AAN 2019 posters #2


Well, here is part deux of the 2019 AAN posters; a veritable smorgasbord of hidden gems on Market St in Philadelphia.

1. Effect of Ibudilast on Neurofilament light chain in Progressive MS Analysis from a Phase II Trial. Fox et al. Cleveland Clinic.

Previous results from the SPRINT-MS study that used 80-100mg/day of Ibudilast, showed slowing of the progression in brain atrophy (i.e. volume loss) by 48% over the 96 week period compared to placebo. They now report the effect of Ibudilast on serum and CSF neurofilament light (NfL) chain levels.

Sadly, Ibudilast treatment was not associated with a change in either serum or CSF NfL (see Figure 1 below). If you recall, the mean number of active MS lesions and relapse rate did not differ between treatment arms, and may explain this negative finding in NfL. NfL is a sensitive biomarker of relapse induced neuronal damage.

Figure 1: Serum and CSF NfL in the full cohort

2. Reduction in 48-week confirmed disability progression after 5.5 years of Ocrelizumab treatment in patients wit progressive multiple sclerosis. Wolinsky et al. The University of Texas Health Science Center at Houston.

Exciting news to finally receive NICE (UK) approval for this drug in PPMS. The Phase III ORATORIO study reported 32.9% with ocrelizumab (OCR) and 39.3% with placebo (PBO) of the percentage of subjects with 12-week confirmed disability progression (CDP). The percentage of PwMS with 24-week CDP was 29.6% with OCR versus 35.7% with PBO. Following this study those completing the ORATORIO study could enter an open-label extension (OLE) study.

They found that the 48-week CDP- EDSS (disability scale) was 44.4% vs 30.5%, and 53.1% vs 43.7% in the PBO-OCR and OCR-OCR groups, respectively (see Figure 2 below). So, there appears to be a sustained benefit over time of OCR treatment. However, in terms of disability accrual there does appear to be an advantage in starting the treatment earlier.

Figure 2: Time to onset of CDP for at least 48 weeks

3. Effect of Alemtuzumab on serum neurofilament light chain levels: comparison to sc IFNB-1a and assessment over 7 years (CARE-MS I). Kuhle et al. University of Basel

Alemtuzumab and IFNB-1a efficacy on lowering sNfL levels were compared in this study. On average sNfL was significantly lower with alemtuzumab at 6 months post-treatment than IFNB-1a (see Figure 3 below). This effect was maintained for the rest of the study. Moreover, over a 7 year period the sNfL levels were comparable to that of healthy controls (see Figure 4 below). But if I was being picky I would say that the effects of dose 1 and 2 are good and subsequently there are signs of subtle breakthrough.

Figure 3: Serum NfL levels over 24 months alemtuzumab versus IFNB-1a
Figure 4: sNfL levels alemtuzumab versus healthy control range

4. Reduced rate of brain atrophy in patients with PPMS receiving Ocrelizumab earlier and continuously versus those initiating ocrelizumab later: results of ORATORIO 5-year follow-up. Arnold et al. McGill University

Over 264 weeks (5.5 years) there is long-term reduction in brain atrophy with continuous OCR versus PBI-OCR switch in PPMS (significant differences from week 168), see Figure 5. Although the trends are in favor of OCR the percentage change in whole brain volume (WBV) doesn’t show any sign of plateauing when you compare it to alemtuzumab.

Figure 5: Brain atrophy from baseline and onward

5. Serum neurofilament light chain in a phase 1 trial of autologous mesenchymal stem cell transplantation in multiple sclerosis. Baldassari et al. Cleveland clinic

This study examines the treatment effect of mesenchymal stem cells (MSCs) on sNFL. There were 22 PwMS who underwent transplant. Although, there was a trend towards a decrease in post-transplant sNfL after 1 month compared to baseline, the differences were not statistically significant (see Figure 6 below, on the left). Also, mean pre- (month -1, month 0) versus post-treatment (month 1-6) were not different (see Figure 6, on the right). Overall, in this small study there doesn’t seem to be any treatment effect from MSCs on sNfL levels.

