Tuesday, 23 May 2017

Be A Hero Ocrevus

Drugs. 2017 May 18. doi: 10.1007/s40265-017-0757-6. [Epub ahead of print]

Ocrelizumab: First Global Approval.

Frampton JE.


Ocrelizumab (Ocrevus™) is a humanised anti-CD20 monoclonal antibody that has been developed by Genentech, Inc. (a subsidiary of Roche) for the treatment of multiple sclerosis (MS). The drug is designed to deplete B cells, which play an important role in the pathogenesis of MS. In March 2017, ocrelizumab was approved in the USA for the treatment of patients with relapsing or primary progressive forms of MS; currently, it is awaiting approval in the EU for the same indications. This article summarizes the milestones in the development of ocrelizumab leading to its first global approval for the treatment of MS.

Figure: Key milestones in the development of Ocrevus in multiple sclerosis

We live in hubristic times. By spending time in an elevated position, we come to think of ourselves as gods among men. Wrongfully, or rightfully we misjudge any attack on this inflated self-perception as mere jealousy. And then comes the downfall, because real life isn't rad like jazz or sweet like cinnamon, it is painful in the lessons it teaches the wilful, and the stupid...

Ocrelizumab (Ocrevus) is a humanised anti-CD20 monoclonal antibody that targets B cells, developed by Genentech, Inc. (subsidiary of Roche Pharma) and Biogen Idec Pharma. Genentech, however, is responsible for development of Ocrevus in MS taking on 100% of the costs, while Biogen Idec will receive tiered, double digit royalties on US sales that will approximate its current 30% interest in Ocrevus. Development of Ocrevus in rheumatoid arthritis was halted in May 2010, quoting safety reasons:

"In March, Roche and Biogen Idec announced the suspension of treatment in the ocrelizumab RA program. This decision followed a recommendation from the independent ocrelizumab RA & Lupus Data and Safety Monitoring Board (DSMB). The DSMB concluded that the safety risk outweighed the benefits observed in these specific patient populations at that time based on an infection related safety signal which included serious infections, some of which were fatal, and opportunistic infections. Subsequently, the U.S. Food and Drug Administration (FDA) placed the RA studies on clinical hold".

Results from the pooled analysis of the Phase III programme are open access and available on the internet from Emery et al. 2014 in PlosOne. The authors noted a greater number of serious infections were observed in the high dose group OCR500 + methotrexate (MTX) vs. placebo + MTX. In their own words:

"The conclusion that the two doses of OCR, in combination with MTX tested in the RA clinical trials did not demonstrate a superior benefit-risk profile compared with available treatments led to the termination of the clinical development program of OCR in RA. OCR500+MTX demonstrated clinical benefit by improving signs and symptoms of RA and radiographic outcomes [10][13]; however this dose was associated with an increased incidence of SIEs. OCR200+MTX did not show superior efficacy compared with existing therapies, but was safe and well-tolerated. The clinical development of OCR is continuing in multiple sclerosis, for which there remains an unmet need for more effective therapies and background immunosuppressant therapy is not used".

Eyes wide open...

Monday, 22 May 2017

What is your Choice?

Grant Idea of the Month

As you know we give away our ideas on this blog so this month this is for the Mousers or maybe a clinical study.

When you make choices of treatments there are sites such as the MS trust Decisions web site. This needs abit of updating.

I expect they will be adding Ocrelizimab soon.

However there are a number of things that you have to think about when making a choice.   Depending on where you live, cost will come into play and whether your government/insurance will cover the cost. Many people in Low and Middle Income Countries make less in a year than the cheapest of the cheap and so get no access. 

One would think that the International MS Federation would be pushing for access for "Treatment for All", but where are we on that one?

But there are others to consider and this is how to do transition off a drug, in case it doesn't work for you.

This can occur because they simply aren't potent enough or maybe because you start to make neutralizing antibodies, which can stop protein drugs from working.

We have the problem of rebound for the anti-migration drugs. This is a well known problem with Natalizumab. It stops the cells from getting into the brain, but is not stopping what is driving their production. They are their waiting to get into the brain as the drug wears off . It is like having sprinters under starters orders ready to race into to your brain once the started gun goes off, there all arrive in the brain at once and this is a rebound (worse than just a relapse) 
You switch after 24 months if you are JC positive.

When the depleting drugs fail the damaging cells will trickle out of the bone marrow/lymph glands into the blood, so the attack is not as intense as with a rebound atttack.

However, after some of the depleting drugs you don't replete, how long do you wait before you start treatment again?

However, this rebound can be a problem for fingolimod, if this really is, an anti-migration drug. The cells are trapped in the lymph glands, (according to Dogma), but I would put money on the Bone Marrow (Site where immune cells are made) being equally if not more important, ready to get into the blood and ready to get into your brain.

