Monday, 31 March 2014

Neuroprotection on top of immunosuppression is required.

Narayanan D, Cheng H, Bonem KN, Saenz R, Tang RA, Frishman LJ. Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler. 2014 Mar. [Epub ahead of print]

BACKGROUND: Neurodegeneration plays an important role in permanent disability in multiple sclerosis.

OBJECTIVE:The objective of this paper is to determine whether progressive neurodegeneration occurs in MS eyes without clinically evident inflammation.
METHODS: Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing-remitting MS (RRMS) patients (149 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed.
RESULTS: GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON). RNFLT and GCIPT decreased with MS duration by -0.49 µm/yr (p = 0.0001) and -0.36 (p = 0.005) for non-ON; -0.52 (p = 0.003) and -0.41 (p = 0.007) for ON. RNFLT and GCIPT decreased with follow-up time by -1.49 µm/yr (p < 0.0001) and -0.53 (p = 0.004) for non-ON, -1.27 (p = 0.002) and -0.49 (p = 0.04) for ON.
CONCLUSIONS: In RRMS eyes without clinically evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of autoimmune responses and inflammation.

In this study they looked in the eye and found changes suggestive of nerve damage irrespective of whether there was inflammation. This is not new and supports other studies. Changes in the eye are in part correlated with events in the brain. This study suggests that you therefore need to put neuroprotection on top of immunosuppressives so not one but two expensive drugs. 

One question not addressed properly yet is, if the immunosuppression is good enough do you need the neuroprotection? 

In some cases it may be a good thing to do both. 

This will be a basis of the PROXIMUS trial of ProfG which will add a neuroprotective on top of a DMT and has now got the green light. Are you going to have to wait 10 years whilst these trials are done and has ProfG mapped out the pathway to get his drug of choice licenced?

Could pharma deliver quicker?

It they went straight to phase III... certainly. Would they do this? 

Teva has been patenting Laquinimod as a neuroprotective left right and centre. It is not much of an immunosuppressive at the doses used in MS, so it may be doomed as a stand alone immunomodulator. But the effect on disability appeared better than its immune modulating effect on relapse rate. Could this be the drug we are waiting for, it has been through phase III and has reasonable safety profile? 

They (Teva) could mix it with another more active DMT...and have been patenting the combinations DMF, GA, Beta interferons, fingolimod etc......They have forgotten a few! such as CD52, maybe they are yet to surface. It takes a year for filed patents to become visible 

The claims are usually based on EAE data....Who would have thought of MS as a GABA-mediated/cannabinoid receptor-mediated disease and Fampridine as an immunosuppressive compound, when it is used to affect walking speed.....If you read the patents these are the claims. Maybe Teva could not get their hands on CD20, CD52 antibodies, maybe Genzyme could get their hands on laquinimod and file the patent....Ooops I have I just invented that and put it in the public domain. 

Claims in patents well that's another story.....but the accepted sort of logic is the Sun causes Ice cream consumption and the Sun causes Sweating, therefore Ice Cream consumption causes Sweating or is that blocking sweating stops you eating ice cream or blocking sweating stops the sun. All true in the words of lawyers :-)

Adding a weak immunomoduator onto a potent immunomodulator could increase efficacy, but it could also increase side-effects. 
Will these studies be done. I hope so, because of the potential benefits.

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