Report: Sotatercept improves clinical outcomes in PAH, but unlikely to be cost-effective

Key takeaways:

• Sotatercept plus background therapy yielded several benefits in adults with pulmonary arterial hypertension over 24 weeks.
• If priced at $400,000 a year, it would go over common cost-effectiveness thresholds.

When added to background therapy for pulmonary arterial hypertension, sotatercept improves 6-minute walk distance and WHO functional class vs. placebo, according to an evidence report by the Institute for Clinical and Economic Review.

However, models in the Institute for Clinical and Economic Review (ICER) report suggested it would exceed typical cost-effectiveness thresholds.

Sotatercept (Merck), a novel activin signaling inhibitor, is given as a subcutaneous injection every 3 weeks. The FDA is expected to make a regulatory decision on its use by March 26, 2024.

Clinical data

ICER’s evidence report considered the use of sotatercept added to background therapy among adults with PAH in WHO functional class II or III vs. background therapy alone.

As Healio previously reported, results from the phase 3 STELLAR trial showed adults with PAH assigned sotatercept achieved greater improvement in 6-minute walk distance (6MWD; median difference, 40.8 m), were more likely to experience an improvement in WHO functional class (29.4% vs. 13.8%) and had a 84% reduced risk for clinical worsening or death at 24 weeks compared with the placebo group.

Sotatercept also outperformed placebo in several secondary endpoints, such as pulmonary vascular resistance (PVR), NT-proBNP level and a multicomponent endpoint that pooled together 6MWD, NT-proBNP level and WHO functional class change.

Notably, patients receiving sotatercept did not appear to have better overall quality of life assessed via a PAH-specific scale, according to the report.

“From discussion with our clinical experts, it’s pretty hard to show improvement in quality of life overall, and it’s not entirely clear why, so it’s hard to know what to make of these quality-of-life results,” Grace Lin, MD, medical director for health technology assessment at ICER, said during the clinical evidence presentation.

Further, compared with the placebo group, the sotatercept group had fewer adverse events (including severe events), discontinuations and deaths.

When evaluating these results and other available data on sotatercept, authors of the report highlighted that it is not yet clear how the drug performs among sicker patients and patients with connective tissue disease. The impact sotatercept has on mortality is also not known because the STELLAR trial only covered 24 weeks.

Overall, the ICER report gave sotatercept a B+ evidence rating, and this grade indicates that there is “moderate certainty of a small to substantial net health benefit, with high certainty of at least a small net health benefit” compared with background therapy alone.

Cost

ICER noted that sotatercept’s pricing is not yet known, but an anticipated price indicates that it will go over thresholds that traditionally are considered cost-effective in the U.S. market.

Using a placeholder net price of $400,000 per year for sotatercept, economic models showed sotatercept plus background therapy conferred more life-years (5.46 years vs. 4.27 years), quality-adjusted life-years (QALYs; 3.41 years vs. 2.51 years) and equal-value life-years (evLYs; 3.69 years vs. 2.51 years) vs. background therapy alone.

Further, the ICER report estimated a cost of $2,380,000 per QALY gained and $1,805,000 per evLY gained with sotatercept plus background therapy.

According to the report, if sotatercept was priced between $18,700 to $36,200 a year, it would reach commonly used thresholds not including nonintervention costs.

Voting

During the public meeting, 13 members of the Midwest Comparative Effectiveness Public Advisory Council (CEPAC) body voted on several questions related to sotatercept for treatment of PAH.

All members believed that the clinical evidence presented is “adequate to demonstrate that the net health benefit of sotatercept added to background therapy is superior to that provided by background therapy alone.”

“Unanimity happens rarely on the CPAC, but when it does, it sends a strong signal,” Steven D. Pearson, MD, MSc, founder and president of ICER, said.

The Midwest CEPAC body was also asked to determine the relative priority that should be given to any effective PAH treatment when making judgments of overall long-term value for money regarding two situations:

• acuity of need for individual patient treatment based on short-term risk for death or progression to permanent disability; and
• “magnitude of a lifetime impact on individual patients of the condition being treated.”

