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Here’s what you missed this week on Managed Healthcare Executive.

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Keith Loria is a contributing writer to Medical Economics.

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Perimenopausal Women with HIV Experience Worse COVID-19 Symptoms 

Study eases some of the concern about Crohn's disease and ulcerative colitis creating undue infection risk.

No Significant Increased Risk of Infection Found in Older Adults with IBD Taking Immunosuppressants

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The Nursing Shortage: Why 'Normalcy' Is Still a Crisis

A number of drugmakers are racing to win the first FDA approval of a Bruton’s kinase (BTK) inhibitor to treat multiple sclerosis (MS). Roche showed it is in the thick of the competition with an announcement of positive results for its BTK candidate, fenebrutinib. In an open-label extension of the phase 2 FENopta study. According to the company's announcement,  96% of participants who received fenebrutinib had no relapses after one year and no change in Expanded Disability Status Scale (EDSS) score over 48 weeks. The overall annualized relapse rate was 0.04.

Furthermore, MRI scans showed that 99% of patients had no new T1 lesions, a measure of active inflammation, according to the Roche news release. T2 lesions, which indicate chronic disease burden, were reduced by three times during the 48-week open-label period compared to the end of the blinded trial. The safety profile was comparable to previously reported results, with the most common adverse effects being urinary tract infection, COVID-19 and pharyngitis.

The FENopta study randomized 109 adults ages 18 to 55 years with relapsing forms of MS to receive oral fenebrutinib or placebo twice daily for 12 weeks. After the three-month period, 99 participants chose to enroll in the open-label extension study, in which all participants will continue to receive daily fenebrutinib for up to three and a half years.

Roche is scheduled to present data from the extension study at the 

40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

 in Copenhagen, Denmark, on September 18, 2024.

Fenebrutinib is an investigational oral, noncovalent (reversible) BTK inhibitor being developed by Genentech, a Roche subsidiary, for treating relapsing forms of MS and primary progressive MS (PPMS). In preclinical studies, fenebrutinib demonstrated 130 times more selectivity for BTK versus other kinases, a feature that, along with its reversibility, that Roche claims may help reduce off-target drug effects and potentially contribute to a favorable safety profile for fenebrutinib.

The investigational molecule is currently in three phase 3 trials for the potential treatment of various forms of MS. The FENhance and FENhance 2 trials are evaluating the use of fenebrutinib compared with Sanofi’s Aubagio (teriflunomide) in adults with relapsing forms of MS. The FENtrepid trial compares fenebrutinib with Roche’s Ocrevus (ocrelizumab) in adults with PPMS.

Other investigational BTK inhibitors in phase 3 studies for treating MS include Sanofi’s tolebrutinib, Merck KGaA’s evobrutinib, and Novartis’ remibrutinib. Trials for the four agents had previously been slammed by the FDA with patrial clinical holds because of problems with liver toxicity.  

Roche's drug is one of a number competing to become the first Bruton's kinase inhibitors approved as a treatment for multiple sclerosis.

Clinical

Fenebrutinib Suppresses and Disability Progression in Majority of MS Patients in Extension Study

The severity of ulcerative colitis (UC) is classified as mild, moderate or severe based on symptoms and clinical findings. The main goal of treatment remains to induce and maintain remission from the mucosal inflammation symptoms associated with the disease. Currently, there are several advanced therapies approved to treat moderate-to-severe UC. These include biologics, such as tumor necrosis factor (TNF) inhibitors, interleukin (IL)-12/23 and IL-23 inhibitors, and an anti-integrin agent. Small molecules, such as Janus kinase (JAK) inhibitors and sphingosine 1-phosphate receptor modulators, are also in the picture.

Although randomized controlled trials are the gold standard for establishing the safety and efficacy of treatments and gaining regulatory approval, results are often not generalizable given the rigid inclusion criteria necessary for minimizing potential confounders in clinical trials. More and more, real-world studies are becoming useful in clinical practice, as they are more likely to represent a generalized population.

