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DENGUE FEVER: Vaccine gives some protection against three out of four virus serotypes

MD-FM Thursday January 3, 2013




GENERIQUE
Carillon

P1

SARAH:
MD-FM: Welcome to a New Year of medical web radio, with Peter Goodwin

PETER:
Hello. Happy New Year everybody!  And with me is Sarah Maxwell.

To start the year we’re looking — in more depth — at important recent developments, beginning with study findings from the first randomized trial of vaccination for dengue fever.

SARAH:
Scientists from Bangkok reported at the American Society of Tropical Medicine and Hygiene meeting that the vaccine raised immunity against three out of the four virus serotypes — incomplete protection: but according to Oxford University’s Jeremy Farrar still a reason to celebrate.  

bob-Jeremy Farrar:
“We’ve been waiting for a dengue vaccine for decades now and so this was the first public announcement of the phase two vaccine trial.  The hopes were that the vaccine efficacy was going to prove more than it was.  So that was disappointing. On the other hand we’ve also been worried about adverse events form the vaccine – that after giving a vaccine that there would be a higher risk of severe disease later. At least after two years follow up —  of these four thousand individuals — there’s no evidence of that!  So the vaccine has been proven — after two years — to be safe:  there are no safety signals, and the efficacy is less than expected, but I think we have to wait for the phase three bigger trial of 30 000-odd patients soon.”
“You in particular were giving a talk about expectations. What did you have to say about this?”
“How you view the results of something very much depends on what you were expecting when you went into he study.  And if our expectation had been [that]: “we want a safe vaccine with some efficacy” — I think there would be room for celebration now. The fact is that perhaps the company — and perhaps the community— was expecting higher and better results than that; and therefore that’s difficult to cope with.”
“So what needs to be done and what will be done on the basis of these results, which are partially promising?”
“Fortunately the company, Sanofi-Pasteur, made a decision to go on with the very large phase 3 trials which are tens of thousands of people in  Latin America and Asia — I think 25 or 30 thousand people in multiple sites.  They’ve done that prior to knowing the results of the phase two studies. So in reality that’s great news, because, otherwise we would have had to wait many more years for those results to be available.  So the key to a vaccine — whether it’s effective or not in preventing disease — doesn’t come from a phase 2 trial: it comes from the phase 3 trial. And we’re in the middle, now, of the phase three trial: all the individuals have now been vaccinated and they’ll wait for  two or three years — the follow up period — and then we’ll have the true impact of the vaccine on a much larger population globally”-
 
SARAH:
Professor Jeremy Farrar of Oxford University’s Unit based in Ho Chi Minh City, Vietnam.

VIRGULE MUSICALE

P2

PETER:
The San Antonio Breast Cancer Symposium a couple of weeks ago reported findings that some patients have “hidden HER2 positivity” so up until now they’ve been missing out on anti-HER2 therapy.

SARAH:
Apparently around 4 000 patients annually — in the USA alone —  are HER2 positive without this being detectable using standard breast caner assays. Ron Bose told us they’ve found hitherto-undetectable “mutated HER2” in some of their patients by using gene sequencing:

Bob-Ron Bose:
“These patients will have normal routine testing — such as immuno-histo-chemistry or FISH tests — but in order to be identified they need to have gene sequencing.  Our prediction — but we don’t know this for fact yet — our prediction is these patients will have an aggressive form of breast cancer and they’ll need an anti HER2 drug for optimal treatment.”
“ So potentially they could be helped, and they’re not being helped?”
“We don’t know how to identify them yet.  This research shows a way of how to identify these women, and we’re going to go forward and do the clinical trial to determine whether these patients will benefit from  HER2 targeted drugs.”
“Trastuzumab has made a big impact in breast cancer: how much of a difference could this refinement of this molecular technique make?”
“It could make a large difference because if we can predict who is going to have aggressive disease — who is more likely to metastasize — we can treat them while they are stage 1 or stage 2.   As we make use of results from breast cancer genome sequencing we want to find out what are the genes that make a difference in terms of patient prognosis and patient treatments, and I would argue that HER2 mutations are one of the things we should be looking for.”
“And you are doing a trial right now, and you’re using an agent that the patients are sensitive to — even if they have the certain mutation that you’ve spotted. So what do you hope to come out of it?”
“We hope that in about 2 to 3 years time we’ll have a demonstration that HER2 targeted drugs — particularly neratinib — are highly effective in this patient population; and that: that will become a standard of care for patients who have a metastatic breast cancer, and have these mutations”

SARAH:
Dr Ron Bose from Washington University in St Louis, Missouri.


P3

PETER:
This illustrates the growing importance of matching treatment to the  molecular characteristics each patient has. And there’s historical precedent for doing this: imatinib therapy for chronic myeloid leukemia made a complete turn-around in patient outcomes. And at the American Society of Hematology meeting in Atlanta we heard about a similar possibility in acute myeloid leukaemia.

SARAH
A molecular therapy for AML has now been found to have a big effect in patients who have the FLT 3 – ITD [FLIT-THREE EYE TEE DEE] mutation. It’s an anti-FLT 3 agent, and it’s brought complete remissions on a 48 hour time-scale! We asked Mark Levis about using the drug — quizartinib —  in FTL3 positive patients.
 