Prior to voting, Katherine Kroner, MSW, vice president of advocacy and patient engagement at the Pulmonary Hypertension Association, noted how receiving a diagnosis of PAH can cause suffering in multiple ways.

“Anecdotally, I would say that there’s a significant portion of the [PAH] community that do either go on to disability or have a major life transition that involves losing their career or losing their ability to work in one way or another,” Kroner said.

Using a scale that captures five different levels of priority, seven members voted the first priority given should be very high, and the remaining six voted high priority. For the second, eight members voted very high priority, four voted high priority and one voted average priority.

The last question that the CEPAC members voted on focused on the relative effects of the addition of sotatercept to background therapy on four different outcomes that suggest the drug’s long-term value.

Members were first asked if sotatercept would have a positive effect, negative effect or no difference on patients’ ability to accomplish major life goals in relation to education, work or family life.

Prior to this vote, Julia Feitner, patient expert, highlighted the increase in 6MWD with sotatercept plus background therapy seen in the STELLAR trial.

“That seems like a small number, but in the day to day, what that equates to is actually pretty drastic,” she said. “For the other medications that I've also been on through the years, the increase of 12 meters might mean that I can now make it through a convenience store to pick up milk and eggs for my family. An increase of 40 [meters] means that perhaps I can now walk through a zoo with my family.

“What looks like just quantitative data is actually hugely impactful qualitatively for the patients,” Feitner added.

For this outcome, seven CEPAC members voted that the drug would have a major positive effect and six voted that it would have a minor positive effect.

Aaron E. Carroll, MD, MS, distinguished professor of pediatrics and chief health officer at Indiana University, voted minor positive effect because he was thinking more about major life goals rather than daily activities.

“Certainly, it sounds like it makes a significant difference on daily activities of life, but I was thinking, will this make a big difference with education or with my ability to go work, and it didn’t feel as if it was a major positive effect for those major life goals,” he said.

Members were next asked to consider the effect sotatercept would have on caregivers’ quality of life and/or ability to accomplish major life goals in relation to education, work or family life. Five voted a major positive effect and eight voted a minor positive effect.

“I felt like on the previous question, there was data to support the impact of the patients,” Bradley Martin, PharmD, PhD, professor in the division of pharmaceutical evaluation and policy at University of Arkansas for Medical Sciences College of Pharmacy, said. “The trial data on caregivers, I think this is likely to happen, but we just didn’t have as close data to match the outcomes of this question.”

In terms of how the drug would impact a patients’ ability to manage and continue treatment given the regimen’s complexity vs. currently available third-line or fourth-line treatments, most members voted a minor positive effect (n = 10), but two voted no difference and one voted a minor negative effect.

The last question asked CEPAC members to determine the effect of sotatercept on society’s goal of reducing health inequities. To help members with this question, Lin discussed what ICER found on health inequities in their research.

“The population from registry data of people diagnosed with PH in terms of race and ethnicity doesn’t appear to be substantially different than the U.S. population, so we didn’t see any particular racial ethnic population that might derive additional benefit,” Lin said. “However, there are inequities in access. For example, patients who are older, who may have difficulty with managing some of the current treatments, who may live in rural areas, who may have access issues and people with limited social support since some of these like infusion therapies require a lot of support.”

Reem Mustafa, MD, MPH, PhD, CEPAC chair and professor of medicine at University of Kansas Medical Center, noted that clarification is needed on where this drug is going to be given (institution vs. home) because that “will have a big impact on inequity.”

In the end, eight members voted no difference, four voted a minor negative effect and one voted a major negative effect.

Importantly, a question on the long-term value for money of sotatercept added to background therapy vs. background therapy alone was not voted on because no price has been given for sotatercept.

Policy roundtable

Following voting, five participants came together for a policy roundtable led by Pearson to discuss different elements related to sotatercept and PAH.

One major topic of the discussion centered around delivery of the drug.