According to Peter M. Irving, M.D., from the gastroenterology department at Guy’s and Thomas’ Hospital in London and his colleagues, there is scant comprehensive research assessing the safety and efficacy of currently available advanced therapies for moderate-to-severe UC in a real-world setting. To address this gap, Irving and his colleagues conducted a systematic review of real-world studies evaluating the safety and efficacy of advanced therapies in adults with moderate-to-severe UC.

The review results were published in the September 2024 issue of the 

Journal of Managed Care and Specialty Pharmacy

The review included 139 studies published between 2005 and 2022. The following treatments were assessed in the included studies: the integrin receptor inhibitor Entyvio (vedolizumab), the JAK inhibitor Xeljanz (tofacitinib), the IL-12/23 inhibitor Stelara (ustekinumab), and the TNF inhibitors Humira (adalimumab), Simponi (golimumab), and Remicade (infliximab).

Results showed Entyvio and Xeljanz as the most commonly studied therapies. When the two were compared, Xeljanz showed higher remission rates. When comparing Entyvio with TNF inhibitors, Entyvio  came out on top in terms of remission rates. When looking at steroid-free clinical remission rates, Xeljanz and Stelara had similar outcomes. Within the group of TNF inhibitors, Remicade was the most effective. Lastly, the safety profiles were similar across all therapies.

The authors noted that study limitations, such as small sample sizes and variations in definitions of clinical remission, study design, and patient characteristics, warrant further research exploring these gaps. However, the current findings can be valuable in guiding clinicians treating patients with moderate-to-severe ulcerative colitis.

This study was sponsored by Pfizer, maker of Xeljanz .

Entyvio (vedolizumab) and Xeljanz (tofacitinib) are the most commonly studied therapies, according to the Pfizer-sponsored review, and when 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

The once-weekly insulin efsitora alfa has been shown to be noninferior to once-daily insulin degludec in a phase 3 trial of adults with type 1 diabetes, according to new 

. Eli Lilly’s insulin efsitora is a basal insulin that is administered subcutaneously.

In the trial, efsitora met the primary endpoint of noninferior A1C reduction at week 26, reducing A1C by 0.53% compared with 0.59% for insulin degludec. But severe hypoglycemic events were higher in the efsitora arm compared with the insulin degludec arm. Hypoglycemia, in which blood sugar is too low, is a side effect of medications used to treat diabetes.

“People with type 1 diabetes need insulin every day. Currently, they can deliver the insulin using an automated insulin delivery system or by taking a daily basal insulin injection and multiple mealtime insulin injections each day,” Richard Bergenstal, M.D., executive director of the International Diabetes Center, HealthPartners Institute, said in a 

. "This new data shows that with one dose a week of basal insulin, efsitora was able to achieve a similar A1C reduction as taking an injection of one of the most used background insulins every day.”

Lilly’s efsitora is being studied in a global phase 3 program. In the open-label QWINT-5, the once-weekly efsitora is being compared with the once-daily insulin degludec in 692 patients with type 1 diabetes who randomly assigned to treatment. The trial consisted of a 52-week treatment period with the primary endpoint measured at 26 weeks. The primary objective was non-inferiority in reducing A1C compared with insulin degludec.

In the trial, however the estimated combined rates of patient-reported clinically significant or severe hypoglycemic events per patient-year of exposure through week 52 were higher in the efsitora arm compared with the insulin degludec arm. About 10% of patients in the efsitoria arm experienced severe hypoglycemia compared with 3% in the degludec arm.

Researchers suggested that there may be a need for additional evaluation of efsitora dose initiation and optimization in people with type 1 diabetes.

Insulin degludec, developed by Novo Nordisk, is a once-daily basal insulin that first received approval in 2016 with the brand name Tresiba to improve glycemic control in patients with type 1 and type 2 diabetes. The FDA approved in July 2022 Novo Nordisk’s unbranded insulin degludec, which launched at a discount of 65% off the list price of Tresiba.

