ADIOS Trial. Does it mean Good-Bye?

Did you know that ProfG came up with the name of Pulse Immune Reconstitution Therapy or PIRT to explain how alemtuzumab worked?

This refers to the long-term benefit from a short-term treatment cycle of an immune depleting agent

But this abbreviation did not last long:-(

We still have IRT and Selective IRT (SIRT) and non-selective (NIRT), which of course can be DIRT (Dangerous Immune reconstitution therapies) because of the infectious complications of wiping out large parts of your immune system.

However, PIRT disappearred as quickly as it came. Not because it is English slang for a drug-induced trip, where people go in the country and smoke lots of weed (cannabis), but because of what it apparently means in German slang…. This seems to have something to do with male private parts :-O. Can,t be that common as DrK didn,t know it…maybe because he is not potty-mouthed, like me

Why worry? There are plenty of English and American Words that don’t cross the pond, which can cause offence. Ladies’ front and back bottom for example :-).

Over last weekend ProfG talked about the ADIOS ( ADaptIve Ocrelizumab dosing Study) trial idea. I thought Genius (Both ProfG and DrK are great with coming up with these acronyms).

This explains the idea of not performing fixed (6 monthly) dosing of ocrelizumab, but by listening to the biology, alter the dosing schedule to keep efficacy but improve safety. Why?

OK the trial data shows that ocrelizumab is well tolerated. However, continous B cell depletion is likely to be an infection time-bomb, at least for some people. Ask the people in the Rheumatoid and Lupus studies of ocrelizumab, where development was stopped because of severe adverse events.

Emery P, Rigby W, Tak PP, Dörner T, Olech E, Martin C, Millar L, Travers H, Fisheleva E. Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.PLoS One. 2014 Feb 3;9(2):e87379

Six monthly dosing in MS permanently removed CD19 B cells from the circulation in about 95% of people according to information on the FDA website. Apparently about 4-5% of people deplete these cells for many years, so some people are paying thousands to get an antibody to deplete something that is not there:-(.

Anti-CD20 Cell Therapies in Multiple Sclerosis-A Fixed Dosing Schedule for Ocrelizumab is Overkill. Avasarala J. Drug Target Insights. 2017 Oct 25;11:1177392817737515.

This is not the smart bit of the naming, it is because ADIOS, means Goodbye in Spanish.

So with success of this trial, Will we be saying adios to some of the other current MS DMT?

Why would you use them? Other disease modifying drugs have more side effects and more monitoring requirements, so if it works as well ….adios. However, you will not be saying adios to your money as you can have fewer doses for the same benefit and reduced risk. If it doesn’t work as well ….Adios

You should ask where is the evidence ProfG? The simple answer is…It’s in the public domain, if you look for it.

As mentioned there is the literature in other conditions. This was summaried in:

Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.Baker D, Pryce G, Amor S, Giovannoni G, Schmierer K. Brain. 2018 Oct 1;141(10):2834-2847. doi: 10.1093/brain/awy239.

There are years and years of experience of rituximab use in other conditions, so we know what happens in the blood, the spleen,the lymph glands and even the brain to some extent. The neurologists in Sweden are going to have a wealth of information of MS. They can capture the real life result by their registries. However, I think they should use their situation, where many people get CD20 treatment to do formal trials such that randomisation occurs to remove the bias and improve validity.

Then there is the other data. Dumped in the ECTRIMS (Biggest International MS trade show….Oooops, I mean conference) bin of unhelpful information, where abstracts appear never to be cited again…..except as often unverifiable (if you didn’t see it presented, how do you know if was really shown?) source information for some pharma slides. Information is shown that no-one sees and knows about, unless it happens to find its way onto the web.

Yep the academic authors who have become international neurology superstars for publishing all the trial papers (Yep Inividual A, B, C etc. as pointed out by Prof Coles A [Authorship of phase 3 trials in multiple sclerosis. Ann Neurol. 2018;83:653-655 ] and hogging the platforms and presenting at ECTRIMS and the Amercan Academy of Neurology meetings) really need to untarnish their reputation for hiding pharma data and ensure that the corporate abstracts [you see the same piece of work at ECTRIMS and AAN but with different names on the abstract to reflect the company people who largely created the poster] to which they put their name, actually see the light of day.

What is this?….Well Prof A (yes we do know who they are, who is the number one pharma mouth piece according to Prof Coles’ work) was the author for the data below. However, it was not published in the peer-reviewed literature, despite in my opinion having apparent risk:benefit balance implications.

