The use in AD treatment, namely anticholinesterases and NMDA

The most common adverse effects were amyloid-related imaging abnormalities (ARIA),Humanized monoclonal antibodies (Mab) are recombinant, second generation Mab(1). Most of the murine derived molecule, apart from the hypervariable region, is replaced by human based domains(1). This modification results in longer half-live and lower immunogenicity(1). They are used in therapies to treat multiple disorders, including inflammatory diseases and malignancies(1).Glioblastoma is a type of malignant astrocytic brain tumour(2). It has a low incidence of 3.2/100 000 but it is the most common primary brain cancer in adults which can also present during childhood(3).  There are multiple forms of glioblastoma but all are categorized by the WHO as grade IV gliomas, the most aggressive subtype(4). Their high infiltration and growth capabilities as well as proliferative properties on microvasculature and necrotic processes contribute to the considerably high fatality(5). Approximately 95% of adult glioblastoma patients succumb to the disease 5 years following diagnosis(6). Conventional treatment consists of surgical resection and subsequent chemo- and radiation therapy(3).

Alzheimer’s disease (AD) describes a neurodegenerative disease characterised by gradual neuronal death in the brain that leads to dementia(7). The generation of ?-amyloid plaques, neurofibrillary tangles from the self-association of hyperphosphorylated tau proteins and dysregulation of microglia in the central nervous system all contribute to the pathophysiology of AD(7).  In UK, AD is one of the main causes of mortality(8). At the moment, there are two classes of drugs that are approved for use in AD treatment, namely anticholinesterases and NMDA receptor inhibitors(7). Nonetheless, all licensed drugs only improve symptoms and quality of life but not the underlying neurodegeneration(7).

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Currently, both the above two types of diseases are incurable therefore it calls for research in the development of more efficacious drugs. Humanized Mab is a newer class of chemotherapeutic drugs that can be utilized in these conditions. The clinical efficacies of Bevacizumab (BEV) and two Beta-amyloid antibodies for treatment of glioblastomas and AD respectively will be discussed in this essay.BEV is classified as an IgG1 antibody and is not developed solely for glioblastoma(9). In 2009, the Food and Drug Administration (FDA) approved BEV provisionally for use in recurrent glioblastoma and it has been marketed in the trade name of Avastin(10). Full approval was only accorded in December, 2017(11). However, BEV remains unavailable for those patients on NHS in the UK(12). Mechanism of Action:

Figure 1. Signalling cascade promoting angiogenesis(15)
Bevacizumab limits stimulation of the VEGFR by binding to the agonist VEGF, therefore the downstream effects leading to angiogenesis are reduced.

BEV targets one of the hallmarks of cancer, inducing angiogenesis(5). Specifically, BEV binds to the vascular endothelial growth factor (VEGF) A, thereby blocking and its interaction with corresponding receptors (VEGF receptors 1 and 2) expressed on endothelium(13). Therefore, the downstream cascade (Figure 1) that encourages the expansion of vascular network is hindered(13). It also makes vessels less permeable, thus limiting oedema and migration(13). The drug is unable to traverse across intact blood brain barrier (BBB) but it gains access to VEGF at disrupted BBB(13). These regions are present in areas with complicated growth of the microvasculature and are the primary sites of VEGF release(13). Normalising the vasculature could promote better delivery of co-administered chemotherapy drugs as well(14). The pivotal trials regarding the efficacy of BEV, focusing on the recurrent setting will be discussed because it is relatively more efficacious in this setting. Small sample size is a common limitation on all of these trials. Efficacy can be assessed based on three parameters. Firstly, overall survival (OS) is the duration from the beginning of treatment till death(16). Secondly, progression free survival (PFS) 6 is the percentage of subjects that do not experience worsening of disease at 6 months from treatment(17). Thirdly, response rate (RR) denotes the percentage of subjects whose tumour diminishes in size or vanishes(18).

 

1.    Recurrent Glioblastomas

With standard treatment, OS, PFS-6 and RR for these patients are estimated to be less than 30 weeks, around 9% to 21% and below 10% respectively(19). Irinotecan, Fotemustine, Lomustine and Temozolomide are conventional chemotherapy drugs(20). The approval to BEV as second line monotherapy for recurrent glioblastoma was first granted by FDA after considering the promising results from two phase II trials, namely AVF3708g and NCI 06-C-0064E(21).

