Part 2: The Coadministration of COVID-19 and Flu Vaccines

Kristen Nichols, PharmD, and senior content management consultant for clinical effectiveness at Wolters Kluwer joins Drug Topics® to discuss the benefits of the coadministration of COVID-19 and flu vaccines in part 2 of this interview.

Drug Topics®: You mentioned a little bit about the buzz about misinformation. Can you clear up any confusion about how long [the COVID-19 and influenza] vaccines should be spaced apart? Does it matter which one you get first?

Kristen Nichols, PharmD: So, the flu vaccine and the COVID-19 vaccine don't need to be spaced apart at all—they can be given at the same time. I think I'm 2 weeks out from getting [them]; I did my COVID-19 vaccine on my left arm and my flu vaccine on my right arm. I got them at the same time. 

If you do have a patient, however, who is really opposed to getting them at the same time, it's definitely better for someone to get both vaccines—even if it's separated by a little bit—than to not get either, or to not get 1 of them. I have had some people who told me they just don't feel comfortable getting them at the same time. And so, what I would recommend, especially if that person hasn't been vaccinated against COVID-19 at all, is: I would do the COVID-19 vaccine first, given that that's associated with a higher risk and a significant risk of hospitalization. 

Do that one [first], and then…even a week is reasonable [to wait]. Almost all of your adverse reactions to vaccines happen within a week, and so that will give you time to tell—if you had a reaction—whether it was from the COVID-19 vaccine before getting the flu vaccine. 

That calculation might change a little bit in someone who's fairly young and healthy, but maybe has an underlying condition. Maybe, given that the COVID-19 vaccines are still shown to really prevent hospitalization and death, maybe the flu vaccine might want to go first, especially if you're seeing flu transmission in your community. Now, in my community in Indianapolis, we're not seeing flu transmission yet. So, I would still go towards COVID-19 first if somebody wants to space them.

Drug Topics®: That makes a lot of sense. Hopefully administering both at the same time will be be helpful for health care providers.

Nichols: Well, I think we have a lot of folks to vaccinate, and I know we have some staffing shortages.

In the beginning of the vaccination efforts, we had huge clinics and a lot of coordinated efforts, [but] a lot of those have been shut down. I think we're going to be seeing heavier reliance on our retail pharmacies and some of our other vaccination clinics. So, clearly being able to give both vaccines at the same time can really save a lot of time and effort for those providers and those pharmacists. 

I personally worked for a chain pharmacy that did long-term care clinic vaccinations, and I've received outreach from them in the last few weeks and know that they have some staffing needs. I actually just got an email from the COVID-19 vaccine clinic that I've been volunteering at from a local hospital, asking for more volunteers. So, I know there's definitely a staffing shortage, but also from that perspective of, our health care providers who are overwhelmed with the number of patients seeking care for COVID-19. If we increase the vaccination rates that can decrease the illnesses and hospitalizations, and hopefully burden on the health care system at large.

I will say one thing, that there have been errors reported in a recent ISMP [Institute for Safe Medication Practices] newsletter; they highlighted some of the errors where [the] flu vaccine was given instead of [the] COVID-19 vaccine or vice-versa. And so, when you're giving both on a busy day, it's still important to slow down and make sure you're only using 1 vaccine, 1 syringe at a time; pay really close attention.

Drug Topics®: With previous doses [of the COVID-19 vaccine], health care providers were recommending that patients not receive any other vaccine during a specific timeframe. Has this changed?

Nichols: That…recommendation at the beginning of the vaccination effort was really due to an abundance of caution, because we didn't really know exactly how people would react. Now, we have all kinds…we have a lot of data telling us what the reaction to the COVID-19 vaccines are. At this point, there's no need to separate from other vaccines, or any specific time they can be given with any interval.

Drug Topics®: Going off of that, how can pharmacists and health care providers encourage patients to get vaccinated?

Nichols: This is a really important question. And really, I think the answer is really pretty complex, but I'll do my best for now. 

I think taking the time to ask patients about whether they're vaccinated, and encouraging them to be vaccinated, is an obvious [question that can] help. I think building those relationships so that patients have someone they can trust—they trust you for, you know, their other medications and health care needs—having someone they can trust, that's going to be the best person to help dispel some of the misinformation out there. 

I think that is important too: being a source—a good source—for truthful information and staying abreast of all the misinformation that's out there. It can be really painful; it pains me to read about the things people are saying about the COVID-19 vaccines. But I think it's more important to know what those things are so you can investigate the science and know what isn’t true and what is true, so that when patients ask those questions you're not taken by surprise with them. 

I also think that actively listening to patient’s concerns and reserving judgment can be really important for building that trust and building that relationship. There are a lot of people that will let you share information and correct some misperceptions if you take that time to listen and hear what their real concerns are.

Expert Interviews

The shift to value-based care (VBC) in the U.S. has been slow in coming, in large part because providers have continued to cling to the traditional “fee for service” (FFS) healthcare model that historically has worked well for them (if not always for the patient). Plus, it’s how they’ve always done business.