So keeping in the vane of non-peer-review disclosure that may not be picked up in the search engines (although that’s how I found it), I again show some public domain data (web address on file)

This looks at the effect of ocrelizumab as a short- term treatment cycle. Does it have long-term benefit?.

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. EBioMedicine. 2017 Feb;16:41-50.

What about side effects? (OK the data is complicated by the fact that the number of people in study changed with time, but you get the results as a percentage, to make them more easily comparable, but as there are 2 groups shown, the real result may be somewhere in between).

If you have 3 ocrelizumab doses over 12 months (0, 6, 12), or 4 doses over 18 months and them nothing for 18 months the risk of adverse events and infections drop by over 50%, but you maintain the benefit.

To get assess to the data you have to agree to informing the company within 24h of any issue that affects risk benefit balance. So they can inform the regulators. I guess this means side-effect.

However what do you think

Annualised relapse rate after three cycles of ocrelizumab and nothing for 18 months

Adjusted annualised relapse rates 3 cycles/ 4 cycles

Relapse rate First 24 after ocrelizumab of 3/4 cycles 0.131 / 0.127

Adverse events First 24 weeks after ocrelizumab 71.7% / 63.6%

Infections First 24 weeks after ocrelizumab 34.0% / 43.6%

Relapse rate Last 24 weeks of 18 month treatment free 0.035/0.068

Adverse eventsLast 24 weeks of treatement free 26.1%/15.2%

Infections Last 24 weeks of treatment free 10.9% /6.5%

Prof A et al. ECTRIMS 2012 p362

Furthermore results from 2 separate arms of the trials show

Relapse rate week 96-144 3 cycles (24, 48,72) 0.116 /0.076

Relapse rate week 96-144 6 cycles (0, 24, 48, 72, 96, 120) 0.102/ 0.072

ECTRIMS 2012, ECTRIMS 2018

So why wouldn’t you want to do the ADIOS trial now? But perhaps I should ask, why wasn’t this done 6-7 years ago when the data first saw the light of day. The studies could have been done by now and you would have knowledge of a safer dosing scheme.

I would say a larger study should be done to to confirm this.

You could have standard dose (standard 6 monthly dosing), adaptive dose (3 cycles and wait and monitor to see if disease reactivates, as we know that 6 cycles of ocrelizumab gives a relapse rate of week 120-144, similar to rate at week 120-144), Adaptive dosing to memory B cell levels, which in other disease reduces the dosing frequency (see Baker et al. 2018 above).

It may be that you need all this or some of this dosing. Is a single dose cycle good enough?. The data is probably known at least for rituximab. I suspect not for some. Also we know that you have to have enough ocrelizumab to stop neutralizing antibodies forming. We have been saying that ocrelizumab only cause anti-drug antibodies in less than 1% of people. However, upon a bit of reading the reason is not because it is humanised (so it is ignored our immune system), it is in part the dose used, because you give less anybody and the number of antibodies increase significantly (Genovese et al. 2008) 58:2652-61

Currently ocrelizumab has no monitoring requirements, compared to monthly bloods for alemtuzumab at the other end of the spectrum. These have to be taken for 4 years after the last dose. This is because, alemtuzumab can cause secondary autoimmunities in pwMS.

Notably an immmune disease related to the platelets. These are central to helping the blood clot. So why 4 years of monitoring?

Because, this is the evidence, all cases occur within 4 years of dosing

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management.Cuker A, Bass AD, Nadj C, Agius MA, Steingo B, Selmaj KW, Thoits T, Guerreiro A, Van Wijmeersch B, Ziemssen T, Meuth SG, LaGanke CC, Thangavelu K, Rodriguez CE, Baker DP, Margolin DH, Jannsens A. Mult Scler. 2019:1352458518816612

BACKGROUND:Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk.

OBJECTIVE:To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials.

METHODS:CAMMS223 and Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion.

RESULTS:Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials.

CONCLUSION:Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.#

Now back to ADIOS and trial design, you could get some jajca (pop it into Google translate and guess the slang. see below) and do head to head with a NIRT, that is if you can recruit people into a study as NIRTs are seem as being more risky and people are not choosing them. If ocrelizumab was worse on brain atrophy and long term outcome, Adios may still be appropriate but we say good bye to a different agent.

Will this happen?

Who has the jajca (updated see below)

COI Multiple