Friday, 5 February 2016

ResearchSpeak & PoliticalSpeak: do we need natalizumab to be self-administered?

Surely a self-administered formulation of natalizumab can only be good for the MS community? #PoliticalSpeak #MSResearch #MSBlog #ResearchSpeak

"The interesting study below shows that you can give natalizumab intravenously, subcutaneously and intramuscularly and they do the job almost as well as the intravenous route. This study refers to actual levels of natalizumab in the blood. What an innovation this would be to allow pwMS to administer their own natalizumab to themselves? It would free them up from their monthly infusion visits and free up all those staff in the infusion units across the world to do other things. A subcutaneous or intramuscular preparation of natalizumab would be so much more cost-effective and this would almost certainly feed through the system increasing access for many more pwMS in need of a high efficacy therapy. 
In other words it would improve healthcare efficiency. From my perspective it would make it much easier to use natalizumab in resource poor environments as well."

"So why haven't Biogen developed a self-administration formulation of natalizumab? Rumour has it from an ex-Biogen employee is that when marketing and sales heard about the plans to develop a self-administered formulation of natalizumab  they stopped the programme. Apparently, one of the big drivers of natalizumab prescribing is the income neurologists, and MS centres, make from running infusion units. In the US the heavy prescribers of natalizumab who have large infusion units are called 'Tysabri Millionaires'. The fact that pharma marketing and sales divisions have such an influence in holding back technological innovation is quite shocking, but not surprising, their job is too keep the gold geese laying the golden eggs. In short sales and marketing have to maximise profits for themselves and their shareholders. We often forget pharma is big business with their primary responsibility to their shareholders."

"However, every decision that is made has some repercussions. For example, I recall an email I received from a desperate person with MS from a few years ago. He was living in San Antonio, Texas. He was unemployed, and uninsured, and had highly active MS. Biogen had kindly agreed to give him natalizumab free, as part of their drug-access scheme. However, he couldn't find any infusion unit in San Antonio to give him the infusions at price he could afford to pay. His local unit wanted to charge him $1200 an infusion. Unfortunately, he was unable to start natalizumab. My heart goes out this man. At this moment I have two visions of him. Firstly, of him sitting in a wheelchair doubly incontinent the victim of uncontrolled active MS. Then a more pleasant second vision, of him self-injecting with a new formulation of natalizumab on the first Monday of each month before he leaves his home and walks to work. Since starting subcutaneous natalizumab 3 years ago he has no evident disease activity and has noticed a marked improvement in all his symptoms and disabilities. In fact he improved so much that he was able to get a job and return to full-time employment. There is little doubt that natalizumab is a transformational drug it is a great pity that it is only the privileged few who have access to it. I sincerely hope Biogen reconsider their decision not to develop a new self-administered formulation of natalizumab; who is really more important, pwMS who need access to highly effective therapies or the business people who prescribe natalizumab to keep their infusion units running smoothly and profitably?"

Epub: Plavina et al. A Randomized Trial Evaluating Various Administration Routes of Natalizumab in Multiple Sclerosis. J Clin Pharmacol. 2016 Feb 2. doi: 10.1002/jcph.707.

Background & Objectives: The primary objective was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of single subcutaneous (SC) or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with multiple sclerosis (MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity of repeated SC and IM natalizumab doses. 

Methods: DELIVER was a 32-week, open-label, multicenter study of natalizumab-naive patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) randomized to receive 300 mg natalizumab by SC injection, IM injection, or IV infusion. PK and PD were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at Week 8 (Part 2). Seventy-six patients (24 with RRMS and 52 with SPMS) were enrolled in DELIVER. 

Results: Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. Mean bioavailability relative to IV administration was 57.1-71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration. Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages. 

Conclusions: No meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or anti-natalizumab antibodies. These findings support the comparability of PD measures of natalizumab administered IV, SC, or IM.

CoI: multiple

More CSF and serum antibodies against EBV

Hecker M, Fitzner B, Wendt M, Lorenz P, Flechtner K, Steinbeck F, Schröder I, Thiesen HJ, Zettl UK.High-density peptide microarray analysis of IgG autoantibody reactivities in serum and cerebrospinal fluid of multiple sclerosis patients.Mol Cell Proteomics. 2016. pii: mcp.M115.051664. [Epub ahead of print]

Intrathecal immunoglobulin G (IgG) synthesis and oligoclonal IgG bands in cerebrospinal fluid (CSF) are hallmarks of multiple sclerosis (MS), but the antigen specificities remain enigmatic. Our study is the first investigating the autoantibody repertoire in paired serum and CSF samples from patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and other neurological diseases by the use of high-density peptide microarrays. Protein sequences of 45 presumed MS autoantigens (e.g., MOG, MBP and MAG) were represented on the microarrays by overlapping 15mer peptides. IgG reactivities were screened against a total of 3991 peptides, including also selected viral epitopes. The measured antibody reactivities were highly individual but correlated for matched serum and CSF samples. We found 54 peptides to be recognized significantly more often by serum or CSF antibodies from MS patients compared to controls (p-values <0.05). The results for RRMS and PPMS clearly overlapped. However, PPMS patients presented a broader peptide-antibody signature. The highest signals were detected for a peptide mapping to a region of the Epstein-Barr virus protein EBNA1 (amino acids 392-411), which is homologous to the N-terminal part of human crystallin alpha-B. Our data confirmed several known MS-associated antigens and epitopes, and they delivered additional potential linear epitopes, which await further validation. The peripheral and intrathecal humoral immune response in MS is polyspecific and includes antibodies that are also found in serum of patients with other diseases. Further studies are required to assess the pathogenic relevance of autoreactive and anti-EBNA1 antibodies as well as their combinatorial value as biomarkers for MS.

So this is another study hunting for the target specificity of antibodies in MS and lo an behold they find antibodies that react with EBV and alpha B crystallin.  Alpha B crystallin is the the  dominant antigen that was reported years ago to be the major target for the immune response in MS. In this study they used peptides (a string of amino acids) as the bait and targets were found however it must be said that rather than seeing linear sequences antibodies often see conformational 3D shapes and so many potential targets may be missed.