But the inefficiencies and inflexibility of FFS were laid bare during the COVID-19 pandemic. Providers suddenly were confronted with the jarring reality that, under a fee-for-service reimbursement model, no service means no fee. Revenues 

 as patients canceled elective surgeries and clinician offices restricted hours and patient volume.

In contrast, value-based care models reimburse providers for delivering better outcomes for patients and populations while reducing costs. The emphasis is on quality care, not quantity.

Key to making VBC work are technologies that enable clinicians to personalize care plans for treating each patient’s unique health risks. Fortunately, huge gains are being made in the areas of genetic testing and precision medicine, which allow clinicians to use a patient’s genetic makeup and other molecular data in the course of providing care.

VBC is especially promising in helping providers treat patients with chronic diseases. The Centers for Disease Control and Prevention (CDC) 

 that 90% of the country’s $3.8 trillion in healthcare spending in 2019 went toward treating people with chronic and mental health conditions.

 shows that 51.8% of adults in the U.S. have at least one chronic condition (such as heart disease, cancer, stroke, chronic obstructive pulmonary disease or diabetes), while 27.2% have two or more chronic conditions. Another 

 shows that more than half of older U.S. adults have three or more chronic diseases.

And that’s when things get expensive. A Rand Corp. analysis 

 that while Americans with five or more chronic conditions comprise only 12% of the population, they account for 41% of total healthcare spending in the U.S. Based on total healthcare spending in 2019, that’s an astounding $1.56 trillion a year.

As the U.S. population ages, the total number of people with chronic diseases – and the costs associated with them – in turn will rise. PFCD projects the total cost of chronic disease (both in terms of medical expenditures and lost worker productivity) in the U.S. from 2016 to 2030 will reach $42 trillion. PFCD also estimates that 1.1 million American lives could be saved annually through better prevention and treatment of chronic disease, reducing healthcare spending by $418 billion each year through 2030.

Better prevention and treatment, however, can only be achieved through VBC payment models that reward quality care along with the use of technologies such as precision medicine, advanced genetic testing and pharmacogenomics.

Through targeted genetic sequencing, clinicians can spot changes in an individual’s chromosomes, genes or proteins. With this information, clinicians can identify those patients most at risk of developing a chronic disease before that condition develops or progresses and requires more expensive care in the long term. Further, early genetics testing can motivate at-risk patients to make lifestyle changes (such as quitting smoking or getting more exercise) or take medications prescribed to control their chronic conditions.

Let’s say targeted next-generation sequencing (NGS) testing panels from a clinical lab show that a patient is at risk for hypertension. Clinicians can use this information to work with the patient on lifestyle changes and strategies to control their blood pressure.

In addition, providers might want to prescribe a medication for that patient based on NGS results. This is where pharmacogenomics is proving invaluable. Pharmacogenetic (PGx) testing can reveal genetic variations that affect a patient’s response to specific medications. These insights save time and money because clinicians don’t have to experiment with different medications.

Knowing precisely which medications to prescribe to a patient also minimizes potentially adverse drug reactions. Reducing adverse drug reactions can reduce medication nonadherence, which is when patients don’t take the medications prescribed by clinicians for chronic conditions, illnesses, and other disorders, often out of fear of harmful or debilitating side effects. “Medication nonadherence accounts for billions of dollars in avoidable health care costs, millions in avoidable inpatient hospital days, and thousands of avoidable ED visits,” the CDC 

Beyond enabling personalized treatment plans for individual patients based on their unique genetic composition, precision medicine and genetics testing provide data for medical researchers to better understand chronic diseases, which over time will lead to improved prevention, diagnoses, and treatment.

The American Medical Association (AMA) has been 

 for several years that precision medicine and genetics testing are essential components of value-based care models. While there remain 

 to large-scale adoption of precision medicine and genetics testing, the benefits of these technologies – along with VBC models that emphasize prevention and holistic care – are becoming increasingly undeniable. It will only be a matter of time before VBC, precision medicine, and genetics testing will enter the mainstream of healthcare.

Ron King is the CEO and Managing Board Member of Tesis Biosciences. King is a seasoned healthcare executive with more than 25 years’ experience in the healthcare industry.

Articles

The shift to value-based care in the U.S. has been slow in coming, in large part because providers have continued to cling to the traditional “fee for service” healthcare model that historically has worked well for them.

Drive Value-based Care With Genetic Testing and Precision Medicine 

Lauren Biscaldi is the Managing Editor of Drug Topics. 

A 3-pronged strategy is underway to address new SARS-CoV-2 variants of concern, including the Omicron variant, according to a Moderna press release.

Omicron—first detected in South Africa on November 24, 2021

—includes Delta SARS-CoV-2 mutations that increase transmissibility and Beta and Delta SARS-CoV-2 mutations that promote immune escape. This combination of mutations, according to a company press release, “represents a significant potential risk to accelerate the waning of natural and vaccine-induced immunity.”

