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Entyvio and Xeljanz as the most commonly studied therapies, according to the Pfizer-sponsored review, and wen the two were compared, Xeljanz showed higher remission rates. 

Results From Review of Real-World Studies of Advanced Therapies in Moderate-to-Severe Ulcerative Colitis

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Any ACO can get ready for downside risk in three years. Here’s three ways to get it done.

Top Strategies for ACO Success

 has scored a major new approval, even as clinicians begin to rethink how the novel therapy will fit into the treatment strategies.

Late last month, the European Commission approved Winrevair (sotatercept) for sale in the 27 member states of the European Union, as well as Iceland, Liechtenstein, and Norway. The therapy was approved for use in combination with other PAH therapies in adult patients with functional class II-III disease. Merck noted that the approval makes the therapy the first (and only) approved PAH therapy that targets the activin signaling pathway.

"We are proud to bring this innovative treatment to more patients and remain committed to further investigating the potential of Winrevair in areas where there are unmet need in the management of PAH, said Joerg Koglin, M.D., Ph.D., the company’s head of general medicine, global clinical development, in 

The European approval came five months after the FDA approved the therapy. 

, 163 patients were treated with sotatercept in combination with standard-of-care background therapies. Compared to a 160-patient placebo group, those receiving sotatercept had significant improvement in six-minute walking distance (6MWD), along with a lower risk of death and clinical worsening.

“These findings are significant and reinforce that Winrevair, in combination with other PAH therapies, should be considered as a new standard of care for the treatment of functional class II and III adult patients,” said Marc Humbert, M.D, PhD, of the Paris-Saclay University, in the press release.

But how exactly Winrevair will fit into current clinical practice remains to be seen. Tyler Pitre, M.D., Ph.D., of the University of Toronto, noted that current international guidelines typically call for dual therapy at first in most patients being treated for PAH. That usually means pairing a phosphodiesterase 5 inhibitor (PDE5i) with an endothelin receptor agonist (ERA). However, he also noted that some patients take additional therapies.

“In both the STELLAR and PULSAR trials, approximately 60% of the participants were already on triple therapy, meaning a combination of ERA plus PDE5i, plus another agent which is typically oral prostanoid therapy,” he said. “Some of the patients in these trials were on continuous epoprostenol therapy as well.” 

Annals of the American Thoracic Society, 

Pitre and colleagues analyzed studies to compare Winrevair with other approved add-on therapies for PAH. Their analysis concluded with moderate certainty that Winrevair likely reduces the risk of clinical worsening compared with add-on ERAs, inhaled prostanoids, and oral prostanoids. They also found — again with moderate certainty — that the therapy improves 6-minute walk distance compared to ERAs and oral prostanoids, though they said the improvement in those cases did not meet the level of clinically important improvement. 

Asked if any findings surprised him, Pitre said he was pleased with the breadth of the new drug's  efficacy. “As for a surprise,” he said, “I was interested to see how stably effective sotatercept was throughout comparisons and also across outcomes.”

Pitre noted that in Canada, where he lives, the Winrevair is not yet readily available. That is likely to change soon, though. Canadian regulators OKed the drug on Sept.4,  and it is now approved for use in adults in combination with standard PAH therapies.

Pitre observed that, in his and his colleagues’ meta-analysis, Winrevair was effective even when compared to dual therapy, “so there is some evidence to suggest Winrevair could be used up front as well.”

However, he also cautioned that the high-cost medication may be subject to prescribing limitations in certain jurisdictions. In Canada, Pitresaid, “I suspect they will require that patients be on at least dual or even triple therapy before we can prescribe it,” he said.

 The approval comes five months after the FDA approved Winrevair.

Clinical

Winrevair Gains EU Nod, Expanding PAH Options

Although they are on opposite sides of the world, Appalachia and Sub-Saharan Africa share HIV similarities when it comes to stigma, geographic isolation and limited resource. However, their regional differences mean each area must be approached differently, according to the results of a project by the Community Education Group, an organization that provides healthcare resources to combat disease in underserved populations in Appalachia. The results were presented in July at the International AIDS 2024 Conference in Munich, Germany.