“I believe it will be specialty. I’m not sure there’s any way around that,” Mindy Bauer, PharmD, BCACP, associate director of clinical pharmacy at IPD Analytics, said. “Other drugs in this class are also managed as specialty. I can imagine — Merck hasn’t said how they’re going to distribute it — but I’m assuming there’s probably going to be limited distribution behind this drug as well, which would then limit the pharmacies that patients could get this from. There is mail order, but there can be delays ... and issues with that as well.”

Thinking back to the voting question on health inequities, Pearson said that pharmacies are going to play a major role in educating patients if this drug will be available for use at home.

“For this to work well and for people to have equitable access to it across different communities, especially pharmacies are going to have to step up and make sure that patients and clinicians ... are going to have to receive the information and the support to feel confident to be able to use this drug if we are all hoping that it can be administered at home, which I think is the general hope because that would seem to offer a lot of advantages to patients,” Pearson said.

Marc A. Simon, MD, MS, professor of medicine and director of pulmonary vascular disease at University of California, San Francisco, emphasized the positive impact this drug would have for patients if they could take it at home.

“I got to say personally, I would really think that access would be much better served with patients being able to administer this at home,” he said. “We serve a huge catchment area. Patients are coming from 5-plus hours away. To do that every 3 weeks is a lot to ask of them.”

Another major topic of discussion from this roundtable was insurance. Feitner said that if sotatercept is added as a treatment for PAH, many patients are unsure if it will be covered by their insurance.

“The current gold standard of care is two or three treatments,” she said. “If this gets tacked on as a fourth treatment ... will insurance companies choose to pay for it? Because that’s not the current guideline, so this is something that is a definite concern for patients.”

Payer policies will most likely limit the drug to those in WHO functional class II and III, as well as those on double or triple therapy, Bauer said.

Another potential limiter may be age, because there is a lack of trials that investigated this drug in children.

“It’s very, very, very likely that insurance coverage will not include class IV,” Pearson said.

When discussing other criteria for drug access, Pearson went through the exclusion criteria of the STELLAR trial and asked Simon what he thought insurance companies would consider in their policy.

“It’s pretty common to have catheter-based data in the criteria, except the PVR of five or greater,” Simon said.

“I don’t think I've seen to date any insurers require a PVR of five,” he added. “I've seen for sure the mean PA pressure greater than 25 and pulmonary wedge pressure or LD and diastolic pressure of 15 or less. I haven’t seen the mark set for PVR.”

Notably, patients with a history of obstructive sleep apnea were excluded from the STELLAR trial.

“This one always gets me because it’s a real cause of pulmonary arterial hypertension,” Simon said. “Even when it’s treated, we generally need to still treat the pulmonary arterial hypertension and, in this current era, there are a ridiculous number of barriers for getting the testing and the CPAP machines at this point for patients.

“I would advocate that it should not be part of any criteria for drug access,” he added.

Bauer said she hopes Merck considers what was said during the meeting when pricing sotatercept.

“I really hope Merck listens to this and doesn’t price it at $300,000 or $400,000 and does price it where the value is with the evidence we have today,” Bauer said.

Simon added, “I would love to see a better oxygen system and a better copay system so patients aren’t relying on the difficulties of assistant programs, which is what the majority of patients seem to have to do.”

To help all patients with PAH, Kroner said more research is needed on this drug, given it has a new mechanism of action, among those newly diagnosed and those with an advanced stage of the disease.

“If nothing else, I think the additional research in those areas is critical and cannot come fast enough,” Kroner said.

References:

• ICER. Sotatercept for pulmonary arterial hypertension: Effectiveness and value. Public Meeting of the Midwest CEPAC. Dec. 1, 2023.
• ICER published evidence report on treatment for pulmonary arterial hypertension. https://icer.org/news-insights/press-releases/icer-publishes-evidence-report-on-treatment-for-pulmonary-arterial-hypertension/. Published Nov. 14, 2023. Accessed Dec. 1, 2023.
• Lin GA, et al. Institute for Clinical and Economic Review. 2023.