Because booster doses are the only strategy currently available to address waning immunity, Moderna has implemented the following updates to their strategy to address SARS-CoV-2 variants of concern.

Moderna has already tested a higher dose booster of mRNA-1273 (100 µg) in healthy adults in a safety and immunogenicity study of 306 adults, and the dose has also been studied by the National Institutes of Health. A 100 µg dose has “generally resulted in the highest neutralizing titers against prior SARS-CoV-2 strains.” Efforts are currently underway to test sera from high-dose booster recipients to determine if this dose provides “superior neutralizing protection” against Omicron.

Moderna has already begun studying 2 multi-valent booster candidates designed to anticipate mutations like those that have emerged with Omircon. The first—mRNA-1273.211—includes several mutations found in the Omircon variant that were also presented in the Beta variant. This dosing was completed in a “potentially pivotal” study of safety and immunogenicity at both the 50 µg and 100 µg doses in 300 and 584 adults, respectively.

The mRNA-1273.213 candidate includes “many” of the Omicron mutations that were present in both Beta and Delta variants. Dosing (100 µg) has been completed in 584 healthy adults; the company intends to evaluate the 50 µg dose in 584 participants.

Moderna also plans to expand sera testing from both completed and ongoing multi-valent booster studies to determine if either of these booster candidates provides superior neutralizing protection.

Finally, Modern plans to rapidly advance an Omicron-specific booster candidate, mRNA-1273.529. This booster follows others specific to the Beta and Delta variants.

“The mutations in the Omicron variant are concerning…and we have been moving as fast as possible to execute our strategy to address this variant,” said Stéphanie Bancel, Moderna CEO, in a company press release.

Moderna announces strategy to address Omicron (B.1.1.529) SARS-CoV-2 varianat. News release. Moderna. November 26, 2021. Accessed November 30, 2021. 

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-strategy-address-omicron-b11529-sars-cov-2

Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. World Health Organization. Published November 26, 2021. Accessed November 30, 2021. 

https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern

The Omicron variant was first identified in South Africa on November 24, 2021. 

Omicron Variant: Moderna Announces Updates to SARS-CoV-2 Strategy for Variants of Concern

Amidst the ongoing focus on getting COVID-19 vaccines into arms and seasonal reminders about the flu vaccine, it’s easy to forget that there are other important vaccines that adults should receive. That’s why it’s especially critical for pharmacists and other healthcare providers to be proactive about keeping their patients up to date when it comes to the CDC’s Recommended Adult Immunization Schedule.

Included on that list is vaccination against herpes zoster (shingles) and its related complications. Shingrix, the recombinant zoster vaccine, is the only shingles vaccine available in the United States, and is recommended for immunocompetent adults aged 50 and older. It is estimated that virtually all individuals in this demographic have been exposed to the varicella zoster virus (VZV), which causes both chickenpox (varicella zoster) and shingles. 

According to the CDC, approximately 1 out of 3 individuals in the United States will develop shingles in their lifetime, a 

 that increases with age.2 Shingles rates have been 

Shingrix is administered in 2 doses delivered 2 to 6 months apart. Pharmacists and other providers do not need to screen for a history of chickenpox infection or test for serologic evidence of prior infection before administering the vaccine.

Under CDC guidelines, individuals can be vaccinated with Shingrix whether or not they report a prior episode of shingles, or prior vaccination with Zostavax.

“There is no specific amount of time you need to wait before administering Shingrix to patients who have had herpes zoster,” the CDC wrote on its website. “However, you should not give Shingrix to patients who are experiencing an acute episode of herpes zoster.”

 In such cases, vaccination should be postponed until the acute stage of the illness has passed and the patient is no longer symptomatic.

Patients with chronic medical conditions like diabetes, rheumatoid arthritis, and pulmonary disease can be vaccinated. Likewise, patients who are taking low-dose immunosuppressive therapy, are anticipating immunosuppression, or have recovered from an immunocompromising illness are also eligible.

Additionally, Shingrix may be administered concurrently with other vaccines on the CDC’s Recommended Adult Immunization Schedule. These include 

There are a few contraindications for herpes zoster vaccination. Shingrix should not be administered to a person who had an allergic reaction after a previous dose of the vaccine or has a history of severe allergic reaction to any component of the vaccine. If a person is known to be seronegative for varicella, providers should follow the CDC’s Advisory Committee on Immunization Practices (ACIP) 

 for the prevention of herpes zoster was shown in the ZOE-50 study (NCT01165177) to be 96% in persons aged 50 to 59 years, and in the ZOE-70 study (NCT01165229) to be 97% in persons aged 60 to 69 years. Its efficacy for preventing 

, a serious neurological complication of shingles, was 91% in adults aged 50 and older and 89% in those 70 and older.

“With high efficacy among adults aged ≥50 years, and modest waning of protection over 4 years following vaccination, RZV has the potential to prevent substantial herpes zoster disease burden,” ACIP guidance concluded.5 “Vaccinating adults starting at age 50 will prevent disease incidence in midlife, and the vaccine will likely continue to provide substantial protection beyond 4 years as recipients age.”

