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 at the Sixth International Cancer immunotherapy Conference (CICON) 2022, Yvonne Chen, PhD and Associate Professor at the University of California, Los Angeles, also breaks down the latest research from her laboratory, where she is engineering CAR proteins that can “wake up” the immune system.

Have these next-generation CAR T-cells proven beneficial to targeting specific treatments?

 I think in recent months, we finally started seeing positive signal in solid tumors. So a very encouraging study had been published by a group at Stanford with Michelle Monje and Crystal Mackell, where they treated pediatric patients with the IPG diffuse midline glioma. They really have seen remarkable clinical response from the patients.

There's also emerging data on CAR T-cells targeting cloud in 6, cloud in 18.2. I think again, the responses are not quite as dramatic as we have seen in B-cell malignancies. But given that we're finally starting to see positive signals, I think there's a lot of room for both optimism and improvement.

I think some of the strategies that we have mentioned so far, as trying to improve T-cell effectiveness or effector function stemness, as well as ability to overcome immunosuppression, can likely be applied in combination so that we can engineer products that that can really be sufficiently potent to make a difference for our patients.

I think as we develop these different strategies, we tend to focus on one thing at a time, right? We develop CAR T-cells, and another group may decide to knock out, or knock in, this specific gene. But provided that one can implement these during the manufacturing process, there’s no reason why you couldn't combine these different strategies.

Of course, I think from a safety perspective, during clinical translation, we may have to do it one step at a time. But one can easily imagine the situation where you can combine a strategy that overcomes immunosuppression together with another strategy that promotes stemness and then generate a product, one that is both more capable of remaining functional in the tumor microenvironment as well as sustaining a prolonged, durable response.

I think it is important to keep in mind that a lot of these pathways are not fully orthogonal, as in they could have crosstalk and they could influence how each other functions. And so a combination is not always a straightforward thing like you know, like 1 plus 1 is 2. Sometimes they actually influence each other, sometimes synergistically sometimes in opposition. So I think the combination strategy requires a detailed investigation— but I imagine that will eventually be the path forward.

 Following the pandemic, what are you currently working on at your lab (Chen Laboratory)?

 My lab is, so far, primarily focused on CAR T-cell engineering, where my life is mostly biomolecular engineers. We really think about what's currently limiting the safety and/or efficacy of the CAR T-cell therapy, and what can we do to overcome these challenges.

A lot of our earlier efforts is focused on rational protein design on the CAR protein itself. We've engineered bispecific CARs that can hopefully reduce the probability of antigen escape because it can recognize two different antigens on the tumor. We focus on engineering CARs that can respond to soluble antigens like transforming growth factor beta (TGF beta). And now we're moving on to trying to find ways to engineer T-cells so that they don't have to do all the work themselves.

We talked about the problem of heterogeneity— tumor cells oftentimes don't uniformly express an antigen. And even though we can build bispecific CAR T-cells, one can even build trispecifics, or quads…I think these hardwired antigen specificities ultimately have a limit. And when you have highly heterogeneous tumors, I think the way to go is to engineer T-cells that can not only attack tumors themselves, but also engage endogenous immunity. And the idea is the T-cells go in, they do the frontline attack, but then at the same time send signals that pull in reinforcements from the endogenous immune system.

Now, the endogenous immune system naturally has a wide antigen repertoire. And the idea is if your T- cells can trigger the immune system to react against the tumor, we will have a better chance of attacking these highly heterogeneous tumors that are not all recognizable to our engineer T-cells. A lot of our ongoing effort is focused on figuring out how to engineer our T-cells to productively interact with endogenous immune.

CAR T-cells themselves still have limited antigen specificity. As I mentioned, we can build bispecifics, maybe even trispecifics and quads. But that's still 2 to 4 antigen recognition capabilities.

What we want to do is engineer these T-cells, even though they themselves have limited antigen specificity. Once they go into the patient, we want them to be able to induce immune response from the naturally occurring immune cells that we did not engineer.

The idea is you want to pull in this naturally occurring immune response with a much wider range of antigen specificities in order to make them reactive against the tumor. So, in a sense it’s waking the immune system up against a target that they don't normally recognize for a number of different reasons.

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Yvonne Chen, PhD, discusses some of the strategies that researchers are using to improve T-cell effectiveness and overcome immunosuppression in CAR T-cell therapy. 

