The investigational product is an extended-release tablet formulation of diazoxide chloride (DCCR), the crystalline salt of diazoxide. In patients with Prader-Willi syndrome, DCCR is expected to reduce hyperphagia through activation of the adenosine triphosphate–sensitive potassium channels in the hypothalamus.

The designation was supported by data from a phase 3 clinical development program that included patients 4 years of age and older with genetically confirmed PWS. In the double-blind, placebo-controlled DESTINY PWS trial (ClinicalTrials.gov Identifier: NCT03440814), study participants were randomly assigned to receive DCCR (n=82) or placebo (n=42). Findings showed DCCR significantly improved hyperphagia in patients with severe hyperphagia at baseline. Significant improvements in body composition were also observed.

In the open-label extension study (ClinicalTrials.gov Identifier: NCT03714373), patients enrolled in the DESTINY PWS trial were assessed following 1 year of DCCR administration. Results showed DCCR was associated with significant improvements in hyperphagia and PWS-related behaviors (eg, anxiety, compulsivity, disordered thinking, aggressive/disruptive behaviors). 

“The granting of Breakthrough Therapy designation, the first for a drug being developed for the treatment of PWS, marks another important milestone for our DCCR clinical development program,” said Anish Bhatnagar, MD, CEO  of Soleno Therapeutics. “This important designation is confirmation that the FDA views PWS as a serious condition and is an indication of DCCR’s potential to be a safe and effective treatment for PWS. We remain focused on preparing our NDA submission for DCCR in PWS, which we continue to expect will occur in mid-2024.”

Diazoxide choline previously received the FDA’s Orphan Drug and Fast Track designations for PWS.

Lupkynis is a calcineurin inhibitor immunosuppressant indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis. It was approved in 2021 based on data from the phase 3 AURORA 1 study (ClinicalTrials.gov Identifier: NCT03021499).

The updated label now includes 3-year data from AURORA 2 (ClinicalTrials.gov Identifier: NCT03597464), a double-blind, placebo-controlled extension study. The trial assessed the long term safety and tolerability of voclosporin, in combination with mycophenolate mofetil (MMF) and low-dose glucocorticoids, vs MMF and low-dose glucocorticoids alone, in adults with active lupus nephritis who completed the AURORA 1 clinical trial.

Results from AURORA 2 showed 36 of the 179 voclosporin-treated patients and 21 of the 178 placebo-treated patients achieved sustained complete renal response (defined as achieving renal response at month 12 of AURORA 1 and maintaining the renal response at each subsequent study visit through month 36). It was noted that 21.8% (n=39) and 23% (n=41) of voclosporin and placebo patients, respectively, had missing data at the end of the first year or by the end of the 2-year extension study and had unknown status for sustained complete renal response. 

“Data from our AURORA 2 extension study included in the Lupkynis label showed a maintenance of sustained complete renal response with Lupkynis in combination with MMF and low-dose glucocorticoids, at every time point assessed through 3 years, relative to MMF and low-dose glucocorticoids alone,” said Dr Greg Keenan, Chief Medical Officer of Aurinia. “This notable outcome is aligned with treatment guidelines calling for use of Lupkynis for at least 3 years to reduce proteinuria.”

The labeling also includes new guidance for monitoring renal function in patients taking Lupkynis. Estimated glomerular filtration rate (eGFR) should be assessed every 2 weeks for the first month, every 4 weeks through the first year and quarterly thereafter. “[…] guidance on monitoring kidney function quarterly after the first year of Lupkynis treatment reflects the reality of clinical practice,” added Dr Keenan.

Additionally, the updated label provides more data regarding the transfer of Lupkynis to breast milk. The prescribing information states that at steady state following a maternal twice daily dosing regimen, the percent of voclosporin dose present in breast milk is expected to be similar to that following a maternal single dose.

Cases of ICP were reported in pregnant patients receiving azathioprine or 6-mercaptopurine to treat inflammatory bowel disease (ulcerative colitis and Crohn disease) or systemic lupus erythematosus. While not FDA-approved to treat these diseases, some guidelines suggest azathioprine or 6-mercaptopurine may be appropriate on an individualized basis to manage certain immunologic conditions during pregnancy.  

In response to these reports, the FDA is requiring manufacturers add additional warnings related to the risk of ICP with thiopurines. These include the following:

• Postmarketing cases of ICP have been reported in women treated with drugs in the thiopurine class during pregnancy. 
• ICP symptoms and elevated bile acid levels improved following azathioprine discontinuation. 
• Pregnant persons should discontinue use of thiopurines if they develop ICP. 