This project explored the connection between the high volume of HIV cases in Africa and Appalachia. It also explained how HIV was reduced using telemedicine and community outreach and how to maintain these successes going forward.

The Appalachian region consists of 14 states. It includes all of West Virginia and portions of Alabama, Georgia, Kentucky, North Carolina, Maryland, Mississippi, New York, Ohio, Pennsylvania, South Carolina, Tennessee and Virginia. Nearly 20% of residents in these areas live in poverty and almost 18% do not have internet access when compared with the rest of rural America, 

In Appalachia in 2022, there were 35,000 people with HIV. Five of the top 10 states with the highest HIV rates are in this region. Those states are Georgia, Mississippi, Maryland, South Carolina and North Carolina. A major contributor to HIV is these areas is injectable drugs. In Cabell County, West Virginia there was a 450% increase in cases and in Kanawha County, West Virginia there was a 110.7% increase.

In Africa in 2022, 25.6 million people were living with HIV with an estimated 20.9 million people receiving antiretroviral therapy.

The project approached each region differently and found that in Africa, telemedicine was the most effective tool to increase treatment adherence and HIV prevention. Treatment adherence improved by approximately 30% and patient follow up care improved 40% from using telemedicine.

Appalachian populations found that the deployment of community healthcare workers was the most beneficial approach because it led to a 25% increase in testing rates and a 20% increase of linkage to care within first year.

Future programs in these regions should continue to follow these pathways. In Africa, telemedicine access should be expanded to more rural areas and include features such as virtual reality consultations. In Appalachia, residents may benefit from even more community healthcare workers. Services could expand to encompass other diseases such as viral hepatitis and opioid addiction.

“The effectiveness of integrating technology and personal outreach in HIV/AIDS interventions underscores the need for continued innovation and community involvement in health strategies,” co-authors A. Toni Young and Kelli Keith, M.P.H., write in the abstract. "Future efforts should focus on expanding successful models, increasing community-led initiatives, and fostering global partnerships to address common challenges.”

Both regions experience disproportionately high HIV case numbers due to social stigmas and isolation.

HIV Epidemic Similarities Between South Africa and Appalachia 

There’s a scene in the iconic 1995 film “Apollo 13” in which NASA aerospace engineer Ken Mattingly (played by actor Gary Sinise) is awoken in the middle of the night. A catastrophic oxygen tank explosion has just damaged Apollo 13’s engine and fuel cells, leaving the spacecraft floating above the far side of the moon, with “barely enough electricity to power a coffee machine for nine hours.”

Mattingly puts on his shirt and tie and makes his way to an Apollo simulator module to see whether he can help figure out a way to get the ship back safely.

“I need the sim cold and dark,” Mattingly orders. “Give me the exact same conditions they’ve got in there now.”

The scene marks a turning point in the film, but the same concept might also mark a turning point for healthcare. NASA’s use of simulators to solve the Apollo 13 riddle is now remembered as the first use of “digital twins.” The space agency used real-world data to power simulations that allowed them to better understand why the accident occurred and how to prevent similar accidents in the future. Now, somefive decades later, scientists are attempting to construct digital twins of human beings, with the goal of predicting the progression of individual patients’ diseases, and modeling whether and why particular therapies might help cure them.

Jun Deng, Ph.D., is in the vanguard of the effort. He helped launch the Digital Twins for Health Consortium after signing up for a workshop held by the National Cancer Institute and the U.S. Department of Energy in 2020. The goal of the workshop was to bring scientists together to build a cancer patient digital twin.

“I was wowed by the whole concept,” says Deng, a professor of therapeutic radiology at the Yale School of Medicine. Yet, he quickly understood the scope of the challenge before his group. The team was doing nothing less than attempting to model perhaps the most complicated system imaginable — the human body. “It’s unknown territory,” he says. “...So anything we do here will be pioneering.”