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Researchers Are Developing Bispecific CAR Proteins to “Wake Up” the Immune Systems of Cancer Patients

Many US adults are reportedly hesitant about getting a COVID-19 vaccination because of misinformation about the vaccine. These misbeliefs, such as the belief that the vaccine contains antifreeze, that it causes autism, or can even increase COVID-19 susceptibility, led researchers at the Annenberg Public Policy Center (APPC) of the University of Pennsylvania to suggest that this vaccination hesitancy could impact the vaccination of children 5 to 11 years of age.

According to the study, primary vaccinations among US adults are 47% higher than vaccinations among children 5 to 11 years of age. If misinformation was greater, the research found that vaccinations were generally lower.

“All of the misconceptions we studied focused in one way or another on the safety of vaccination, and that explains why people’s misbeliefs about vaccinating kids are so highly related to their concerns about vaccines in general,” said Dan Romer, lead author and APPC research director in the press release. “Unfortunately, those concerns weigh even more heavily when adults consider vaccinating children.”

From April to September 2021, vaccinations among the most skeptical US adults sat at 40%, compared to 96% among those who were not skeptical. But in January 2022, only 55% of participants were “very likely” to recommend children in this age group getting vaccinated. Researchers set out to find why adults, even those vaccinated against COVID-19, were less willing to support vaccinations for children 5 to 11 years of age.

APPC used data taken from a national probability survey that was conducted by independent research firm SSRS. SSRS surveyed more than 1600 US adults over 4 waves in April, June, and September 2021, and January 2022. Participants were surveyed on their knowledge of COVID-19 vaccines and were asked about their beliefs and behaviors. Among participants, 31% were vaccinated in April 2021, increasing to 71% in September 2021.

The APPC team found that misinformation about vaccine safety, as well as safety misconception, made vaccinated parents reluctant to vaccinate their young children aged 5 to 11 years.

One of the most common misconceptions suggested that the COVID-19 vaccine could cause infertility in maternal-aged women, but this belief is not proven, according to the FactCheck.org project by APPC. Additional safety concerns about the vaccine include the false belief that it could change an individual’s DNA, may cause allergic reactions, is more dangerous than contracting SARS-CoV-2, and it can cause death. There is no evidence proving that the vaccine causes death.

“Concerns about vaccine safety are clearly a powerful predictor of reluctance to vaccinate oneself and children,” said co-author Kathleen Hall Jamieson, director of the Annenberg Public Policy Center, in the press release. “It is easy to understand why adults would be particularly concerned about adverse reactions, impacts on the DNA, the potential fertility of children, and the possibility that a vaccine might contain toxins or cause autism. Allaying these unwarranted concerns should be a public health priority.”

Annenberg Public Policy Center of the University of Pennsylvania. Misinformation about vaccine safety drives reluctance to vaccinate children, study finds. EurekAlert! October 3, 2022. Accessed on October 3, 2022. https://www.eurekalert.org/news-releases/966638

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Vaccines reduce the risk of COVID-19 infection and hospitalization, but a recent study suggests that misinformation could make adults hesitant to vaccinate children 5 to 11 years of age. 

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Vaccination Rates Among Children May Be Impacted by Safety Concerns 

Scientists have identified promising broadly neutralizing antibodies (bnAbs) that could be used to create a vaccine against HIV, according to a study conducted by Scripps Research, IAVI, the Ragon Institute, and Moderna, Inc.

Human genes make bnAbs, which are antibodies that can fight against multiple variants of a virus. The idea behind creating this vaccine is to identify the right types of bnAbs and human genes to create an mRNA vaccine that prevents the infection or spread of HIV.

“Our 2 studies describe a collaborative effort to genetically and structurally understand bnAbs, and ultimately ‘reverse engineer’ vaccines to elicit these bnAbs,” said senior author William Schief, PhD, a Scripps Research professor and executive director of vaccine design at IAVI's Neutralizing Antibody Center at Scripps Research, in a press release.

The research teams from Scripps and IAVI first engineered a priming immunogen for (what would be) the first dose of the HIV vaccine. This manufactured spike protein would bind to specific naïve B cells, also called germline precursors.

Naïve B cells are antibody-producing white blood cells, and bnAbs come from these cells. The team analyzed 1.2 billion antibody sequences in a large database, which revealed 2 bnAbs that contained the most naïve B cells. The team suggested that these 2 bnAbs would thus be the best defense against HIV.