If it is true that fingolimod can stops (in about 25% of people) alemtuzumab from working because it traps the white blood cells into places where the antibody does not deplete very well, then is this problem also going to happen with ocrelizumab too. Alemtuzumab and ocrelizumab both target the MS-causing cells and both deplete via the same mechanism (antibody-dependent cellular cytotoxicity). This means the antibody binds to the B memory cells (MS causing cell...if you are still a T cell fan read T cell here) and natural killer cells and neutrophils bind to the antibody and relate their contents, which puts holes in the B cells and kills the memory B cell. 

Can the killer cells get into the bone marrow and lymph glands to do this killing?  Not as well as it gets in the blood. 

I don't know the ocreliziumb data, but we do know about rituximab.
We need to see the data in the humanised CD20 mouse and see if they use complement (A set of proteins that punch holes in cells, abit like the Killer cells) to kill, which Alemtuzumab didn't. 

To do this you use Cobra Venom and that depletes complement. simples, we could block ADCC.

Alemtuzumab kills natural killer cells (~40%), so it could be different from ocrelizumab in this respect but we need to be be vigilant and monitor for this.

So will fingolimod interfere how CD20 depleting drugs work?
We know there are people who have done this with rituximab

P.S. Happy to do this study, if you are interested.

CoI. None.

Sunday, 21 May 2017

#NeuroSpeak: DMF as a second-line agent or not

Did you know that dimethyl fumarate is not as effective when used 2nd- or 3rd-line? #NeuroSpeak #MSBlog

The Mouse Doctor did a good deed this weekend; he kindly agreed to speak about MS treatments at a meeting the allied HCPs hosted at Queen Square our former Institution. At the meeting he was asked about why dimethyl fumarate (DMF) had not being recommended by NICE as a second-line therapy for patients with highly-active or rapidly-evolving severe MS? He wasn't sure so he dropped me an email.  The reason is that DMF is a much more effective treatment in pwMS who are naive to treatment. When DMF is used 2nd-line it has an impact on relapses, but in the post-hoc analysis it had no impact on disability progression. All the NICE cost-effective models are driven by disability progression and hence in this subgroup of patients it was not considered cost-effective.

This data was presented at ECTRIMS in 2013, but has not subsequently been published. I have uploaded the poster for you so that you can see the data for yourself. The answer to your question is in Figure 4 in relation to disability progression. Please note that the data on DMF in newly diagnosed patients, which is very good has been published. I have suggested to Biogen that they should also publish the 2nd-line data, but my request seems to have fallen on deaf ears. I wonder why?

Based on the post-hoc analysis below I don't recommend DMF second-line unless the reason for switching treatments is due to a tolerance issue or there are specific reasons for someone requesting DMF. The latter is usually linked to fingolimod or teriflunomide being contraindicated. Whilst we are the topic of 1st-line vs. 2nd-line efficacy some of you may be remember a post I did on Terifluomide being more effective as a 2nd- or 3rd-line DMT compared to when it is used 1st-line. It the only DMT to be more effective when used later than earlier. The finding was consistent across both phase 3 trials and therefore must be linked to real biology. If you can work out why Teriflunomide is an outlier in this regard you may be able to explain something important about the biology of MS. We have some ideas, but I will keep you in suspense. We are trying to get a grant from Genzyme-Sanofi to explore our hypothesis in more detail and will keep you posted. 

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.

OBJECTIVE: To evaluate delayed-release DMF in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.

METHODS: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.

RESULTS: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.

CONCLUSION: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

CoI: multiple

Blast from the Past...Memory B cells depleted by HSCT

Storek J, Zhao Z, Lin E, Berger T, McSweeney PA, Nash RA, Akatsuka Y, Metcalf MD, Lu H, Kalina T, Reindl M, Storb R, Hansen JA, Sullivan KM, Kraft GH, Furst DE, Maloney DG. Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases).
Clin Immunol. 2004;113:285-98.
To ascertain the consequences of severe leukopenia and the tempo of recovery, we studied the immunity of 56 adult patients treated for multiple sclerosis or systemic sclerosis with autologous CD34 cell transplantation using extremely lymphoablative conditioning. NK cell, monocyte, and neutrophil counts recovered to normal by 1 month; dendritic cell and B cell counts by 6 months; and T cell counts by 2 years post-transplant, although CD4 T cell counts remained borderline low. Initial peripheral expansion was robust for CD8 T cells but only moderate for CD4 T cells. Subsequent thymopoiesis was slow, especially in older patients. Importantly, levels of antibodies, including autoantibodies, did not drop substantially. Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7-24 months pos-transplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pre-transplant plasma cells.

I didn't have the MS HSCT data one our B cell paper, So thanks to Luis for finding this one. 

