Drugs

Chen, Brian; Yang, Y.; Bennett, Charles

doi: 10.1007/s40265-018-1009-0pmid: 30446980

Biologics and biosimilars are medicines made from living cells that treat common and serious diseases such as cancer, diabetes, rheumatoid arthritis, and other inflammatory diseases. They are highly targeted, efficacious, and represent an increasingly important part of physicians’ armamentaria in the combat against these medical conditions. Yet they are extremely expensive, costing on average $10,000–$30,000 per year and exceed $500,000 for the most expensive biologics. The advent of biosimilar drugs, or high similar copies of biologics, was supposed to help reduce costs, but thus far the cost of treatment with biologics or biosimilars has not fallen sharply in the USA. We argue that a primary hurdle is the extent of patent protection for the reference biologics that impedes greater numbers of biosimilars entering into the market. To date, of the 12 biosimilars approved for marketing by the US Food and Drug Administration (FDA), only five are commercially available. All but one of the remaining biosimilars are withheld from commercialization due to patent disputes. We argue that the market for biologics and biosimilars will become price competitive only if more biosimilars are available to patients. To this end, the process to eliminate marginally inventive patents held by the reference drug makers must be streamlined and improved. In this perspective article, we suggest actions to improve the pre-FDA approval patent resolution process known as the patent dance, the streamlined patent invalidation process known as Inter Partes Reviews, and the process of granting patents.

Cicero, Arrigo; Kuwabara, Masanari; Borghi, Claudio

doi: 10.1007/s40265-018-0999-ypmid: 30426333

β-Adrenergic receptor blockers (β-blockers) are well-known useful and cost-effective drugs for managing hypertensive patients with coronary heart disease, stroke, and heart failure. However, it is often difficult to use β-blockers for patients with asthma or chronic obstructive pulmonary disease (COPD). Moreover, most β-blockers negatively influence glucose or lipid metabolism. Nebivolol is a third-generation lipophilic β-1 receptor-selective blocker with nitric oxide-mediated vasodilatory effects, metabolically neutral and usually well tolerated by patients with asthma or COPD. Nebivolol has significant effects of reduction in central blood pressure and improvements in endothelial dysfunction and arterial stiffness. To summarize the merits and demerits of nebivolol in different clinical situations, we conducted a review using the word ‘nebivolol’ on Pubmed and Embase, limiting the search to hypertension, clinical trials, and meta-analyses. This review summarizes the clinical studies on nebivolol itself and on the combination of nebivolol with other antihypertensive drugs, such as hydrochlorothiazide, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and amlodipine. Most studies showed the safety and well-tolerated profile of nebivolol and the combination of nebivolol with other antihypertensive drugs, which suggests that new fixed combinations of nebivolol with other antihypertensive drugs would be useful for patients who are unable to tolerate traditional β-blockers.

Lattanzi, Simona; Brigo, Francesco; Trinka, Eugen; Zaccara, Gaetano; Cagnetti, Claudia; Giovane, Cinzia; Silvestrini, Mauro

doi: 10.1007/s40265-018-0992-5pmid: 30390221

Deeks, Emma

doi: 10.1007/s40265-018-1007-2pmid: 30471002

Tapentadol prolonged release (tapentadol PR) [Palexia® SR in EU] is a long-acting tablet formulation of the strong central analgesic tapentadol, which acts as both a μ-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor. Tapentadol PR is approved for chronic pain in various countries, with its EU indication (severe chronic pain manageable only with opioid analgesics) being the focus here. Well-designed trials and clinical practice data support tapentadol PR use in this setting. Short term, tapentadol PR was an effective and generally well tolerated analgesic for moderate to severe pain of varying aetiologies, including neuropathic pain. It provided analgesia at least as good as that of conventional strong opioids and appeared more favourable in terms of gastrointestinal tolerability, likely due to less potent MOR binding. Severe back pain with a neuropathic component responded well to moderate-dose tapentadol PR in some patients, while for others, an increase to the maximum recommended tapentadol PR dosage provided analgesia at least as good as that of moderate-dose tapentadol PR plus pregabalin and appeared to have some CNS tolerability benefits. Data also support the use of tapentadol PR in opioid rotation, including when conventional opioids are intolerable. Longer-term data in musculoskeletal pain conditions indicate continued benefit over up to 2 years’ treatment with tapentadol PR with no evidence of tolerance. Thus, tapentadol PR is a useful option for the management of severe chronic pain.

Deeks, Emma

doi: 10.1007/s40265-018-1010-7pmid: 30460547

Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy®). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virological suppression in treatment-naïve adults through 96 weeks’ treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virological rebound over 48 weeks in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for ‘rapid start’ treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CRCL) ≥ 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co-infected with HBV, and provides the first non-pharmacologically boosted, INSTI-based, triple-combination STR suitable for patients with CRCL 30–50 mL/min.

Hoy, Sheridan

doi: 10.1007/s40265-018-1004-5pmid: 30406901

Fremanezumab-vfrm (hereafter referred to as fremanezumab) [AJOVY™] is a fully humanized monoclonal antibody (IgG2Δa) developed by Teva Pharmaceuticals to selectively target calcitonin gene-related peptide (a vasodilatory neuropeptide involved in the pathophysiology of migraine). Its use has been associated with significant reductions in migraine frequency, the requirement for acute headache medication use and headache-related disability compared with placebo in multinational, phase III studies, and in September 2018 fremanezumab was approved by the US FDA for the preventive treatment of migraine in adults. A regulatory assessment for fremanezumab as a preventive treatment of migraine in adults is underway in the EU. Fremanezumab is also undergoing phase III development for the preventive treatment of cluster headache (although a phase III chronic cluster headache study has been suspended due to the results of a prespecified futility analysis) and phase II development for the preventive treatment of post-traumatic headache disorder. This article summarizes the milestones in the development of fremanezumab leading to this first approval in the USA for the preventive treatment of migraine in adults.

Keam, Susan

doi: 10.1007/s40265-018-1006-3pmid: 30411311

Vibegron is a selective beta 3 adrenergic receptor (β3AR) agonist that is being developed in Japan jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and in other regions worldwide (except in several other Asian countries) by Urovant Sciences for the treatment of overactive bladder (OAB). Based on results from Japanese phase III trials, vibegron received approval in Japan in September 2018 for this indication. This article summarizes the milestones in the development of vibegron leading to this first global approval for the treatment of OAB.

Markham, Anthony; Duggan, Sean

doi: 10.1007/s40265-018-1012-5pmid: 30456447

Cemiplimab (LIBTAYO®; cemiplimab-rwlc), a human programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and blocks its interaction with programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Regeneron Pharmaceuticals and Sanofi Genzyme. The drug is being investigated as a treatment for various cancers and in September 2018 received approval in the USA for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. This article summarizes the milestones in the development of cemiplimab leading to this first global approval for the treatment of advanced cutaneous squamous cell carcinoma.

Blair, Hannah

doi: 10.1007/s40265-018-1013-4pmid: 30430368

Duvelisib (Copiktra™) is a small-molecule inhibitor of phosphatidylinositol-3 kinase that has been developed as an oral treatment for various cancer indications. In September 2018, duvelisib received its first global approval in the USA for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib was also granted accelerated approval in the USA for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Clinical development for various haematological malignancies is ongoing worldwide, as well as preclinical development for solid tumours in the USA. This article summarizes the milestones in the development of duvelisib leading to these first approvals for CLL/SLL and FL.

Lamb, Yvette N.

doi: 10.1007/s40265-018-1014-3pmid: 30430369

The original article can be found online.