Bob-Mark Levis:
“This is a patient group that we saw years ago before we recognized the impact of the mutation.  They would come in with an extraordinary white blood cell count.  We would work very hard to get them into some semblance of remission. They would quickly relapse and once they had relapsed it was rapidly down-hill from that point.”
“And it was the mutation that was the cause of it?”
“The mutation drives the disease.”
“Tell me about this mutation?”
“This is a mutation that’s in an enzyme that we all have in our body: it’s active only in a very rare subset of cells in the bone marrow that tell the bone marrow stem cells to regenerate some bone marrow.  The leukemia cell — by mutating this — allow themselves to: a) recover or survive chemotherapy;  b) proliferate at a tremendous rate. And so an AML case with this mutation is incredibly proliferative.  There’s a huge amount of the disease when they are present”.
“Could you tell me about the study: what youd did?”
“We tested the drug quizartinib which is a very selective potent FLT 3 inhibitor —  much more potent than anything we’d looked at before — and we gave it as single therapy to patients who had not only relapsed but relapsed and failed a “desperation” round of chemotherapy. So this was the most desperate group of patients. So they take the drug once a day —extremely well tolerated — and the results were seemingly like magic to both the investigator and the patient: the patient walking around with all this leukemia around, and you casually give the drug, and two days later the leukemia’s disappeared from the bloodstream!  No side effects other than the things we’ve been monitoring in the lab very closely. One of these side effects was this QT prolongation. So the poor patients got “trotted” off to the ECG machine many times while we looked very carefully at this. In the meantime the leukemia was almost melting away in front of our eyes!
“So almost like imatinib for AML ”
“Precisely the same mechanism. When imatinib was approved ten years ago we had just discovered the FLKT3 enzyme and we said: we now need to get imatinib for AML.”
“These patients were relapsed or refractory: they only had weeks to live.  What happened to them?”
“Quite a large number of them actually were maintained on the drug.  We were hoping they were going to be maintained for months or even years. However — much like imatinib: when we first used imatinib on the blast phase of CML patients they had a magic response and two or three  months later they had developed the resistance mutations that are now the subject of these new drugs.  Like clockwork, within months, many of these FLT 3 patients developed the resistance mutations so they began to progress and that really accounts for the disease progression and ultimate death of the these patients. We learned that — during the course of the study — anybody who was young enough and had a donor very quickly began being marched off to an allogeneic transplant. And towards the end of the study a very high proportion of youger patients were being moved to transplant earlier and earlier”

SARAH:
Dr Mark Levis from the Kimmel Cancer Center at Johns Hopkins University in Baltimore.



VIRGULE MUSICALE

P4

PETER:
Pre-clinical rheumatoid arthritis could soon be targeted for therapy with great benefit, according to research just released from Leeds University in England.

SARAH
Research has already shown that the earlier you treat RA the better, but how do you go about recognizing it before the patient is even ill?

PETER
Well Professor Paul Emery has been looking at pre-cursor symptoms, and he told me they can now spot people who’ll get RA in the future.  And the new research shows that treatment with standard disease-modifying anti-rheumatic drugs — “DMARDs” — and possibly a new agent — could bring even more benefit than in established RA.

Bob-Paul Emery:
“We’ve been looking at people who have the antibody but no significant arthritis.  Some of them just have joint pains. We image them with MRI or ultrasound, we do all their antibodies, and then we look to see what happens over the next few months. And what we now know is that the patients who progress to inflammatory arthritis in the next 6 months have different imaging and different immunology to those patients who maintain their stable status but still have the antibody so therefore for the first time we can actually have a population we can identify who will get arthritis in the next six months; and that will enable us to intervene — that’s the next step.”
“Could you give me some of the nitty-gritty of this? Typically what sort of patients do you get?”
“Well they can be relatives of patients with rheumatoid arthritis; they can be people who are picked up accidentally as having these antibodies; but they are essentially people who are normal. And the whole idea is to retain their normal status.”
“Which antibodies specifically are you looking for?
“The antibody that’s most specific and has the best predictive value is ACPA which is a series of citro- related auto-antibodies.”
“And what do you do then?”
“Well for the moment we haven’t had ethics to intervene; but it’s likely that relatively safe drugs can be used at this early stage.  There are data for methotrexate stabilizing disease and preventing progression; there’s a bit of data for hydroxy-chloroquine; and there’s some data for a drug called abatacept: which is a costimulation blocker, and we’ll know the full results of the much bigger study relatively quickly.”
“What about the other biologics?”
“The other biologics, as yet, have not been used in this disease, and it may be that they won’t work as well as one might thinks — because they may be designed for established disease rather than prevention, and we’re beginning to think that initiation is different from progression and maintenance of disease.”
“What’s your tip to docs about how much benefit there might be?”
“I think there’s no doubt that if you are at risk of arthritis you should be assessed at the best centers as rapidly as possible.  The results that we’re seeing are so good, now, that it may be hard to improve on even earlier diagnosis; but if we’re looking to actually switch-off the disease then the time to do it is before you get significant synovitis.”
“And to put this into perspective of the rest of treatment for rheumatoid arthritis: how have things improved? And how much further could they improve with the use of this new pre-clinical testing?”
“I think the standard of care now suggests that half of all new patients should be in remission at the end of the year. And what we’d like is to make that near 80 or 90 per cent and have a much higher proportion stay in remission off therapy. That’s what patients want: they all say: “How long do I have to take therapy for.”  To be able to say to them you have a 50 per cent chance of not taking therapy long term would be a revolution compared to the previously fatal disease of rheumatoid arthritis.”

PETER:
Paul Emery of Leeds University.

And that’s all from MDFM for today.  Lots more in a week’s time.  Until then it’s good-bye and Happy New Year from Sarah Maxwell, from all of the team in Paris, London, and around the world — and from me, Peter Goodwin: good-bye!
 
 
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