DODO study

D

When you are fighting a war, even if it is only a marketing war, small effects can be the difference between winning and losing.

The TENERE study below would indicate that teriflunomide has similar efficacy to interferon-beta-1a (Rebif). However, this study was underpowered to show a difference between these two DMTs. Based on this and other data I suspect teriflunomide is more effective than IFN-beta. Why?

(1) Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both phase 3 placebo-controlled trials were positive on this outcome. (2) Teriflunomide also has a significant effect on brain volume loss compared to placebo; in comparison, subcutaneous IFN-beta-1a does not. (3) Teriflunomide is also more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real finding. (4) Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. 

Putting all these factors together I think teriflunomide will perform better than expected in head-2-head studies than Rebif has done in the past. Why is this important? Two of our top guns alemtuzumab and ocrelizumab were compared to Rebif and had a relative reduction in relapses of ~45%.

A 45% relative reduction in relapse rate has to be the new target in phase 3 active comparator trials. This is if you want your DMT to bat in the same division as alemtuzumab and ocrelizumab.

Yesterday Novartis announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. The following is an excerpt of Novartis’ press release:

In ASCLEPIOS I and II, ofatumumab (OMB157) met primary endpoints to reduce the annualized relapse rate over Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS).

  • Key secondary endpoints of delaying time to confirmed disability progression were also met;  additional secondary endpoints will be presented at ECTRIMS
  • Ofatumumab, a potent, fully-human antibody targeting CD20 positive B-cells, delivered sustained efficacy with a favourable safety profile
  • Novartis plans to initiate submissions to health authorities by the end of 2019. If approved, ofatumumab will potentially become a treatment for a broad RMS population and the first B-cell therapy that can be self-administered at home

If ofatumumab’s relative reduction in annualised relapse rate is not in the order of 45% the MS community is going to assume it is not as effective as alemtuzumab and ocrelizumab. Based on my comments above I suspect the relative reduction will be less than 40%. In other words, the effectiveness of teriflunomide may have been underestimated. Or the effectiveness of ofatumumab may have been over-interpreted and over-modelled.

An aspect that needs to be considered is that ofatumumab may be underdosed in these trials. Ofatumumab is being given at a dose of 20mg subcutaneously monthly. This dose was chosen to keep B-cells depleted, but not severely depleted, so as to allow rapid repopulation of peripheral B-cells numbers if ofatumumab is stopped. In other words, B-cell depletion is relatively mild compared to ocrelizumab 600mg every 6 months. With ocrelizumab, it takes 6 months or longer to start to see B-cell reconstitution. Is this important? I suspect yes. 

At the AAN this year Stephen Hauser presented early data suggesting that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab makes a difference. The greater the ocrelizumab exposure the more effective it was. This could be related to deep tissue and end-organ B-cell depletion. There is mounting evidence that the B-cells and plasma cells within the brain and spinal cord of MSers are driving some of the slow-burn we see clinically and on MRI (smouldering MS). 

Slide from Hauser et al. AAN 2019.

What I am trying to say is that if ofatumumab does not bat in the same league as ocrelizumab when it comes to relative relapse reduction to an active platform comparator then all these factors will come to the fore and make ocrelizumab 600mg 6-monthly a more effective anti-CD20 than ofatumumab 20mg sc monthly.

My response to the Stephen Hauser’s presentation at AAN was to immediately design a study of double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab 6-monthly (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose. The study will include next-generation MRI and other biomarkers to test the hypothesis. If this study was positive it will not only tell us a lot about how anti-CD20 therapies work in MS, but it may answer the question of whether or not we need to target the intrathecal or CNS B-cell response in MS. The latter hypothesis is being tested by our group in two studies at present. We would love to add a third study to the portfolio.

So please watch this space. We will soon hear about the ofatumumab results; they are being presented at ECTRIMS in 2 weeks time.  And if you work at Roche please tell the powers that be that we are really, really, interested in doing the DODO study 😉

Vermersch et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014 May;20(6):705-16. 

BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression.

OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a).

METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNβ-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised.

RESULTS: Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings.

CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

13 comments

  • Not sure if this comment belongs here but I want to hear about other B cell depletion in addition to CD20. I was in one of the ofatumumab trials and had 2 major relapses back to back as soon as I came off of it. In fact the first of those relapses really started while I was still within 4 weeks of my last dose (but who knows what would have happened if timing would have been different and I’d had another dose as by coincidence it was end of trial for me). My CD19/20 were still unreadable low 3 months later when I started Ocrevus (which I’m still not sure is the right drug given they are both touted to target CD20).

    Why is there no published data on other markers? Clearly they matter. I did see some evidence about rituximab and CD27 but why so little information?

    • Heidi, there is biomarker data out there for anti-CD20 therapies, but not much on what happens within the brains of pwMS. The latter is what really counts.

      Antibodies, penetrate the blood-brain-barrier in proportion to their concentration. Therefore, more ocrelizumab will penetrate compared to ofatumumab. Is this important in terms of effectiveness of the two agents? I not sure, which is why we need to study it in more detail, hence the proposed DODO study and other studies like it.

  • I agree that teriflunomide is likely to have performed much better than expected for all the reasons you point out but one in particular: it’s efficacy as a 2nd or 3rd line drug – 60% of enrolled patients in ASCLEPIOS had been previously treated with another DMT.

  • A few months ago you were suggesting another trial to de-risk Ocrevus with adaptive dosing. How does the DODO study fit in with this?

    • These two studies are testing two different hypotheses. However, the hypotheses clash with each other. In the ADIOS (adaptive dosing) study the aim is to give less ocrelizumab to make it safer and cheaper. In the DODO study, it is to see if giving more will improve the efficacy of ocrelizumab by targeting intrathecal B cells more.

  • What if you are wrong at the relative reduction in relapse rate relative to teriflunomide is 45% or higher. Would this mean that ofatumumab is superior to ocrelizumab?

    • Possibly yes. The devil will be in the detail. I have said many times that relapses and focal MRI activity are not MS. These are simply markers of the immune response to what is causing the disease. What is important is how effective these treatments are on the end-organ and smouldering MS. Is ofatumumab effective in ‘normalising’ whole brain and grey matter volume loss? Can it stop slowly expanding getting larger? Can it scrub the brain and spinal cord clean of B-cells and plasma cells?

    • In subgroup analyses, ocrelizumab performed better in patients previously treated vs naive patients when it comes to relapses. However, the opposite was seen with disability, i.e. naive patients performed better.

      Taking this into account, and all that Gavin mentioned, I would suggest that ofatumumab will be slightly better in relapses but worse in disability outcomes.

      • I think with relapse rate and MRI activity (new T2 lesions and Gd-enhancing lesions) there is a ceiling of what you can achieve once you have rebaselined. I suspect ocrelizumab is almost at that ceiling. It is hard to imagine ofatumumab going above this. The question is the comparator. Will teriflunomide do worse than interferon-beta?

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