Valoctocogene Roxaparvovec and Etranacogene Dezaparavovec: Novel Gene Therapies for Hemophilia A and B.

OBJECTIVE: To review efficacy and safety data of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparavovec (Hemgenix), novel gene therapies for the treatment of the life-threatening bleeding disorders hemophilia A and B, respectively. DATA SOURCES: A PubMed/Google Scholar search from inception through August 11, 2023 was conducted using the following keywords: gene therapy, hemophilia A, hemophilia B, etranacogene dezaparavovec, valoctocogene roxaparvovec, and bleeding. STUDY SELECTION AND DATA EXTRACTION: Data, including phase 1 to 3 clinical trials (non-comparator), were obtained from primary literature and package inserts. These reports evaluated clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions. DATA SYNTHESIS: Valoctocogene phase 3 study in males (n = 134): 87% had factor VIII (FVIII) levels that at least met criteria for mild hemophilia. Etranacogene phase 3 study in males (n = 54): within 3 weeks of infusion, mean factor IX (FIX) levels had reached 26.8 IU/dL. Both therapies provided clinically and statistically significant decreases in bleeding events and prophylactic factor infusions. Most common adverse event was elevations in liver function tests that were treated with glucocorticoids. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: The endogenous production of clotting factors mimics physiological production while decreasing morbidity and mortality related to bleeding events similar to the effects of existing replacement strategies. Gene therapy was also shown to increase patient quality of life. CONCLUSION: Valoctocogene and etranacogene provide another treatment for selected patients with hemophilia. Treatment for the patient with hemophilia (gene therapy vs replacement strategy) must be personalized as new clinical data are published being cognizant of drug affordability.

Managing Multiple Myeloma in the Face of Drug-Induced Adverse Drug Reaction.

Drug-induced liver injury has been reported to cause up to 10% of adverse drug reactions in the United States. Risk factors for druginduced liver injury include female gender, older age, interacting medications and drugs that are metabolized by the liver. This case report describes a patient who was newly initiated on tizanidine, an alpha2 adrenergic agonist used for muscle spasm and musculoskeletal pain, and bortezomib, a proteasome inhibitor used for multiple myeloma. Both medications are metabolized by cytochrome P450 isoenzyme 1A2. The medications were suspected of causing acute hepatitis based on the timing of their initiation and evidence to suggest that they can cause acute hepatitis. The Naranjo adverse drug reaction scale was scored as possible. In addition, the drugs' blood levels may have been increased by acyclovir and hydralazine, both inhibitors of cytochrome P450 isoenzyme 1A2. A dilemma for the team was how to best manage bortezomib. It is part of first line treatment for multiple myeloma when combined with lenalidomide and dexamethasone. Other proteasome inhibitors are available for multiple myeloma treatment. When starting chemotherapy, it is important to be aware of medications that cause a rise in liver enzymes, potential drug interactions, and how best to manage the clinical consequences.

Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance?

OBJECTIVE: To review the spectrum of activity, efficacy, safety, and role in therapy of all antibiotics and related biologics approved by the Food and Drug Administration (FDA) in the last decade. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to end May 2021) with the search terms' name of the antibiotic or the biologic. Data were also obtained from the prescribing information, FDA, and ClinicalTrials.gov websites. STUDY SELECTION: All relevant English-language, late phase clinical trials assessing the safety and efficacy of the identified drugs were included. Review articles and references of retrieved articles were evaluated for relevant data. DATA SYNTHESIS: Antibiotic resistance is a public health crisis, and antibiotic development is imperative to outpace the ability of bacteria to develop resistance. Only 17 new systemic antibiotics and 1 related biologic have been approved by the FDA since 2010. Among these drugs, 14 were approved for common bacterial infections, 1 was approved for Clostridioides difficile infection (CDI), 1 was licensed to prevent CDI recurrence, and 2 were approved for drug-resistant tuberculosis. Very few antibiotics are in clinical development. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The arrival of these new antibiotics was welcomed with great enthusiasm, particularly when they met previously unmet medical needs. Unfortunately, the majority of them represent modifications to existing chemical structures rather than new drug classes. Despite the availability of these antibiotics, managing patients with deep-seated infections and those with extensively resistant gram-negative organisms remains challenging. CONCLUSIONS: The number of new antibiotics and their indications are not keeping up with resistance and the needs of the patients.

