New multiple sclerosis drug can 'cut relapses by nearly 50%'

[Bob]

This seems like quite a major development for MS. Results of phase iii trial for MS using Ocrelizumab (a humanized anti-CD20 monoclonal antibody.) The therapeutic benefits described below are in comparison with existing treatments rather than no treatment, so they seem very impressive.

New multiple sclerosis drug can 'cut relapses by nearly 50%'
http://www.theguardian.com/society/...-sclerosis-drug-can-cut-relapses-by-nearly-50

A new drug for multiple sclerosis can cut relapses by almost 50% more than the current standard treatment, its manufacturer claims, raising the hopes of sufferers of the disease.

The announcement was warmly welcomed by patients, not least because Roche claims the drug also has an impact on a form of the disease, called primary progressive, which affects 10-15% of people with MS in the UK and for which there are no treatments. Roche claimed it cut disability in those patients by nearly a quarter.

“These phase-3 trial results will provide a great deal of hope for people with primary-progressive MS, who currently don’t have any treatments available that can slow down the worsening of their condition,” said Nick Rijke Executive Director for Policy and Research at the MS Society.

 

[Bob]

Some more info about ocrelizumab:
https://en.wikipedia.org/wiki/Ocrelizumab
https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline/ocrelizumab
http://www.roche.com/investors/updates/inv-update-2015-09-28.htm

 

[Bob]

Ocrelizumab is a humanized anti-CD20monoclonal antibody. It targets mature B lymphocytes[1] and hence is animmunosuppressive drug candidate.

https://en.wikipedia.org/wiki/Ocrelizumab

I wonder in what ways it differs to Rituximab.

 

[barbc56]

I'll pass this on to my step mother as she has MS.

Thanks.

Barb

ETA I didn't see that the drug is for progressive MS. She has relapsing/remitting form of MS. Fortunately, she is doing well but does tire easily. I can relate to that.

 

[Bob]

ETA I didn't see that the drug is for progressive MS. She has relapsing/remitting form of MS. Fortunately, she is doing well but does tire easily. I can relate to that.

I'm not sure if I've understood you correctly but the drug is for both types of MS. The article emphasises progressive MS because it says there's not a treatment available for that currently. For relapsing/remitting MS, it says it can cut relapses by nearly 50% more than current treatments. (It's not a very clear article.)

 

[barbc56]

Somehow, I missed that. I have to admit I read it in a hurry but intend to read it more throughly later. I did catch that it helps with relaspes, but I processed it as for progressive MS. Thanks for the clarification.

It's great we can rely on one another to sift through this fog.

Barb

 

[Valentijn]

https://en.wikipedia.org/wiki/Ocrelizumab

I wonder in what ways it differs to Rituximab.

Maybe @Jonathan Edwards knows?

 

[Bob]

Two other thoughts/questions...
Has rituximab never been trialled with MS patients?
And would Roche like to carry out a large trial of Ocrelizumab for ME patients?

 

[Bob]

Low side effect profile...

Overall, the incidence of adverse events associated with ocrelizumab was similar to placebo; the most common adverse events were mild-to-moderate infusion-related reactions. The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to placebo.

http://www.roche.com/investors/updates/inv-update-2015-09-28.htm

 

[Sidereal]

I understand that the development of this drug was halted a few years ago in RA and SLE due to deaths from opportunistic infection.

 

[Sidereal]

Medscape write-up on primary progressive MS trial:

The Genentech press release notes that ocrelizumab significantly reduced the risk for progression of clinical disability sustained for at least 12 weeks by 24% compared with placebo, as measured by the Expanded Disability Status Scale (P = .0321).

Additionally, ocrelizumab was superior to placebo in significantly reducing the risk for progression of clinical disability for at least 24 weeks by 25% (P = .0365) and the time required to walk 25 feet by 29% (P = .0404).

Ocrelizumab decreased the volume of hyperintense T2 lesions by 3.4% over 120 weeks compared with placebo, which increased T2 volume by 7.4% (P < .0001). Ocrelizumab reduced the rate of whole brain volume loss over 120 weeks by 17.5% compared with placebo (P = .0206).

Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to that in the placebo group (95.1% vs 90.0%, respectively); the most common adverse event associated with ocrelizumab was infusion-related reactions (39.9% vs 25.5% for placebo).

