HealthDay News — In a living clinical guideline issued by the American College of Physicians (ACP) and published online January 3 in the Annals of Internal Medicine, updated recommendations are presented for the pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults.

Based on a systematic review and grading of the evidence, Amir Qaseem, MD, PhD, from ACP in Philadelphia, and colleagues developed four recommendations. To reduce the risk for fractures in postmenopausal women diagnosed with primary osteoporosis, ACP strongly recommends use of bisphosphonates for initial pharmacologic treatment; for men diagnosed with primary osteoporosis, bisphosphonates are suggested for initial pharmacologic treatment to reduce the risk for fracture. For postmenopausal women and for men diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates, the receptor activator of nuclear factor κB ligand inhibitor denosumab is suggested as second-line pharmacologic treatment. For women with primary osteoporosis with a very high risk for fracture, the sclerostin inhibitor romosozumab or recombinant human parathyroid hormone teriparatide, followed by a bisphosphonate, is suggested. For women older than the age of 65 years with osteopenia, an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate is suggested.

“Future studies should aim to identify which patients will benefit from medication, and when to initiate an anabolic medication versus a bisphosphonate,” write the authors of an accompanying editorial.

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Chia-Yu Huang, from Taichung Tzu Chi Hospital in Taiwan, and colleagues conducted a propensity score-matched cohort study involving 23,226 patients with newly diagnosed RA between January 1, 1997, and December 31, 2010. The acupuncture cohort included patients who were administered acupuncture therapy from the initial date of RA diagnosis to December 31, 2010; the no-acupuncture cohort included patients who did not receive acupuncture during the same time interval.

The researchers found that the cumulative incidence of ischemic stroke was lower in the acupuncture cohort. At the end of the study, 341 and 605 patients in the acupuncture and no-acupuncture groups, respectively, experienced ischemic stroke (5.95 and 12.4 per 1,000 person-years, respectively; adjusted subhazard ratio, 0.57). The reduction in incidence of ischemic stroke was independent of sex, age, types of drugs used, and comorbidities.

“Our study demonstrates that the ischemic stroke risk could be reduced by acupuncture treatment in patients with RA in Taiwan,” the authors write. “The possible mechanism may involve reducing proinflammatory cytokines through acupuncture therapy, thereby attenuating cardiovascular disease, including ischemic stroke.”

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Adalimumab-adbm injection, a biosimilar to Humira^® (adalimumab), has been made available by Boehringer Ingelheim.

Adalimumab-adbm injection is an interchangeable biosimilar and can be substituted for the reference product without requiring a prescription change. The substitution may occur at the pharmacy similar to how generics are substituted for brand name drugs. According to the Company, Adalimumab-adbm injection has been priced at an 81% discount to Humira.  

Adalimumab-adbm injection is indicated for the treatment of adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderately to severely active Crohn disease, moderately to severely active ulcerative colitis, moderate to severe plaque psoriasis, moderate to severe hidradenitis suppurativa, and noninfectious intermediate, posterior, and panuveitis.

The product is also approved to treat moderately to severely active Crohn disease in children 6 years of age and older, as well as moderately to severely active polyarticular juvenile idiopathic arthritis in children 2 years of age and older.

Adalimumab-adbm injection is a citrate-free formulation and is supplied as 40mg/0.8mL, 20mg/0.4mL and 10mg/0.2mL prefilled syringes and as a 40mg/0.8mL prefilled autoinjector.

In July 2023, Boehringer Ingelheim launched a branded version of adalimumab-adbm called Cyltezo^®. This product will remain available at a 5% discount to Humira.

“Biosimilars are intended to contribute to the economic sustainability of health care systems, and it is our hope that this dual pricing approach will contribute to that sustainability, improve access to Adalimumab-adbm and help meet the varied needs of people with a variety of chronic inflammatory diseases,” said Stephen Pagnotta, Executive Director and Biosimilar Commercial Lead at Boehringer Ingelheim.

Trisha N. Peel, MB, BS, PhD, from Monash University in Melbourne, Australia, and colleagues conducted a multicenter, superiority, placebo-controlled trial in which adult patients without known methicillin-resistant Staphylococcus aureus (MRSA) colonization who were undergoing arthroplasty were randomly assigned to receive 1.5g vancomycin or normal saline placebo in addition to cefazolin prophylaxis. The modified intention-to-treat analysis included 4113 patients: 2233 undergoing knee arthroplasty; 1850 undergoing hip arthroplasty; and 30 undergoing shoulder arthroplasty.

