drug development, creating products that can treat 90% of the patient population. Last year, the biotech recorded $6.2 billion in revenue, and expects another almost $7 billion for 2021. Yet, that track record has investors questioning where Vertex could find success next.

On that front, Vertex has run into obstacles. For example, the company stopped work on an earlier AAT drug because of safety issues. And in pain, the company is still looking for a breakthrough moment after two candidates didn't deliver promising enough results in clinical tests.

Vertex does think it's heading in the right direction in AAT deficiency, though. In the study of VX-864, all the tested doses of the drug showed "highly statistically significant increases" in functional levels of the protein compared to placebo.

Specifically, patients treated with Vertex's drug had a mean increase of 2.2 to 2.3 micromolars in functional protein compared to placebo. But the improvement was too small to increase patients' protein levels above what Vertex thinks will be protective against disease, about 11 micromolars.

After treatment was withdrawn, per the study plan, protein levels in treated patients returned to baseline, which Vertex says is evidence of its drug's activity. 

And unlike its predecessor, VX-864 didn't elicit safety issues. Vertex said the drug was generally well tolerated, with all but one patient completing treatment. The company noted how no patients discontinued treatment due to adverse events, and that there were no serious adverse events tied to its drug.

Still, with VX-864 now shelved, Vertex may find itself under greater pressure to make sure other programs pan out, including a gene editing treatment for blood disorders that it's co-developing with CRISPR Therapeutics.

Vertex recently amended its partnership with CRISPR so that, in the event their treatment gets approved, it will get a larger split of any resulting profits. The revised deal, which Vertex spent $900 million to secure, suggests the biotech sees a multibillion opportunity for the program, according to analysts.

Shares in Vertex fell by more than 10% in postmarket trading on news of the study data, while Arrowhead climbed by more than 5%. 

https://www.biopharmadive.com/news/vertex-stops-work-on-second-rare-disease-drug-after-study-results-disappoin/601638/