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Apar Kishor Ganti, MD, is professor of internal medicine, Division of Oncology & Hematology at the University of Nebraska Medical Center. He specializes in research and care for patients with head and neck and lung cancer at the Omaha VA Medical Center and the University of Nebraska Medical Center. Dr Ganti is a member of the Respiratory Committee of the Alliance for Clinical Trials In Oncology, which is responsible for designing clinical trials in lung cancer. He chairs the Small Cell Lung Cancer Committee of the National Comprehensive Cancer Network. Dr Ganti spoke with 

) about current issues in small cell lung cancer, including the need to include patients in clinical trials who are more representative of those in clinical practice. This interview is lightly edited for clarity. 

: Let’s discuss recent data presented in April at the American Association for Cancer Research Annual Meeting regarding adebrelimab plus carboplatin and etoposide in extensive-stage small-cell lung cancer. What are your clinical takeaways from these results?

 The trial that you're referencing is a randomized phase 3 trial of adebrelimab

 which is a PD-L1 antibody, in combination with standard chemotherapy—carboplatin and etoposide—for the first-line treatment of extensive stage small cell lung cancer. In this study, 462 patients were randomized, with 230 to the adebrelimab and about 232 to the chemo arm. Investigators found that adding the checkpoint inhibitor to the chemotherapy significantly prolonged overall survival. The median overall survival was 15.3 months in the chemoimmunotherapy arm, compared with 12.8 months in the chemotherapy alone arm. Impressively, in the chemoimmunotherapy arm, almost 63% of patients were alive at 1 year, and 31% of patients were alive at 2 years; this compared with 52% and 17% in the chemotherapy alone arm. So, there was a significant improvement in overall survival and a higher proportion of patients were alive at 1 year and 2 years in the chemoimmunotherapy arm, compared to the chemotherapy arm. There were no major untoward side effects noted which we do not already know about. So, in that regard, the addition of adebrelimab significantly improved overall survival in a Chinese population with extensive stage small cell lung cancer. And that would be another standard of care, at least in China, for this patient population.

Now putting these things into perspective, this trial in the United States and actually worldwide, there have been 2 other studies that have shown that adding a checkpoint inhibitor to platinum etoposide chemotherapy improves overall survival in this group of patients—the CASPIAN study that looked at durvalumab with chemotherapy, and prior to that, the IMpower 133 study that looked atezolizumab with chemotherapy. Both showed almost similar findings in terms of improvement of overall survival in this patient population. So, my takeaway is this is a third trial that shows that an immune checkpoint inhibitor added to chemotherapy improves overall survival compared with chemotherapy alone. Will this study change practice? I'm not sure, simply because I did not see anything in this particular trial that is significantly different or an improvement over our current standards of care, which is the addition of atezolizumab or nivolumab to platinum etoposide chemotherapy. You could argue that if you look at the individual trials and the overall survival, numerically, this particular trial had a higher overall survival of over 15 months, whereas the 2 other trials were about 12.8 to 13 months. But again, the other thing to look at is in this trial, the comparator arm, or the standard of care arm also had a higher overall survival numerically compared to the 2 other studies that we discussed. And so, I'm not sure this study or this particular drug necessarily is better than the 2 that we currently have in practice. So, in that regard, I think it is “me, too” study rather than a real practice changer.

: As you mentioned, this study is in a Chinese population. Based on studies you see done domestically here in the United States, what are some of the greatest challenges you see when we are researching, and treating small cell lung cancer?

 Small cell lung cancer is an interesting disease in the sense that it is very aggressive from the beginning, and patients need treatment almost immediately once they're diagnosed—especially in extensive stage small cell lung cancer, where the median life expectancy without treatment is approximately 6 weeks. So, there is a push to try and get these patients treated as soon as possible. In that sense, any trial with extensive stage small cell lung cancer that is able to enroll these many patients must be commended. Because there's simply not that much time to treat these patients and we have to start treatment right away. The challenge is anyone who's enrolled patients onto clinical trials knows is that getting all the regulatory paperwork once you approach a patient for a trial takes some time. And that has been one of the biggest challenges in trying to enroll patients onto small cell lung cancer trials.

The other challenge is that most of these patients are quite sick, and so they need to be treated in the hospital. Many clinical trial designs want patients in good performance status, so by definition, if someone is hospitalized, their performance status is not all that great. So, these patients are automatically excluded from clinical trials. These are some of the major challenges that we have faced in trying to enroll patients onto small cell lung cancer clinical trials.

Our understanding of small cell lung cancer is fairly rudimentary compared with some of the other diseases that we deal with—the classic example being non-small cell lung cancer, lung adenocarcinoma. We know that lung adenocarcinoma has multiple different subtypes based on driver mutations. We know also in lung adenocarcinoma slightly more than half of the patients are eligible for targeted therapies. We have no such thing in small cell lung cancer, and one of the biggest reasons is our rudimentary understanding of the biology of small cell lung cancer. Why does that happen? It's because the biopsies that we get in small cell lung cancer are often very small needle biopsies, and most of those are full of dead cells. There are very few active living cells in a typical biopsy specimen that would enable us to understand the disease biology of this condition, and since we don't understand the disease very well, it's difficult to develop treatments that will target it. Having said that, there are current studies that are under way, which are looking at various subtypes of small cell lung cancer based on the molecular distribution. And those seem to have improved our understanding of the disease. We are slowly finding out that not all subtypes of small cell lung cancer are the same, and I'm hoping that in the future we will have better treatments for these various subtypes, similar to what we have for lung adenocarcinoma or breast cancer, for example.

: You talked about the barriers to clinical trial enrollment. How can we design clinical trials that are more inclusive to the true population of patients that you are treating day to day in small cell lung cancer?