Recommended adult immunization schedule for ages 19 years or older, United States, 2021. CDC. Updated February 12, 2021. Accessed November 24, 2021. 

https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html

Shingles burden and trends. CDC. Updated August 14, 2019. Accessed November 24, 2021. 

https://www.cdc.gov/shingles/surveillance.html

Shingles vaccination. CDC. Updated January 25, 2018. Accessed November 24, 2021. 

https://www.cdc.gov/vaccines/vpd/shingles/public/shingrix/index.html

Shingrix recommendations. CDC. Updated October 5, 2020. Accessed November 24, 2021. 

https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html

Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines.

 Morb Mortal Weekly Rep. 2018;67(3):103-108. doi:10.15585/mmwr.mm6703a5

The CDC recommends Shingrix for prevention of herpes zoster 

Shingles Vaccine Remains Important for Adults 50+	

A new COVID-19 variant known as Omicron has global health officials concerned as scientists race to discover how mutations will impact the transmission and severity of the virus. Here’s what we know.

Omicron, officially known as B.1.1.529, was designated a variant of concern on November 26 by the World Health Organization (WHO).

The designation was made based on evidence presented to the WHO's Technical Advisory Group on Virus Evolution that Omicron has several mutations that may affect how the variant behaves, ie, the severity of disease it causes, its degree of transmissibility, and the variant's immune escape potential--that is, whether it can bypass protection offered by current COVID-19 vaccines.

Omicron was first identified in South Africa and reported to the WHO on November 24; it has now been detected in Australia, Belgium, Botswana, Britain, Denmark, Germany, Hong Kong, Israel, Italy, the Netherlands, France, Canada, and South Africa. At least 44 countries have imposed travel restrictions from several African countries, reports CNN.

 Japan and Israel have banned all foreign nationals from entering their countries. Health officials in Canada confirmed the country's first 2 cases in Ottawa on Sunday, November 28.

There have been 50 mutations identified in the B.1.1.529 lineage, the most concerning being more than 30 in the spike protein region, the area that facilitates a virus' entry into the host cell, enhancing its transmissibility as well as the potential for immunoescape.

WHO notes, however, that it is not clear yet whether the variant is more transmissible compared to other recent variants, including Delta. While the number of persons testing positive for Omicron has increased in areas of South Africa where circulation has been identified, studies have been launched to understand if the variant is to blame or if other factors may be implicated.

There are as yet no data to clarify whether Omicron causes more severe disease compared to other variants, and WHO again points to Delta as the primary comparator. “Preliminary data suggest that there are increasing rates of hospitalization in South Africa, but this may be due to increasing overall numbers of people becoming infected, rather than a result of specific infection with Omicron,” states WHO. Nor is there any suggestion that symptoms associated with Omicron infection are different from those seen with currently circulating variants.

 a South African physician who was among the first clinicians to suspect a different strain of the coronavirus among patients he saw said that “the symptoms of the Omicron variant were so far mild and could be treated at home.” The chair of South African Medical Association, also speaking to Reuters, said that no patients so far have reported loss of smell or taste and there has been no major drop in oxygen levels observed.

According to WHO, initial reported infections were among university students who overall tend to have milder infection and symptoms.

Better understanding of both infectivity and transmissibility of Omicron will likely take several weeks, the WHO stressed, as will accruing information on whether the variant can potentially render current vaccinations less effective.

“Work is already under way to look at the immune escape potential of B.1.1.529 in the laboratory setting,” note scientists with South Africa’s National Institute for Communicable Diseases (NICD) in a statement.

 “Based on our understanding of the mutations in this lineage, partial immune escape is likely, but it is likely that vaccines will still offer high levels of protection against hospitalization and death.”

Effectiveness of current tests is currently not in question, according to WHO, as the widely used PCR assays continue to detect infection, including with Omicron. Research is underway to assess any potential impact of the variant on other tests including rapid antigen detection tests. Treatments for COVID-19 also are being assessed for efficacy against Omicron infection but WHO stresses that both corticosteroids and IL-1 receptor antagonists will continue to be effective against severe COVID-19.

In statements to Reuters leaders from both Pfizer-BioNTech and Moderna said virus mutations have been anticipated since the beginning and that the companies are working closely with authorities to process information as soon as it is available.

Update on omicron. World Health Organization. Published November 28, 2021. Accessed November 30, 2021. https://www.who.int/news/item/28-11-2021-update-on-omicron

Sangal A, Regan H, Wagner M, et al. November 29 Omicron COVID-19 variant news. CNN. Updated November 30, 2021. Accessed November 30, 2021. https://www.cnn.com/world/live-news/covid-variant-omicron-11-29-21/index.html

Piper E, Sterling T. Omicron variant detected in more countries as scientists race to find answers. Published November 28, 2021. Accessed November 30, 2021. https://www.reuters.com/world/new-coronavirus-variant-omicron-keeps-spreading-australia-detects-cases-2021-11-28/

Frequently asked questions for the B.1.1.529 mutated SARS-CoV-2 lineage in South Africa. National Institute for Communicable Diseases. Published November 26, 2021. Accessed November 30, 2021. https://www.nicd.ac.za/frequently-asked-questions-for-the-b-1-1-529-mutated-sars-cov-2-lineage-in-south-africa/ 

The Omicron variant of COVID-19 is spreading quickly, jumping continents through infected travelers. Here’s the latest on what global health officials know.