“Finding the bnAbs we need is like searching for a needle in a haystack,” said co-first author Zachary Berndsen, PhD, assistant professor of biochemistry at the University of Missouri, in a press release. “To make an effective vaccine, we must first find the precursor antibodies that can eventually become bnAbs, while also seeing if those precursor antibodies are common enough throughout the general population to stimulate.”

The researchers then collaborated with researchers from Ragon Institute. They tested the engineered HIV spike protein in mice and found that it did elicit a response in germline precursor cells. This results in a naïve B cell that expresses the apex bnAbs, which can defend against the virus.

“This is a very important step, as it shows that vaccinating with our immunogen can actually elicit responses from the precursors we were targeting,” said co-first author Jordan Willis, PhD, senior principal scientist at the IAVI Neutralizing Antibody Center at Scripps Research, in the press release. “We also showed that vaccinating with an unmodified HIV protein could not elicit those responses, which proves that our affinity engineering was required."

The HIV mRNA vaccine, which would come from Moderna, would be similar to the COVID-19 vaccine. The benefits are that mRNA vaccines are easier and faster to manufacture, and provide better antibody responses compared to a normal vaccine. The researchers anticipate that they will eventually test this vaccine in human clinical trials.

“We and our collaborators are building on this approach, developing and testing immunogens to drive the later stages of bnAb maturation,” said Facundo Batista, PhD, associate director of the Ragon Institute, in the press release.

Scripps Research Institute. Scientists design and validate promising HIV vaccine strategy. EurekAlert. October 3, 2022. Accessed on October 5, 2022. https://www.eurekalert.org/news-releases/966725

A large collective of researchers may be one step closer to developing a vaccine against HIV after engineering a protein that triggers a widespread antibody response.

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Researchers Suggest That Engineering Specific B Cell Response Could Make the First HIV Vaccine Possible

Hamdi Labadidi is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey.

Krupal Ray is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey.

Venous thromboembolism (VTE) results from abnormal clot formation leading to venous thrombosis.

The primary forms of VTE are deep venous thrombosis (DVT) and pulmonary embolism (PE). A range of 300,000 to 600,000 cases of VTE occur annually, with 60,000 to 80,000 deaths attributed to DVT or PE.

 Pharmacologic options for prevention and treatment of VTE include direct oral anticoagulants (DOACs); fondaparinux, an indirect synthetic inhibitor of activated factor Xa; low-molecular-weight heparins (LMWHs); unfractionated heparin; and vitamin K antagonists (VKAs).

In late 2021, the American College of Chest Physicians published an update of its CHEST guidelines for the treatment of VTE, which includes 29 guidance statements.

 This review provides a brief summary of those statements. For the management of acute isolated distal DVT, anticoagulation is suggested over serial imaging in patients with severe symptoms or risk factors for extension. Otherwise, serial imaging for 2 weeks is suggested over anticoagulation. After serial imaging, anticoagulation is not recommended if there is no thrombus extension present. If the thrombus extends but remains confined to the distal veins, anticoagulation is suggested, but if it extends to the proximal veins, then anticoagulation is strongly recommended.

In managing patients with a subsegmental PE and no proximal DVT in the legs, clinical surveillance is suggested over anticoagulation if there is a minimal risk of recurrent VTE, especially as findings of subsegmental PE are more likely to be false-positive.

 If there is an elevated risk of recurrent VTE, then anticoagulation is suggested over clinical surveillance. Regarding acute PE, it is suggested that anticoagulant therapy for patients with an incidentally diagnosed asymptomatic acute PE not differ from comparable patients with symptomatic PE based on observational data suggesting a similar prognosis of asymptomatic versus symptomatic PE.

For management of cerebral vein thrombosis (CVT), anticoagulation is strongly recommended for at least the treatment phase during the first 3 months, regardless of whether an intracranial hemorrhage occurs as a complication of CVT. Initial anticoagulant therapy should be given with dose-adjusted heparin or LMWH, and patients stabilized on heparin should be switched to oral anticoagulation.

When considering interventional (mechanical, pharmacomechanical, or thrombolytic) therapy, the increased risk of bleeding, including intracranial bleeding, must be considered.

 Anticoagulation alone is suggested over interventional therapy in managing acute DVT. As for interventional therapy in acute PE, the guidelines strongly recommend against systemic thrombolysis in most patients with acute PE not associated with hypotension. In selected patients with acute PE who deteriorate after receiving anticoagulant therapy, are not yet hypotensive, and have an acceptable bleeding risk, systemic thrombolysis is suggested. Systemic thrombolysis is also suggested if hypotension is present (eg, systolic blood pressure <90 mmHg) and there is no elevated risk of bleeding. An alternative mode of therapy, catheter-assisted thrombus removal, is suggested if hypotension is present along with a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect. Otherwise, systemic thrombolysis is suggested over catheter-directed thrombolysis.