 One of the big things that we need to do is liberalize the inclusion and exclusion criteria in clinical trials. For example, like I mentioned earlier, most of these studies will currently allow only good performance status patients to be enrolled into small cell lung cancer trials—for that matter, any clinical trial for any type of cancer—thus avoiding that and making it more liberal to replicate what we normally see in clinic would be very important. The American Society of Clinical Oncology has taken the lead in this and has put together some guidelines for clinical trials and drug development. And I think sponsors should be to take that into account and try to make criteria as liberal as possible compared with the current restrictive inclusion criteria.

: To shift gears a bit, let’s go back to the discussion of metastases in small cell lung cancer, specifically brain metastases. Could you characterize the incidence of brain metastases in small cell lung cancer, along with the treatment approaches are available to patients them?

 Brain metastases are very common in small cell lung cancer. If you look at the lifespan of life cycle of small cell lung cancer, the vast majority of patients will develop brain metastasis at some point in time during their cancer course. Estimates have ranged from anywhere between 50% to 60% to about almost a 100%. So, it is a significant problem in the small cell lung cancer. As far as treatment of brain metastases are concerned, I tend to look at brain metastases in terms of whether they are present at diagnosis or develop afterwards. If they're present at diagnosis and the patient is not symptomatic from their brain metastasis, my approach is to trying to treat them with chemotherapy and immunotherapy and have systemic treatment with this combination control the brain metastases. And that usually happens most of the time. If, on the other hand, the patient is symptomatic at diagnosis, then whole brain radiation has been the mainstay of treatment of brain metastasis. However, more recent studies have shown that similar to other cancers, stereotactic radiosurgery is almost equivalent; again, these approaches have not been tried compared in head-to-head in randomized clinical trials, but based on what we currently understand, stereotactic radiation therapy may be an option in patients who have limited metastatic disease. And that number seems to depend on individual to individual in terms of radiation oncologists. If you have few specific lesions, you could treat them with stereotactic radiation.

Another approach being researched is hippocampal sparing whole-brain radiation. The problem with whole-brain radiation is cognitive difficulties down the road; studies have found that if you spare the hippocampus and do not radiate the hippocampus, but radiate the rest of the brain, the memory issues that we typically see with whole-brain radiation are significantly reduced. That is the subject of an ongoing trial right now in prophylactic brain radiation, but it has the potential to improve our effectiveness while at the same time decreasing the toxicity of all brain radiation. We know that the hippocampus is not a common area for brain [metastases] to spread, so avoiding the hippocampus does not necessarily increase the incidence of brain metastases in those areas.

One issue that I like to talk about is this concept of prophylactic cranial irradiation (PCI). As I said, in small cell lung cancer, the vast majority of patients will develop brain metastases. There has been this concept of radiating the brain prior to the development of metastasis or prophylactically in an attempt to decrease the incidence of brain metastasis and associated morbidities. There have been studies done in the 90s, which suggested that there would be an improvement in overall survival with prophylactic brain radiation in patients with limited state small cell lung cancer. And in the early 2000s, there was a study out of Europe that looked at the same issue in extensive stage, small cell lung cancer patients, and found that prophylactic cranial radiation seems to be better in improving overall survival as opposed to no prophylactic brain radiation. However, about 5 years ago or so, there was a similar Japanese study that did not show a benefit for prophylactic cranial radiation. And so right now, there is a debate about PCI and there is an ongoing study underway in the United States called Maverick, which seeks to answer the question of is prophylactic cranial irradiation relevant in small cell lung cancer. Does it improve overall survival? What kind of side effects does it have? So, we eagerly hope to the results of that study.

: You've touched on some emerging clinical trials. What other treatments or upcoming trials are you most looking forward to, to help better understand small cell lung cancer?

There are a number of various agents currently being studied. And there was a recent study that I saw a press release for using a novel class of agents called TIGIT inhibitors, T-I-G-I-T, which is a type of immune therapy in combination with immunotherapy. And that study did not show an improvement in progression-free survival when compared to chemo immunotherapy with atezolizumab. But I think that that group of drugs that TIGIT inhibitors, we need to study them and not throw them away. So that is an exciting group of drugs that I would like to see. There are other novel combinations of immunotherapy agents, which I would like to see there is a drug called relatlimab, which is a LAG3 inhibitor. It has been approved from melanoma that seems to improve the efficacy of immune checkpoint inhibitors. So that is something that I would interested in, but more importantly, I'm interested in future studies looking at various subtypes of small cell lung cancer that I mentioned earlier, and targeted therapies driven specifically to those individual subtypes.

We are slowly starting to understand the different subtypes of small cell lung cancer. There may be specific ones that may be more responsive for immunotherapy, and there are other subtypes that I have potential targets for which we could focus on using agents directed against the targets. So those are what I'm looking forward to in the near future.

: Would you like to offer any closing thoughts?

I know I talked a lot about how small cell lung cancer is a recalcitrant disease, and we need to do better in times of identifying better treatments. But one thing that I'd like to emphasize is that our uptake of the currently available treatments itself is not all that great for various reasons. People have done real-world studies and have found that a significant minority of patients don't get guideline specific treatment based on what we know about small cell lung cancer today. So yes, while we have a long way to go in terms of research, I would emphasize that patients who are currently being diagnosed and treated with small cell lung cancer should get the guideline appropriate care that they need and deserve in order to try and improve outcomes.

Articles

Apar Kishor Ganti, MD, who chairs the Small Cell Lung Cancer Committee of the National Comprehensive Cancer Network, spoke with The American Journal of Managed Care® (AJMC®) about current issues in small cell lung cancer, including the need to include patients in clinical trials who are more representative of those in clinical practice.

Dr Apar Kishor Ganti: More Inclusive Clinical Trials Needed in SCLC

A recently published health care spending analysis found working-age Americans with commercial health insurance and 

 (SCD) pay almost 4 times more in out-of-pocket (OOP) medical costs over their lifetimes, a total of $44,000, compared with those without the disease.