COVID-19: What We Know, What We Don’t About the Omicron Variant

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: 

There’s some additional competition in the marketplace with similar products. I’m curious how you think this may affect things in terms of formulary and price considerations in the marketplace with insulin.

Thomas C. Blevins, MD, ECNU, FACE, FNLA: 

It’s interesting. The biologics are never going to be as cheap as generics because even though they’re biosimilars, they’re still very complicated. The way to make a generic—it’s not inexpensive—is you just crunch out a pill of a statin or something, apparently fairly inexpensively. That’s a generic. This is a biosimilar, and that’s different. Look at some of the pricing strategies. Let’s talk about Semglee [insulin glargine-yfgn]. Basaglar [insulin glargine] is out already as a biosimilar—it’s a follow-on biologic because it was approved under a different pathway. Now we have Semglee [insulin glargine-yfgn] out, and there are others around the world. The pricing can be quite a bit lower potentially. I’m not going to give numbers—they change all the time, and I’m not sure they’re totally accurate every time—but they’re a considerably lower cost. Then comes the complexity of the formularies. Sometimes the formularies have different pricing that they can offer, or they can get from pharmaceutical companies.

Then comes the idea of translating data into practice. Will doctors feel comfortable? In general, it’s safe to say biosimilars are less expensive, making them more affordable, making access better, which is huge in the United States and around the world too. Making a good basal insulin available, to everyone who needs it, is very important. Lots of people have diabetes, and the number of people with diabetes is not going to get smaller. It’s going to be greater everywhere. There’s a real potential for cost saving with a product that’s highly similar—so similar that the FDA says it’s interchangeable. From a practitioner standpoint, I’m pretty happy about that because every time somebody switches from 1 type of insulin to another based on formulary, even though it’s the same insulin almost—sometimes not, sometimes the rapid acting might be a little different from the other rapid acting—I have to prove it. Because the formulary says, “we prefer 1 over the other,” I have to approve it, or my staff does. It costs us a ton of time. If someone could just change it up at the pharmacy, I’ll say yes, go for the 1 that has the best price. I’m very confident that the quality is good. They’re highly similar, they’re interchangeable based on the data, and the FDA agrees. So interchangeability things a big deal.

I totally agree. I can also commiserate with some of the challenges of when you send a prescription in for Lantus [insulin glargine] and it ends up being Basaglar [insulin glargine]. The follow-on biologic is preferred, but the pharmacist can’t make that automatic substitution. Then that requires either unnecessarily trying to submit prior authorization for Lantus [insulin glargine] or going back and forth having to change it. It does add a lot of time to everyone, but it can end up being a delay in the patient being able to get insulin, which is a huge problem. In terms of cost, it’s interesting because our cost structure for insulin is very complicated. Just because 1 product has a lower cost, doesn’t mean it’s going to be preferred by the insurance plan because there are a lot of other dynamics going on with the pharmacy benefit managers and rebates.

Each person’s insurance plan might be a little different, and some may prefer the reference product. They may prefer Lantus [insulin glargine]. In some case, they may prefer Basaglar [insulin glargine]. In some cases, they may prefer Semglee [insulin glargine-yfgn]. It’s very complicated. For sure, for someone who’s paying out of pocket, who didn’t have insurance but now has this interchangeable insurance, it will be less. I recently had to look up all these drug costs. You’re right—they change month to month. I’m updating the standards-of-care table for the ADA [American Diabetes Association], so I had to look all this up. I can tell you Semglee [insulin glargine-yfgn] is about half the price of the reference. It’s a cost savings, and we hope that will translate to everyone—to patient insurance plans, health systems, and across the board. That would be great.

Videos

Thomas C. Blevins, MD, ECNU, FACE, FNLA, and Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, discuss the impact of interchangeable insulin biosimilars on biologic products in the marketplace for diabetes management.

Impact of Interchangeable Insulin Biosimilars on Cost of Biologics

Ms. Hester is Content Specialist with Contemporary OB/GYN and Contemporary Pediatrics.

For most children with Kawasaki disease, the use of intravenous immunoglobulin therapy is effective. However, 10% to 20% of children will require additional treatment. A recent multicenter investigation compared the efficacy of a second infusion of intravenous immunoglobulin with infliximab to treat resistant cases.1

Investigators recruited patients aged 4 to 17 years with intravenous immunoglobulin resistant cases of Kawasaki disease and fever at least 36 hours after receiving the first infusion from 30 hospitals across the United States. They randomized patients (1:1) to either receive a second immunoglobulin transfusion or to receive infliximab (10 mg/kg over 2 h without premedication). Participants with fever 34 hours to 7 days after completing the first treatment given for the study were crossed over to get the other study treatment.