In the years since, digital twin pioneers have set off down a number of paths. Some efforts aim to build digital twins of individual organs of particular patients. Others are pursuing the goal of creating digital versions of a patient’s entire body.

In the case of Unlearn, an artificial intelligence (AI) firm in San Francisco focused on healthcare, digital twins are being used to optimize clinical trials. The company developed a statistical methodology that utilizes digital twins to predict a participant’s likely clinical outcome had they been assigned to a trial’s control group. By doing so, investigators can more precisely understand the impact of the therapy being evaluated.

“Where humans may make outsized judgments regarding the impact of particular factors due to their social and environmental context, the power of AI lies in its ability to reliably gauge the relative impact of multiple pieces of (occasionally conflicting) information to the clinical trajectory of a particular person, pulling the signal from the noise,” says Jess Ross, Ph.D., the company’s senior government affairs lead.

Earlier this year, Unlearn announced that it had received comments from the FDA indicating that the company’s proposed digital twin methodology aligns with the agency’s current guidance on statistical methodology, essentially giving the methodology a seal of validity.

Unlearn’s progress with the FDA represents a vote of confidence for digital twins, but like so much in the era of big data, digital twins are only as valuable as the data used to create them. One challenge in making them reliable is the fact that their subjects — human beings — are not always reliable themselves. Human health and the efficacy of a particular therapy can be significantly impacted by factors such as missing doses of medicine or engaging in unhealthy behaviors.

Reinhard C. Laubenbacher, Ph.D., a professor of systems medicine at the University of Florida, has studied digital twins extensively and is involved in a project to use them in the context of pulmonary hypertension. He says the problem of human behavior can be overcome. “It is certainly possible to incorporate imperfect adherence to medication protocols if there are data about prevalence, frequency or individual behaviors,” he says. One example, he says, is “self-reporting” pills, which are designed to send a signal when they enter the stomach, enabling a truly accurate indication of whether and when patients take their medications.

Deng notes that because digital twins are modeled after particular patients, the models can be personalized in ways that account for specific factors, such as a particular person’s risk factors or habits. But he adds that there will be an element of personal responsibility with digital twins. If patients conceal health data or do not follow a plan of care, they might affect their twin’s accuracy while also affecting their own health. “It’s your data and your model,” he says.

Still, digital twins are not solely reliant on an individual’s data. They are also built with the help of AI and machine learning trained on big data. All of this raises certain ethical questions, says Brandon Ferlito, M.Sc., a bioethicist at Ghent University, in Belgium.

He argues that although technology like digital twins may ultimately improve human health, there is a risk that technological momentum will steamroll important ethical considerations, including a lack of representation in the data used to build the models.

“If the data mainly [come] from middle-aged White male [patients], the DT [digital twin] may not accurately predict disease progression or treatment responses for women or people of different ethnic backgrounds,” says Ferlito, who is completing his Ph.D. at the Bioethics Institute Ghent.

Privacy and consent are also important issues, he says. For instance, it may prove difficult to ensure patients have a clear understanding — and control — of what their data will be used for and by whom it will be used. Furthermore, he worries the technology could be limited to wealthy patients and regions and thus exacerbate existing health disparities.

“We also need to keep talking to patients, healthcare professionals and ethicists to navigate the ethical issues and create policies that promote fairness and inclusivity in healthcare technology,” he says.

Ross, at Unlearn, says privacy concerns and the novelty of the technology are currently limiting factors for digital twins. Without consumer trust, she says, there will not be sufficient data to develop the kind of precise models that could lead to truly personalized care.

“For this reason, we are hopeful that adoption of digital twins in clinical trials will demonstrate value to patients and improve trust in the technology, enabling greater data availability,” she says.

Deng agrees that ethicists should be part of the digital twin discussion, noting that the concept is by its very nature interdisciplinary.

“It overlaps a lot with AI, but it also relies on other experts from other fields and backgrounds: mathematics, physics, biology, medicine and engineering, in addition to AI/computer science,” he says.

In addition to multidisciplinary subject matter experts, the project will also require significant resources, something Laubenbacher says has been challenging. “This type of project is extensive — essentially bench to bedside — and the current funding models at NIH [National Institutes of Health] and other agencies are not well suited for this kind of project,” he says.