The researchers found that surgical site infections occurred in 4.5 and 3.5% of patients in the vancomycin and placebo groups, respectively, among the modified intention-to-treat population (relative risk, 1.28; 95% CI, 0.94 to 1.73; P =.11). Surgical site infection occurred in 5.7 and 3.7% of patients in the vancomycin and placebo groups, respectively, among those undergoing knee arthroplasty (relative risk, 1.52; 95% CI, 1.04 to 2.23). For those undergoing hip arthroplasty, the corresponding proportions were 3.0 and 3.1% (relative risk, 0.98; 95% CI, 0.59 to 1.63). Adverse events occurred in 1.7% of patients in both the vancomycin group and the placebo group.

“In this pragmatic, randomized trial involving adult patients undergoing arthroplasty who had a low prevalence of MRSA colonization, the addition of vancomycin was not superior to surgical antimicrobial prophylaxis with cefazolin,” the authors write.

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Vamorolone is a novel corticosteroid that acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which vamorolone exerts its effect in patients with DMD is unknown. 

The approval was based on data from the randomized, double-blind, placebo- and active-controlled phase 2b VISION-DMD study (ClinicalTrials.gov Identifier: NCT03439670), which evaluated the efficacy and safety of vamorolone in ambulant boys 4 to less than 7 years of age with DMD. Patients (N=121) were randomly assigned to receive vamorolone orally at daily doses of 2mg/kg or 6mg/kg, prednisone 0.75mg/kg/day, or placebo.

Treatment with vamorolone 6mg/kg/day met the primary endpoint demonstrating superiority in change from baseline in time to stand test (TTSTAND) velocity at 24 weeks vs placebo (treatment difference, 0.06 [95% CI, 0.023-0.098] rises/second from baseline [P =.002]). This corresponded to a clinically relevant improvement in TTSTAND in the vamorolone 6mg/kg/day arm (from 6.0 to 4.6 seconds) and deterioration in the placebo arm (from 5.4 to 5.5 seconds).

Vamorolone was also found to be superior to placebo across multiple secondary endpoints, including TTSTAND velocity for 2mg/kg/day (P =.02), 6-minute walk test (6MWT) for 6mg/kg/day (P =.002) and 2mg/kg/day (P =.004), and time to run/walk 10 meters (TTRW) for 6mg/kg/day (P =.002).

No statistically significant differences were observed between vamorolone 6mg/kg/day and prednisone across all endpoints. The analysis showed that height percentile declined in patients treated with prednisone but not among those who received vamorolone (P =.02).

The use of vamorolone in patients 2 years to less than 4 years of age and 7 to less than 18 years of age is supported by findings of efficacy and safety in patients 4 to less than 7 years of age with DMD and by pharmacokinetic and safety data.

The most common adverse reactions reported were cushingoid features, psychiatric disorders, vomiting, increased weight, and vitamin D deficiency. The prescribing information includes warnings and precautions related to alterations in endocrine function, immunosuppression and increased risk of infection, alterations in cardiovascular and renal function, gastrointestinal perforation, behavioral and mood disturbances, and effects on bones and eyes.

Agamree is supplied as a 40mg/mL oral suspension. The product is expected to be available in the first quarter of 2024. Prior to starting treatment, all age-appropriate immunizations should be administered.

Allopurinol and febuxostat are similarly effective in controlling flares in patients with gout, including those with stage 3 chronic kidney disease (CKD), according to trial results published in the New England Journal of Medicine.

In double-blind CSP594 Comparative Effectiveness in Gout: Allopurinol vs Febuxostat trial (ClinicalTrials.gov identifier: NCT02579096), investigators randomly assigned 940 patients with hyperuricemia to receive allopurinol or febuxostat at titrated doses to achieve a serum urate target of 6mg/dL or lower (or 5mg/dL or lower if tophi were present). Approximately a third of patients in both groups had stage 3 CKD (30-59 mL/min/1.73 m² using the Modification of Diet in Renal Disease study formula for estimated glomerular filtration rate). The allopurinol and febuxostat groups received daily doses of 100 and 40mg, respectively, to start, then therapies were titrated until attainment of target uric acid levels or maximal dose. Patients also received guideline-directed anti-inflammatory prophylaxis with colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids. After the maintenance phase, no study drug dose adjustments were allowed, and all anti-inflammatory treatments were discontinued except in the event of gout flare.