Regarding the use of an inferior vena cava (IVC) filter, it is only recommended in patients with acute proximal DVT who have a contraindication to anticoagulation. Otherwise, the guidelines recommend against the use of IVC filter in addition to anticoagulants in treating acute DVT.

It is also strongly recommended to treat patients with low-risk PE on an outpatient basis provided the adequacy of home circumstances and access to outpatient care. Specifically, patients must be clinically stable with good cardiopulmonary reserve, be compliant with treatment, feel well enough to be treated at home, and have no contraindications such as severe renal disease.

For patients who have an acute VTE, the strongly recommended treatment is apixaban, dabigatran, edoxaban, or rivaroxaban over a VKA during the treatment phase for the first 3 months. This choice is also based on payor considerations and patient-specific factors, such as bleeding risk, preference, and renal function. For patients with cancer with an acute VTE, a DOAC, such as apixaban, edoxaban, or rivaroxaban is strongly recommended over a LMWH for the initiation and treatment phases of therapy. LMWH has been associated with a decreased risk of VTE. However, it is considered a lifestyle burden and is costly for many patients.

 Cancer patients do present with a higher risk of major bleeding than those without cancer, but a DOAC has led to a decrease in VTE risk in many trials.

Additionally, in patients with antiphospholipid syndrome (APS), patients should be treated with an adjusted dose of VKA over DOAC therapy during the treatment phase. For initiating VKA therapy, an overlap dose of anticoagulation should be included as well.

 Reasons why DOACs are not chosen include inhibition of only 1 coagulation factor versus several with VKA, low adherence to treatment, and their short half-lives, but further literature is needed to evaluate DOACs in patients with APS.

Regarding superficial venous thrombosis (SVT), though it has historically been classified as benign, recent experience has demonstrated its seriousness. Hence, it is recommended that anticoagulation be continued for 45 days to lessen the risk of progression to DVT or PE. A dose of Fondaparinux 2.5 mg is recommended daily over other anticoagulation treatments. If the parenteral route is inappropriate, then a DOAC, such as rivaroxaban, can be used. In the open-label SUPRISE (NCT01499953) study, patients were randomly assigned to receive 10 mg oral rivaroxaban or subcutaneous fondaparinux.

 This non-inferiority study found that rivaroxaban was non-inferior to fondaparinux for the treatment of SVT in terms of diagnosis of DVT or PE events.

 The use of rivaroxaban simplifies treatment for many patients, because of its oral route of administration.

For patients with acute VTE with no contraindications, a 3-month treatment phase is strongly recommended. At 3 months, all patients should be properly assessed for an extension of therapy. For patients who have a provoked VTE, an extended phase of treatment is recommended against, but in patients with an unprovoked VTE, the use of a DOAC is strongly recommended. For patients who do undergo extended-phase therapy, it is weakly recommended to use a low-dose DOAC and there is not much literature supported.

 Specifically, the guidelines prefer apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily. Additionally, in the case of choosing between aspirin and an anticoagulant for extended-phase therapy, a low-dose anticoagulant is strongly recommended over aspirin, as the latter has been much less effective in secondary VTE prevention.

 However, if a patient chooses to completely stop anticoagulation, then aspirin is weakly recommended over completely discontinuing therapy. With patients with DVT in the leg, compression stockings are also not recommended to prevent any post-thrombotic syndrome.

Overall, the updated CHEST guidelines are a valuable resource, as they are backed by many randomized controlled trials that would lead health care professionals in the right direction in treating VTEs. Health care professionals should look into the weak, moderate, and strong recommendations and assess for the most relevant ones to provide individualized patient care.

1. Freedman JE, Loscalzo J. Arterial and venous thrombosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. 

Harrison's Principles of Internal Medicine. 

2. Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. 

 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442

3. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. 

 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055

4. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report (executive summary). 

 2021;160(6):2247-2259. doi:10.1016/j.chest.2021.07.056

5. Carrier M, Righini M, Le Gal G. Symptomatic subsegmental pulmonary embolism: what is the next step? 

 2012;10(8):1486-1490. doi:10.1111/j.1538-7836.2012.04804.x

6. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. 

 2006;354(22):2317-2327. doi:10.1056/NEJMoa052367

7. van der Hulle T, den Exter PL, Planquette B, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. 

