Will These New Drugs Change Your Practice?

A quartet of new medications may improve care of patients with hypertension, urinary tract infections (UTIs), hot flashes, and liver disease, said Gerald W. Smetana, MD, professor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, in a presentation at the American College of Physicians (ACP-IM) Internal Medicine Meeting 2src25.

Many novel drugs are more relevant for subspecialists, but of the six first-in-class medications approved by the US Food and Drug Administration (FDA) in 2src24, four have the potential to affect primary care practice, he said.

These four novel drugs are aprocitentan for resistant hypertension, sulopenem etzadroxil plus probenecid for uncomplicated UTIs in women, fezolinetant for menopausal hot flashes, and resmetirom for metabolic dysfunction–associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease).

Aprocitentan: Effective but Not Cost-Effective

Approximately 45% of adults in the United States have hypertension if defined as blood pressure greater than 13src/8src mm Hg, Smetana said.

Resistant hypertension affects approximately 12% of patients with hypertension and is defined as blood pressure above a patient’s goal despite the use of three drugs, one of which should be a diuretic, he said.

Aprocitentan, a novel dual-endothelin receptor antagonist, inhibits the binding of endothelin (ET)-1 to the ETA and ETB receptors. Aprocitentan is related to drugs used for the treatment of primary hypertension and was well-tolerated in phase 2 studies. 

In the PRECISION study, which led to the drug’s approval, approximately 7srcsrc adults with resistant hypertension were randomly assigned to one of the two doses of aprocitentan or placebo after starting on a standardized triple-pill background therapy. 

Although the effect of aprocitentan was statistically superior to placebo, the absolute effect was relatively modest, he said. The most common adverse event was edema, which was mild to moderate in most cases, he said.

The drug is also potentially teratogenic, and the need to enroll in a risk mitigation program is a limitation for use in practice, as is the relatively high cost, said Smetana. All other drugs for resistant hypertension are in the $5-$15 range vs approximately $8srcsrc for aprocitentan, he said.

Based on efficacy, cost, and convenience, Smetana gave aprocitentan a mixed review.

“While this is potentially a fourth-line option for resistant hypertension, I would recommend labetalol or spironolactone first before moving to this new drug,” he said in the presentation.

Easing Uncomplicated UTIs

Women with uncomplicated UTIs are a large part of most primary care practice patients, and approximately 15% of women with UTIs will have recurrent UTIs, defined as at least three infections per year, Smetana said. Although many antibiotic options are available, not all patients respond to empiric therapy, and some may have allergies or contraindications, he said.

Quinolones, a longtime second-line option for women with uncomplicated UTIs, are no longer recommended based on reports of tendinopathy, neuropathy, and other joint and muscle side effects, some of which may be permanent, Smetana said. Carbapenems have been used for inpatient infections but were intravenous only and used mainly in combination with other therapies, he noted.

New on the scene is sulopenem etzadroxil combined with probenecid, Smetana said. Sulopenem is an oral thiopenem that works against quinolone-resistant Gram-negative bacteria and extended-spectrum beta-lactamase–producing organisms; adding probenecid extends its half-life, he explained.

The new drug is potentially effective for both complicated and uncomplicated UTIs, especially for patients with multiple drug intolerances and highly resistant organisms, he added.

The manufacturers conducted several studies, and Smetana highlighted two outpatient studies. In one study, sulopenem was noninferior to ciprofloxacin for uncomplicated UTIs in women aged 18 years or older. “Most of the benefit was seen in the first 6 days,” Smetana said in his presentation. There was a significant difference in women who ultimately had ciprofloxacin-resistant isolates, he added. A second phase 3 study compared 5srcsrc mg of sulopenem twice daily with amoxicillin/clavulanate. Similarly, sulopenem was not inferior to amoxicillin/clavulanate. The data were unpublished but presented to the FDA to support approval.

As for side effects, pooled data from the uncomplicated UTI studies showed more reports of diarrhea among patients receiving sulopenem (8.9%) compared with approximately 3% in those receiving other treatments.

Sulopenem was approved by the FDA in October 2src24 but is not yet available, so the cost is unknown, Smetana said. Although it is not indicated for complicated UTIs, it is the first oral carbapenem drug and is preferable to quinolones for potential or known multidrug-resistant infections, he said.