In addition, insurers pay $1.7 million on average for each individual with SCD, compared with those without. The study was published in 

SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 people, with a high degree of morbidity and mortality. According to the CDC, SCD affects 1 out of every 365 Black or African American births and 1 out of every 16,300 Hispanic American births.

Researchers analyzed commercial health insurance claims from the Truven Health Marketscan database filed between 2007-2018 by 20,891 patients with SCD younger than age 65, and compared those claims to those filed by 33,588 people matched by age and sex without SCD in the Medical Expenditure Panel Survey. Results were adjusted for average life expectancy.

The mean age of patients with SCD in this study was 25.7 and 58% were female. Average life expectancy was age 51 for women and age 50 for men.

Without SCD, the average life expectancy was age 62 for women and age 60 for men.

Those with SCD had more medical appointments, more urgent care and emergency medical visits, and more prescriptions, compared with those without the disease. Patients had higher OOP medical costs, which averaged about $1300 each year.

There was no significant difference in total medical costs or OOP costs between males and females.

Costs peaked between ages 13-24, a time when many individuals with SCD transition from pediatric to adult care and may have additional medical visits. Costs declined as patients aged.

The peak in costs for adolescents and young adults could be explained by patients having problems accessing SCD specialists as well as with providers who do not understand their needs, the authors said.

Patients with SCD have less access to care than patients with other inherited diseases, the CDC has noted.

In addition, patients with SCD may experience a backlash when trying to obtain pain relief during a vaso-occlusive crisis and may encounter institutional racism in emergency departments or elsewhere, which can result in patients switching providers.

The authors noted that because they limited their review to commercial health insurance, which is used by just one-third of those living with SCD, health care costs may vary. 

 nationwide for hospitalizations and ED visits, according to a study published last year.

Future studies should include the indirect costs of living with SCD, including those associated with family caregiving and reduced productivity, the authors said. Some researchers have estimated that patients with SCD 

The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, supported the study, along with the Cure Sickle Cell Disease Initiative, an NHLBI-led research partnership created to identify curative SCD therapies that could be used in clinical research studies between 2023-2028.

Johnson KM, Jiao B, Ramsey SD, Bender MA, Devine B, Basu A. Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance. 

. Published online May 16, 2022. doi:10.1182/bloodadvances.2021006281

The findings highlight the significant financial burden of sickle cell disease.

Patients With SCD Face OOP Costs 4 Times Higher Than Those Without the Disorder

Julia is an associate editor of The American Journal of Managed Care

since 2022 after receiving her Bachelor's degree at Rutgers University–New Brunswick in English and Creative Writing.

 found an association between patients with chronic obstructive pulmonary disease (

) and mucosal-associated invariant T (MAIT) cell count in relation to risk of hospitalization. This association was independent of forced expiratory volume in 1 second (FEV

) and categorization according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

The study included patients with COPD from the Tools for Identify Exacerbations study in Uppsala. Patients were excluded if they had an established diagnosis of asthma, the asthma-COPD overlap syndrome, speech difficulties, dementia, psychotic disorders, and severe comorbidities associated with expected survival of less than 12 months. Patients with long-term oxygen treatment were also excluded.

Patients were classified according to the GOLD 2017 guidelines based on the COPD Assessment Test, which is a questionnaire meant to assess the impact of COPD on a patient over time. This assessment was conducted during the 3-year follow up.

Patients were recruited and blood was sampled while they were in the stable disease phase. All patients had 3 years of follow-up to record all-case hospitalizations. Patients who required hospitalization in the 3-year follow-up were classified as hospitalized patients and compared with patients who were never hospitalized. Hospitalized patients had lower MAIT cell count at study inclusion but did not differ in CD8 or CD4 T cell counts. Patients who were hospitalized also had lower MAIT cell percentage.

Patients who were hospitalized had MAIT cells that demonstrated a more activated phenotype with higher CD38 expression and MAIT cells and conventional CD8 T cells did not differ between hospitalized and never hospitalized patients.

A multi-variable logistic regression analysis found that MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression in both MAIT and CD8 T cells were all associated with risk of hospitalization. The FEV

 measure did not correlate with MAIT cell count, MAIT cell frequency, or CD38 or LAG-3 expression of MAIT cells. According to the findings, MAIT cells do not mirror the severity of airflow obstruction and MAIT cells may reflect a FEV

-independent immunological dimension of COPD.

In a logistic regression analysis, hospitalizations were more likely in patients with higher CD38 and LAG-3 expression in MAIT cells that was independent of treatment with inhaled corticosteroids. This test was done due to previous studies finding that patients with COPD treated with inhaled corticosteroids had lower MAIT cell frequency compared with steroid-naïve patients.

There were some limits to this study. The focus of this study was on all-cause hospitalizations rather than COPD exacerbations, which may have limited the study. MAIT cell data was only recorded at a single time-point at baseline when patients were in their stable phase which prevented detecting changes over time. There is also the possibility of selection bias due to the nature of the study.

The researchers concluded that MAIT cell count and expression of the activation markers of CD38 and LAG-3 on MAIT cells in peripheral blood of patients with COPD were associated with risk of hospitalization.

“Our findings support the hypothesis that MAIT cells might reflect a novel FEV

-independent immunopathological dimension in the complexity of COPD,” the authors wrote.

Pincikova T, Parrot T, Hjelte L, et al. MAIT cell counts are associated with the risk of hospitalization in COPD. 

. 2022;23:127. doi:10.1186/s12931-022-02045-2

Mucosal-associated invariant T (MAIT) cell count was associated with risk of hospitalization in patients with chronic obstructive pulmonary disease (COPD) independent of forced expiratory volume during a 3-year follow-up.