 2016;14(1):105-113. doi:10.1111/jth.13172

8. Kearon C, Gu CS, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial. 

 2019;119(4):633-644. doi:10.1055/s-0039-1677795

9. Wang TF, Li A, Garcia D. Managing thrombosis in cancer patients. 

 2018;2(3):429-438. doi:10.1002/rth2.12102

10. Zuily S, Cohen H, Isenberg D, et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. 

 2020;18(9):2126-2137. doi:10.1111/jth.14935

11. Beyer-Westendorf J, Schellong SM, Gerlach H, et al. Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial. 

 2017;4(3):e105-e113. doi:10.1016/S2352-3026(17)30014-5

12. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. 

 2016;41:32-67. doi:10.1007/s11239-015-1317-0

13. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. 

 2012;366(21):1959-1967. doi:10.1056/NEJMoa1114238

14. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. 

 2014;383(9920):880-888. doi:10.1016/S0140-6736(13)61902-9

The American College of Chest Physicians' update of its CHEST guidelines for the treatment of VTE includes 29 guidance statements.

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 As we shift gears, we’re going to think about another product, called SER-109. This product differs from RBX2660 because it’s a capsule formulation, but it’s a narrow consortium. As opposed to RBX2660, which has spore- and non-spore-forming bacteria and a broader group of microorganisms, SER-109 is made up of firmicutes spores. It’s dosed as 4 capsules daily for 3 days, following the standard-of-care antimicrobial. Within this clinical trial, patients who had at least 2 recurrences of 

, and received fidaxomicin or vancomycin, had a brief washout period. They received a magnesium citrate bowel lavage, then were randomized to receive SER-109 or placebo.

They were followed for 8 weeks for occurrence, 24 weeks, or 6 months for safety. Overall efficacy within this treatment cohort was 88% for SER-109, vs 60% in the placebo arm, a statistically significant difference, and form fit function once again. Specifically, there were decreases in the proinflammatory 

 and increases in the firmicutes, specifically 

. Once again, we see that supplementation of the deficiencies helping the microbiota give that spore phase a specific knockout punch. RBX2660 and SER-109 have both finished phase 3 trials, but there are 2 products in phase 2 trials: CP101 and VE303. Bincy, can you walk us through those products and their data?

Sure. CP101 was a randomized, double blinded placebo-controlled trial. There’s going to be a phase 3 trial looking at CP101, which is a fecal matter transplant as a single oral dose, to look at prevention of recurrent 

 infection. The study is called PRISM4, so look out for that when you’re looking at abstracts in the future. They’re similar to all the other studies. This will be given after completing the standard-of-care antibiotics, after their most recent 

 recurrence. They’ll be randomized to get this vs placebo. The plan for the study is to evaluate 

 recurrence and safety up to week 8 as their primary end point. But we also want to look further out, to about week 24. That’s the goal of the study.

CP101 is an interesting product because it’s a broad consortium in a capsule form. It’s given as 10 capsules on a single day following the standard of care, vs VE303, which is a little different. VE303 is what we call a defined consortium, and it has 8 specific bacterial species. It also reported encouraging data at the major national conference in San Diego in May. That will also probably proceed to a phase 3 trial.

Drs Abraham and Feuerstadt share recent data with emerging live biotherapeutic products, SER-109, CP101, and VE303, for treatment of recurrent C difficile infection (rCDI).

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SER-109, CP101, VE303 for Treatment of Recurrent C. difficile Infection (rCDI)

With that fundamental concept in mind, let’s talk about RBX2660 and what it is. RBX2660 is what we call a broad consortium, meaning it includes broad range of microorganisms, including both spore- and non-spore-forming bacteria. It’s rectally instilled as a onetime dose. It’s phase 3 data have been presented in abstract form at a major national conference. But to understand the phase 3 data, we have to understand the phase 2 data. The phase 2 study structure included patients with at least 2 recurrences of 

. They were all given a standard-of-care antimicrobial and then randomized to either 2 doses of placebo a week apart—a dose of RBX2660, followed a week later by placebo—or 2 doses of RBX2660. They were then followed for 8 weeks for recurrence and for 2 years for safety. As a result of that clinical trial, a single dose of RBX2660 was proceeded ahead to the phase 3 trial because of its efficacy. Within the phase 3 trial, patients with a single recurrence of 

 all received standard-of-care antimicrobial. Then they were randomized to receive a placebo, or a single rectal installation of RBX2660, followed for 8 weeks for recurrence and 24 weeks for safety.