A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To evaluate glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl-peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT) inhibitors to treat nondiabetic and type 2 diabetes mellitus (T2DM) nonalcoholic fatty liver disease (NAFLD) as it relates to improvement in hepatosteatosis (HS) or steatohepatitis (SH). DATA SOURCES: MEDLINE and CINAHL were searched from inception through May 1, 2020. Search terms included nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, fatty liver, dipeptidyl-peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose transporter 2 inhibitors. STUDY SELECTION AND DATA EXTRACTION: Full-text observational and randomized controlled studies in English were included. Patients diagnosed with NAFLD, treated with GLP-1 RAs, DPP-4 inhibitors, and SGLT2 inhibitors, with measures to evaluate HS or SH were evaluated. DATA SYNTHESIS: Eight GLP-1 RA trials were reviewed; 7 GLP-1 RA trials showed improvement in HS. Two studies demonstrated improvement in liver histology in patients with SH. Seven SGLT2 inhibitor studies were reviewed; 6 studies demonstrated improvements in NAFLD. Five studies showed improvements in HS, whereas 1 displayed improvement in liver histology in NASH. Six studies that included DPP-4 inhibitors were evaluated, and only 2 demonstrated improvement in NASH. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Based on evidence reviewed, GLP-1 RAs and SGLT2 inhibitors decreased HS and SH in NAFLD patients, whereas DPP-4 inhibitor therapy was not effective for patients with HS. CONCLUSIONS: Based on study data utilizing imaging studies and biopsy results, GLP-1 RAs or SGLT2 inhibitors can benefit NAFLD T2DM patients. Clinical trials with larger patient populations may augment these results.

Intravenous Immune Globulin (IVIG) for Treatment of Autoimmune Heparin-Induced Thrombocytopenia: A Systematic Review.

OBJECTIVE: To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported. DATA SOURCES: PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin. STUDY SELECTION AND DATA EXTRACTION: Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included. DATA SYNTHESIS: Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post-nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 109/L) within 5 days of initial IVIG dosing. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight. CONCLUSIONS: Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.

Peanut Allergen Powder-dnfp: A Novel Oral Immunotherapy to Mitigate Peanut Allergy.

OBJECTIVE: To review data on efficacy and safety of peanut allergen powder-dnfp (PAP; Palforzia), a novel oral immunotherapy for peanut allergy, a common food allergy. DATA SOURCES: A PubMed/CINAHL search in English was performed from inception to June 30, 2020, using the search words peanut allergy, desensitization, ARA101, and peanut oral immunotherapy. STUDY SELECTION AND DATA EXTRACTION QUANTIFICATION: Published phase 2 and 3 clinical trials, documents presented to the Food and Drug Administration, and supplemental study documentation were reviewed. Articles evaluated PAP's pharmacology, pharmacokinetics, mechanism of action, efficacy, and safety. DATA SYNTHESIS: PAP was efficacious and safe for treatment of peanut allergy in mostly Caucasian children, 4 to 17 years old. A key phase III clinical trial showed a statistically significant difference (primary end point) between PAP 600 mg and placebo groups (67.2% vs 4%; P < 0.001). During initial dose escalation and updosing phases, gastrointestinal and respiratory tract allergic reactions (ARs) were more common in the PAP group. More epinephrine rescue was used in the PAP group. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Oral immunotherapy for desensitization of peanut allergy was shown to reduce the severity of reactions if accidental allergen exposure occurs. Risk evaluation and mitigation strategy certification is required for pharmacies, health care providers, and clinics. More data in real-world populations will enhance its effectiveness. CONCLUSIONS: In patients 4 to 17 years old, PAP mitigated ARs, including anaphylaxis, that may occur with accidental peanut exposure. Although there are risks, it was efficacious in more than two-thirds of participants in phase 2 and phase 3 efficacy trials.

Osilodrostat: A Novel Steroidogenesis Inhibitor to Treat Cushing's Disease.

