Drugs

Whayne, Thomas

doi: 10.1007/s40265-018-0867-9pmid: 29396831

The clinical importance and benefit of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appears well established for the high-risk cardiovascular (CV) patient. This applies especially to the statin-intolerant patient or the patient who does not attain an appropriate low-density lipoprotein cholesterol (LDL-C) target. Therefore, the barriers to appropriate clinical use of the PCSK9 inhibitors involve cost and not the documented CV benefit or LDL-C lowering. Multiple roadblocks affect many high-risk CV patients in arranging approval of a PCSK9 inhibitor. Overcoming these roadblocks may require legal pressures, some increased regulation, and facilitation by competitive forces.

Shorrock, Hannah; Gillingwater, Thomas; Groen, Ewout

doi: 10.1007/s40265-018-0868-8pmid: 29380287

Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons, leading to progressive paralysis and premature death in the most severe cases. SMA is caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene, leading to low levels of SMN protein. However, a second SMN gene (SMN2) exists, which can be therapeutically targeted to increase SMN levels. This has recently led to the first disease-modifying therapy for SMA gaining formal approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Spinraza (nusinersen) is a modified antisense oligonucleotide that targets the splicing of SMN2, leading to increased SMN protein levels, capable of improving clinical phenotypes in many patients. In addition to Spinraza, several other therapeutic approaches are currently in various stages of clinical development. These include SMN-dependent small molecule and gene therapy approaches along with SMN-independent strategies, such as general neuroprotective factors and muscle strength-enhancing compounds. For each therapy, we provide detailed information on clinical trial design and pharmacological/safety data where available. Previous clinical studies are also discussed to provide context on SMA clinical trial development and the insights these provided for the design of current studies.

Holtkamp, Martin

doi: 10.1007/s40265-017-0859-1pmid: 29368126

Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA)A receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N-methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABAA receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.

Hamelmann, Eckard; Szefler, Stanley

doi: 10.1007/s40265-018-0862-1pmid: 29368127

Asthma is one of the most common chronic diseases in children, with a high proportion of patients demonstrating poor control despite the availability of disease management guidelines. Global Initiative for Asthma guidelines include tiotropium as an add-on therapy option at Steps 4 and 5 in patients aged ≥ 12 years with a history of exacerbations, and tiotropium delivered via the Respimat® Soft Mist™ Inhaler has recently been approved for use as once-daily maintenance therapy for children with asthma over the age of 6 years in the USA. A large clinical trial program has been conducted in children, adolescents, and adults across the spectrum of asthma severity. Findings from these clinical studies and pooled analyses in children and adolescents with symptomatic moderate or severe asthma have demonstrated that tiotropium Respimat® as add-on to inhaled corticosteroids, with or without other maintenance therapies, is a well-tolerated and efficacious bronchodilator, showing improved lung function and trends towards improved asthma control, mirroring findings in adult studies. This review discusses the evidence to date for tiotropium Respimat® for the management of asthma in adolescents and children with symptomatic moderate and severe asthma, and considers the challenges of asthma management in these patients. Factors affecting this population group, such as poor adherence, underreporting of symptoms, and social and psychological issues, are highlighted, along with the need for active review and management of treatment to help achieve optimal control.

Steyaert, Arnaud; Lavand’homme, Patricia

doi: 10.1007/s40265-018-0866-xpmid: 29380289

Chronic postsurgical pain affects between 5 and 75% of patients, often with an adverse impact on quality of life. While the transition of acute to chronic pain is a complex process—involving multiple mechanisms at different levels—the current strategies for prevention have primarily been restricted to perioperative pharmacological interventions. In the present paper, we first present an up-to-date narrative literature review of these interventions. In the second section, we develop several ways by which we could overcome the limitations of the current approaches and enhance the outcome of our surgical patients, including the better identification of individual risk factors, tailoring treatment to individual patients, and improved acute and subacute pain evaluation and management. The third and final section covers the treatment of established CPSP. Given that evidence for the current therapeutic options is limited, we need high-quality trials studying multimodal interventions matched to pain characteristics.