Essentially, the phase 3 and phase 2 trials had very similar designs, the same product, and the same diagnostics. As a result, it was decided that something called a Bayesian analysis would be used for this. A Bayesian analysis leverages data across 2 studies to create a larger data set. Essentially, they look at the signal of efficacy of the placebo arm and of the intervention arm to see if they’re similar in both trials. If they are, then you can leverage the data. That was the case with RBX2660: the overall efficacy was 70.4% for 2660 vs 58.1% in the placebo arm. The posterior probability of superiority was 0.986, achieving statistical significance. These are very exciting data for this product.

Several abstracts have been presented about this product. Bincy, at a major national conference in May 2022 in San Diego, California, 2 specific abstracts were presented. One was a subgroup analysis, and the other was an assessment of the Kaplan-Meier curve time to recurrence. Can you walk us through some of those data?

Sure, Paul. The first abstract looking into the subgroup analysis of this was yours, which you presented, so I’m honored to present your data. This subgroup analysis looked at a pool rate of treatment success. This was defined as recurrence free of 

 infection for 8 weeks post-treatment. You found that in the RBX treatment arm, this recurrence-free rate was 68.3%, compared with 55% with the placebo group. All these patients did get initial antibiotic treatment, but with the addition of the RBX, it was 68% recurrence-free. This was statistically significant, with a 

Another abstract looked at time to recurrence of infection using a Kaplan-Meier curve estimate. We looked at the 20% percentile of this. When they compared RBX with placebo, the time to recurrence was 14 days for placebo vs 30 days for the RBX group. This separation between the placebo and RBX was sustained through 6 months of assessment…. This was very similar to the phase 2 trial that they found.

In effect, what we’re seeing across those 2 abstracts is that 2660 seems to have efficacy across multiple subgroups, regardless of risk factor for 

. Even patients who received RBX2660 are still with that supplementation with some delayed recurrence, meaning there was some benefit there. There were a couple of other abstracts presented at the same conference. One looked at the metabolomics: what was happening metabolically as a result of RBX2660. The other looked at sick patients, those with multiple medical comorbidities. Teena, can you walk us through those abstracts?

Sure. At DDW [Digestive Disease Week], Ken Blount presented studies that looked at more than 600 clinical trial participants for reducing recurrent 

. The study reported both microbiome and metabolic analysis of participants in these three trials of RBX2660. The end point in these studies was no 

 at 8 weeks, and they looked at something called MHI, the Microbiome Health Index, which is a microbiome marker of postantibiotic dysbiosis and restoration. In all 3 trials, the MHI was restored from dysbiotic to healthy levels, which was amazing. That’s what the end point of the study was, and that’s what the real end point for our patients is. Clinical response to RBX2660 was associated with restoration of not only the microbiome but also the secondary bile acids. We talked about how the secondary bile acids are good for us because they inhibit the growth of 

. Both microbiome and bile acid restoration were in these big trials with more than 600 participants.

What about comorbidities? There was an interesting abstract that looked at comorbidities and the Charlson Comorbidity Index.

That was done by Dr Glenn Tillotson, and it also showed treatment success of RBX2660 in a randomized 2:1 trial. RBX2660 and placebo were used, and they showed a reduction of recurrent 

 in patients but underlying comorbidities. These were anti-CD3 trials, so it was considered a success if there was no recurrence at 8 weeks. They looked at the mITT [intent to treat] population, and there were about 262 participants. Across all comorbidity scores, including the Charlton Comorbidity Index, the patients who got RBX2660 showed consistent and greater treatment success compared with placebo, so it was both safe as well as efficacious.

With RBX2660, we’re seeing that the form fits function, and that the metabolomic effect that you’d want to see with microbiota replacement therapy with a live biotherapeutic product seems to work, regardless of your medical comorbidities. In fact, the group that had moderate vs severe comorbidities had very similar efficacy. That speaks to the fact that supplementing this deficiency can go a long way in reducing future recurrence.

Drs Feuerstadt, Abraham, and Chopra discuss clinical trial data for RBX2660, a live biotherapeutic product, in treatment of recurrent C difficile infection (rCDI), as well as data with RBX2660 that were presented at DDW 2022.