Adverse events related to medication use should be reported to the FDA’s MedWatch program.

Dr Charles Raison, the Director of Clinical Research at the Usona Institute and Professor in the Department of Psychiatry at the University of Wisconsin–Madison, talks to MPR about the potential of psilocybin as a therapy for major depressive disorder.

The conversion from accelerated to traditional approval was based on data from the phase 3 innovaTV 301 clinical trial (ClinicalTrials.gov Identifier: NCT04697628), which evaluated tisotumab vedotin vs investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502 patients with recurrent or metastatic cervical cancer who received no more than 2 prior systemic regimens in the recurrent or metastatic setting. 

The primary outcome of the study was overall survival (OS). Progression free survival (PFS) and objective response rate (ORR) were assessed as secondary outcomes.

Results showed treatment with tisotumab vedotin statistically significantly improved OS compared with chemotherapy (hazard ratio [HR], 0.70 [95% CI, 0.54-0.89]; P =.0038). Median OS was 11.5 months (95% CI, 9.8-14.9) with tisotumab vedotin and 9.5 months (95% CI, 7.9-10.7) with chemotherapy. Improvements in PFS (HR, 0.67 [95% CI, 0.54-0.82]; P <.0001) and ORR (17.8% vs 5.2%; P <.0001) were also observed for tisotumab vedotin vs chemotherapy. 

The most common adverse reactions reported with tisotumab vedotin were decreased hemoglobin, peripheral neuropathy, conjunctival adverse reactions, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, fatigue, decreased sodium, epistaxis, and constipation.

“The full FDA approval of Tivdak represents a significant achievement for women with recurrent and metastatic cervical cancer, reinforcing Tivdak as a treatment option that has proven to extend survival in patients whose disease has advanced after initial treatments,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “This milestone underscores the importance of our ongoing clinical development program to assess the full potential of tisotumab vedotin as a treatment option in other indications.”

According to the FDA, results from innovaTV 301 fulfill the postmarketing requirement of the previous accelerated approval.

The double-blind, active comparator-controlled phase 3 STRIDE-10 trial (ClinicalTrials.gov Identifier: NCT05569954) evaluated the safety and immunogenicity of V116 in pneumococcal vaccine-naïve adults 50 years of age and older (N=1484). Study participants were randomly assigned to receive a single dose of either V116 or PPSV23. 

The primary outcome measures included serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) at day 30 post vaccination and the percentage of participants with at least a 4-fold rise from baseline in serotype-specific OPAs. 

Results showed V116 elicited noninferior immune responses compared with PPSV23 for the 12 serotypes common to both vaccines. Additionally, superior immune responses were observed for the 9 serotypes included in V116 but not in PPSV23, and for 8 of 9 serotypes to V116 compared with PPSV23, as measured by the proportions of participants with at least a 4-fold rise in immune responses. 

“Even with the availability of current pneumococcal conjugate vaccines for adults, gaps in serotype coverage for invasive pneumococcal disease persist,” said Dr Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “These data add to the evidence supporting the potential for V116 to become an important new preventive option for adults, with results showing V116 elicited immune responses to the serotypes responsible for the majority of adult invasive pneumococcal disease.”

V116 is currently under Priority Review by the Food and Drug Administration (FDA) for the prevention of invasive pneumococcal disease and pneumococcal pneumonia caused by S. pneumoniae serotypes 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B in adults 18 years of age and older.

Amid an ongoing outbreak of bird flu in US dairy cows, the early findings should reassure the public that the milk sold in stores remains safe, officials added.

In the online update, the US Food and Drug Administration said the initial test findings likely mean the pasteurization process is killing the virus.

“These results reaffirm our assessment that the commercial milk supply is safe,” the agency wrote, but testing efforts are continuing.

“The FDA is further assessing retail samples from its study of 297 samples of retail dairy products from 38 states,” the agency added. “All samples with a PCR-positive result are going through egg inoculation tests, a gold standard for determining if infectious virus is present.”

“These important efforts are ongoing, and we are committed to sharing additional testing results as soon as possible,” the FDA added.

FDA officials also tested infant and toddler formulas, which used powdered milk, and did not find any evidence of the virus, the agency noted.

The story is different when it comes to viral fragments of bird flu: genetic bits of the virus have been discovered in roughly 20% of retail milk samples tested in a national survey, the US Food and Drug Administration said last week.

That earlier finding suggests bird flu has spread far more widely among dairy cows than officials first thought.