 

AVF3708g

AVF3708g trial randomized the participants into two groups, either BEV or BEV and Irinotecan and defined PFS-6 and RR as its primary outcome for the study(22). PFS-6 was 42.6% for BEV and 50.3% for combination group, while RR was 28.3% and 37.8% respectively(22). However, both the researchers and subjects were aware of the allocated treatment arm, only the radiology assessment was blinded. This could potentially introduce bias into the study. Ethnicity of the participants were predominately white, approximately 90%, which did not reflect the actual demography of the population.

 

NCI 06-C-0064E

This study also inferred that BEV had oedema limiting and antiglioma properties for recurrent glioblastoma(23). Compared to historical data, remarkable improvements were observed in OS, PFS-6 and RR parameters(23). The study highlighted that PFS prediction based on MRI assessment using Levin criteria was superior over the Macdonald criteria(23). Yet, the study was single armed, thus the positive clinical advantages might not be completely attributed to the action of BEV. Moreover, enhanced RR can be resulted from rectified permeability but not death of tumour cells(24).

 

BELOB

Early trials compared BEV to BEV plus active drug which are considered not ideal for evaluation of its efficacy. The multicentred, randomized, phase II BELOB trial was the first to have a BEV free control arm (Lomustine alone) in its design(25). 98% of the recruited subjects, mostly because of disease progression, did not complete the treatment(25). The primary outcome, OS after 9 months for BEV group was unsatisfactory(25). Yet, there was a higher proportion of BEV treated patients with an unmethylated MGMT promoter compared to that in the Lomustine group and an unmethylated status has been reported to be associated with poorer survival(26). Furthermore, the performance status at the start of trial was generally higher(25), denoting a greater disruption to physical performance, in the BEV group. A separate analysis indicated that a combinational regimen (BEV plus Lomustine) is a more favourable approach(25).

 

AVAREG

The more recent phase II trial showed that BEV is inferior to Fotemustine in minimizing death, with an OS-6 rate of 62.1% versus 73.3%(27). Nevertheless, there was a sex imbalance in the study cohort, with 66% and 72% of men in the BEV and Fotemustine groups respectively. There is evidence from BEV use in the treatment of Stage IV Non-Small-Cell Lung Cancer that noted disparity in the effectiveness between the genders(28). The study identified that female patients had little added improvements in survival(28). However, this data may not necessarily be transferable and so more robust evidences are required to establish this in glioblastoma cases. Also, more participants used corticosteroids (10% higher) in the BEV arm. Retrospective human studies and mouse models have shown that corticosteroids shorten survival times(29), so those on corticosteroid in BEV group maybe predisposed to higher mortality.

 

EORTC 26101

This phase 3 study offered the latest evidence for the efficacy of BEV as an adjunctive therapy with Lomustine(30). The PFS was significantly extended in patients receiving the combination compared to the control but the OS, i.e. the primary outcome, failed to demonstrate notable benefit on survival(30). The crossover of drugs, which occurred in approximately one third of the Lomustine alone group(30), could account for this observation. In addition, the administered doses were inconsistent in the combination group as participants were permitted to lower the dosing while on the trial and some participants did not adhere to the dosing timeline(30).

 

2.    Newly diagnosed Glioblastoma

Figure 2. Clinical trials on Bevacizumab in newly diagnosed cases
The table summarizes the main findings from four clinical trials that studied the efficacy of BEV. BEV=Bevacizumab, IRI= Irinotecan, TMZ= Temozolomide

Findings from four main efficacy trials are summarized in Figure 2. None of the trials proved that BEV is effective in improving OS. Although BEV treatment generally boosted PFS, not all trials reached an addition that meet the pre-specified criteria of enhancement. Only two of the main trials (AVAglio(31) and RTOG 0825(32)) were randomized, double blinded, placebo controlled trials and AVAglio was manufacturer sponsored(31). TEMAVIR trial excluded patients that are surgically operable, therefore their findings are only applicable to a specific subset of patients(33). Questionnaires were used in GLARIUS trial to evaluate quality of life but it is highly subjective and some patients might not be mentally capable to complete the task(34). Despite limited advantage on OS, Japan has approved BEV as first line treatment in combination with standard chemo-radiotherapy based on the positive impact on PFS(35).

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