MAIT Cells Linked With Hospitalization in Patients With COPD, According to Study

Sharon Phares, PhD, MPH, chief scientific officer of the National Pharmaceutical Council, describes the lasting equity concerns regarding the use of health technology assessments (HTAs) for women.

What about other equity issues? Are HTAs considering equity systematically?

So, currently, they are not. There has been a lot of discussion in the HTA community around trying to address disparity in a better way. For instance, a medication that is found to be less valuable may be a medication that's more useful for someone who is poor because they have to take it less often. So, you don't have as many scheduling issues or need the same handling, like they don't need a special refrigerated space for that if you're sharing housing with other people or if you have homelessness issues. But also, to be able to address how medications impact the outcomes of different groups differently. So, this is where we need more real world evidence to come into play to really look at differences by various groups.

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Dr Sharon Phares Explores Equity Issues Regarding HTAs Among Women

Karen Kobelski is the Vice President and General Manager of Clinical Surveillance, Compliance & Data Solutions at Wolters Kluwer. She brings more than 25 years of experience to her position, which expands her previous leadership role over the Safety & Surveillance group to also include the Health Language portfolio of data normalization solutions.

Vikram Savkar is the senior vice president and general manager, Medicine Segment of the Health Learning, Research & Practice business, at Wolters Kluwer. In his role, Savkar leads product innovation to advance the digital evolution of information and productivity solutions for medical researchers, clinicians, medical students, and faculty to inform evidence-based decisions on care and outcomes.

Real-world evidence (RWE) is playing an increasingly important role in life science research due to its potential to enhance understanding of treatment effects, disease burden, patient safety, and indications for use. These benefits became especially clear when the COVID-19 pandemic created unprecedented urgency in the scientific community and drove researchers to quickly leverage accessible patient data from sources outside of formal research studies.

Using RWE alongside traditional research methods in a complementary manner, while not the traditional approach, ultimately delivered the rapid insights needed to better understand the SARS-CoV-2 virus and accelerate the development of life-saving vaccines and treatments for millions of patients.

Although the pandemic showed that RWE can jumpstart, and even direct, research efforts, conventional peer-reviewed medical research remains at the heart of the investigational journey. These experiments take longer to conduct, verify, and publish; however, they are also carefully executed and well-controlled, offering the scientific rigor and repeatability necessary to confidently align clinical practice with the latest medical evidence.

Both sources of data have distinct advantages and offer an increased level of understanding to ensure patients receive the best possible care, but they mustn’t be thought of as mutually exclusive in surfacing new clinical discoveries.

The FDA acknowledges the value of real-world data sources such as electronic health records (EHRs), patient disease registries, wearable devices, genomic data sets, medical claims registries, and social determinants of health (SDOH). Regulators, however, also have very specific requirements around how these sources can be used as evidence to drive conclusions. Specifically, the data must be high quality, meaning they are complete, transparent, nonbiased, and able to be codified to industry standards for broad use.

Once these standards are met, stakeholders can apply data analytics to produce evidence for clinical interpretation. We’ve seen this process work as intended in supporting new drug indications and in surfacing evidence backing the use of a completely new drug, as was the case for the COVID-19 vaccine.

Making real-world data regulatory grade is no easy feat, which creates a hurdle to realizing the full potential of these critical insights efficiently and at scale. Fortunately, emerging technology that leverages AI and natural language processing is helping to accelerate the transformation of real-world data into useable evidence.

As advances in this space continue to mature and become more accessible, widely used, and cost-effective, the power of RWE in driving research and fueling medical discoveries will only grow. Today, we’ve barely scratched the surface in realizing the value of massive troves of health data and there is much more opportunity ahead.

Karen Kobelski is the vice president and general manager of Clinical Surveillance, Compliance, & Data Solutions at Wolters Kluwer.

The potential for RWE is vast because it is derived from patterns found across a very broad data set, but peer-reviewed literature is a much more controlled exercise from the start. The medical community inherently trusts in these carefully calculated experiments, as do the patients they serve. Implementing the resulting medical evidence into practice is therefore a more straightforward, albeit longer, process.

The quality control measures that define peer-reviewed medical research are widely regarded as the best way of ensuring medical treatments are safe and effective for patients. This rigor is necessary and valuable to ensure evidence can stand the test of time, but today we know this care and stringency must be balanced with the need for speed, particularly when patients’ lives hang in the balance.

The tension between rigor and speed was best evidenced by the spotlight on preprints at the height of the pandemic, which both challenged and reinforced the skepticism stakeholders had about medical research that had yet to be peer-reviewed. RWE became a major feeder for preprint work, with observational studies gleaning insights from COVID-19 patient outcomes, contagion trends, and more. In the end, peer-reviewed research has a more defined role than ever before, after the crucible of COVID-19, but the utility of RWE became much clearer as well.

As an industry, it would be advantageous to foster an environment in which these 2 research methods can work hand-in-hand. For example, it is now possible for RWE to help redirect formal research when appropriate or to retrospectively expand upon previously published research, creating entirely new data models for discovery and therapeutic development.

With these and many other potential applications in mind, trust remains a cornerstone of clinical discovery that can’t be overlooked. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system is commonly used to assess the quality of evidence in new medical research.

Creating a similar system uniquely tailored for RWE could provide the transparent framework the scientific community needs to embrace these data sources. Such a system would help in developing and presenting summaries of evidence and providing a systematic approach for making clinical practice recommendations or offering guidance for more focused research. With developments like this already in the works, we may see RWE rapidly evolve to produce meaningful, vetted insights in which stakeholders can be confident.

Vikram Savkar is the senior vice president and general manager, Medicine Segment of the Health Learning, Research & Practice business, at Wolters Kluwer.