Samples from parts of the country that have infected dairy herds were more likely to test positive, the agency noted, and regulators stressed there is no evidence yet that cow milk poses a danger to consumers.

Still, 33 herds across 8 states have been confirmed to have been infected with bird flu, also known as H5N1.

“It suggests that there is a whole lot of this virus out there,” Richard Webby, a virologist and influenza expert at St. Jude Children’s Research Hospital, told the New York Times.

While it is still possible to eradicate bird flu from the nation’s dairy farms, Webby noted it is hard to control the outbreak without knowing its full scope.

To that end, the US Department of Agriculture on Wednesday announced mandatory testing of dairy cows moving across state lines. Until now, testing of cows had been voluntary and focused on cows with obvious symptoms of illness.

As of Wednesday, 23 people had been tested for the virus, while 44 people were being monitored after exposure to H5N1, the Times reported. Just one human infection has been reported so far, in a dairy worker in Texas who had direct contact with sick cows. The case was mild.

Still, sustained spread among cows would give the virus more chances to become more transmissible among humans. Experts believe pasteurization, in which milk is briefly heated, should kill the virus.

“And when you destroy the virus, it’s going to release genetic material,” Samuel Alcaine, a microbiologist and food scientist at Cornell University in New York, told the Times.

“It’s not surprising” to find them in milk, he added. “It doesn’t mean that the milk is not safe.”

Dr Jeanne Marrazzo, director of the National Institute of Allergy and Infectious Diseases, said during a Wednesday media briefing that some researchers had tested for live virus in retail milk but didn’t find any, the Times reported.

Even though the results only involved a small sample, the findings were “welcome news,” she added.

Still, “to really understand the scope here, we need to wait for the FDA efforts,” she noted.

More information

The US Centers for Disease Control and Prevention has more on bird flu.

SOURCES: US Food and Drug Administration, updates, April 25/26, 2024; New York Times

Instead, patients are presenting with headaches or disruptions in their vision or hearing, said a team co-led by Amy Nham, PharmD, MPH Nham is a first-year epidemic intelligence service officer assigned to the Chicago Department of Public Health.

Nham and two coauthors gave an overview of these “neurologic, ocular, and otic (NOO)” forms of syphilis, which can often be severe. The team found 36 potential NOO syphilis cases in the Chicago area, reported between January and August of 2023. Twenty involved a brain-targeted neurosyphilis, 17 were syphilis affecting the eyes, and one case involved hearing.

Men were most likely to be affected, with more than half identifying as heterosexual, the team said. NOO syphilis has traditionally most often been seen among HIV-positive people, but in the Chicago cases, two-thirds of those affected were not infected with HIV.

“Signs or symptoms consistent with NOO syphilis were often the only presentation” symptom, the researchers noted. “Clinicians should consider NOO syphilis even in persons presenting without typical syphilis signs and symptoms and persons without HIV.”

Speaking with CNN, Nham said that “providers definitely need to be screening more and be aware that this is what we’re seeing,” adding that “they’re not the most specific symptoms, which is why it’s really important that providers are doing appropriate screening and asking patients for risk factors,” including a patient’s sexual history.

Abstract

More Information

Jennifer K. Saper, M.D., from the Ann & Robert H. Lurie Children’s Hospital of Chicago, and colleagues characterized interest in RSV vaccination during pregnancy among women who were pregnant or planning to become pregnant. A cross-sectional online survey was conducted among individuals aged 18 to 45 years who were currently pregnant or trying to become pregnant in March 2023.

Overall, 1,528 of the 1,619 completed surveys were analyzed. The researchers found that 54 percent of respondents indicated being “very likely” to get vaccinated against RSV during pregnancy. The strongest predictor of vaccination likelihood was the perception of RSV as a serious illness. Predicted proportions of those “very likely” to vaccinate against RSV followed a similar pattern in the full regression model (63, 55, and 35 percent if RSV infection was perceived as serious and likely, serious and unlikely, and not serious, respectively).

“Educational efforts about protection against RSV illness in infants through vaccination during pregnancy and the consequent positive health implications for children may be a key component of public health and health care strategies to encourage RSV vaccination among pregnant individuals,” the authors write.

Abstract/Full Text

Mia Cokljat, M.B.Ch.B., from the University of Oxford in the United Kingdom, and colleagues compared the COVID-19 treatment guidelines of each World Health Organization (WHO) member state to the WHO COVID-19 therapeutic guidelines. The analysis included COVID-19 therapeutic national guidelines for 109 of the 194 WHO member states.