Results showed that 36.5% of the allopurinol group and 43.5% of the febuxostat group experienced the primary outcome of 1 or more gout flares during the observation phase; a 7% difference that met a criterion for noninferiority, James R. O’Dell, MD, of Veterans Affairs (VA) Nebraska-Western Iowa Health Care System in Omaha, Nebraska, and colleagues reported. Among patients with stage 3 CKD, allopurinol also proved noninferior to febuxostat with 31.9% vs 45.3% experiencing a gout flare, respectively, the investigators reported.

In both the allopurinol and febuxostat groups, 80% of patients, including those with stage 3 CKD, achieved and maintained target serum urate levels at 1 year.

“Our randomized double-blind trial demonstrates that allopurinol, when dosed appropriately as part of a titrate-to-target strategy, is noninferior to febuxostat with respect to flares of gout,” Dr O’Dell’s team wrote.

In 2019, the FDA issued a boxed warning concerning the cardiovascular safety of febuxostat based on results of the CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout) trial. The 2020 FAST trial (Febuxostat versus Allopurinol Streamlined Trial), however, showed no increased risk for cardiovascular events. In the current study, the investigators found no evidence that febuxostat increases cardiovascular morbidity or overall mortality compared with allopurinol. Serious adverse events (26.7% vs 26.1%), including cardiovascular events (8.1% vs 6.8%) and death (8 patients in each group), occurred in comparable proportions of the allopurinol and febuxostat arms, respectively. Dr O’Dell and colleagues suggested that the nearly ubiquitous use of colchicine in the early phases of the trial might have mitigated cardiovascular risks.

Dr O’Dell’s team made other observations that also warrant additional research. Hospitalization for heart failure was numerically higher among patients treated with allopurinol (23 vs 10 hospitalizations). A post hoc analysis showed that acute kidney injury occurred in 15 allopurinol-treated patients compared with 4 febuxostat-treated patients who had stage 3 CKD. Most AKI events were related to volume depletion or congestive heart failure, the investigators noted. All but 3 AKI events were transient.

Reference

O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. N Engl J Med. Published online February 3, 2022. doi:10.1056/EVIDoa2100028

Alpha blockers do not increase the risk for falls, fractures, or death in the hemodialysis population, a new observational study concludes.

In phases 4 to 6 of the Japan Dialysis Outcomes and Practice Patterns (J-DOPPS) Study, 5149 patients on hemodialysis (mean age 65 years, 68% men) received anti-hypertensive drugs, including 717 patients (14%) prescribed alpha blockers such as doxazosin, bunazosin, prazosin, or urapidil. During a mean 2 years of follow-up, 247 fractures, 525 falls, and 498 deaths occurred in the overall cohort.

Multivariable analysis of the intent-to-treat population showed that patients prescribed alpha blockers had no higher risks of falls or fractures than patients not prescribed these agents, Ken Iseri, MD, PhD, of Showa University School of Medicine in Tokyo, Japan, and colleagues reported in Kidney Medicine. This result included patients at greater risk for falls due to advanced age, systolic blood pressure less than 140 mmHg, anemia, low body mass index, or large fluid removal volume.

“The face-to-face meeting with nephrologists three times per week may permit avoidance of undesirable events through achievement of optimal blood pressure management,” Dr Iseri’s team suggested. Pre-dialysis blood pressure levels were significantly higher in alpha blocker users, indicating that these agents were commonly prescribed for resistant or refractory hypertension.

Alpha blockers also conferred no higher risk for all-cause mortality in the total hemodialysis population, the investigators reported. Alpha blockers were significantly associated with a decreased risk of death among older patients (by 29%), women (32%), patients with a cardiovascular disease history (33%), and those with a pre-dialysis systolic blood pressure of 140 mmHg or greater (31%).

“We could not fully explain why this favorable effect was found only in specific hemodialysis populations, but not in total populations,” Dr Iseri’s team wrote. “However, recent studies have shown that alpha blockers may prevent cardiac remodeling and the development and progression of heart failure and have protective benefits against hyperinflammation and cytokine storm syndrome.”

Since this was an observational study of a single ethnicity and lacked data on patient strength, frailty, history of hypotension, bone mineral density, medication adherence, and other factors, more research is needed.

Amjevita (adalimumab-atto), a citrate-free biosimilar to Humira^® (adalimumab), is now available in the US.