OBJECTIVE: To review data on efficacy and safety of osilodrostat (Isturisa), a novel oral steroidogenesis inhibitor for treatment of Cushing's disease (CD), a life-threatening endocrine disorder. DATA SOURCES: A PubMed/CINAHL search from inception to September 25, 2020, was performed using the following keywords: osilodrostat, 11-beta hydroxylase, pituitary, ACTH hypersecretion, and Cushing's disease. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials and supplementary documents investigating osilodrostat were obtained from a primary literature search, the manufacturer's website, and the Food and Drug Administration website. These articles evaluated the clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions for osilodrostat. DATA SYNTHESIS: Osilodrostat was efficacious and safe in the treatment of CD in mostly middle-aged Caucasian women. A pivotal phase 3 study revealed a significant difference in 24-hour mean urinary free cortisol (primary end point) between osilodrostat and placebo (86% vs 29%; P < 0.001). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Osilodrostat provides a potent and consistent effect in reducing life-threatening supraphysiological levels of cortisol in patients with CD. Hypocortisolism adverse effects can be mitigated by slowly increasing osilodrostat's dose at ≥2-week intervals. QT interval prolongation was noted; therefore, the QT interval must be monitored by the electrocardiogram. Increased levels of cortisol precursors during treatment with osilodrostat may increase the risk of hypokalemia, edema, and hypertension. CONCLUSIONS: Osilodrostat was efficacious in decreasing cortisol levels and safe in treating patients who have failed or are ineligible for pituitary surgery. Although risks exist, a pivotal clinical trial revealed efficacy in 86% of participants.

Omadacycline: A New Tetracycline Antibiotic.

OBJECTIVE: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. DATA SOURCES: A literature search through PubMed, Google Scholar, and clinicaltrials.gov was conducted (2008 to October 2018) using the search terms omadacycline and PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer's website were reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical data and published phase 1, 2, and 3 studies were evaluated. DATA SYNTHESIS: Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally once is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice: Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. CONCLUSION: Omadacycline is an alternative treatment option for ABSSSI and CABP.

Providing Additional "Muscle" for Older Adults Through Optimal Influenza Vaccine Selection.

Immunization is the best strategy to protect individuals from influenza; however, older adults tend to respond less favorably to vaccines because of immunosenescence. The Centers for Disease Control and Prevention states that any licensed, recommended, and age-appropriate influenza vaccine may be used in older adults despite reasonable evidence suggesting that the high-dose and, to a lesser extent, the adjuvanted and recombinant influenza vaccines provide better protection than the standard-dose vaccines in this vulnerable population. In this era of precision medicine, clinicians can preferentially recommend these contemporary vaccines to equip their older patients with the best possible protection against influenza.

Reducing HIV and partner violence risk among women with criminal justice system involvement: a randomized controlled trial of two motivational interviewing-based interventions.

Women with histories of incarceration show high levels of risk for HIV and intimate partner violence (IPV). This randomized controlled trial with women at risk for HIV who had recent criminal justice system involvement (n = 530) evaluated two interventions based on Motivational Interviewing to reduce either HIV risk or HIV and IPV risk. Baseline and 3, 6, and 9-month follow-up assessments measured unprotected intercourse, needle sharing, and IPV. Generalized estimating equations revealed that the intervention groups had significant decreases in unprotected intercourse and needle sharing, and significantly greater reductions in the odds and incidence rates of unprotected intercourse compared to the control group. No significant differences were found in changes in IPV over time between the HIV and IPV group and the control group. Motivational Interviewing-based HIV prevention interventions delivered by county health department staff appear helpful in reducing HIV risk behavior for this population.

Heparin-induced thrombocytopenia: treatment options and special considerations.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect that typically manifests several days after the start of heparin therapy, although both rapid- and delayed-onset HIT have been described. Its most serious complication is thrombosis. Although not all patients develop thrombosis, it can be life threatening. The risk of developing HIT is related to many factors, including the type of heparin product administered, route of administration, duration of therapy, patient population, and previous exposure to heparin. The diagnosis of HIT is typically based on clinical presentation, exposure to heparin, and presence of thrombocytopenia with or without thrombosis. Antigen and activation laboratory assays are available to support the diagnosis of HIT. However, because of the limited sensitivity and specificity of these assays, bedside probability scales for HIT were developed. When HIT is suspected, prompt cessation of all heparin therapy is necessary, along with initiation of alternative anticoagulant therapy. Two direct thrombin inhibitors--argatroban and lepirudin--are approved for the management of HIT in the United States, and bivalirudin is approved for use in patients with HIT who are undergoing percutaneous coronary intervention. Other agents, although not approved to manage HIT, have also been used; however, their role in therapy requires further evaluation. A comprehensive HIT management strategy involves the evaluation of numerous factors. Many patients, including those undergoing coronary artery bypass surgery, those with acute coronary syndromes, those with hepatic or renal insufficiency, and children, require special attention. Clinicians must become familiar with the available information on this serious adverse effect and its treatment so that optimum patient management strategies may be formulated.

