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  1. Analysis
August 19, 2022

Mapping Endpoints in Psoriasis: beyond the mirage of complete skin clearance

As plaque psoriasis treatments prove more effective, the field is debating new approaches to measure efficacy and address remaining unmet need.

By William Newton

On the surface, the plaque psoriasis space seems like a prime example of drug development success: treatment efficacy has steadily increased over time, many patients experience complete skin clearance, and there are now over a dozen FDA-approved treatments. But boiling underneath are tensions over how the field should evolve to address unmet needs beyond complete skin clearance.

As a new generation of highly effective biologics enters clinical trials, many experts and regulators disagree on the optimal endpoints for measuring objective disease response. Meanwhile, patients and clinicians alike are pushing for a greater focus on subjective endpoints that more holistically assess the impact of psoriasis on quality of life (QOL).

In addition, with a wave of small molecule candidates entering the psoriasis pipeline, experts disagree on what role—if any—oral drugs will eventually play. If small molecules fail to match the efficacy of biologics, experts say new disease-modifying biologics could present the next therapeutic breakthrough in psoriasis.

Over eight million people in the US and 125 million people worldwide have psoriasis, 80–90% of whom experience plaque psoriasis. Despite substantial therapeutic progress, the field is contending with new approaches to measuring efficacy beyond the clearance of psoriatic skin lesions.

Mapping psoriasis endpoints

When it comes to psoriasis disease measures, regulatory bodies stand divided, says dermatologist Dr Kristian Reich, partner at Dermatologikum Berlin. The FDA prefers the Investigator Global Assessment (IGA), which ranks psoriasis disease severity on a scale of 0 to 6. The most common primary endpoint using IGA measures the proportion of patients achieving scores of “clear” or “almost clear,” corresponding to scores of 0 or 1.

Meanwhile, the EMA prefers the Psoriasis Area and Severity Index (PASI), which measures disease severity on a scale of 0 to 72. Both PASI and IGA, also known as physician global assessment (PGA), measure lesion severity according to induration (skin hardening), erythema (skin redness), and scaling of skin patches.

Reich notes PASI is much more sensitive and precise than IGA, since PASI has a wider range of available scores. PASI is the most common endpoint in psoriasis clinical trials, and it has been used in hundreds of thousands of patients in previous studies, he adds.

The evolution of PASI

After PASI was developed in 1978, most clinical trials using the endpoint measured average or mean PASI improvement. However, many sponsors argued that this outcome could mask low efficacy, pushing the field toward cut-off thresholds for PASI, explains Dr George Han, director of clinical trials at Zucker School of Medicine in New York. This gave birth to the PASI-50 and PASI-75 endpoints, which measure the proportion of patients with at least a 50% and 75% PASI improvement, respectively.

As the efficacy of biologics steadily increased, so did PASI thresholds. Over the past decade, PASI-75 has been the most common PASI threshold in psoriasis trials. But PASI-90 is quickly gaining steam as a psoriasis primary endpoint choice, according to GlobalData’s Clinical Trials Database. GlobalData is the parent company of Clinical Trials Arena.

In 2010, no Phase II–Phase III psoriasis studies initiated used PASI-90 as a primary endpoint while 29% of trials used PASI-75. By 2021, 15% of trials had PASI-90 as a primary outcome and 22% had PASI-75. Other psoriasis endpoints used include IGA, adverse event measures, and pharmacological comparisons to active comparators.

Endpoints for skin clearance

Similarly, PASI-100 has gained popularity as a secondary endpoint choice for measuring complete skin clearance. In 2010, just one Phase II–III plaque psoriasis trial used PASI-100 as a secondary endpoint, compared to 16 trials in 2021, according to GlobalData’s database.

PASI-100 has a clear advantage over other PASI benchmarks because it is straightforward for patients to interpret, Han says: “If you’re 100% clear, you’re 100% clear.” Meanwhile, there is not a huge difference between hitting PASI-75 and PASI-90, though it makes sense for higher-functioning medicines to target PASI-90, he adds.

However, Reich points to a growing debate about using complete clearance measures like PASI-100 as key endpoints. “There is also a big resistance to move above PASI-90 because full skin clearance is too confounded by how well you look,” he adds. “If you have a spot on your ear, theoretically that’s not a positive PASI-100.”