Blair, Hannah; Duggan, Sean

doi: 10.1007/s40265-018-0872-zpmid: 29396833

Belimumab (Benlysta®) is a human immunoglobulin G1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells. It is the only biological agent currently approved for the treatment of non-renal systemic lupus erythematosus (SLE). Belimumab is approved in the EU, the USA and other countries as add-on therapy in adult patients with active, autoantibody-positive SLE despite standard therapy. In phase III trials, treatment with IV or SC belimumab plus standard therapy was effective in terms of reducing overall disease activity and reducing the incidence and severity of flares, without worsening of patients’ overall condition or the development of significant disease activity in new organ systems. Sustained disease control was maintained during longer-term (up to 10 years) treatment with IV belimumab. Belimumab also demonstrated steroid-sparing effects and was associated with clinically meaningful improvements in health-related quality of life and fatigue. Belimumab was generally well tolerated in clinical trials, with low rates of immunogenicity. In view of the flexibility regarding the route of administration and the convenience of the once-weekly, self-administered, SC regimen, add-on therapy with belimumab is a useful treatment option for patients with active, autoantibody-positive SLE despite standard therapy.

Dhillon, Sohita

doi: 10.1007/s40265-018-0875-9pmid: 29435915

The humanized monoclonal antibody eculizumab (Soliris®) is a complement inhibitor indicated for use in anti-acetylcholine receptor (AChR) antibody-positive adults with generalized myasthenia gravis (gMG) in the USA, refractory gMG in the EU, or gMG with symptoms that are difficult to control with high-dose IVIg therapy or PLEX in Japan. It is the first complement inhibitor to be approved for use in these patients. In the well-designed, 26-week REGAIN study in patients with anti-AChR-positive refractory gMG, although a statistically significant benefit of eculizumab over placebo in the prespecified primary endpoint analysis (change from baseline in MG-activities of daily living (ADL) score assessed by worst-rank ANCOVA) was not formally demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as well as other secondary outcomes supported the efficacy of eculizumab. Overall, patients receiving eculizumab experienced significant improvements in the ADL, muscle strength and health-related quality of life (HR-QOL) parameters relative to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed that treatment benefits with eculizumab were sustained during continued therapy for at least 52 weeks. Eculizumab was generally well tolerated in these studies, with a tolerability profile similar to that reported previously in other indications. Although several questions remain, such as duration of treatment, cost effectiveness and long-term efficacy and tolerability, current evidence indicates that eculizumab is a valuable emerging therapy for patients with refractory gMG.

Syed, Yahiya

doi: 10.1007/s40265-018-0883-9pmid: 29470800

Intravenous landiolol [Rapibloc® (EU)], an ultra short-acting highly cardioselective β1-blocker, is approved in the EU for the rapid short-term control of tachyarrhythmias in the perioperative and intensive care settings. It has long been used in Japan to treat perioperative tachyarrhythmias. The efficacy of landiolol has been demonstrated in a large number of randomized controlled clinical trials. Landiolol significantly reduced heart rate in patients with postoperative or intraoperative supraventricular tachycardia relative to placebo and in those with atrial fibrillation/flutter and left ventricular dysfunction relative to digoxin. It was more effective than diltiazem in converting postoperative atrial fibrillation (POAF) to normal sinus rhythm. Perioperative prophylactic administration of landiolol significantly reduced the incidence of POAF during the first week after cardiac and other surgeries, compared with diltiazem, placebo or no landiolol treatment. Landiolol also attenuated adverse haemodynamic and other responses to invasive procedures such as percutaneous coronary intervention, tracheal intubation, extubation and electroconvulsive therapy. Landiolol was generally well tolerated, with a relatively low risk of hypotension and bradycardia. Landiolol has more favourable pharmacological properties than esmolol, a short-acting β-blocker commonly used for the rapid control of heart rate. Although additional comparative studies are warranted to define the place of landiolol relative to esmolol, current evidence suggest that landiolol is a useful option for the rapid short-term control of tachyarrhythmias. Landiolol offers a simple dosage scheme and is available in two easy-to-use formulations (concentrate and powder).

Hoy, Sheridan

doi: 10.1007/s40265-018-0877-7pmid: 29453668

Netarsudil ophthalmic solution 0.02% (hereafter referred to as netarsudil 0.02%) [Rhopressa®] is a Rho-associated protein kinase inhibitor that is thought to lower intraocular pressure (IOP) by increasing aqueous humour outflow through the trabecular meshwork. It has been developed by Aerie Pharmaceuticals and was recently approved in the USA for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension. The recommended dosage is one drop in the affected eye(s) once daily in the evening. Phase III development in the EU and phase II development in Japan are underway for this indication. This article summarizes the milestones in the development of netarsudil 0.02% leading to this first approval for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.

Blair, Hannah

doi: 10.1007/s40265-018-0873-ypmid: 29363041

The author has alerted us to the following error in Sect. 4.2.2.1, and the following correction should be noted: