Structural determinants of rotavirus subgroup specificity mapped by cryo-electron microscopy.

The rotavirus double-layered particle (DLP) is a molecular machine that transcribes 11 genomic segments of double-stranded RNA into full-length mRNA segments during viral replication. DLPs from the human Wa strain of virus, belonging to subgroup II (SG II), possess a significantly reduced level of transcriptase activity compared to bovine UK DLPs that belong to subgroup I (SG I). Cryo-electron microscopy and icosahedral image analysis was used to define the structural basis for this difference in transcriptase activity and to derive three-dimensional density maps of bovine UK and human Wa DLPs at 26 angstroms and 28 angstroms resolution, respectively. The two rotavirus strains had the same diameter, T = 13 l icosahedral lattice symmetry and size of the VP6 trimers on the surface of the DLPs. However, the Wa particles displayed a remarkable absence of VP6 trimers surrounding each 5-fold vertex position. To further explore these structural differences, three-dimensional reconstructions were generated of DLPs decorated with Fab fragments derived from subgroup-specific monoclonal antibodies. The X-ray structures of VP6 and a generic Fab fragment were then docked into the cryo-electron microscopy density maps, which allowed us to propose at "pseudo-atomic" resolution the locations of the amino acid residues defining the subgroup-specific epitopes. Our results demonstrate a correlation between the structure of the VP6 layer and the transcriptase activity of the particles, and suggest that the stability of VP6 trimers, specifically those at the icosahedral 5-fold axes, may be critical for mRNA synthesis. Thus, subgroup specificity of rotavirus may reflect differences in the architecture of the double-layered particle, with resultant consequences for viral mRNA synthesis.

Dichlorphenamide: A Review in Primary Periodic Paralyses.

Oral dichlorphenamide (Keveyis™) is a carbonic anhydrase inhibitor that is approved in the USA for the treatment of primary hyperkalaemic and hypokalaemic periodic paralyses and related variants. The efficacy and safety of dichlorphenamide in patients with primary periodic paralyses have been evaluated in four 9-week, randomized, double-blind, placebo-controlled, phase III trials [two parallel-group trials (HOP and HYP) and two crossover trials]. In two trials in patients with hypokalaemic periodic paralysis, dichlorphenamide was associated with a significantly (eightfold) lower paralytic attack rate and fewer patients with acute intolerable worsening compared with placebo. In two trials in patients with hyperkalaemic periodic paralysis, the attack rate was lower with dichlorphenamide than placebo, with this comparison reaching statistical significance in one trial (crossover) but not the other (HYP), although the attack rate was approximately fivefold lower with dichlorphenamide than placebo in the HYP trial. In 52-week, open-label extensions of the HOP and HYP trials, dichlorphenamide provided sustained efficacy in patients with hypokalaemic or hyperkalaemic periodic paralysis. Dichlorphenamide was generally well tolerated in all four phase III trials and during the extension trials; the most common adverse events were paraesthesia, cognitive disorders and dysgeusia. As the first agent to be approved in the USA for this indication, dichlorphenamide is a valuable treatment option for patients with primary hyperkalaemic or hypokalaemic periodic paralysis.

Obiltoxaximab: First Global Approval.

Obiltoxaximab (Anthim(®), ETI-204) is a monoclonal antibody that is being developed by Elusys Therapeutics and the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority for the prevention and treatment of inhalational anthrax due to Bacillus anthracis. Obiltoxaximab has been designed to neutralize the free protective antigen of B. anthracis, thereby inhibiting the lethal effects of anthrax toxins. In March 2016, intravenous obiltoxaximab was approved in the USA for the treatment (in combination with appropriate antibacterial drugs) and prophylaxis of inhalational anthrax. Obiltoxaximab is being developed under the US FDA Animal Rule, in which marketing approval is based on its efficacy in relevant animal models and safety in phase I studies in healthy human volunteers. An intramuscular formulation of obiltoxaximab has also been evaluated in animal studies and a phase I study in healthy human volunteers. This article summarizes the milestones in the development of obiltoxaximab leading to this first approval for the treatment and prevention of inhalation anthrax.

Talimogene Laherparepvec: First Global Approval.

Talimogene laherparepvec (Imlygic™) is an oncolytic viral therapy that is being developed by BioVex (a subsidiary of Amgen) for the intralesional treatment of various cancers, including malignant melanoma. Talimogene laherparepvec is a genetically modified, live, attenuated, herpes simplex virus type 1 that is designed to promote an antitumour response through selective viral replication in tumour cells and stimulation of systemic antitumour immunity. In October 2015, talimogene laherparepvec was the first genetically modified, oncolytic viral therapy to be approved in the USA for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery, although it has not been shown to improve overall survival or have an effect on visceral metastases. Talimogene laherparepvec has been recommended for approval in adults with unresectable metastatic melanoma in the EU, and is being evaluated in several countries for use as neoadjuvant or combination therapy in malignant melanoma; it is also in development for soft tissue sarcoma and liver cancer in the USA. This article summarizes the milestones in the development of talimogene laherparepvec leading to this first approval in malignant melanoma.

Osimertinib: First Global Approval.

Osimertinib (Tagrisso(™), AZD9291) is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that is being developed by AstraZeneca for the treatment of advanced non-small cell lung cancer (NSCLC). Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as detected by an FDA-approved test) who have progressed on or after EGFR TKI therapy. Osimertinib has also been granted accelerated assessment status for this indication in the EU, and is in phase III development for first- and second-line and adjuvant treatment of advanced EGFR mutation-positive NSCLC in several countries. Phase I trials in patients with advanced solid tumours are also being conducted. This article summarizes the milestones in the development of osimertinib leading to this first approval for NSCLC.

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma.

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3-4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.

Brodalumab: First Global Approval.

Brodalumab (Lumicef(®)) is a human monoclonal immunoglobulin G antibody that is being developed by Kyowa Hakko Kirin in Japan, where it has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. Regulatory applications for brodalumab in plaque psoriasis are also under review in the USA, EU and Canada. This article summarizes the milestones in the development of brodalumab leading to this first approval for the treatment of psoriasis.

Sofosbuvir/Velpatasvir: A Review in Chronic Hepatitis C.

A once-daily, single-tablet, pangenotypic regimen comprising the hepatitis C virus (HCV) NS5B polymerase inhibitor sofosbuvir and the HCV NS5A inhibitor velpatasvir (sofosbuvir/velpatasvir; Epclusa®) was recently approved for the treatment of adults with chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection in the USA, EU and Canada. In the phase III ASTRAL trials, once-daily oral sofosbuvir/velpatasvir for 12 weeks provided very high rates of sustained virological response at 12 weeks post treatment (SVR12) in treatment-naive and -experienced patients with chronic HCV genotype 1-6 infection, including those with compensated cirrhosis or HIV-1 co-infection. High SVR12 rates were also observed with sofosbuvir/velpatasvir plus ribavirin for 12 weeks in patients with chronic HCV genotype 1-6 infection and decompensated cirrhosis. Sofosbuvir/velpatasvir was generally well tolerated, with low rates of adverse events. Thus, sofosbuvir/velpatasvir represents a valuable treatment option in adults with chronic HCV genotype 1-6 infection, including those with compensated or decompensated cirrhosis, previous treatment experience or HIV-1 co-infection.

Alirocumab: A Review in Hypercholesterolemia.

Alirocumab (Praluent(®)) is a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered via subcutaneous injection every 2 weeks. Across ten phase III studies from the ODYSSEY clinical trial program in patients with heterozygous familial hypercholesterolemia (heFH) or nonfamilial hypercholesterolemia (nonFH), including some with mixed dyslipidemia, subcutaneous alirocumab 75 or 150 mg every 2 weeks was significantly more effective with regard to reducing low-density lipoprotein-cholesterol (LDL-C) over 24 weeks than comparator agents (i.e. matching placebo, once-daily oral ezetimibe, or modified oral statin therapy), including when administered as monotherapy or in combination with statin therapy, and when administered with non-statin lipid-lowering therapy (LLT) in patients with statin intolerance. Alirocumab provided sustained LDL-C-lowering efficacy over 52-78 weeks' treatment in longer-term trials, and was associated with significantly favorable effects on several other lipid parameters, including non-high-density lipoprotein-cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)]. Alirocumab was generally well tolerated in phase III trials, with no apparent increase in muscle-related adverse events compared with placebo. Thus, alirocumab is a valuable emerging option for use in patients with hypercholesterolemia, particularly patients with statin intolerance or inadequately-controlled LDL-C despite statin therapy; however, more data are needed to establish its potential cardiovascular benefits.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection.

Tenofovir alafenamide (tenofovir AF) is a novel oral prodrug of the nucleos(t)ide reverse transcriptase inhibitor (NRTI) tenofovir that has several pharmacological advantages over tenofovir disoproxil fumarate (tenofovir DF), including increased plasma stability and reduced tenofovir systemic exposure. Tenofovir AF has been coformulated with elvitegravir, cobicistat and emtricitabine as a once-daily, single-tablet regimen (elvitegravir/cobicistat/emtricitabine/tenofovir AF; Genvoya(®)) for the treatment of adults and adolescents with HIV-1 infection. With regard to establishing and/or maintaining virological suppression over 48 weeks in randomized, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF was noninferior to elvitegravir/cobicistat/emtricitabine/tenofovir DF in antiretroviral therapy (ART)-naive adults, and statistically superior (subsequent to established noninferiority) to ongoing treatment with tenofovir DF-containing regimens in ART-experienced adults with virological suppression. In single-arm, phase III trials, elvitegravir/cobicistat/emtricitabine/tenofovir AF also provided high rates of virological suppression among ART-naive adolescents and ART-experienced adults with stable renal impairment. In general, elvitegravir/cobicistat/emtricitabine/tenofovir AF was well tolerated and associated with more favourable renal and bone parameters, but a less favourable lipid profile, than tenofovir DF-containing regimens. Thus, elvitegravir/cobicistat/emtricitabine/tenofovir AF is an alternative single-tablet regimen for adults and adolescents with HIV-1 infection, particularly those with an estimated creatinine clearance of ≥30 to <50 mL/min or an increased risk of tenofovir DF-related bone toxicity.

Carbidopa/Levodopa ER Capsules (Rytary(®), Numient™): A Review in Parkinson's Disease.

A new extended-release (ER) capsule formulation of carbidopa/levodopa (Rytary(®), Numient™, IPX066) is available for the treatment of Parkinson's disease (PD). Carbidopa/levodopa ER capsules contain beads of carbidopa and levodopa, designed to release the drugs at different rates in the gastrointestinal tract and provide constant therapeutic levodopa concentrations that are maintained for 4-5 h (after an initial peak at ≈ 1 h). In randomized phase III trials, oral carbidopa/levodopa ER was significantly more effective than placebo with regard to improving motor symptoms and activities of daily living in patients with early PD after 30 weeks' treatment, and provided significantly greater reductions in daily 'off-time' in patients with advanced PD than immediate-release (IR) carbidopa/levodopa or carbidopa/levodopa IR plus entacapone after a treatment period of 13 and 2 weeks, respectively, without increasing troublesome dyskinesia. The efficacy of carbidopa/levodopa ER was maintained during a 9-month open-label extension in patients with early or advanced PD. Carbidopa/levodopa ER was generally well tolerated in clinical trials, with the most common adverse events in the extension study being nausea and insomnia in patients with early PD and falls and dyskinesia in patients with advanced PD. Thus, carbidopa/levodopa ER is an effective and generally well-tolerated treatment option for the motor symptoms of PD, reducing periods of 'off-time' compared with carbidopa/levodopa IR without increasing troublesome dyskinesia.

Intravenous Minocycline: A Review in Acinetobacter Infections.