Along a similar vein, Reich says some trialists are advocating to use absolute benchmarks for PASI improvement rather than relative benchmarks like PASI-90. There is growing support for an endpoint that measures the percentage of patients who achieve an absolute PASI score of under three along the 72-point scale. “Relative improvements are unfair for patients who start very high on the scale,” he explains.

Moving beyond skin clearance

For many patients, PASI is only part of the efficacy picture. Preferred psoriasis endpoints can vary widely depending on where patients are in their disease journeys, notes Brenda Kong, a psoriasis and psoriatic arthritis patient advocate.

When Kong was younger, she says she was very vocal with her dermatologist about her goal of becoming 100% clear. However, after gaining more experience managing her condition, Kong says she strives for improved QOL.

When choosing QOL measures, sponsors should note that psoriasis can have mental health effects beyond its more obvious physical effects, Kong adds. Psoriasis trials would benefit from endpoints with mental health components assessing a patient’s mindset before, during, and after treatment, she explains.

According to Reich, the Dermatology Life Quality Index (DLQI) is the most effective subjective assessment because it covers a range of patient experiences and is well-understood in the field. DLQI is a 10-question patient assessment on the impact of psoriasis on areas including working, leisure, daily activities, and emotional well-being.

However, Reich notes that trials could risk muddying their results if they mix objective signs with subjective patient experiences into a single QOL measure.

Can small molecules disrupt the paradigm?

In a crowded slate of ongoing psoriasis trials, the pipeline for biologics is beginning to cool as small molecules are gaining steam, Han explains. Small molecules include restricted peptides, which could potentially change the landscape by providing biologic-like efficacy in oral pills, he adds. Under current standards of care, patients with moderate-to-severe plaque psoriasis typically receive biologics such as tumour necrosis factor (TNF) alpha blockers and antibodies targeting interleukins involved in the IL-23/Th17 pathway.

Overall, there is a trend toward new psoriasis trials testing small molecules. In 2012, there were roughly equal numbers of Phase I–III trials for biologics and small molecules initiated in psoriasis, according to GlobalData’s database. By 2019, before trials across the board dipped during the Covid-19 pandemic, new trials for small molecules had a clear edge: there were 70 trials initiated for small molecules, compared to 50 for biologics.

However, Reich is not convinced small molecules will ever reach the benefit-risk ratio seen in biologics. The most effective oral small molecules in psoriasis still use PASI-75 as a primary endpoint, unlike the recent approvals in biologics using PASI-90, he explains.

In addition, many patients prefer injections over oral pills, Reich notes. In his clinic, Reich’s patients prefer a once-monthly shot to the inconvenience of daily dosing, as everyday treatment can serve as a constant reminder of the disease.

A future of disease-modifying therapies?

If there were to be another therapeutic breakthrough in psoriasis, it would likely be disease-modifying therapies, Reich says. This would entail demonstrating a treatment is effective after dosing ends, eliminating the rebound effect seen in most current treatments, he explains. However, it is also possible psoriasis drug development will slow down given the abundance of already approved therapies, he notes.

Further along in the pipeline, a new generation of psoriasis drugs is aiming to change the microbiome through probiotic active strains, Han adds. If effective, this approach could similarly lead to disease-modifying effects, he notes.

The push for longer-lasting treatments could help the psoriasis field tackle one of its biggest remaining unmet needs. “I have patients who have been on almost all the biologics already, and they seem to improve and then eventually get worse,” Han says. “It's still a big issue that we haven't answered.”

Takeaways

  • Psoriasis clinical trials are moving toward more stringent benchmarks for PASI improvement as treatment efficacy increases. However, the psoriasis field is debating whether PASI endpoints should focus on absolute or relative change.
  • Many patients and clinicians want the field to move beyond skin clearance and refocus on QOL measures that paint a fuller picture of the patient experience.
  • Though the psoriasis field has many approved biologics, the drug development pipeline now favours small molecules. Still, experts are mixed on whether small molecules can match the benefit-risk ratio already seen in biologics.
  • The next revolution in psoriasis drug development could be disease-modifying therapies, which could address the remaining unmet need for durable treatments.

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