Drugs

Cohen, Alexander C.; Roane, Brandon M.; Leath, Charles A.

doi: 10.1007/s40265-019-01249-zpmid: 31939072

While screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the USA annually. Early-stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being > 90%. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective treatment options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the Phase III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the US FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after one or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a Phase III trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued involves PARP inhibitors (rucaparib and olaparib are both in Phase II) based on earlier study results.

Gencer, Baris; Mach, François

doi: 10.1007/s40265-019-01243-5pmid: 31916186

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person’s lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20–50%. AKCEA-APO(a)-LRX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50–80%. A Phase III study with AKCEA-APO(a)-LRX will start in order to evaluate the effect on cardiovascular outcomes.

Reguart, Noemí; Marin, Elba; Remon, Jordi; Reyes, Roxana; Teixido, Cristina

doi: 10.1007/s40265-019-01240-8pmid: 31912414

Small-cell lung cancer has defied our scientific community for decades. Chemotherapy has been the mainstay treatment for small-cell lung cancer (SCLC) and unlike its counterpart, non-small cell lung cancer, no significant therapeutic breakthroughs have been made since the 1970s. Among the reasons for this slow-paced therapeutic development, one that stands out is the distinctive and almost universal loss of function of the tumour suppressor genes TP53 and RB1 in this disease, for which pharmacological activation has yet to be achieved, despite having been highly sought after. Although no molecularly targeted approach has been approved for clinical practice thus far, several strategies are currently exploring the potential to drug the tumour’s “Achilles heel” that stems from essential pathways regulating DNA-damage response. Most recently, we have witnessed newfound reasons to hope, as the combination of immunotherapy and systemic chemotherapy has improved survival outcomes, representing the first landmark achievement in decades and a new standard of care for patients with extensive disease SCLC. However, continuous efforts are still needed towards a better understanding of the molecular pathways that singularise this tumour to eventually identify the predictive biomarkers that might result in the development of a more rational therapeutic approach, including the use of immunotherapy combinations. In this review we aim to uncover critical aspects of the immune microenvironment and biology of SCLC and provide an overview of the current and future landscape of promising therapeutic opportunities. The challenge still stands, but regardless, we are living in exciting times to finally check SCLC off the ”bucket list” of our scientific community.

Schimmel, Jonathan; Dart, Richard C.

doi: 10.1007/s40265-019-01242-6pmid: 31919755

Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a ‘drug of concern’, and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2–49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24–10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.

Zhanel, George G.; Esquivel, Jenine; Zelenitsky, Sheryl; Lawrence, Courtney K.; Adam, Heather J.; Golden, Alyssa; Hink, Rachel; Berry, Liam; Schweizer, Frank; Zhanel, Michael A.; Bay, Denice; Lagacé-Wiens, Philippe R. S.; Walkty, Andrew J.; Lynch, Joseph P.; Karlowsky, James A.

Syed, Yahiya Y.

doi: 10.1007/s40265-020-01263-6pmid: 32034692

Ramucirumab (Cyramza®), a fully human anti-VEGFR-2 monoclonal antibody, has been approved as monotherapy for the treatment of patients with hepatocellular carcinoma (HCC) and α-fetoprotein levels ≥ 400 ng/mL who have been treated with sorafenib. Ramucirumab significantly prolonged overall survival (OS) and progression-free survival (PFS) relative to placebo in this population in the randomized, double-blind phase 3 REACH 2 trial. These benefits were seen in key prespecified subgroups based on demographic and disease characteristics. Ramucirumab had an acceptable tolerability profile and manageable safety profile in these patients, with the majority of treatment-related adverse events being mild or moderate in severity. The safety profile of ramucirumab was consistent with that expected for agents targeting the VEGF/VEGFR axis. Currently, ramucirumab is the only therapy specifically tested in patients with α-fetoprotein levels ≥ 400 ng/mL, which is associated with an aggressive disease and poor prognosis. Therefore, ramucirumab is an important treatment option for patients with HCC and α-fetoprotein levels ≥ 400 ng/mL who have been treated with sorafenib.

Scott, Lesley J.

doi: 10.1007/s40265-020-01264-5pmid: 32020557

Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults.

Heo, Young-A

doi: 10.1007/s40265-020-01267-2pmid: 32026421

Golodirsen (Vyondys 53™), an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been developed by Sarepta Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). In December 2019, intravenous golodirsen received its first global approval in the USA for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, based on positive results from a phase I/II clinical trial. Golodirsen is in phase III clinical development for the treatment of DMD worldwide. This article summarizes the milestones in the development of golodirsen leading to this first approval for DMD.

Scott, Lesley J.

doi: 10.1007/s40265-020-01269-0pmid: 32034693

Givosiran (Givlaari™) is an aminolevulinate synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to a ligand to enable specific delivery of the siRNA to hepatocytes. This results in downregulation of ALAS1 mRNA and prevents accumulation of neurotoxic δ-aminolevulinic acid and porphobilinogen levels that are associated with acute porphyria attacks. Givosiran is being developed by Alnylam Pharmaceuticals for the treatment of acute hepatic porphyria (AHP). In November 2019, givosiran was approved in the USA for the treatment of adults with AHP based on the positive results from the multinational, phase III ENVISION trial. In the EU, givosiran received a positive opinion in January 2020 for the treatment of AHP in adults and adolescents aged 12 years and older. This article summarizes the milestones in the development of givosiran leading to this first approval for the treatment of adults with AHP.