Intravenous minocycline (Minocin®) is approved in the USA for use in patients with infections due to susceptible strains of Gram-positive and Gram-negative pathogens, including infections due to Acinetobacter spp. Minocycline is a synthetic tetracycline derivative that was originally introduced in the 1960s. A new intravenous formulation of minocycline was recently approved and introduced to address the increasing prevalence of multidrug-resistant (MDR) pathogens. Minocycline shows antibacterial activity against A. baumannii clinical isolates worldwide, and exhibits synergistic bactericidal activity against MDR and extensively drug-resistant (XDR) A. baumannii isolates when combined with other antibacterial agents. In retrospective studies, intravenous minocycline provided high rates of clinical success or improvement and was generally well tolerated among patients with MDR or carbapenem-resistant A. baumannii infections. While randomized clinical trial data would be useful to fully establish the place of minocycline in the management of these infections for which there are currently very few available options, clinical trials in patients with infections due to Acinetobacter spp. are difficult to perform. Nevertheless, current data indicate a potential role for intravenous minocycline in the treatment of patients MDR A. baumannii infections, particularly when combined with a second antibacterial agent (e.g. colistin).

Loxoprofen: A Review in Pain and Inflammation.

Loxoprofen (Loxonin(®), Loxonin(®) Pap, Loxonin(®) Tape) is a prodrug-type NSAID that is available in several formulations, including 60 mg tablets, 100 mg hydrogel patches and 50 or 100 mg tape. In active comparator-controlled trials, oral loxoprofen therapy (ranging from 2 days to 6 weeks' duration depending on the pain type) provided analgesic efficacy that generally did not significantly differ from that of celecoxib for postoperative pain or frozen shoulder, ibuprofen for knee osteoarthritis or naproxen for lumbar pain. In double-blind, double-dummy, multicentre trials, loxoprofen hydrogel patches were noninferior to oral loxoprofen with regard to rates of final overall symptomatic improvement over 1-4 weeks in patients with knee osteoarthritis, myalgia or trauma-induced swelling and pain. Loxoprofen hydrogel patches were also noninferior to other commercially available patches (ketoprofen and indometacin) over 2 or 4 weeks in patients with knee osteoarthritis or myalgia in open-label studies. Oral and topical loxoprofen were generally well tolerated in clinical trials. Thus, loxoprofen is a useful analgesic option for patients with pain and inflammation, with topical loxoprofen potentially reducing the risk of gastrointestinal, cardiovascular and renal complications associated with oral NSAID use.

Apixaban: A Review in Venous Thromboembolism.

Apixaban (Eliquis®) is an oral, direct factor Xa inhibitor that is available for use in the treatment and secondary prevention of venous thromboembolism (VTE). Like other direct oral anticoagulants (DOACs), apixaban has generally predictable pharmacological properties and does not require routine anticoagulation monitoring. In large phase III trials, oral apixaban was noninferior to subcutaneous enoxaparin sodium overlapped with and followed by oral warfarin (enoxaparin/warfarin) in the treatment of adults with acute VTE over 6 months with regard to the incidence of recurrent VTE or VTE-related death (AMPLIFY), and was significantly more effective than placebo in the prevention of recurrent VTE or all-cause mortality over 12 months in patients who had completed 6-12 months' anticoagulation treatment for VTE (AMPLIFY-EXT). Apixaban was generally well tolerated in these trials; the risks of major bleeding and the composite endpoint of major or clinically relevant nonmajor (CRNM) bleeding with apixaban were significantly lower than enoxaparin/warfarin in AMPLIFY and not significantly different from that of placebo in AMPLIFY-EXT. Similarly, in Japanese adults with acute VTE (AMPLIFY-J), apixaban was associated with a significantly lower risk of major or CRNM bleeding than unfractionated heparin plus warfarin, and no cases of recurrent VTE or VTE-related death over 24 weeks. Thus, apixaban is useful therapeutic alternative for the management of adults with VTE.

Memantine ER/Donepezil: A Review in Alzheimer's Disease.

A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10 mg (Namzaric™) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28 mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil-treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents.

Brexpiprazole: First Global Approval.

Brexpiprazole (Rexulti®) is an atypical antipsychotic that has been developed by Otsuka Pharmaceutical Co. Ltd and H. Lundbeck A/S as an oral treatment for several psychiatric disorders. Brexpiprazole is a novel serotonin-dopamine activity modulator that acts as a partial agonist of serotonin 1A (5-HT1A) and dopamine D2 receptors, as well as a potent antagonist of 5-HT2A receptors and noradrenergic α1B and α2C receptors. In July 2015, brexpiprazole received its first approval in the USA for use as an adjunctive treatment of major depressive disorder (MDD) and the treatment of schizophrenia. In several countries, brexpiprazole is in development for MDDs, schizophrenia, post-traumatic stress disorder and agitation in patients with dementia of the Alzheimer's type. This article summarizes the milestones in the development of brexpiprazole leading to its first global approval in MDD and schizophrenia.

Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection.

A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

Sucroferric oxyhydroxide: a review in hyperphosphataemia in chronic kidney disease patients undergoing dialysis.

Sucroferric oxyhydroxide (Velphoro®), an iron-based oral phosphate binder, is available for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. In a pivotal phase III trial, sucroferric oxyhydroxide 1000-3000 mg/day for 24 weeks was noninferior to sevelamer carbonate 4800-14,400 mg/day with regard to lowering serum phosphorus levels. Additionally, sucroferric oxyhydroxide at maintenance dosages was significantly more effective than low dosage sucroferric oxyhydroxide (250 mg/day) with regard to maintaining controlled serum phosphorus levels during weeks 24-27 of treatment. Sucroferric oxyhydroxide had a numerically lower mean daily pill burden and better treatment adherence than sevelamer carbonate. Treatment with sucroferric oxyhydroxide was generally well tolerated over 24 weeks' treatment, with the most frequently reported treatment-emergent adverse events being mild, transient diarrhoea and discoloured faeces. In a 28-week extension study, the efficacy and tolerability profile of sucroferric oxyhydroxide remained similar to sevelamer carbonate for up to 52 weeks. In conclusion, sucroferric oxyhydroxide is a valuable treatment option for hyperphosphataemia in CKD patients on dialysis, providing an effective and generally well tolerated noncalcium-based phosphate binder therapy with a lower pill burden than sevelamer carbonate and the potential for improved treatment adherence.

Brinzolamide/brimonidine: a review of its use in patients with open-angle glaucoma or ocular hypertension.

Brinzolamide 1 %/brimonidine 0.2 % ophthalmic suspension (Simbrinza(®)) is a fixed-combination of a carbonic anhydrase inhibitor and an α2-adrenergic receptor agonist that is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension in both the USA and EU (with the EU indication restricted to patients for whom monotherapy provides insufficient IOP reduction). In phase III randomized trials, both three-times-daily and twice-daily administration of brinzolamide/brimonidine provided significantly greater IOP-lowering efficacy over 3-6 months than either of its individual components alone, and twice-daily brinzolamide/brimonidine was noninferior to concomitant administration of brinzolamide plus brimonidine over 6 months in this regard. Brinzolamide/brimonidine was generally well tolerated, with a tolerability profile that was consistent with its individual components and with no unexpected safety findings. Therefore, brinzolamide/brimonidine is an effective treatment option for patients with open-angle glaucoma or ocular hypertension, providing a convenient alternative for those patients who require multiple IOP-lowering medications. Brinzolamide/brimonidine is the first available fixed-combination that does not contain timolol, and maybe particularly suited to patients with comorbidities that restrict treatment with ß-adrenergic receptor antagonists.

Naltrexone ER/Bupropion ER: A Review in Obesity Management.

Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave(®), Mysimba(™)) is available as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index (BMI) of ≥ 30 kg/m(2) (i.e. obese) or a BMI of ≥ 27 kg/m(2) (i.e. overweight) in the presence of at least one bodyweight-related comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. In 56-week phase III trials in these patient populations, oral naltrexone ER/bupropion ER 32/360 mg/day was significantly more effective than placebo with regard to percentage bodyweight reductions from baseline and the proportion of patients who achieved bodyweight reductions of ≥ 5 and ≥ 10%. Significantly greater improvements in several cardiometabolic risk factors were also observed with naltrexone ER/bupropion ER versus placebo, as well as greater improvements in glycated haemoglobin levels in obese or overweight adults with type 2 diabetes. Naltrexone ER/bupropion ER was generally well tolerated in phase III trials, with nausea being the most common adverse event. Thus, naltrexone ER/bupropion ER 32/360 mg/day as an adjunct to a reduced-calorie diet and increased physical activity, is an effective and well tolerated option for chronic bodyweight management in obese adults or overweight adults with at least one bodyweight-related comorbidity.