Novo Nordisk is studying a different insulin, insulin icodec, as a once-weekly treatment patients with diabetes. In July 2024, however, FDA has 

 for the biologics license application for insulin icodec. The FDA is asking for information about the manufacturing process, as well as the type 1 diabetes indication.

In May 2024, an FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting was convened with a panel of independent scientific experts to discuss the benefit-risk of once-weekly basal insulin icodec in type 1 diabetes. The panel determined that the data available were not sufficient to conclude on a positive benefit-risk in type 1 diabetes.

In a briefing document ahead of the advisory committee meeting, the FDA indicated that the rate of hypoglycemic episodes was significantly higher in the insulin icodec arm compared with the insulin degludec arm.

Lilly’s insulin efsitora is also being studied in 928 patients with type 2 diabetes. In the QWINT-2 phase 3 trial, efsitora helped adults naïve to insulin therapy currently using and not using GLP-1 receptor agonists achieve an A1C below 7% when compared with once-daily insulin degludec. No severe hypoglycemia was reported with efsitora; six episodes were reported with degludec. The incidence of adverse events was similar in the two groups. Results 

Insulin efsitora was able to lower A1C in patients with type 1 diabetes but more patients experienced severe hypoglycemic events than patients taking insulin degludec.

Lilly’s Once-Weekly Efsitora is Noninferior to Degludec in Type 1 Diabetes

Nothing has changed the treatment of inflammatory diseases such as psoriasis, rheumatoid arthritis and inflammatory bowel disease quite as much s the advent of antiinflammatory biologics. But in rare cases, and sometimes years after starting a biologic, patients develop psoriasis. Researchers are beginning to understand these cases of “paradoxical psoriasis” and are looking for biomarkers that might help predict which patients will be affected, according to a review paper published in

Corresponding author William Damsky, M.D., Ph.D., of Yale School of Medicine, and his colleagues say that patients with mild cases of paradoxical psoriasis can often stay on the medication causing the condition while the psoriasis is treated with a topic agent. In more serious cases, the treatment with “inciting drug” may need to stop, which usually results in the paradoxical psoriasis going away. The authors suggest that patients treated with biologics should be closely monitored for paradoxical psoriasis, the development of other inflammatory conditions that arise when people are taking antiinflammatory biologics and for cutaneous T-cell lymphoma.

Paradoxical psoriasis is a well-recognized condition that has been studied extensively. A Pubmed search on the term yielded 100 citations going back decades. 

According to the review by Damsky and his colleagues, research shows that between 3.8% and 10.7% of patients treated with anti-tumor necrosis factor-alpha (TNF-a) biologics are affected. The anti-TNF-a biologics include Humira (adalimumab) and Enbrel (etanercept). It occurs less often among treated with Dupixent (dupilumab) affecting between 1.88% and 3.88% of those treated with biologic, which blocks interleukin (IL) -4 and IL-13. Damsky and his co-authors described paradoxical psoriasis among those treated with Stelara (ustekinumab) as being exceedingly rare. Only nine cases have been reported in the published medical literature.

Paradoxical psoriasis most often occurs among those who have never had psoriasis but a small percentage of the time — about 10% —someone with psoriasis experiences an exacerbation of the disease, according to the 

 review.It typically occurs as psoriasis vulgaris, the most common type of psoriasis, and in about one-third of patients, the palms of the hands and the soles of the feet (palmoplantar involvement) are affected.

The understanding of paradoxical psoriasis and how biologics that quell inflammation can sometimes generate a condition that is itself cause by inflammation is still incomplete. “It remains unclear what triggers PP [paradoxical psoriasis] in that only 2% to 5% of patients develop PP and the latency is often protracted, indicating that there is likely another key (and unknown) determining factor,” wrote Damsky and his co-authors. Nonetheless, they shared some ideas about the pathogenic mechanisms that may underline of the paradoxical psoriasis. Inhibition of TNF-a may result in a “negative cross talk” with type 1 interferons, they note, citing a 2018 research finding by Swiss researchers that type 1 interferons levels (interferon-a and interferon-b) were higher in paradoxical psoriasis than in normal psoriasis vulgaris. The Swiss team also found that levels of plasmacytoid dendritic cells, which produce type 1 interferons in abundance, were also higher. According to Damsky and his colleagues, other research since has produced similar results. 