As technology and data analytics capabilities advance, so too will the exciting field of RWE. Similarly, the established research process of peer review is evolving with the increased emergence of preprints and new strategies for incorporating discoveries into practice faster. It’s time that researchers and other industry stakeholders acknowledge the power of using different data sources in a complementary manner to tackle some of health care’s most difficult problems.

 from when new medical discoveries are made to when they are adopted into clinical practice, often requiring several generations of publications. Imagine a COVID-19 vaccine only getting widely adopted in 2038. Modern medicine can do better: COVID-19 was a rich training ground where researchers cautiously set aside some long-held principles for the sake of accelerated discovery, but we can go so much further from here.

Research as we know it today, done in isolation and seemingly protected from RWE, may one day soon be the exception vs the norm, as our ability to amass and extract insights from RWE grows.

Research as we know it today, done in isolation and seemingly protected from real-world evidence (RWE), may one day soon be the exception vs the norm, as our ability to amass and extract insights from RWE grows. It’s time that researchers and other industry stakeholders acknowledge the power of using different data sources in a complementary manner to tackle some of health care’s most difficult problems.

Contributor: Fusing Real-world Evidence With Peer-Reviewed Research

Gianna is an associate editor of The American Journal of Managed Care

 since 2019 and has a BA in philosophy and journalism & professional writing from The College of New Jersey. 

We have a lot of future potential treatments for this disease, said Gary Owens, MD, president of Gary Owens Associates.

Can you decribe recent advancements in therapies for pulmonary arterial hypertension (PAH)?

One that comes to mind right off the top of the head is Ralinepag. It's a selective, non-prostanoid prostacyclin receptor agonist. That's quite a mouthful by the way, and it's in phase 3 studies now. It's part of the ADVANCE clinical program, and it's really going to assess this agent, the impact on morbidity and mortality. And just as an aside, most of the agents we use to treat PAH right now improve outcomes, improve patient quality of life, improve symptoms, but very few of them have shown any impact on mortality. So, you know, this trial hopes to show some impact on mortality.


Another agent out there in the pipeline is sotatercept. It's a selective ligand trap for members of the [transforming growth factor β (TGF-β)] superfamily. It rebalances signaling, and hopefully will restore vascular homeostasis. So, you know, maybe even this drug has a potential to reverse vascular remodeling. Now, the difference here is it is a [subcutaneous] injection, [it] needs to be given fairly frequently, at least in the clinical trials, once every 3 weeks. It's in phase 2 trials in the STELLAR program. And they're really looking at adding this agent on to background therapy and here, it looks like those trials should read out towards the end of 2022. The primary endpoint of the trial is going to be change in baseline of the 6 minute walk test, as well as improvement in the WHO functional categories. [It's] also looking at time to death or clinical worsening for this drug.


And then there's some other agents that are in development that are not quite as far along. One is an actual drug we know well in the treatment of [chronic myeloid leukemia], a tyrosine kinase inhibitor, imatinib and they're looking at an inhaled version for that because it targets platelet-derived growth factor, or PDGF. And that's being investigated.


One with another bit of a tongue tying name is pemziviptadil. It's a subcutaneous vasoactive intestinal polypeptide. Bardoxolone is the nuclear factor erythroid 2–related factor 2 (Nrf2) drug and then there's even an albumin bound mTOR inhibitor investigation.


So we have a lot of potential future treatments for this disease, many of which will be add-on therapies or in some cases, replacement therapies for existing drugs. And I mean, the ultimate hope is to improve not only clinical outcomes, but to show impact on mortality. So certainly a ripe area for investigation and an area I think payers have to be very cognizant of because it's going to be continuously changing.

Gary Owens, MD, president of Gary Owens Associates, describes mechanisms, trials of treatments in the works for pulmonary arterial hypertension (PAH).

Dr Gary Owens Describes Treatments in the Pipeline for PAH

Steven Yeh, MD, professor of ophthalmology at the Truhlsen Eye Institute at the University of Nebraska Medical Center, talks about what he sees in the future of suprachoroidal administration and other unmet needs in ophthalmology.

What else do you see in the future for suprachoroidal administration?

This is a really exciting time when we think about drug delivery, and there are a number of studies that are underway looking at suprachoroidal drug delivery for other indications. After its FDA approval for the treatment of uveitis, it's also being studied for other conditions, including diabetic retinopathy, macular degeneration, [and] tumors that affect the eye. As we understand the medication's efficacy and its safety signals for other indications, I see a future in suprachoroidal drug delivery for a number of retinal disease conditions, as well as ocular inflammation.

This is the first FDA-approved medication where medication is being delivered into the suprachoroidal space. Uveitis, as we know, is a vision-threatening disease indication and the visual acuity benefits, as well as the benefits to the anatomy of the eye, were really substantial and benefit patients both in terms of visual acuity and in terms of quality of life. So we're really excited about this technology and how it looks in the clinic in the future.

What are some other unmet needs in ophthalmology?

As we know that suprachoroidal delivery is effective for the treatment of non-infectious uveitis and, in particular, retinal swelling associated with non-infectious uveitis, we're going to continue to use this technique in other indications. So it's important that we continue to look at clinical trial data for the other indications where suprachoroidal drug delivery is being explored, including retinal disease conditions that are more common, such as age-related macular degeneration, diabetes, ocular tumors, and potentially disease-specific outcomes within the realm of intraocular inflammation and uveitis. There are other unmet needs certainly in the field of retina and uveitis care, and so we look forward to these results in the future.

Dr Steven Yeh Discusses Future of Suprachoroidal Drug Delivery

Miruna Sasu, PhD, MBA, president and CEO of COTA Healthcare, discusses 3 ways in which the FDA can provide, and has provided, assistance on the capture of real-word data (RWD) in electronic medical records.

Can you go into more detail on what else the FDA needs to do to facilitate use of real-world data?

So, they've done a lot. I used to work for the federal government, so I’m a big believer that they need to see industry innovate and then respond to that. And they've done a lot so far. I think one thing I really respect that they did was ensuring the enablement of electronic medical records in general—that was a big deal.