A total of 103 participants were included in the intention-to-treat population with 54 randomized into the infliximab group and 49 into the second intravenous immunoglobulin treatment group. The primary outcome, which was resolution of fever at 24 hours following the initiation of study treatment as well as recurrence of fever that could be attributed to Kawasaki disease within 7 days post-discharge, occurred in 40 of 52 patients in the infliximab group and 25 of 49 patients in the second IVIG infusion group (odds ratio 0.31, 95% CI 0.13–0.73, p=0.0076). Crossover treatment was given to 31 patients: 9 received a second immunoglobulin treatment after initial infliximab study treatment and 22 were given infliximab after receiving standard treatment. Five patients did not receive crossover treatment. On average, participants who received infliximab had fewer fever days (1.5) and days in the hospital (3.2) than those who received a second treatment of standard care who had 2.5 fever days and 4.5 days in the hospital. The only serious adverse event that was considered either definitely or probably linked to study treatment was hemolytic anemia, which was reported in 9 of the patients who were given intravenous immunoglobulin as either the initial study treatment or crossover treatment whereas no cases were seen in patients who were only given infliximab.

The investigators concluded that in the case of resistant Kawasaki disease, infliximab is a safe, effective treatment. Furthermore, it led to better outcomes, such as shorter hospital stays and shorter periods of fever, than the use of a second infusion of intravenous immunoglobulin.

1. Burns J, Roberts S, Tremoulet A, et al. Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki Disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial. 

. 2021;5(12):852–861. doi:10.1016/s2352-4642(21)00270-4

Sometimes Kawasaki disease doesn’t respond to treatment. An investigation looks into whether a second course of standard treatment performed better than treating with infliximab.

Resistant Kawasaki Disease Treatment Efficacy

I’d love to hear about these clinical studies that were done to support that Semglee [insulin glargine-yfgn] can be interchanged with the reference product.

I’m going to ask the audience a question. Diana, you said earlier this insulin is called glargine-yfgn, and that’s Semglee [insulin glargine-yfgn]. So I’m going to ask the audience, what does YFGN mean? What does it stand for? I’m going to go ahead and answer. It means nothing—4 lowercase letters and any biosimilar now just has to have a dash from the reference. Instead of glargine-yfgn, you could choose, zzzz or something.

You’re right. Remember, you have to study these biosimilars in humans with diabetes. There’s an INSTRIDE 1, guess what, that’s type 1; INSTRIDE 2, for type 2; and INSTRIDE 3, which is the study that helps get the interchangeability. I’ll talk about each 1. Let me just give you a brief. In INSTRIDE 1, there were 558 people with type 1 diabetes. This is a study in which 1 group is going to be put on reference—the originator—and 1 is going to be put on the biosimilar. They’re going to be followed for a period of time—24, 52 weeks. As it turns out, the different end points are going to be looked at at those times. They’re going to be looked at for [hemoglobin] A1C changes, hypoglycemia. We’ll talk about it in a minute. In INSTRIDE 2, there were 560 people with type 2 diabetes. These are people who need basal insulin. The reference is compared with the biosimilar. We’ll talk about the INSTRIDE 3 separately.

Let’s talk about INSTRIDE 1. It turns out that if you look at the A1C data—I wish I could show it to you, but I’ll summarize it—they’re the same. There was no difference between the start and finish of the study and between the 2 groups, Lantus [insulin glargine] and biosimilar insulin glargine. We’re talking about -yfgn insulin. The A1Cs were the same from start to finish in this group of people with type 1 diabetes. If you look at the fasting plasma glucose, it’s the same. There’s no significant difference, and that goes for the A1C. The bottom line is noninferiority in A1C results. The doses of the insulin were similar. The A1C results were close to the same. As I mentioned, the fasting glucose, incidence of adverse events, serious adverse events are all very similar. Incidence of hypoglycemia is also similar. No clinically meaningful differences between treatment groups. That’s the type 1 study.

The type 2 study can summarize easily too if you look at the A1C changes at week 12 and 24, between the 2 insulins. It’s very close—no significance there, and no significant difference. If you look at safety—and the same thing goes for serious adverse events, hypoglycemia—if you look at the glargine dose over time, it’s very similar in terms of dosing over time. There are no significant differences. There are no clinically significant or meaningful differences between the 2. There were immunogenicity studies—the INSTRIDE 1 and INSTRIDE 2 studies—looking at antidrug antibodies studies—antibodies to insulin. Does 1 type of insulin cause more antibody production than another? That’s a big deal in terms of safety. The answer is, long story short, the INSTRIDE 1 and INSTRIDE 2 studies over the time period looked at—we have 50-week data in the type 1 study and 24-week data in type 2 and no significant cross-reactive, antidrug antibody presence between the 2—were very similar. Those are the data on the core studies.