They work by inhibiting inflammatory cytokines. But in a small percentage of patients antiinflammatory biologics may stir up “paradoxical psoriasis.”


A Paradox of Antiinflammatory Biologics

Thomas P. Leist, MD, PhD, shares the unmet needs for patients with SPMS, and for the average patient likely to have MS.


Unmet Needs for All and Most Vulnerable Secondary Progressive MS Patients

Thomas P. Leist, MD, PhD, says one of the things secondary progressive multiple sclerosis professionals struggle with is making the most effective treatment available to patients, very early on, most likely due to financial reasons.

The Struggle of Making an Effective SPMS Treatment Early on

Thomas P. Leist, MD, PhD, explains that there is no such thing as "one size fits all" for patients with SPMS. Patients can be impacted differently based on how they present themselves and how they behave.


How Patients Present SPMS, How to Act on it

Fred Lublin, MD, says a new labeling indication of Secondary Progressive Multiple Sclerosis broadens whom you can treat. He adds this will be very helpful to patients because it will treat groups that are progressing slowly without agents of activity.


A Labeling Indication of SPMS Can Treat More Patients

Defining active SPMS

Thomas P. Leist, MD, PhD, says doctors working with patients diagnosed with SPMS don't necessarily have prognostic biomarkers to detect SPMS. The best prognostic biomarkers they have currently are MRI and potentially neurofilament light. He adds their techniques need to improve in order to harness the full benefit of potentially individualizing care to the most optimal fashion in a given patient.

Biomarkers Used to Detect Secondary Progressive MS Needs Improvement for the Care of Patients

Thomas P. Leist, MD, PhD, discusses secondary progressive MS, more specifically how very early control of the disease gives the patient the best chance for long term stability and gives the patient, the best chance of not entering the secondary state.


Tackling Secondary Progressive Multiple Sclerosis Early on Benefits Patients in a Number of Ways

Fred Lublin, MD, says it's possible health professionals can develop some biomarkers and find some differences in advanced MRI metrics in finding Secondary Progressive Multiple Sclerosis.


Determining SPMS as Biological Instead of Classification

Secondary Progressive Multiple Sclerosis: Patient Impact and Coverage Implications for New Therapies

The Clinical and Economic Burden of SPMS

Evolving Treatment Strategies and Coverage Implications

Challenges Regarding Coverage for New SPMS Therapies

Secondary Progressive Multiple Sclerosis Series

Efforts are under way by health plans and technology providers, aided by new standards developed by the Centers for Medicare and Medicaid Services (CMS), to make the prior authorization (PA) of prescription drugs more seamless. Panelists during a session at the Pharmacy Benefit Management Institute’s Annual National Conference in Orlando discussed how technology is advancing to allow the prior authorization process to operate behind the scenes through electronic systems that are integrated with health plan information.

Eventually, the hope is that the systems set up to manage e-prescribing and prior authorization will be integrated with electronic medical records to allow providers to see which drugs require prior authorization at the point of prescribing and facilitate that process

“Instead of PA being something that engages members and providers, in this day and age where we have the access to data, this can be something behind the scenes that we would just code for in the benefit design,” said Kerri Tanner, Pharm.D., chief pharmacy officer, PayerAlly, a specialty pharmacy consulting firm, who moderated the session.

Before that goal of an integrated electronic prior authorization process can be realized, however, several challenges need to be addressed, including the adoption of new standards and the integration of systems. Even more critical, however, is convincing providers of the benefit such a system.

Technology is advancing to allow the prior authorization process to operate behind the scenes through electronic systems that are integrated with health plan information. 

Bart Valdez

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