And second was the guidance of how the real-world data should be used for clinical trial regulatory approvals. I think that was a big deal as well—just issuing that guidance to say, “We’re looking and we’re doing this work, and we are open to receiving external controls and databases,” and so on.

The third thing that I think that they can do and should do goes along with the electronic medical records piece. Now that we're going into using electronic medical records for clinical trials and augmenting clinical trials, to ease the burden on patients, to ease the burden on providers, one area of expansion of that would be to capture the data in a way such that it looks more like a clinical trial. And that is at the provider level. Statisticians have a saying, “Garbage in, garbage out.” So, if the electronic medical record, the input into that, is really, really messy, you can only do so much to clean it up and place it in a database for use. But if, at the source, when entering the data, you were very, very clean about how you entered it—and it was processed in an almost clinical trial–like way—then what you can segment out of that data is a lot cleaner and better.

So, I would argue that the FDA should help us figure out a way and help providers figure out a way to work on their electronic medical record data capture, so that it looks a little closer to clinical trial data.

Miruna Sasu, PhD, MBA, president and CEO of COTA Healthcare, discusses 3 ways in which the FDA can provide, and has provided, assistance on the capture of real-word data (RWD) in electronic medical records.


Dr Miruna Sasu: The FDA Can Help to Clean Up and Improve RWD Capture

A new report suggests the gut microbiota of patients with type 1 diabetes (T1D) are significantly different from those of healthy controls, a finding that could play an important role in understanding the pathogenesis of the disease.

The Journal of the Federation of American Societies for Experimental Biology

It is not yet clear exactly what factors lead to the development of T1D, but study co-author Kartik Shankar, PhD, of the University of Colorado Anschutz Medical Campus, and colleagues explained that both genetic factors and immune dysfunction are believed to play a role.

In recent years, the scientific community has paid increasing attention to the potential influence of the gut microbiota on immune dysfunction. The microbiota is believed to play a role not only in a person’s risk of developing recurrent infections such as 

, but also in developing certain types of diseases, such as autoimmune disease.

Shankar and colleagues wanted to see whether there might be a link between the gut microbiome and the risk of developing T1D. They also sought to determine the associations, if any, between gut microbes and clinical and dietary factors in T1D, and to see whether certain features might enable the prediction of T1D.

The investigators recruited 30 adolescents with T1D, along with 35 adolescents without T1D, to serve as healthy controls. The patients each provided stool samples, which then underwent microbial profiling using deep shotgun metagenomic sequencing. The authors analyzed the results to determine the type and abundance of specific bacterial species in the samples, and then conducted correlation analysis and modeling to see whether specific features might be predictive of the disease.

The analysis showed that patients with T1D had greater alpha diversity than healthy adolescents, based on the Simpson Diversity Index. Alpha diversity is a measure of the overall heterogeneity within a sample. Beta diversity, on the other hand, was similar between the 2 cohorts. Beta diversity refers to the diversity between individual samples.

Using linear discriminant analysis effect sizes, the investigators found that there were significant differences in the microbial communities of the 2 groups at different taxonomic levels. Seven taxa were enriched at the species level in patients with T1D, while 3 were enriched in healthy controls.

“Further, 33 out of 400 microbial metabolic pathways were significantly different between the 2 groups,” the authors found. “Importantly, biosynthesis of amino acids, vitamins, enzyme cofactors, and electron carriers were downregulated whereas fermentation pathways were upregulated in adolescents with T1D as compared to healthy adolescents.”

A further analysis suggested that specific bacterial species were linked with glycated hemoglobin levels, skin carotenoids, dietary factors, and physical activity, the investigators said, but they added that “most of the bacterial species associated with these measures were different between the 2 groups.”

Collectively, the authors said the evidence suggests “extensive alteration” in both the composition and the functional capacity of the gut microbiota of people with T1D. They said their findings offer new insights that could help investigators better understand and predict how the disease develops.

Pon Velayutham AB, Mokhtari P, Metos JM, Jambal P, Shankar K. Gut microbial and metabolic signatures are altered in adolescents with type 1 diabetes.

. Published online May 13, 2022. doi:10.1096/fasebj.2022.36.s1.r3170

The findings could lead to new insights into how type 1 diabetes develops.

Study: Gut Microbiota of People With T1D Varies Significantly From Healthy Controls

Drawing Distinctions Between Mental Health, Gun Control

On Tuesday, an 18-year-old gunman killed at least 19 children and 2 adults and injured others at Robb Elementary School in Uvalde, Texas. The shooting—which was the deadliest elementary school shooting since Sandy Hook in 2012—has renewed a debate about gun control and mental health in the United States, 

. According to mental health experts, individuals experiencing mental health issues are more likely to be victims of gun violence rather than act perpetrators, and directly linking mental health to gun violence adds to other issues surrounding mental health. Experts also argue that mental health screening should be part of the gun purchase process.

CVS to Stop Filling Controlled-Substance Prescriptions for Cerebral, Done

CVS announced that it will stop filling controlled-substance prescriptions ordered by clinicians who work for Cerebral Inc and Done Health beginning Thursday, 

 reported. The 2 telehealth startups treat tens of thousands of patients for ADHD and gained popularity during the COVID-19 pandemic, prescribing stimulants such as Adderall that clinicians were previously prohibited from prescribing without an in-person visit. In March 2022, it was reported that employees of the 2 companies said clinicians were pressured into prescribing stimulants and that evaluations were not thorough enough—claims that the companies have denied. This announcement follows last week’s news that Cerebral will stop prescribing almost all controlled substances and will replace its CEO.

FTC Launches Inquiry Into Ongoing Baby Formula Crisis

The Federal Trade Commission (FTC) announced Tuesday that they have launched an inquiry into the ongoing baby formula shortage in the United States. 