When sulopenem does become available, clinical considerations include trying to minimize use outside of the approved indications to avoid creating resistant organisms, Smetana said. In addition to concerns about resistance, the cost will likely be an important barrier to expanding sulopenem use, he added.

Fezolinetant Cools Hot Flashes

Hormone replacement is the most effective therapy for hot flashes, but safety concerns persist, Smetana said. “Existing nonhormonal therapies work but are only modestly effective,” he said in the presentation.

The novel drug fezolinetant works by binding to the same receptor as estrogen but does not carry the same risks, he noted.

The SKYLIGHT 1 study was one of the trials that supported the FDA approval of fezolinetant and included women aged 4src-65 years with an average of at least seven hot flashes per day.

At 4 and 12 weeks, fezolinetant was significantly more effective than placebo at reducing overall symptoms. The benefit was maintained for at least 1 year for both studied doses, and the companion SKYLIGHT 2 trial confirmed improvement in the frequency and severity of symptoms. “Due to postmarketing reports of rare severe acute liver injury, liver function test monitoring is required,” Smetana told Medscape Medical News.

Liver Care Leaps Forward

Resmetirom, a novel thyroid hormone receptor agonist, is set to be a game changer for the treatment of MASLD. MASLD can progress to metabolic dysfunction–associated steatohepatitis (MASH), Smetana said in the presentation.

Resmetirom works by regulating hepatic lipid metabolism and reducing intrahepatic triglycerides, which results in decreased serum triglycerides, low-density lipoprotein cholesterol, and alanine transaminase, he said.

Resmetirom was approved in March 2src24 for the treatment of MASH in adults with moderate to advanced fibrosis. The approval was supported by a study in which significantly more adults with MASH who received 8src mg or 1srcsrc mg daily of the drug met the primary endpoint of MASH resolution and/or improvement in fibrosis at 52 weeks compared with those who received a placebo.

At 52 weeks, 25.9% of patients who received 8src mg and 29.9% of patients who received 1srcsrc mg had MASH resolution vs 9.7% of placebo patients (P <.srcsrc1 vs placebo for both doses). Similarly, 24.2% and 25.9% of patients in the 8src-mg and 1srcsrc-mg groups, respectively, showed improvement in fibrosis vs 14.2% of placebo group.

Nausea and diarrhea were the most common adverse events and occurred approximately twice as often in the resmetirom patients as in the placebo patients.

The drug was approved on an accelerated schedule based on proxy outcomes because of the huge potential public health benefit, Smetana said. However, the potentially beneficial impacts come with a steep price tag of approximately $47,7srcsrc per year, he noted. 

Clinical outcome studies are ongoing, with results expected in 2src27, said Smetana. In the meantime, given the high cost, limited clinical experience, and likely prior authorization barriers, the drug should only be prescribed by hepatologists for now, but it could become a primary care treatment in the future given the high prevalence of MASLD, he said.

Clinical Practice Perspective

Of the four recent approvals, the two likely to have the greatest impact on primary care are fezolinetant and resmetirom, said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, in an interview.

Fezolinetant is an important addition that addresses a common and significant problem, he said. “It provides an effective nonhormonal option for women who are experiencing distressing hot flashes and is well-tolerated and easy to use in primary care,” he said. However, clinicians need to follow the FDA guidance for checking liver enzymes in patients receiving this drug, he added.

Resmetirom is the first and currently only treatment for MASH with F2 or greater fibrosis, Skolnik said. “MASH is a serious problem, and the prevalence is increasing, but until now, there have been no effective treatments with a strong evidence base,” Skolnik told Medscape Medical News. The availability of a medication that can lower and even reverse fibrosis highlights the importance of identifying MASH at the primary care level, although, for the foreseeable future, the medication itself will require referral to a hepatologist, he noted.

As for potential barriers to adopting the new drugs, “Cost and access are always issues with new medications,” Skolnik added.

Smetana had no financial conflicts to disclose. Skolnik disclosed serving on advisory boards and as a consultant for AstraZeneca, Teva Pharmaceuticals, Lilly, Sanofi, Sanofi Pasteur, GSK, Abbot, and Novo Nordisk. Skolnik also disclosed serving as a speaker for AstraZeneca, Lilly, GSK, Teva Pharmaceuticals, Heartland, and Takeda Pharmaceuticals and receiving research support from AstraZeneca, GSK, Novo Nordisk, and Novartis.