Venous thromboembolism prevention in acutely ill nonsurgical patients.

OBJECTIVE: To review recent advances in the prevention of venous thromboembolism (VTE) in acutely ill nonsurgical inpatients. DATA SOURCES: A MEDLINE search (1966-March 2005) was done to identify relevant articles relating to prevention of VTE in acutely ill nonsurgical inpatients. STUDY SELECTION AND DATA EXTRACTION: Four major prophylaxis trials, one registry, one guideline, and supporting articles representative of the subject matter from the last few years were included. DATA SYNTHESIS: Enoxaparin, dalteparin, fondaparinux, and unfractionated heparin 5000 units every 8 hours are effective in reducing the risk of VTE in acutely ill medical patients, but such prophylaxis is currently underused. Barriers to be overcome include recognition of the importance of VTE in this population, definition of the optimal strategy to assess risks, optimal timing of the risk assessment, optimal prophylactic regimen for a given level of risk or disease state, and optimal duration of prophylaxis. We recommend that acutely ill medical inpatients should be risk-stratified early in their hospitalization. At this time, the specific risk-assessment protocol should be derived from the trial(s) of the available formulary agent(s). Decisions about providing prophylaxis must also be made considering anticoagulant contraindications and renal function. Mechanical methods of prophylaxis should be considered as monotherapy only if an anticoagulant contraindication exists. The optimal duration of prophylaxis is not known, but 14 days was used in recent studies. CONCLUSIONS: Prophylaxis of VTE in acutely ill medical inpatients is underused. Data provide some guidance for increasing awareness and optimizing patient care.

Long-acting inhaled beta 2-agonists for stable COPD.

OBJECTIVE: To describe the pathogenesis of chronic obstructive pulmonary disease (COPD) and mechanisms of benefit, formulations available, drug costs, pharmacokinetic profiles, and pertinent clinical studies for long-acting beta(2)-agonists. DATA SOURCES: A MEDLINE search was conducted from July 1966 through October 2002. STUDY SELECTION AND DATA EXTRACTION: Pertinent articles related to COPD and long-acting beta(2)-agonists. DATA SYNTHESIS: The incidence and subsequent morbidity and mortality of COPD have increased during the last 4 decades, prompting worldwide initiatives to formulate guidelines to decrease the burden of this disease. COPD is a progressive, irreversible disease state characterized by chronic cough, dyspnea, sputum production, and wheezing, in which no medication has been shown to decrease mortality, excluding oxygen supplementation. Bronchodilators have been a mainstay of COPD treatment through their ability to work by both smooth- and non-smooth-muscle mechanisms. Long-acting beta(2)-agonists (i.e., formoterol, salmeterol) dosed twice daily provide more convenient dosing than 4-times-daily regimens of traditional short-acting bronchodilators. Both formoterol and salmeterol have acceptable adverse event profiles when used at recommended doses. There have been no direct clinical outcome studies comparing formoterol and salmeterol, but both have shown some benefits over ipratropium and theophylline in improving the symptoms, spirometric indices, exacerbations, and quality of life of patients with COPD. CONCLUSIONS: Based on current evidence, long-acting beta(2)-agonists are acceptable first-line agents for patients with COPD.

Risedronate for the prevention and treatment of corticosteroid-induced osteoporosis.

OBJECTIVE: To evaluate the role of risedronate in corticosteroid-induced osteoporosis. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-February 2001). Key search terms included risedronate, corticosteroid, osteoporosis, and bisphosphonate. DATA SYNTHESIS: Corticosteroid-induced osteoporosis (CIO) is clinically challenging and can lead to fractures. Risedronate, an oral bisphosphonate, has been studied for use in CIO. Trials focusing on the use of risedronate in these patients were reviewed. CONCLUSIONS: Risedronate 5 mg/d increased bone mineral density at lumbar, femoral neck, and trochanter skeletal sites in patients recently initiated on or receiving long-term corticosteroid therapy. Further investigation is needed to determine risedronate's effects on fracture prevention. The drug was well tolerated.