, this investigation aims to understand the factors leading up to the crisis, including how the concentration in the baby formula market came to be, and the fragility of supply chains. The inquiry will also look into whether and how families are being taken advantage of by deceptive, fraudulent, or generally unfair business practices.

The latest mass shooting in a school has sparked a renewed a debate on mental health and gun control in the United States; CVS will stop filling controlled-substance prescriptions ordered by clinicians who work for telehealth companies Cerebral and Done; the FTC launched an inquiry into the ongoing baby formula shortage.

What We’re Reading: Gun Violence, Mental Health; CVS to Stop Fills for Cerebral, Done; FTC Probes Baby Formula Shortage

Researchers are calling for a review and possible reconsideration of diuretic use among patients whose 

 (HF) is stable and who are experiencing thirst or severe thirst following a regimen of loop diuretics.

, and they recommend clinicians review fluid restriction in these patients to alleviate their thirst by considering such influential factors as actual fluid intake and sodium intake.

“There is ongoing debate on the role of fluid restriction in HF management,” the authors wrote. “There is only scarce data about the relationship between (severe) thirst, actual fluid intake, and other variables that can be related to thirst in a stable HF population.”

The 100 patients covered by the authors’ cross-sectional analysis were receiving care at 1 of 2 outpatient HF clinics in the Netherlands, Hospital Group Twente in Almelo and Hengelo; they were recruited between January 2017 and November 2018, and all had New York Heart Association class II (74%) or class III-IV (23%) disease. Thirst was assessed using a visual analogue scale (VAS) of 0 (no thirst) to 100 (worst possible thirst), and thirst-related distress was evaluated via the Thirst Distress Scale-HF, which contains 9 statements on thirst and a scale of 1 (strongly disagree) to 5 (strongly agree). After 3-day food diaries were completed (n = 68) and following 24-hour urine collection, the patients were subdivided into severe and low thirst groups.

Among the study population (mean [SD] age, 72 [12] years; 40% female), 25% were experiencing severe thirst and 94% had their fluids restricted. Thirty-seven percent were restricted to between 1500 and 2000 mL, and 32% were restricted to 1500 mL. The overall mean thirst score was 28 (25), with severe thirst defined as a VAS score above 49.

A potential link was seen between a higher dose of loop diuretics and higher urine output with severe thirst. There was a 2.25-times greater risk of severe thirst seen with loop diuretics (odds ratio [OR], 3.25; 95% CI, 1.01-10.45; 

 = .048) and a slightly increased risk of 0.002 seen with higher 24-hour urine output (OR, 1.002; 95% CI, 1.00-1.003; 

Within the food diary group, higher sodium intake, a higher dose of loop diuretics, and excess fatigue were linked to severe thirst. The risk associated with higher sodium intake was 0.002 (OR, 1.002; 95% CI, 1.001-1.003; 

 = .003); with higher-dose loop diuretics, 21.69 greater odds were evident (OR, 22.69; 95% CI, 2.78-185.04; 

 = .004); and with fatigue, there was a 10.2-times greater risk of severe thirst (OR, 11.2; 95% CI, 1.54-82.12; 

Among those who completed a food diary, the mean sodium intake was 2168 (958) mg and the mean fluid intake, 1823 (459) mL. For those classified as having severe thirst, the mean fluid intake ranged from 2026 to 1903 mL from days 1 to 3, while for those with low thirst, their fluid intake ranged from 1853 to 1739 mL, respectively.

Most of the patients (53%) had HF with reduced ejection fraction, defined in this study as a left ventricular ejection fraction below 40%.

Overall, 62% did not adhere to their prescribed fluid intake, 43% drank more fluids, and 19% drank less than what was prescribed. The mean thirst score was lowest in patients who adhered to their prescribed fluid intake, at 23 (17) compared with 26 (25) in the patients who drank less and 34 (26) in those who drank more than prescribed.

However, the greatest difference was seen between patients with severe thirst, whose mean thirst score was significantly higher vs the low-thirst group: 53 (29) vs 28 (23). These patients also experience fatigue at a rate that was more than twice vs the rest of the study population: 64% vs 31%.

“We realize that there could be other variables that might influence the severity of thirst in HF patients,” the authors concluded. “However, this is the first study in which the actual fluid and sodium intake is related to thirst in HF patients.”

They recommend that future studies verify their findings in other patient populations, taking into consideration the influence of both food intake and weather. In addition, clinicians should continuously review prescribed diuretic doses and perhaps update fluid restriction guidance.

van der Wal MHL, Jaarsma T, Jenneboer LC, Linssen GCM. Thirst in stable heart failure patients; time to reconsider fluid restriction and prescribed diuretics. 

 Published online May 12, 2022. doi:10.1002/ehf2.13960

Thirst outcomes were investigated among patients with stable heart failure (HF), due to the limited data available on this relationship and how it, along with fluid and sodium intake, influences clinical outcomes in this population.


New Research Calls for a Reconsideration of Loop Diuretic Use, Fluid Restriction in HF

Worse baseline cognitive function, cognitive decline, and increased risk of incident cognitive impairment without dementia (CIND) and dementia demonstrated an association with mild 

A longitudinal cohort study was conducted with the ASPREE trial population in Australia and the United States, which was a randomized, placebo-controlled trial of low-dose aspirin in health older individuals with a mean of 4.7 years of follow-up. Patients who were free from cardiovascular disease (CVD), physical disability, dementia, and being expected to survive for at least 5 years were included. Patients with a self-report or physician diagnosis of dementia at recruitment were ineligible.

Cognitive assessments were administered by trained staff at baseline and year 1 and then biennially. The cognitive assessments included the Modified Mini-Mental State Examination (3MS), a 100-point measure of global cognition; the Delayed Recall component for episodic memory of the Hopkins Verbal Learning Test-Revised (HVLT-R); the Controlled Oral Word Association Test (COWAT); and the Symbol Digit Modalities Test (SDMT).