The researchers found considerable variation in guidelines and in disease severity stratifications. There were also substantial differences in therapeutic recommendations in many national guidelines versus the WHO guidelines. In late 2022, 93 percent of national guidelines were recommending at least one treatment that had been proven to be ineffective in large, randomized trials and was not recommended by WHO. For example, corticosteroids were not recommended in severe disease in nearly 10 percent of national guidelines, despite overwhelming evidence of their benefit. For countries categorized as low-resource settings, national guidelines showed the greatest divergence.

“The formalization of processes in the development of national guidelines for COVID-19 and other infectious diseases is essential for ensuring that these guidelines are grounded in the best available evidence,” the authors write. “A systematic and structured approach would not only enhance the credibility of the guidelines but could also contribute to their effectiveness in guiding public health interventions, especially in a pandemic setting.”

Abstract/Full Text

Tapinarof is an aryl hydrocarbon receptor agonist currently marketed under the brand name Vtama^® for the topical treatment of plaque psoriasis in adults.

The sNDA is supported by data from the phase 3 ADORING-1 and ADORING-2 trials (ClinicalTrials.gov Identifier: NCT05014568, NCT05032859, respectively), which included pediatric and adult patients with atopic dermatitis that was present for at least 6 months for individuals 6 years and older or 3 months for those 2 to 5 years of age. 

The primary endpoint for both studies was the proportion of patients who achieved a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) with a minimum 2-grade improvement from baseline to week 8. In both trials, a significantly greater proportion of patients treated with tapinarof cream achieved vIGA-AD success compared with those who received vehicle.

“The FDA acceptance of our sNDA is an important milestone in our efforts to bring Vtama cream, as a potentially safe and well-tolerated nonsteroidal treatment option, to adults and children as young as 2 years old who suffer from atopic dermatitis,” said Todd Zavodnick, CEO of Dermavant. “Our commitment to patients is unwavering, and we remain highly focused on preparing for the commercial launch of Vtama cream, subject to FDA approval, for its second indication of atopic dermatitis.”

A regulatory decision is expected in the fourth quarter of 2024.

Beqvez (fidanacogene elaparvovec-dzkt)

Beqvez is indicated for the treatment of adults with moderate to severe hemophilia B who currently use factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes and, do not have neutralizing antibodies to adeno-associated virus serotype Rh74var (AAVRh74var) capsid as detected by an FDA-approved test.

The nAbCyte cell-based neutralizing antibody assay detects AAVRh74var pre-existing neutralizing antibodies, which could impact the efficacy of Beqvez. Patients should be tested for pre-existing antibodies prior to treatment. Test results are reported as being negative (not detected) or positive (detected). If a patient tests positive for antibodies to AAVRh74var, Beqvez should not be administered.

“The approval of the nAbCyte companion diagnostic represents a first for a gene therapy that treats eligible patients with hemophilia B, helping to bring clarity to physicians and patients who are considering Beqvez as a treatment option,” said Dr Sonal Bhatia, MD, Head of US Specialty Care Medical Affairs, Pfizer. “We believe this companion diagnostic is an important tool for evaluating patients who may be suitable for gene therapy as the treatment paradigm advances with the introduction of gene therapies like Beqvez.”

The Food and Drug Administration (FDA) has approved Xolremdi (mavorixafor) for the treatment of patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes.

WHIM syndrome is a hereditary immune deficiency caused by gain of function mutations in the chemokine receptor (CXCR4) gene. This leads to increased responsiveness to the CXCR4 ligand, CXCL12, and retention of leukocytes in the bone marrow. Xolremdi works by blocking the binding of CXCL12, resulting in increased mobilization of neutrophils and lymphocytes from the bone marrow into peripheral circulation. 

The approval was based on data from the randomized, double-blind, placebo-controlled phase 3 4WHIM trial (ClinicalTrials.gov Identifier: NCT03995108), which evaluated the efficacy and safety of mavorixafor in 31 patients 12 years of age and older with WHIM syndrome. Study participants were randomly assigned to receive mavorixafor (n=14) or placebo (n=17) orally once daily. Efficacy was based on improvement in absolute neutrophil counts (ANC), improvement in absolute lymphocyte counts (ALC), and a reduction in infections.