RBX2660 for Treatment of Recurrent C. difficile Infection (rCDI)

A new study has found that gestational diabetes mellitus is associated with an increased risk of overall and type-specific cardiovascular and cerebrovascular diseases in women, according to results published in the 

Data have estimated that the prevalence of gestational diabetes ranged from 1% to more than 30% and is associated with higher risks of adverse maternal and neonatal outcomes, including pre-eclampsia, preterm birth, still birth, large size for gestational age, and neonatal hyperinsulinemia. Although it typically resolves after birth, a growing number of studies suggest that the impacts of gestational diabetes can persist over time.

One earlier study found that women with gestational diabetes both with and without future development of diabetes have increased risks of coronary artery diseases. However, knowledge about specific cardiovascular diseases such as myocardial infraction and heart failure in women with gestational diabetes is still limited.

In order to quantify the risks of overall and type-specific cardiovascular and cerebrovascular diseases as well as venous thromboembolism in women with a history of gestational diabetes, investigators conducted a systematic review and meta-analyses.

Fifteen studies rated as moderate or serious risk of bias were included in the analysis. Out of 513,324 women with gestational diabetes, 9507 had cardiovascular and cerebrovascular disease. Out of more than 8 million control women without gestational diabetes, 78,895 had cardiovascular and cerebrovascular disease.

Compared with women without gestational diabetes, the researchers found that women with a history of gestational diabetes had a 45% increased risk of overall cardiovascular and cerebrovascular diseases. Specifically, women in this population had a 72% increased risk for cardiovascular diseases and 40% for cerebrovascular diseases.

The investigators also found that women with gestational diabetes showed increased risks of incident coronary artery diseases, myocardial infarction, heart failure, angina pectoris, cardiovascular procedures, stroke, and ischemic stroke. The risk of venous thromboembolism was observed to increase by 28% in women with previous gestational diabetes.

Subgroup analyses of cardiovascular and cerebrovascular disease outcomes were also performed and were stratified by study characteristics and adjustments. They showed differences by region, study design, source of data, study quality, adjustment for smoking, body mass index, socioeconomic status, and comorbidities.

However, the risk of cardiovascular and cerebrovascular diseases was attenuated, but remained significant when limited to women who did not develop subsequent overt diabetes. This heightened risk could not be solely attributed to conventional cardiovascular risk factors, although they were partially mediated by subsequent diabetes. The authors concluded that there is a need for early intervention in women at high risk of gestational diabetes mellitus and for continuous monitoring of women with gestational diabetes.

Xie W, Wang Y, Xiao S, Qiu L, et al. Association of gestational diabetes mellitus with overall and type specific cardiovascular and cerebrovascular diseases: systematic review and meta-analysis. 

https://www.bmj.com/content/378/bmj-2022-070244

Women with a history of gestational diabetes had a 45% increased risk of overall cardiovascular and cerebrovascular diseases.

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Gestational Diabetes Associated with Increased Risks of Cardiovascular, Cerebrovascular Diseases

New data presented at the American Academy of Ophthalmology (AAO) show that aflibercept 8 mg produced sustained improvements in vision and anatomic measures of retinal fluid across a 48-week treatment period with both 12- and 16-week dosing regimens.

Aflibercept injection 2 mg is indicted for the treatment of patients with neovascular age-related macular degeneration (wAMD), macular edema following retinal vein occlusion, diabetic macular edema (DME), and diabetic retinopathy. The PHOTON trial is investigating its use in DME and the PULSAR trial is investigating its use in wAMD.

DME is a common complication for individuals living with diabetes and occurs when high levels of blood sugar lead to damaged blood vessels in the eye that leak fluid into the macula. This can result in vision loss and, for some patients, blindness.

wAMD is a retinal disease that can affect people as they age. It occurs when abnormal blood vessels grow and leak fluid under the macula, which can damage it and cause vision loss. An estimated 1.1 million individuals in the United States have wAMD, and this is expected to double by 2050.

“Our presentations at AAO demonstrate that aflibercept 8 mg 12- and 16-week dosing regimens have achieved a high bar, sustaining improvements in visual acuity and anatomic measures of retinal fluid across 48 weeks in patients with diabetic macular edema and wet age-related macular degeneration,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, in a press release.

The PHOTON and PULSAR trials both met the same primary endpoint. Aflibercept 8 mg demonstrated non-inferiority in vision gains in both the 12- and 16-week dosing regimens after initial monthly doses at 48 weeks compared to an 8-week dosing regimen with the brand-name Eylea, a 2-mg dose of aflibercept. Furthermore, 91% and 89% of DME patients and 77% of wAMD patients, respectively, randomized to 12- and 16-week dosing maintained those intervals through 48 weeks.