INSTRIDE 3 is the switching study. The way this study worked is that people were taken from the INSTRIDE 1 study and were offered to continue into this switch study. One group is left on references in glargine throughout the study, and we’re looking at 36 weeks. Another group is given the biosimilar for 12 weeks, then given the reference insulin for 12 weeks, then given the biosimilar for 12 weeks. It’s a switch study, and their results are looked at. The results again showed that there was no significant difference between the treatment groups when it came to A1C during the different treatment periods. There was no difference in fasting glucose and monitor glucose, and immunogenicity looked very similar too. Those data show us that we can have the confidence, and the FDA has the confidence, that a pharmacist can change without us saying it’s OK because we have an insulin extremely similar in every way that we talked about. That’s a big deal.

Thank you. That was such a good summary of the different studies. That should be reassuring that the clinical outcomes are almost the same between the 2 products, and it should give people peace of mind that if they’re switching between insulins, they can expect the same clinical effect.

Experts in diabetes management discuss data from key clinical trials—INSTRIDE 1, INSTRIDE 2, and INSTRIDE 3—and evaluate the use of insulin glargine-yfgn as an interchangeable product with biologics.

Results of INSTRIDE Studies for Diabetes Management

I want to switch gears and talk about biosimilars. We have insulin glargine-yfgn. The brand name is Semglee. This is the first interchangeable biosimilar approved by the FDA. Tom, I know you have so much expertise in this area. Can you define for our audience what a biosimilar is? Maybe talk through how the FDA approves biosimilars and how these compare with the original reference product.

Diana, I’d be happy to talk about out that. This is important to understand. Let me throw out a couple definitions. No. 1, a biologic is essentially a pharmaceutical agent created in living cells. That’s what we’re dealing with here. Insulin is a biologic. This is a very complicated process. Making a biologic is not like making a generic statin or a generic other kind of medicine; this is complicated. A biosimilar is a biologic medicine that’s highly similar to the reference biologic with no clinically meaningful or notable or significant differences in terms of the safety, purity, and potency. We’re talking about insulin. We’re talking about glargine. The reference biologic, the reference glargine, will always be the Sanofi Lantus insulin. Anytime somebody wants to do a biosimilar glargine, they’re going to reference to the original, essentially Lantus.

Another point is that a biosimilar is an approved version of a biologic medicine with identical amino acid structure sequencing to the originator, which would again be the reference. The intent is to make it as close as possible in every way to the reference biologic. Biologics are complex; therefore, biosimilars are complex proteins. If you look at a small molecules—things that are generics, that are pills—they’re very different from a biologic. I won’t dwell on that, but the biologics are much larger and complicated. There are quite a few biologics available.

The approval process for a biosimilar requires the person who wants approval of their biosimilar to go to the FDA with data that show that the pharmacokinetic/pharmacodynamic data are very similar. Also, they have to show mitogenicity. They have to look at things that are from the bench to the clinic. Then they need to do large, but not terribly large, studies with people who have type 1 or type 2 diabetes and show that the insulin is highly similar in terms of efficacy, safety, and immunogenicity. Those are the standards set by the FDA. The Semglee [insulin glargine-yfgn] people and the Viatris people had to do that. That’s what Eli Lilly had to do when they got Basaglar [insulin glargine] approved. It had to show that all those things, from the bench to the clinic, were highly similar. Then they get approved if their insulin was highly similar. We can talk more about that in a minute, as far as the studies that were done.

Thanks. That’s so informative and helpful. What exactly is an interchangeable product? Are there any other biosimilars that also have this status of being interchangeable?

Everyone may be surprised to hear that there was no insulin, until now, approved as an interchangeable insulin. Now Semglee [insulin glargine-yfgn] has that approval. The FDA requires that a company does studies that show that you get the same clinical result as the reference product, with no diminished efficacy, no sign of safety issues, and no sign of difference in immunogenicity. What the FDA requires can change, and this is an evolution. The FDA encourages switching studies. That’s a study where you take people with type 1 or 2 diabetes, and you put 1 group on the reference product—the originator, like Lantus [insulin glargine]—and other people on the biosimilar. Then you treat them for periods like 3 months at a time. Then you switch them to the other side to see if there’s any difference, then you switch them back. The question is, how many switching periods will there be? As long as the safety, efficacy, and all that are highly similar, you have a chance of getting approved. You have to show that to get interchangeability. This is the bottom line, and it’s surprising to everyone I think. Interchangeability has not been approved until now, and I suspect there will be others down the road. This is a big deal. I wanted to talk more about the design. We can in a bit or anytime you’d like about the advantage of having an interchangeable insulin.

I’ll just add that 1 of the big things about interchangeable insulin is it means if a prescription is sent to the pharmacy for insulin glargine or for Lantus [insulin glargine], the pharmacist can change it to Semglee [insulin glargine-yfgn] and not have to contact the prescriber to be able to do that. That’s a big deal, and we’ll definitely talk more about that in a bit.