Findings showed mavorixafor was associated with statistically significant and clinically relevant longer times above threshold levels for both absolute neutrophil counts (least squares [LS] mean [SE]: 15.0 [1.89] hours vs 2.8 [1.52] hours, respectively; P <.0001) and absolute lymphocyte counts (LS mean [SE]: 15.8 [1.39] hours vs 4.6 [1.5] hours, respectively; P <.0001) compared with placebo. Treatment with mavorixafor also resulted in reductions in the rate, severity, and duration of infections vs placebo.

The most common adverse reactions reported with mavorixafor were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness. 

“Until now, supportive care for people with WHIM syndrome has focused on symptom management and not the underlying cause of disease, the dysfunction of the CXCR4 pathway,” said Teresa K. Tarrant, MD, Associate Professor of Medicine, Rheumatology, and Immunology at Duke University School of Medicine and a principal investigator in the 4WHIM trial. “I am thrilled that with the approval of Xolremdi, a therapy designed to address dysregulated CXCR4 pathway signaling, we now have a targeted treatment that has demonstrated the ability to elevate absolute neutrophil and lymphocyte counts, increasing WHIM patients’ ability to fight infections.”

Xolremdi is supplied as a 100mg strength capsule.

The approval was based on safety and efficacy data from clinical trials evaluating diazepam rectal gel, as well as adult bioavailability studies comparing Libervant with diazepam rectal gel, adult and pediatric pharmacokinetic data, and an open-label safety study of Libervant. Pharmacokinetic data indicate that in pediatric patients 2 to 5 years of age, administration of the buccal film is expected to provide adequate therapeutic exposures under both fed and fasted states.

Libervant is supplied as a buccal film in 5mg, 7.5mg. 10mg, 12.5mg, and 15mg dosage strengths. The recommended dose is dependent on the patient’s weight. The buccal film is applied to the inside of the mouth on top of the surface of the cheek. 

As Libervant contains diazepam, a benzodiazepine, the prescribing information includes Boxed Warnings regarding the risks of concomitant use with opioids, abuse, misuse, addiction, dependence, and withdrawal reactions. The most common adverse reactions reported in patients 2 to 5 years of age were somnolence and headache.

“We are thrilled to have received FDA approval for Libervant in patients between the ages of 2 and 5,” said Daniel Barber, CEO  of Aquestive. “Patients have been waiting years for Libervant, the first and only FDA approved orally-administered rescue product for the treatment of seizure clusters.”

According to the Company, distribution of the product has already begun and will be expanded in the coming weeks and months.

Hercessi, a a HER2/neu receptor antagonist, is indicated for:

• Adjuvant treatment of HER2-overexpressing node positive or node negative (ER/PR negative or with 1 high risk feature) breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as a single agent following multi-modality anthracycline based therapy.
• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer, and as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received 1 or more chemotherapy regimens for metastatic disease.
• In combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.

The approval of Hercessi was based on a comprehensive package of analytical, preclinical, and clinical data demonstrating that the biosimilar product is highly similar to the reference product, Herceptin. The application was supported by two phase 1 pharmacokinetic (PK) studies and a phase 3 comparability study (ClinicalTrials.gov Identifier: NCT03084237), which showed the biosimilar was equivalent, both in safety and efficacy, to the reference product in patients with HER2-positive recurrent or metastatic breast cancer. 

Hercessi is supplied as a 150mg lyophilized powder in a single-dose vial for intravenous infusion after reconstitution. The FDA is expected to make a decision on the 420mg dosage strength of Hercessi in the fourth quarter of 2024.

“The approval of Hercessi, our first biosimilar to be approved in the US, marks an important milestone for Accord BioPharma in our efforts to improve access for patients,” said Chrys Kokino, US president of Accord. “Because breast and gastric cancers are among the most common types of cancer and cancer can have a high-cost burden for patients, there is a need to provide these patients with additional treatment options that may be more affordable, such as biosimilars.”

Compared with traditional SCS devices, the closed-loop feature of the Inceptiv SCS senses neural responses (50 times per second) and is able to automatically adjust stimulation in real time, providing more consistent therapy. The device is implanted through a minimally invasive procedure and utilizes signals generated by the spinal cord in response to electrical stimuli (evoked compound action potentials), which allows a proprietary algorithm to respond and make adjustments in order to maintain the physician’s prescribed stimulation.

The Inceptiv system also offers full-body 1.5T and 3T MRI access with no power or impedance restrictions.

“For patients dealing with chronic pain, every day is a struggle,” said David Carr, vice president and general manager, Pain Interventions within the Neuromodulation business, which is part of the Neuroscience Portfolio at Medtronic. “They deserve personalized and effective relief, without compromising future access to MRI. They deserve the comfort that the smallest and thinnest device on the market can provide. We are proud to offer the most cutting-edge solution available today with Inceptiv SCS.”