Figure 6: Treatment effect of MSC on sNfL levels

6. Effect of MD 1003 (high dose Pharmaceutical grade Biotin) in the treatment of progressive MS: Earlier treatment results in Lower disability over 48 months. De Seze et al. France

The MS-SPI study of MD 1003 versus placebo showed reversal of EDSS and/or timed 25-foot walk in 12.6% of progressive MS in the MD 1003 group versus 0 % in the placebo group. The initial double-blind phase was then followed by a 36 month extension phase in which all were treated with MD 1003.

At month 9 and month 12, there was statistically significant difference in the mean change in EDSS between MD 1003 and placebo in favor of MD 1003 (see Figure 7). After, switching from placebo to MD 1003 in the extension phase, the trend in the switched group was to track the mean change in EDSS score in those initially treated with MD 1003. The average change in EDSS was numerically lower in the MD 1003/MD 1003 group versus placebo/MD 1003 group. However, this trend was lost after month 24. So, MD 1003 buys time in disability progression but not for too long.

Figure 7: Average change in EDSS from baseline, months 0 to 48

About the author

Neuro Doc Gnanapavan


  • Thank you for the poster summary, Doc Gnanapavan. These are very helpful after a conference.

    On the ocrelizumab atrophy numbers, how can we compare these to alemtuzumab when there have been very limited data published for PPMS patients? Obviously, these atrophy numbers don’t look that great comparing alemtuzumab RRMS numbers to ocrelizumab PPMS numbers, but my understanding was they look very similar when comparing them on RRMS patients.

    It would be very helpful if someone on the blog could do a comparison of ocrelizumab vs alemtuzumab!

      • I hate being a party pooper, but Cladribine should be used as 1st line. BVL on 3.5mg/kg dose at week 48 is 0.48% and at week 96 is 0.68%. A note of caution though as there are no head-to-head comparative studies, but the figures do give you a rough ball park.

        • Confused….if Cladribine is not one of the ‘top’ drugs and you think it should be used 1st line, why has it been approved for patients with ‘highly active’ or ‘rapidly evolving, severe relapsing MS’ ?

          • Because unlike the 1st line drugs with 30% relapse rate reduction, Cladribine offers 55-57% relapse rate reduction. But, on the basis of this alone it is difficult to say where one drug should sit relative to the other.

        • “”

          “… no head-to-head comparative studies, but the figures do give you a rough ball park.”
          Do they? You have to account for disease duration till start of treatment… Alem had younger patients with more nerve reserve, so maybe this was the reason?
          Is there a BVL study of Alem patents with longer disease duration?
          Or, is there an analysis of patents in the original CIS Cladribine study? Are these patients still monitored, so we could see how they progressed? I don’t believe that H2H will ever happen, so just trying to compare apples to apples is all we got…

    • Yes, you’re correct I would not expect the effect of an immunosuppressant in RRMS to behave in the same way as PPMS. But I’m extrapolating across from their RRMS figures which is around 0.4% annually even at year 5 and alemtuzumab after switching from IFNB-1a was 0.08% at year 4 versus 0.5% initially on IFNB-1a alone.

  • I am perplexed by the ibudilast results. How could a drug with such good neuroprotective results in earlier trials (48% reduction in BVL) show no decrease compared to placebo with respect to NfL, a supposed sensitive marker of neuronal damage?

    Either ibudilast is not working and the trial was flawed using MRI as a marker with BVL for progression or the NfL is not a sensitive marker of neuronal damage. Your thoughts NDG?

    • It may related to the type neuronal injury that’s occurring in progressive disease as opposed to early MS. The former is thought to be slow burn neurodgeneration, whereas early MS is very much typified by focal inflammatory activity with gadolinium enhancement, increased T2 lesion load etc. NFL correlates well with gadolinium enhancement and is probably more reflective of this process. Or another possibility is that ibudilast effect on brain atrophy is via a different mechanism, but I doubt this, or like you said a drugs effect on brain volume measures by MRI are unpredictable. To explain further with the latter a lot of anti-inflammatory drugs result in pseudo atrophy by getting rid of all the oedema that is associated with inflammation giving rise to false brain shrinkage



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