Drugs

Torres, Tiago

doi: 10.1007/s40265-017-0794-1pmid: 28770513

The history of psoriasis treatment has been marked by several milestones. Corticosteroids, cyclosporine, tumor necrosis factor alpha (TNF-α) inhibitors and, more recently, interleukin (IL)-17A inhibitors have revolutionized the treatment of psoriasis, each in its own way and time. The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis and selective IL-23p19 inhibition may bring several advantages with respect to IL-12/23p40 inhibition, or distal blockade of IL-17A or its receptor. In fact, IL-12 axis inhibition does not appear to be essential in psoriasis and IL-12 inhibition may even have a negative effect in the treatment of psoriasis and have potential risks in tumor immune surveillance and in host defense against intracellular pathogens. On the other hand, contrary to IL-17 inhibition, IL-23p19 blockade does not increase the risk of candida infection, nor is it associated with inflammatory bowel disease worsening. Several IL-23p19 inhibitors are currently being developed for the treatment of psoriasis, such as tildrakizumab, guselkumab, and risankizumab. Although clinical data on risankizumab is still scarce, it has shown characteristics that signify a major advance in the treatment of this disease, offering comparable or higher efficacy than IL-17 inhibitors, without the safety concerns of this therapeutic class, combined with the excellent dosing regimen of ustekinumab. Currently, only phase II trial data is available; thus, the results of the large phase III trials will be essential to establish the efficacy and safety profile of risankizumab and its value in the biological armamentarium for the treatment of psoriatic patients.

Gonzalez-Lara, Maria; Sifuentes-Osornio, Jose; Ostrosky-Zeichner, Luis

doi: 10.1007/s40265-017-0805-2pmid: 28840541

Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT-1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed.

Rogers, Jane; Eng, Cathy

doi: 10.1007/s40265-017-0792-3pmid: 28770514

Anal squamous cell carcinoma (SCCA), among other malignancies, is associated with the human papillomavirus (HPV) and its incidence continues to rise. Anal SCCA will likely remain an existing healthcare concern given compliance issues with the HPV vaccination seen in the US. Localized disease is predominantly treated with standard of care (SOC) definitive chemoradiation that has remained unchanged for decades. Clinical and molecular prognostic factors have emerged to characterize patients unresponsive to SOC, revealing the need for an alternate approach. Metastatic disease is an extremely small subset and understudied population due to its rarity. Recent prospective trials and mutational analysis have opened treatment options for this subset in need. Our review details the pharmacotherapeutic treatment in localized and metastatic anal SCCA chronologically, while also describing future outlooks.

Heijdra, Jessica; Cnossen, Marjon; Leebeek, Frank

doi: 10.1007/s40265-017-0793-2pmid: 28791655

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more “personalized” approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients’ needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries.

Tremblay, Douglas; Marcellino, Bridget; Mascarenhas, John

doi: 10.1007/s40265-017-0797-ypmid: 28791654

Myelofibrosis (MF) is a myeloproliferative neoplasm that is pathologically characterized by bone marrow myeloproliferation, reticulin and collagen fibrosis, and extramedullary hematopoiesis. Constitutive activation of the Janus associated kinase (JAK)-signal transducers and activators of transcription signaling pathway with resultant elevation in pro-inflammatory cytokine levels is the pathogenic hallmark of MF. JAK inhibitors, namely ruxolitinib, have been successful in alleviating symptoms and reducing splenomegaly, but therapy-related myelosuppression has led to the further development of highly selective JAK2 inhibitors. Additionally, ruxolitinib does not appear to affect the malignant hematopoietic clone substantially, evidenced by lack of molecular remissions, bone marrow histopathologic responses, and a proportion of treated patients developing progressive disease and leukemic transformation while receiving therapy. A number of other pharmacotherapeutic strategies are currently being explored in the clinic. Non-JAK inhibitor strategies being evaluated in MF include non-JAK signaling pathway inhibitors, epigenetic-directed therapies, immune-modulating agents, anti-fibrotic agents, and telomerase inhibitors. This review highlights the current landscape of MF pharmacotherapy and explores therapeutic advances underway.