The Inceptiv SCS is expected to be available in the coming weeks.

Beqvez is a one-time AAV-based gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity factor IX variant. The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. A single intravenous (IV) infusion of Beqvez results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

The approval was based on data from the ongoing, open-label, single-arm phase 3 BENEGENE-2 study (ClinicalTrials.gov Identifier: NCT03861273), which evaluated the efficacy and safety of fidanacogene elaparvovec in 45 adult males with moderately severe to severe hemophilia B (defined as factor IX circulating activity of ≤2 IU/dL). 

Eligible patients were required to have completed 6 months of routine factor IX prophylaxis therapy during the lead-in period (ClinicalTrials.gov Identifier: NCT03587116) after which they received a single IV infusion of fidanacogene elaparvovec. Median follow-up was 2 years (range, 0.4-3.2) from the time of infusion.

The primary endpoint was noninferiority in the annualized bleeding rate (ABR) of total bleeds after fidanacogene elaparvovec infusion compared with baseline ABR during the lead-in period.

Results showed a mean ABR of 4.5 bleeds/year (95% CI, 1.9-7.2) during the baseline period and 2.5 bleeds/year (95% CI, 1.0-3.9) after fidanacogene elaparvovec (treatment difference of -2.1 bleeds/year [95% CI, -4.8, 0.7]), meeting the noninferiority success criterion (upper bound of the 95% CI in the difference was less than 3.0 bleeds/year).

Sixty percent of patients had no bleeds during the post-infusion efficacy evaluation period compared with 29% of those in the prophylaxis arm. A median ABR of zero (range, 0-19) was observed during the efficacy evaluation period vs 1.3 (range, 0-53.9) during the lead-in period.

Six patients (13%) resumed routine factor IX prophylaxis after fidanacogene elaparvovec infusion, starting from 0.4 years to 1.7 years after the gene therapy treatment. One patient had intermittent exogenous factor IX use and a higher ABR after fidanacogene elaparvovec infusion (5.0 bleeds/year) compared with baseline (1.2 bleeds/year) with factor IX activity <5% starting at 0.4 years.

The most common adverse reaction reported was an increase in transaminases. The prescribing information for Beqvez includes risks associated with hepatotoxicity, infusion reactions, and malignancy (eg, hepatocellular carcinoma).

Beqvez is supplied as a vial containing a preservative-free suspension for IV infusion. Treatment is provided as a customized kit containing the number of vials required to meet dosing requirements for each patient based on their weight.

The update was based on data from an open-label clinical trial (ClinicalTrials.gov Identifier: NCT03960645) that included 33 virologically-suppressed pregnant adults with HIV-1 and no known substitutions associated with resistance to the individual components of Biktarvy. Study participants received Biktarvy once daily from the second or third trimester through postpartum. At baseline, the median CD4+ cell count was 558 cells/μL.

Findings showed viral suppression was maintained during pregnancy, at delivery, and through week 18 postpartum in the 32 participants who completed the study. The median change in CD4+ cell count from baseline to week 12 postpartum was 159 cells/μL. Twenty-nine neonates who received testing at birth and/or at 4 to 8 weeks after birth were reported to have negative/undetectable HIV-1 PCR results. 

In pregnant patients, viral load should be monitored closely as lower exposures of Biktarvy were observed during pregnancy compared with the postpartum period. According to the prescribing information, the exposure changes during pregnancy are not considered clinically significant in virologically suppressed pregnant individuals.

The overall safety profile of Biktarvy was consistent with that seen in previous studies; no new safety or tolerability concerns were observed with Biktarvy during pregnancy and postpartum.

“This label update marks an important milestone for Biktarvy, reinforcing its efficacy profile for pregnant [people living with HIV-1], an often understudied and most vulnerable community in clinical research,” said Jared Baeten, MD, PhD, Vice President, HIV Clinical Development, Gilead Sciences. “Not only is Biktarvy an alternative regimen for use in pregnancy, but people of childbearing potential can also remain on Biktarvy if they become pregnant.

Biktarvy is a 3-drug combination of bictegravir, an HIV-1 integrase strand transfer inhibitor, and emtricitabine and tenofovir alafenamide, both HIV-1 nucleoside analog reverse transcriptase inhibitors. It is supplied as a tablet in 2 dosage strengths: 30mg/120mg/15mg and 50mg/200mg/25mg. The recommended dosage for pregnant individuals is one 50mg/200mg/25mg tablet once daily.