Amjevita, a tumor necrosis factor (TNF) blocker, is indicated for:

• Rheumatoid arthritis (RA): reducing signs/symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA; may be used alone or with methotrexate (MTX) or other non-biologic DMARDs.
• Juvenile idiopathic arthritis (JIA): reducing signs/symptoms of moderately to severely active polyarticular JIA in patients 2 years of age and older; may be used alone or with MTX.
• Psoriatic arthritis (PsA): reducing signs/symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA; may be used alone or with non-biologic DMARDs.
• Ankylosing spondylitis (AS): reducing signs/symptoms in adult patients with active AS.
• Crohn disease (CD): moderately to severely active CD in patients 6 years of age and older.
• Ulcerative colitis (UC): moderately to severely active UC in adult patients.
• Plaque psoriasis (PsO): treating adult patients with moderate to severe chronic PsO who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.

The Food and Drug Administration (FDA) approved Amjevita in September 2016 based on data demonstrating that the biosimilar product and the reference product were highly similar, and that there were no clinically meaningful differences between the agents. Amjevita is not interchangeable with Humira. 

Amjevita is supplied in a 40mg/0.8mL single-dose prefilled SureClick autoinjector, and in 20mg/0.4mL and 40mg/0.8mL single-dose prefilled syringes. 

References

1. Amjevita (adalimumab-atto), first biosimilar to Humira^®, now available in the United States. News release. Amgen. Accessed January 31, 2023. https://www.prnewswire.com/news-releases/amjevita-adalimumab-atto-first-biosimilar-to-humira-now-available-in-the-united-states-301734177.html.
2. Amjevita. Package insert. Amgen; 2022. Accessed January 31, 2022. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Amjevita/amjevita_pi_hcp_english.pdf.

The Food and Drug Administration (FDA) has granted Fast Track designation to AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy is a rare, genetic muscle disorder caused by an abnormal expression of DUX4 (double homeobox 4) leading to skeletal muscle wasting and progressive muscle function loss. AOC 1020 is designed to reduce the expression of DUX4 mRNA and DUX4 protein in muscles. The investigational treatment consists of a monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a small interfering RNA targeting DUX4 mRNA.

The Company is currently investigating AOC 1020 in the phase 1/2 FORTITUDE study in adults with facioscapulohumeral muscular dystrophy. The double-blind, placebo-controlled study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of AOC 1020 administered intravenously. Though the study is not powered to assess functional benefit, assessments of efficacy will be made using key biomarkers, including magnetic resonance imaging measures of muscle volume and composition. Mobility, muscle strength, patient reported outcomes, and quality of life measures will also be analyzed.

“The FDA Fast Track designation for AOC 1020 reinforces the importance of finding an effective treatment to help people living with FSHD, a devastating and debilitating muscular dystrophy disorder with no treatment options,” said Steve Hughes, MD, chief medical officer at Avidity. “AOC 1020 is designed to directly target the disease-causing gene, DUX4, to address the underlying cause of FSHD. We look forward to working collaboratively with the FDA to bring the first RNA therapy directly targeting DUX4 to patients as quickly as possible.”

Reference

Avidity Biosciences granted FDA Fast Track designation for AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy. News release. Avidity Biosciences. Accessed January 18, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-granted-fda-fast-track-designation-for-aoc-1020-for-the-treatment-of-facioscapulohumeral-muscular-dystrophy-301724062.html.

Chintan V. Dave, PharmD, PhD, from Rutgers University in New Brunswick, New Jersey, and colleagues conducted a retrospective cohort study using target trial emulation for data obtained from 29,648 older longer-term care nursing home residents in the Veterans Health Administration to examine the association between antihypertensive medication initiation and fracture risk.

The researchers found that the incidence rate of fractures per 100 person-years was 5.4 for residents initiating antihypertensive medication vs 2.2 in the control arm in a propensity score-matched cohort of 64,710 residents (mean age, 77.9 years). The finding corresponded to an adjusted hazard ratio of 2.42 and an adjusted excess risk of 3.12 per 100 person-years. There was also an association seen for antihypertensive medication initiation with a higher risk for severe falls requiring hospitalizations or emergency department visits and syncope (hazard ratio, 1.80 and 1.69, respectively). A numerically higher magnitude of fracture risk was observed for subgroups of residents with dementia, systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 80 mm Hg or higher, and no recent antihypertensive medication use (hazard ratios, 3.28, 3.12, 4.41, and 4.77, respectively).

“This study sheds light on the potential impact of fracture risk associated with antihypertensive medication use among long-term nursing home residents, emphasizing the need for caution when initiating therapy, especially in the high-risk period after drug initiation,” the authors write.

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