Scott, Lesley

doi: 10.1007/s40265-017-0799-9pmid: 28819727

Oral abiraterone acetate (Zytiga®) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC.

Deeks, Emma; Scheen, André

doi: 10.1007/s40265-017-0801-6pmid: 28836175

Canagliflozin (Invokana®) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in various countries worldwide for the once-daily oral treatment of type 2 diabetes (T2D). Canagliflozin lowers blood glucose levels independently of insulin, with the inhibition of SGLT2 reducing renal reabsorption of glucose and increasing excretion of glucose in the urine. In well-designed clinical trials, canagliflozin (as first-line monotherapy or add-on therapy to other antihyperglycaemic agents) improved glycaemic control in adults with T2D, including those of older age and/or at high cardiovascular (CV) risk, and also had beneficial effects on their bodyweight and blood pressure (BP). CV risk reduction, as well as possible renal benefits, were also seen with canagliflozin in T2D patients at high CV risk in the CANVAS Program, an integrated analysis of two large CV outcomes studies. Canagliflozin was generally well tolerated, had a low risk of hypoglycaemia and was most commonly associated with adverse events such as genital and urinary tract infections and increased urination, consistent with its mechanism of action. Although the amputation and fracture risk observed among recipients of the drug require further investigation, canagliflozin is an important option for T2D management in adults.

Kim, Esther

doi: 10.1007/s40265-017-0808-zpmid: 28864863

Oral fampridine prolonged release (PR) [Fampyra®] is a lipid-soluble selective potassium channel blocker that is approved in the EU for the improvement of walking in adult multiple sclerosis (MS) patients with walking disability (expanded disability status scale score of 4–7). In clinical trials (MS-F203 and MS-F204) using an objective measure of walking improvement [the timed 25-foot walk (T25FW)], more than one-third of patients receiving fampridine PR achieved a consistent on-treatment improvement in walking speed (i.e. became TW responders) over 9–14 weeks of treatment. Fampridine PR recipients who fulfilled the definition of TW responder had mean improvements of ≈25% from baseline in T25FW walking speed. In a clinical trial (ENHANCE) that used a patient-rated measure of walking improvement [12-item MS walking scale (MSWS-12)], a significantly greater proportion of fampridine PR recipients than placebo recipients achieved a ≥8-point improvement on the MSWS-12 with 24 weeks of treatment. Where reported, adverse events were mostly mild or moderate in severity, and generally consistent with the underlying disease or mechanism of action of fampridine PR. Fampridine PR is a useful treatment option to consider in adult MS patients with walking disability.

Lamb, Yvette

doi: 10.1007/s40265-017-0802-5pmid: 28819740

Intravenous inotuzumab ozogamicin (Besponsa®; Pfizer) is an anti-CD22 monoclonal antibody-calicheamicin conjugate that binds to CD22-expressing tumour cells. Upon binding, the complex is internalised and the cytotoxic calicheamicin derivative is released inside the cell, inducing double-strand DNA breakage and subsequent cell death. In June 2017, the EMA granted inotuzumab ozogamicin approval as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). The use of inotuzumab ozogamicin in adult patients with Philadelphia chromosome-positive, relapsed or refractory CD22-positive B-cell precursor ALL is restricted to those who have failed treatment with at least one tyrosine kinase inhibitor. Inotuzumab ozogamicin was granted priority review for the treatment of relapsed or refractory B-cell precursor ALL by the US FDA in February 2017. In the USA, a phase III trial evaluating inotuzumab ozogamicin in combination with frontline chemotherapy in adults with newly diagnosed B-cell ALL has recently been initiated and inotuzumab ozogamicin is under phase II evaluation in childhood CD22-positive B-cell ALL. Inotuzumab ozogamicin combination therapies are also being evaluated in the phase I/II or II setting in ALL and chronic myeloid leukaemia and in the phase I setting in Burkitt’s lymphoma. This article summarises the milestones in the development of inotuzumab ozogamicin leading to this first approval for ALL.

St. Peter, Wendy; Wazny, Lori; Weinhandl, Eric; Cardone, Katie; Hudson, Joanna

doi: 10.1007/s40265-017-0798-xpmid: 28786038