The safety of aflibercept 8 mg was similar to Eylea in both trials and was consistent with the known safety profile from previous clinical trials. Comparing aflibercept 8 mg to Eylea, ocular adverse events occurred in 31% versus 28%, respectively, in the PHOTON trial and 38% versus 39%, respectively, in the PULSAR trial. There were no cases of retinal vasculitis, occlusive retinitis, or endophthalmitis in either trial. 

“These results were all achieved in patients who were rapidly initiated on extended dosing intervals with the vast majority not requiring regimen modification,” Yancopoulos said in the press release. “Altogether, the pivotal data support aflibercept 8 mg as providing a longer duration of action while maintaining a safety profile similar to Eylea.”

Aflibercept 8 mg positive pivotal results in diabetic macular edema and wet age-related macular degeneration presented at AAO. News release. Regeneron; September 30, 2022. Accessed October 4, 2022. 

https://investor.regeneron.com/news-releases/news-release-details/aflibercept-8-mg-positive-pivotal-results-diabetic-macular-edema

Aflibercept 8 mg demonstrated non-inferiority in vision gains in both the 12- and 16-week dosing regimens.

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Aflibercept Leads to Sustained Improvements in Vision for Patients with Diabetic Macular Edema, Wet Age-Related Macular Degeneration

When we think of practice change or implementing new patient care services, what comes to mind are often behemoth projects or things that require momentous changes in workflow, organizational culture, and use of advanced technology. However, pharmacists can draw upon their education and training, along with years of experience to seize an opportunity to make incremental changes that ultimately mean a lot for patients and also promote the profession and the business operation. These changes can be assisted sometimes through very simple adaptations or modified techniques of what we’ve always known and been doing.

Journal of the American Pharmacists Association

 examined the results of modified communication training on pharmacists’ dispensing of naloxone. The research was conducted in Illinois, where since 2015, regulators authorized entities such as pharmacies, pharmacists, and opioid overdose education and naloxone distribution programs to obtain and distribute naloxone, mucosal atomizer devices, syringes, and naloxone kits to an individual at risk of suffering an opioid-related overdose. However, even in spite of such autonomy, uptake by pharmacists to act had been slow.

The researchers hypothesized that active learning initiatives could help spur pharmacist knowledge and confidence to distribute naloxone. As such, they designed a Communication Technique Training (CTT) program. Pharmacists were recruited from 1 pharmacy chain (Jewel-Osco) in the Chicago area. The CTT was a simple intervention involving a patient case scenario activity and a pocket card. The pocket card was a quick reference with information on who to consider for naloxone distribution, morphine milligram equivalence, counseling points on side effects of opioids, how to start a conversation with patients on naloxone, and key phrases to use during the naloxone conversation. The case scenarios were designed to reinforce and apply concepts provided on the pocket card.

A total of 21 pharmacists from 6 pharmacies participated in the study. The researchers observed a statistically significant increase in naloxone dispensing rates pre- versus post-intervention, with approximately 6 units versus 24 units per pharmacist, respectively, during each 3-month period. This occurred despite a reduction in opioid dispensing during the same time period. The study saw no significant differences in naloxone dispensing rates between pharmacists varying by gender, years of work experience, or time of day (shift) upon naloxone dispensing.

In this study, an appeal to simplicity was made. In spite of previous training, pharmacists simply needed a bit of a confidence boost, a pocket card, and a few active learning exercises to substantially boost their dispensing of naloxone. Might the same be possible for uptake of other pharmacy interventions, whether it be dispensing of other products, refined methods of counseling, limited prescribing, or others? Evidence dictates that this is probably the case, but we cannot discern that just from this study. What we can discern is that a relatively simple intervention and investment by a pharmacy or group of pharmacies could possibly mean a great deal for the pharmacy staff and the patients they serve. Pharmacy managers can bear this in mind when entertaining new ideas and promoting a culture of innovation.

Additional information about Operations Management and Implementing Value-Added Pharmacy Services can be found in Pharmacy Management: Essentials for All Practice Settings, 5e.

Gandhi N, Hanes S, Candelario DM, Clough C, Highland J. Impact of a communication technique training on rates of naloxone dispensing. J Am Pharm Assoc. 2020;6(3):S37-S40.

 is a professor of social and behavioral pharmacy at Touro University California College of Pharmacy.

Dispensing naloxone provides an example of how small changes can make a significant difference.

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