The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to that in placebo recipients (20.4% vs 22.2%, respectively).

Fairly modest results but when you consider how catastrophic PPMS is and how there is no treatment for it, any benefit is surely welcome.

 

[Jonathan Edwards]

Maybe @Jonathan Edwards knows?

Ocrelizumab is very similar to rituximab and was developed as a way of getting around the patent lifespan problem, showing some rather marginal advantage in B cell killing if I remember rightly. There are now what look like significantly better antibodies coming along but ocrelizumab is what Roche has been taking forward in development. It is essentially the same as rituximab but probably slightly more potent.

 

[Jonathan Edwards]

And yes, I was forgetting that ocrelizumab is human rather than chimaeric but in reality because these drugs deplete the B cells that might make anti-antibodies (HACA or HAMA) it is doubtful whether humanisation is a big deal here. Killing efficacy is what matters - and particularly killing of hidden poopulations that might be untouched by rituximab.

 

[Jonathan Edwards]

I understand that the development of this drug was halted a few years ago in RA and SLE due to deaths from opportunistic infection.

I am unclear why ocrelizumab has not been progressed for RA. I think there was a rather disappointing trial at one point and it may be that the company decided to reap the benefit of rituximab in what is a relatively small part of their market for B cell antibodies and not spend money developing ocrelizumab for everything. (Roche knew they had even better looking antibodies coming on stream around that time.) Clearly they have taken it forward for MS. The problem with lupus was that an early trial with rituximab appeared to show no benefit - probably because of poor design. Many lupus physicians use it and I have seen dramatic responses to it in lupus. So over the last ten years I am not sure any CD20 antibody has been progressed in lupus. That is now changing with combination therapy trials.

 

[Jonathan Edwards]

Medscape write-up on primary progressive MS trial:



Fairly modest results but when you consider how catastrophic PPMS is and how there is no treatment for it, any benefit is surely welcome.

I think the results may look modest simply because once the disease has established the best you can hope for is some damage limitation. Scoring systems often have a 'glass ceiling' beyond which in practice you cannot get. What will be important to see is what happens if patients are treated within days of their first clinical presentation.

 

[Sidereal]

There were two large RCTs of rituximab for lupus and neither of them met the primary endpoint. The issues with design of those studies are discussed in this review paper. They also discuss the positive results from clinical practice and uncontrolled, open-label studies.

As for ocrelizumab in lupus and RA, here's a press release: http://www.roche.com/media/store/releases/med-cor-2010-03-08.htm

Basel, 8 March 2010

Roche and Biogen Idec decide to suspend Ocrelizumab treatment - Rheumatoid Arthritis development programme on hold
Future of the Ocrelizumab RA clinical programme under evaluation

Roche and Biogen Idec announced today their decision to suspend Ocrelizumab treatment of patients in the Rheumatoid Arthritis (RA) programme. The decision follows the recommendation of the independent Ocrelizumab RA & Lupus Data and Safety Monitoring Board (DSMB) based on their assessment of the studies in RA (SCRIPT, FEATURE, FILM and STAGE) and lupus (BELONG and BEGIN).

The DSMB concluded that the safety risk outweighs the benefits observed in these specific patient populations at this time. The DSMB review detected an infection related safety signal which included serious and opportunistic infections, some of which were fatal.

As previously announced, the FILM study in MTX-naïve RA patients was placed on clinical hold following an assessment of benefit to risk in this specific RA patient population. In addition, the BELONG study in lupus nephritis patients was previously halted due to serious and opportunistic infection signals.

 

[Jonathan Edwards]

There were two large RCTs of rituximab for lupus and neither of them met the primary endpoint. The issues with design of those studies are discussed in this review paper. They also discuss the positive results from clinical practice and uncontrolled, open-label studies.

As for ocrelizumab in lupus and RA, here's a press release: http://www.roche.com/media/store/releases/med-cor-2010-03-08.htm

Yes the review paper came from my department - and the optimism was based on the lupus patients I entered into the first lupus study carried out by my PhD student Maria Leandro (they were under the overall care of David Isenberg) and continued usage in the department. Venkat Reddy is still doing a PhD with us on new anti-CD20s. I don't put my name on papers these days.