Thomas C. Blevins, MD, ECNU, FACE, FNLA, provides an overview of biosimilars and discusses interchangeability status among biosimilars such as for insulin glargine-yfgn for the management of diabetes.

Role of Interchangeable Biosimilars in the Management of Diabetes

 presentation titled “Interchangeable Insulin Biosimilars: A Game Changer in Diabetes Management.” I’m Diana Isaac from Cleveland Clinic in Cleveland, Ohio. I’m joined today by Dr. Thomas Blevins from Texas Diabetes and Endocrinology in Austin, Texas. Our discussion will focus on insulin therapy and approval of the first interchangeable insulin biosimilar. We’ll also discuss the role of biosimilars in endocrinology. Welcome, and let’s begin. Tom, I want to start by asking you to just briefly describe the pathophysiology of diabetes and the whole rationale for insulin therapy.

Thank you for asking, and thanks everyone for listening. This is interchangeability, which we’re going to get to; it’s a big deal. Pathophysiology in type 1 diabetes is straightforward. People don’t make insulin; therefore, they need insulin replacement and a hormone replacement treatment. We use basals and bolus, and we use insulin pumps and things like that. They have to have insulin. If they’re using multiple daily injection, then they’re going to need to have a basal insulin. We’ll talk more about those in a minute. For type 2 diabetes, many people don’t need insulin at all. They don’t make enough insulin, as you all know. We do use insulin in those who can’t control with other means. We use basal, and we use the bolus pre-meal. Sometimes we need basal alone to give them that supplemental amount, to give them just enough to get the control we want. So they are 2 different pathophysiologies. Both need insulin, but not everyone with type 2 needs insulin.

All great points. People with type 1 diabetes are always going to need kind of a basal and a bolus. As we see, people with type 2 diabetes are being diagnosed earlier in life. Through the natural progression of diabetes, even though we have a lot of great noninsulin medications, it’s very natural that over time people do need to supplement with insulin. Very commonly, we start with a basal insulin. Many people progress to needing a bolus insulin with type 2 diabetes as well. With that, I’m hoping that you might be able to provide us with maybe a brief historical overview of the FDA-approved basal insulins.

You may be saying I’m a little historic. But you’re probably right. I was in training in the 1980s and medical school starting in the 1970s. I’ve seen, as many of us have, quite a bit of evolution. We had long-acting insulins, like Ultralente—most people don’t even know what that is nowadays. Don’t even try to know by the way—let me give you that advice. It was once a day. For the most part, though, we used an insulin, the Neutral Protamine Hagedorn, the NPH, which was the protamine-based insulin that was more of an intermediate acting. We called it basal. The way we used it back then—diabetes management was an art and a science. A little more art than science sometimes because with NPH you had to use multiple doses to get any a leveling in the background. NPH was a true mess. It would peak in 6 to 8 hours, and then it dropped off after 14 to 16 to 18 hours depending on the dose. I’d have some patients use NPH in the morning, some at dinner, and some at bedtime to try to spread out the effect.

Then, about 20 years ago, came detemir, which is a once a day. It’s an insulin that we use now. I’ll say the drug name Levemir [insulin detemir] because people are familiar with that name. It lasts for about 24 hours. Then along came insulin glargine. You add a glycine to the A chain of insulin and 2 arginines to the B chain, and voilà—you have an insulin that lasts longer, and you get into this manipulation of the molecule to make it work better and longer and to suit our needs better.

Glargine came along; it’s once a day. That was a huge change. We had much more predictable usage of basal. glargine is probably the most commonly used basal around the world at this point. I think that’s true. Later, around 2005 or so, we got degludec, which is Tresiba [insulin degludec]. Then we got the U300 glargine, and we got that 10 or 15 years ago. So we’ve had this nice evolution of where we’re going with basal insulin.

We use these in people with type 1. We try to simulate physiology as best we can. That’s what we try to do. We use them in type 1, and we use them in type 2 to get our basal effect. We’re not going to talk about bolus much here, but we’re talking basal. We’ll get into this as we talk more about these in a minute. Now we’ll get into the biosimilars that will offer some better access and affordability.

Thanks. Those are all great points. Having an insulin that truly can last 24 hours a day has been a big game changer in diabetes because back with the NPH, patients had to dose it twice a day, and it’s challenging to remember to take something that many times. Unfortunately, it would wear off before 24 hours, and then your glucose levels go up. So it was much more challenging. It’s so nice to have basal insulins that can truly last 24 hours or even longer than 24 hours that we see with degludec and with glargine U300, the more concentrated version.

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, and Thomas C. Blevins, MD, ECNU, FACE, FNLA, review FDA-approved basal insulins for the management of diabetes.

Impact of Interchangeable Insulin Biosimilars on Cost of Biologics

Resistant Kawasaki Disease Treatment Efficacy

Results of INSTRIDE Studies for Diabetes Management

Role of Interchangeable Biosimilars in the Management of Diabetes

Basal Insulin Therapies for Diabetes Management