In the INSPIRE trial (Intelligent Stewardship Prompts to Improve Real-time Empiric antibiotic selection; ClinicalTrials.gov Identifier: NCT03697096), investigators compared a novel antibiotic stewardship including computerized provider order entry (CPOE) prompts with routine antibiotic stewardship among 127,403 adults admitted with UTI to 59 private community hospitals. Prompts were tailored to the specific extended-spectrum antibiotic ordered: cefepime orders triggered evaluation for low risk of Pseudomonas UTI; carbapenem orders triggered evaluated for low risk of extended-spectrum β-lactamase-producing Enterobacterales (ESBLs) or resistant Pseudomonas. Although uncommon, prompts were also generated for vancomycin orders for gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus for UTI. The automated approach included each hospital’s prevalence of syndrome-specific multidrug-resistant organism (MDRO). Mean age of the cohort was 69.4 years, 30.5% were male, and the median Elixhauser Comorbidity Index was 4.

The intervention group experienced a significant 17.4% reduction in the number of days on empiric extended-spectrum antibiotics compared with the routine stewardship group, Shruti K. Gohil, MD, MPH, of the University of California Irvine, and colleagues reported in JAMA. The empiric extended-spectrum days of therapy (per 1000 empiric days) for the CPOE bundle group decreased from a mean 392.2 to 326.0 days, whereas it increased from a mean 431.1 to 446.0 days for the routine stewardship group. Use of antipseudomonal antibiotics decreased by one-fifth.

Only 3.4% or less of urine cultures were positive for Pseudomonas and 8.0% or less for ESBL. Antibiotic escalation was comparable between the intervention and control groups (10.0% vs 10.2%). Less than 6% of patients deemed low risk in the intervention group were found to have a MDRO. ICU transfers (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not increase in the intervention vs control group.

In an accompanying editorial, Anurag N. Malani, MD, and Preeti N. Malani, MD, MSJ, of University of Michigan Health in Ann Arbor, noted the hurdles in implementing the complex system and commented:

“Even with the CPOE bundle and significant reductions, extended-spectrum antibiotic use remained high in both the pneumonia and UTI studies, while the rate of multidrug-resistant organisms isolated in cultures was low. Future studies should also consider cost savings, effects on local antibiograms, the nuances surrounding diagnostic certainty (for both pneumonia and UTI), and how to develop policy that incentivizes this type of innovation.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Margaret Slavin, PhD, from the University of Maryland in College Park, and colleagues examined the association between migraine and severe headache prevalence and use of acid-suppression therapy. Data were obtained from adults in the 1999 to 2004 National Health and Nutrition Examination Survey.

The researchers found that use of acid-suppression therapy was associated with higher odds of migraine or severe headache in 11,818 US adults, with higher odds for all types of acid-suppression therapy and use of any type versus nonuse (adjusted odds ratios [95% CI], 1.70 [1.32 to 2.18], 1.40 [1.00 to 1.95], and 1.30 [1.05 to 1.61] with use of proton pump inhibitors, H2 receptor antagonists, and generic antacids, respectively). No significant differences were seen between acid-suppression therapies. There was an interaction observed for H2 receptor antagonist use with magnesium intake.

“These results suggest that there is a need for more intentionally designed prospective work to inform the extent to which associations between migraine and acid-suppression therapy are merely detecting comorbidities or to what extent migraine is an adverse event associated with the medications,” the authors write.

One author disclosed ties to the pharmaceutical industry.

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Jiseung Kang, PhD, from the University of Oxford in the United Kingdom, and colleagues conducted a nationwide birth cohort study to examine the potential association between prenatal opioid exposure and the risk for neuropsychiatric disorders in children in South Korea. Data were included for 3,128,571 infants, from 2,299,664 mothers; 2,912,559 infants had no prenatal opioid exposure and 216,012 had prenatal opioid exposure. Three cohorts were formed: full unmatched, propensity score-matched, and child screening cohorts, all of which were paired with sibling comparison cohorts.

The researchers found that in children with prenatal opioid exposure, the fully adjusted hazard ratio for neuropsychiatric disorders was 1.07 in the matched cohort, but no significant association was seen in the sibling comparison cohort. Increased risks for neuropsychiatric disorders in children were seen in association with prenatal opioid exposure during the first trimester, higher opioid doses, and long-term opioid use of 60 days or more (hazard ratios, 1.11, 1.15, and 1.95, respectively). A modestly increased risk for severe neuropsychiatric disorders (hazard ratio, 1.30), mood disorders, attention-deficit/hyperactivity disorder, and intellectual disability in the child were seen with prenatal opioid exposure.