There were 18,560 and 18,131 of the 19,114 ASPREE participants who had baseline measures of eGFR and UACR respectively. The median age of the participants was 74 years, 56% were female, 74% had hypertension, and 11% had diabetes. The median (IQR) estimated glomerular filtration rate (eGFR) was 74 (63-84) mL/min per 1.73 m2; median urine albumin-creatinine ratio (UACR) was 0.8 (0.5-1.5) mg/mmol (7.1 [IQR, 4.4-13.3] mg/g).

In adjusted analyses, baseline eGFR was not associated with scores on any of the 4 cognitive tests. UACR greater than or equal to 3 mg/mmol (greater than or equal to 26.6 mg/g) was significantly associated with baseline scores for 3 of the 4 tests in adjusted models, with the association with SDMT clinically significant (b, –1.24; 95% CI, –1.66 TO –0.81) as it was more than double the size of the mean change in SDMT in all participants.

A mean of 3.2 annual cognitive assignments per participant was performed during the follow-up. eGFR at baseline was statistically associated with decline of 3MS and SDMT scores but the associations were clinically negligible. Baseline albuminuria was associated with cognitive decline on all cognitive tests except the COWAT, and most strongly associated with the SDMT (b, –0.76; 95% CI, ­–1.18 to –0.33).

There were 2777 cases of CIND and 563 cases of incident dementia with eGFR or UACR measures in the median 4.7 years follow up. There was no statistic significant association between baseline eGFR and time to CIND or dementia. Both binary and continuous measures of UACR were associated with increased risk of incident CIND and dementia. Baseline albuminuria demonstrated a 19% increased risk of CIND (HR, 1.19; 95% CI, 1.07-1.33) and 32% increased risk of incident dementia (HR, 1.32; 95% CI, 1.06-1.66).

This study had some limitations. There was a minor decline in cognitive function during the follow-up overall which could have decreased the ability to detect associations between kidney function and cognitive decline. Fewer participants had cognitive assessments as the study went on as some were recruited later in the study and others were not willing to participate in cognitive testing as they were aware of their own cognitive decline.

The results are likely not generalizable to older populations with a higher risk of CVD and advanced CKD. Urine samples were also harder to obtain in the older population.

The researchers concluded that mild albuminuria was associated with lower baseline performance, decline on tests of global cognitive function, and increased risk of incident CIND and dementia.

“Our findings suggest that screening global cognitive tests could be considered for those greater than or equal to 70 years with a UACR of greater than or equal to 3 mg/mmol and without an eGFR of less than 45 ml/min per 1.73 m2 to identify those at highest risk of cognitive decline and dementia,” the authors wrote.

Murray AM, Thao LTP, Ryan J, et al. CKD biomarkers, cognitive impairment, and incident dementia in an older healthy cohort. 

. 2022;3:435-445. doi:10.34067/KID.0005672021

A longitudinal cohort study found that mild albuminuria was associated with cognitive decline, worse baseline cognitive function, and increased risk of incident cognitive impairment and dementia.

Study Finds Albuminuria Associated With Cognitive Decline, Increased Risk of Dementia

The legalization of recreational marijuana has become a hot button topic in politics, with 18 states and Washington, DC, 

 the use of recreational marijuana as of 2021. New Jersey and Connecticut have both announced the opening of recreational marijuana dispensaries in 2022, with New Jersey dispensaries opening on 

 marijuana, including the aforementioned 18, it stands to reason that the way that medical marijuana is prescribed and dispensed will change. With medical marijuana proving to be a valuable pain medication among other uses, how can doctors, dispensaries, and marijuana consumers help prevent the medical benefits from becoming less effective with increased recreational consumption?

Medical Marijuana: A Valuable Medical Industry

With both forms of marijuana becoming more common and accessible, it’s important to note the differences between them. Recreational marijuana is entirely made of 

 a chemical compound that binds to receptors in the brain that control pain and mood among other feelings. Medical marijuana is usually made up of THC to ease symptoms of multiple sclerosis, nerve pain, Parkinson disease, and nausea among others. Cannibidiol, or CBD, is often taken for medical uses such as Crohn disease, anxiety, arthritis, diabetes, and insomnia among others. However, there is limited evidence that CBD is helpful in any of these areas.

“The main difference between medical and recreational use is the end desired result and how it is consumed,” said Gregory Carter, MD, MS, a doctor at Providence Medical Center in Spokane, Washington. “Medical users seek relief from a symptom and would typically use edibles…whereas recreational users often will smoke with the end result of getting high [or intoxication].”

Medical marijuana requires state registration before a prescription is written and can be used; approximately 

 million United States citizens were registered for medical marijuana use in 37 states as of 2021. With several states without legalization of any form of marijuana, the benefits of medical marijuana cannot be utilized for all United States residents.

Mitchell Prywes, MD, medical director at the Center for Pain Rehabilitation, said that marijuana doesn’t have the capability of mortality overdose the way that opiates do, which makes it an appealing medication to prescribe for pain.

 system is an ancient regulatory system of the body found in mammals which synthesizes marijuana-like chemicals that activate receptors to maintain homeostasis in the body; medical marijuana similarly activates those receptors.

Although future research is needed, this relationship demonstrates how instrumental marijuana is and can be to treating numerous medical conditions. But with legal recreational marijuana on the rise, can the effectiveness of medical marijuana be reduced?

Recreational Marijuana a Potential Medical Disruptor?

Marijuana had limited legality in the United States prior to 2012, when Colorado and Washington became the 

With recreational marijuana dispensaries becoming more common across the country, the benefits of medical marijuana could be neutralized. How can doctors and dispensaries make sure the benefits of medical marijuana are still felt in a post-legalization nation?