Still, Deng is optimistic that funding will follow the enthusiasm arounddigital twins. He sees the emergence of technology around AI, big data and advanced computer chips as coming at an opportune time for healthcare to take advantage of digital twins.

“So definitely, this is the right time and the right moment,” he says.

Individualized digital twins offer the prospect of better predicting individual patients’ disease progression and response to therapy. 

Digital Twins Could Be the Crystal Balls of Healthcare

 Incyte’s Jakafi (ruxolitinib) for treatment of chronic graft-versus-host disease (GVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

 that occurs when the graft's immune cells recognize the host as foreign and attack the recipient’s body cells. It can occur in up to half of patients receiving hematopoietic stem cell transplantation.

“In the United States, there are over 14,000 people living with chronic GVHD, many of whom face significant complications that may impair daily activities and linger for years,” Susan Stewart, executive director, BMT InfoNet, said in a statement. “The approval of Jakafi is an exciting development for the GVHD community and an important step forward in the treatment of a disease with few options.” The Blood & Marrow Transplant Information Network (BMT InfoNet) is a leading advocacy organization for bone marrow, stem cell and cord blood transplant patients.

The approval was based on the REACH3 study, a phase 3 study of Jakafi in comparison to best available therapy for treatment of steroid-refractory chronic GVHD after allogeneic stem cell transplantation. The primary end point of overall response rate at week 24 was 49.7% for Jakafi compared with 25.6% for best available therapy. The most common nonhematologic adverse reactions (incidence ≥ 20%) were infections. Full results from the REACH3 study were 

This approval is the fourth FDA-approved indication for Jakafi, which received FDA-approval in 2019 for steroid-refractory acute GVHD in adult and pediatric patients 12 years and older.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi outside the United States.

This is the fourth approval for Jakafi, a JAK1/JAK2 inhibitor.

Formulary Watch

FDA Approves Jakafi for GVHD

 for priority review Incyte’s biologics license application (BLA) for axatilimab to treat patients with chronic graft-versus-host disease (GVHD) after failure of at least two prior lines of systemic therapy. The Prescription Drug User Fee Act (PDUFA) date is Aug. 28, 2024.

Graft-versus-host disease is a complication of stem cell transplants, where the body’s immune system attacks the new cells. Acute graft-versus-host 

 in about half of patients receiving hematopoietic stem cell transplantation from matched donors. The occurrence can be higher in unmatched donors

Axatilimab, developed by Incyte and Syndax Pharmaceuticals, is a monoclonal antibody that targets colony stimulating factor-1 receptor, or CSF-1R, a cell surface protein.

The BLA is supported by data from the AGAVE-201 trial, which showed that treatment with axatilimab resulted in clinically meaningful results and was generally well-tolerated, with a safety profile that was manageable and consistent with the mechanism of action of CSF-1R inhibition. This phase 1/2 study enrolled 40 patients who received at least one dose of axatilimab. At least one treatment-related adverse event (TRAE) was observed in 30 patients. The overall response rate in the first six cycles, an endpoint for regulatory review, was 82%. Additionally, 58% of patients reported improvement in symptoms.

 at the American Society of Hematology Annual Meeting 2023. The trial met the primary endpoint across all cohorts receiving axatilimab. Patients who received axatilimab at 0.3 mg/kg every two weeks achieved the highest overall response rate of 74% within the first six months of treatment. This is the recommended dose of axatilimab that will be used for future trials in chronic graft-versus-host-disease.

In the overall trial population, 33% of patients experienced at least one grade ≥3 treatment-emergent adverse event, with 15.5% experiencing adverse events leading to discontinuation of treatment. For the 79 patients who received axatilimab at 0.3 mg/kg grade ≥3 treatment-emergent adverse events occurred in 17.7% of patients, with 6.3% leading to discontinuation of treatment.


The Prescription Drug User Fee Act action date is Aug. 28, 2024.


Tim Gronniger

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