I would take the press release with a pinch of salt. The US rheumatology community never liked the idea of rituximab for RA because they did not get much in the way of infusion fees (this was said quite openly at the first general advisory board when my phase 2 data showed it worked). Genentech subsequently have put out frankly frightening information sheets for rituximab for RA. Presumably because they do not want to be sued. I am aware that one particular trial with ocrelizumab caused the companies a problem, which may have been an infection signal. But I am doubtful that across the board there is evidence for ocrelizumab being different from rituximab in this respect. There will have been opportunist infections in lupus because seriously ill lupus patients are full of opportunistic infections anyway. There was also some head scratching when a tiny number of people developed PML.

These drugs routinely get mothballed apparently for medical or scientific reasons when the real reason is commercial. I may be wrong but if they really thought ocrelizumab was dangerous it would be odd that they are pursuing it in MS.

I have a suspicion that ocrelizumab is going to be irrelevant to ME anyway since the data so far are with rituximab and if companies want to move on from that it will probably be something further down the development line or from a different company.

 

[Sidereal]

The US rheumatology community never liked the idea of rituximab for RA because they did not get much in the way of infusion fees (this was said quite openly at the first general advisory board when my phase 2 data showed it worked). Genentech subsequently have put out frankly frightening information sheets for rituximab for RA.

Very interesting.

I am aware that one particular trial with ocrelizumab caused the companies a problem, which may have been an infection signal. But I am doubtful that across the board there is evidence for ocrelizumab being different from rituximab in this respect. There will have been opportunist infections in lupus because seriously ill lupus patients are full of opportunistic infections anyway. There was also some head scratching when a tiny number of people developed PML.

Yeah, the PML stuff seems vastly overblown. From what I've gathered, two patients with lupus died of PML on rituximab but they were also concurrently receiving their regular immunosuppressants.

Regarding the trial of ocrelizumab (ludicrous name, btw) which showed an infection signal, is it this one on lupus nephritis which was terminated early?

http://www.ncbi.nlm.nih.gov/pubmed/23740801

Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab-treated patients, and 22.0% of 1,000 mg ocrelizumab-treated patients. Corresponding serious infection rates (events/100 patient-years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen.

CONCLUSION:
In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.

What struck me as odd about this is that the patients on 400 mg of ocrelizumab had more serious adverse events and serious infections than the patients on 1,000 mg. The patients who were on 1,000 mg of ocrelizumab had fewer SAEs than the ones on placebo.

 

[Jonathan Edwards]

Very interesting.



Yeah, the PML stuff seems vastly overblown. From what I've gathered, two patients with lupus died of PML on rituximab but they were also concurrently receiving their regular immunosuppressants.

Regarding the trial of ocrelizumab (ludicrous name, btw) which showed an infection signal, is it this one on lupus nephritis which was terminated early?

http://www.ncbi.nlm.nih.gov/pubmed/23740801



What struck me as odd about this is that the patients on 400 mg of ocrelizumab had more serious adverse events and serious infections than the patients on 1,000 mg. The patients who were on 1,000 mg of ocrelizumab had fewer SAEs than the ones on placebo.

All I can really remember about this episode is that a trial flagged up a problem but, as you say, it did not seem to make much sense. That made me think it was a fluke problem. But it's a long time ago now. A bit like trying to figure out who shot Jack Kennedy.

 

[Sidereal]

All I can really remember about this episode is that a trial flagged up a problem but, as you say, it did not seem to make much sense. That made me think it was a fluke problem. But it's a long time ago now. A bit like trying to figure out who shot Jack Kennedy.

It does indeed look like a statistical fluke. They saw the infection rate, freaked out and terminated the trial early. Obviously, the problem is that they were only powered to detect a difference on the primary outcome measure (efficacy), not on these secondary outcomes, so whether the difference in rates of side effects is real is more of a judgement call. Of course if a ton of people are dying in one arm of your trial you'd stop early but these data look indeterminate to me. There is no dose-response relationship which makes me further question their interpretation, although I don't know jack about immunology so for all I know there is some plausible biological mechanism by which high dose of a drug could cause fewer serious adverse events than placebo while low dose of the same drug could cause more serious adverse events than placebo.

Oh well, as you say, it's all ancient ancient history anyway.