“Although a slightly increased risk was observed for neuropsychiatric disorders, given the observational nature of the study, these results should not be considered clinically meaningful,” the authors write.

One author disclosed ties to the pharmaceutical industry.

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Anjali A. Dixit, MD, MPH, from Stanford University in California, and colleagues used a claims database to evaluate the risk for postoperative respiratory complications among patients with type 2 diabetes and a prescription fill for GLP-1 RAs who underwent one of 13 emergency surgeries. The analysis included data identified from the Merative MarketScan Commercial Database (2015 through 2021).

The researchers found that among 23,679 patients with diabetes and emergency surgery, 14.8 percent had a GLP-1 RA fill. A GLP-1 RA fill was associated with a greater likelihood of being male, using more antidiabetic agents, and having diagnoses of obesity. The overall incidence of postoperative respiratory complications was similar for those with a GLP-1 RA fill and those without (3.5 vs 4.0%; odds ratio, 0.85; 95% CI, 0.70 to 1.04). Findings were similar in an adjusted analysis (odds ratio, 1.03; 95% CI, 0.82 to 1.29).

“Results of this study suggest that liberalizing the withholding guidelines for GLP-1 RAs preoperatively should be considered,” the authors write.

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Daniel J. Merenstein, MD, from Georgetown University Medical Center in Washington, D.C., and colleagues evaluated the impact of antibiotic use on the duration and severity of LRTI. The analysis included 718 adult patients presenting to US primary or urgent care sites with a chief complaint of cough and symptoms consistent with LRTI.

The researchers reported that 29% of presenting patients had an antibiotic prescribed at baseline, most commonly amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin. In patients with viral, bacterial, or mixed infections, provision of an antibiotic had no effect on the duration or overall severity of cough. However, antibiotic receipt did cut the likelihood of a follow-up visit (14.1 vs 8.2%; adjusted odds ratio, 0.47). Patients receiving an antibiotic were also significantly more likely to receive a systemic corticosteroid (31.9 vs 4.5%) and an albuterol inhaler (22.7 vs 7.6%). Patients believed that an antibiotic would cut the duration of their illness by nearly 4 days.

“Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics which should be the target of antibiotic stewardship efforts,” the authors write.

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Cynthia Gyamfi-Bannerman, MD, from the University of California, San Diego, and colleagues evaluated whether administration of late preterm (34 to 36 completed weeks) corticosteroids (12mg of intramuscular betamethasone administered twice 24 hours apart) to persons at risk for late preterm delivery affected childhood neurodevelopmental outcomes. The analysis included 949 children aged 6 years and older followed from birth as part of the Maternal-Fetal Medicine Units Network cycle.

The researchers found no differences in the primary outcome of a general conceptual ability score less than 85, which occurred in 17.1% of the betamethasone group vs 18.5% of the placebo group (adjusted relative risk, 0.94; 95% CI, 0.73 to 1.22). Similarly, there no differences in secondary outcomes of gross motor skills, social responsiveness, or behavior.

“In this follow-up study of a randomized clinical trial, antenatal corticosteroids in persons at risk of late preterm delivery were not associated with adverse effects on childhood neurodevelopmental outcomes at age 6 years or older,” the authors write. “These data provide reassurance with regard to the administration of antenatal corticosteroids in the late preterm period.”

One author disclosed ties to the pharmaceutical industry.

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Haydar Frangoul, MD, from the Sarah Cannon Research Institute at the Children’s Hospital at TriStar Centennial in Nashville, Tennessee, and colleagues conducted a phase 3, open-label study of exa-cel in patients aged 12 to 35 years of age with sickle cell disease with at least 2 severe vaso-occlusive crises in each of the 2 years before screening. Patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan before exa-cel infusion. Forty-four patients received exa-cel and were followed for a median of 19.3 months.

The researchers found that in each patient, neutrophils and platelets were engrafted. Twenty-nine of the 30 patients with sufficient follow-up to be evaluated were free from vaso-occlusive crises for at least 12 consecutive months; all 30 were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months.

“Improvements were seen in all markers of hemolysis evaluated, including normalization of lactate dehydrogenase and detectable haptoglobin levels, findings that indicated resolution of intravascular hemolysis,” the authors write. “Patients also had clinically meaningful improvements in quality of life.”

The study was funded by Vertex Pharmaceuticals and CRISPR Therapeutics.

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