This is paper on HSCT, using cyclophosphamide and anti-Thymocyte globulin. Many people had MS. 

The repopulation kinetics are here.

What can you see?

Massive overshoot of B cells, due to mature B cell over population, that masks a major deletion of memory B cells. CD4 T cells disappear for over 2 years , CD8 are down for  8 months. Black bars 5th and 95th percentile of health and dotted line is the medium of health. No reports of autoimmunity in the report. Does this say anything, but the memory B cells were down

What does it look like?

Saturday, 20 May 2017

#ThinkSpeak: social medicine and meat

How much red and processed meat are you consuming? #ThinkSpeak #SocialMedicine

Unless I am travelling a typical Friday night is a take-away pizza, a bottle of good quality wine, watching 'Have I got news for You' and an early night with the latest issue of the Economist. Last night was no different except we ditched the pizza and went for a vegetarian curry. We are trying to reduce our red, and processed, meat intake based on the latest data that was published in the BMJ a few week's ago. I am also currently reading 'Homo Deus: A Brief History of Tomorrow' by Yuval Noah Harari and the section on how we are treating our domesticated farm animals is enough to make anyone vegetarian. If you have the time to read I would highly recommend this book; it is a wake-up call for Homo sapiens to get their act together. 

Last night, however, I had difficult unwinding due to the germ of an idea occupying my thoughts. I had just finished running one of our Barts-MS 2-day teaching courses, or MS Preceptorships, and it struck me how important the social interactions were for patients who are on natalizumab. As you know if you are on natalizumab you have to come up for monthly infusions, which typically happen in an infusion suite in which several patients are receiving their natalizumab at the same time. This allows fellow patients to speak to each other, form friendships, engage in each other problems and help each other with the management of their MS. I am aware of several patients forming deep and lasting friendships that extend beyond the infusion unit. Some arrange to socialise outside the hospital, have dinner together and invite each other to weddings and special events. I am not aware of any marriages yet, but I suspect there may be several natalizumab-weddings in the world.  It is not uncommon that if one patient delays their infusion by week the others in the group want to do so as well. Occasionally when one person in the group comes off natalizumab the others in the group go into mourning. Thankfully we have not had a case of PML yet, within our unit, but I could imagine the devastating effect a death might have on the group. What is clear is that people with MS on natalizumab value these relationships and the support and help they receive from their fellow MSers. 

These observations are a reminder that we are social animals and we like to be part of a group and to belong. Most of our healthcare is based on keeping people with diseases apart. If we can make medicine, and in this context MS care, more social we will almost certainly improve outcomes. The most used Apps on the web are social Apps. Can we learn from the tech industry and create a social app that will allow people with MS to interact with each other and their healthcare professionals to improve outcomes? This is the challenge I have set myself. The blog is not the platform for this; the blogger software is not designed to be social in the way it would need to be. Could we use Google+, Facebook or WhatsApp to do this? The problem is the curation of the content and allowing new users to navigate the platform and to find friends and to interact with each other in private or in the open. 

Etemadi et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ. 2017 May 9;357:j1957. doi: 10.1136/bmj.j1957.

Objective:  To determine the association of different types of meat intake and meat associated compounds with overall and cause specific mortality.

Design: Population based cohort study.Setting Baseline dietary data of the NIH-AARP Diet and Health Study (prospective cohort of the general population from six states and two metropolitan areas in the US) and 16 year follow-up data until 31 December 2011.Participants 536 969 AARP members aged 50-71 at baseline.Exposures Intake of total meat, processed and unprocessed red meat (beef, lamb, and pork) and white meat (poultry and fish), heme iron, and nitrate/nitrite from processed meat based on dietary questionnaire. Adjusted Cox proportional hazards regression models were used with the lowest fifth of calorie adjusted intakes as reference categories.

Main outcome measure: Mortality from any cause during follow-up.

Results: An increased risk of all cause mortality (hazard ratio for highest versus lowest fifth 1.26, 95% confidence interval 1.23 to 1.29) and death due to nine different causes associated with red meat intake was observed. Both processed and unprocessed red meat intakes were associated with all cause and cause specific mortality. Heme iron and processed meat nitrate/nitrite were independently associated with increased risk of all cause and cause specific mortality. Mediation models estimated that the increased mortality associated with processed red meat was influenced by nitrate intake (37.0-72.0%) and to a lesser degree by heme iron (20.9-24.1%). When the total meat intake was constant, the highest fifth of white meat intake was associated with a 25% reduction in risk of all cause mortality compared with the lowest intake level. Almost all causes of death showed an inverse association with white meat intake.

Conclusions: The results show increased risks of all cause mortality and death due to nine different causes associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat. They also show reduced risks associated with substituting white meat, particularly unprocessed white meat.