Re: More on the Trophos drug

[Guest guest]

:

Thanks for posting the update. I'm curious as to what

" success " they've seen with ALS & SMA. One would have

to assume that aside from safety being measured and

seen as tolerable during the Phase 1, the researchers

would have to see some positive clinical or functional

benefit from the use of the Trophos drug to move on to

1b for ALS & begin Phase 1 for SMA.

Their earlier FAQ section listed maintaining strength,

etc. along with regaining lost strength/function as

possible benefits - are they seeing this

preliminarilly? I don't see why the

makers/researchers couldn't be more blunt/open about

their early results - its not like

non-trial-participants can go out and trial this

medication on their own (its not an approved drug for

anything yet it seems).

Oh well, I suppose one needs to be patient. Pretty

cool, nonetheless, that a private company is driving

research for therapeutic treatments as well as private

charities & government funded efforts. I have a

changing attitude torward the French as a

result-Yay-Go France-Hooray for France (actually

-hooray for Trophos, Go Trophos!)...Mitch

--- Senior <jsenior@...> wrote:

> I just received a reply from Trophos to an e-mail I

> sent asking about

> clinical trials for SMA. While they did not give a

> definite date, it

> seems a trial is likely to start this year in

> France.

>

> They also sent me an updated version of their FAQs

> on TRO19622. It

> isn't on their website yet, so here are the

> highlights:

>

> ------

> WHAT IS TRO19622, HOW WAS IT DISCOVERED, WHAT IS ITS

> DEVELOPMENT STATUS?

>

> TRO19622 is a new chemical entity derived from the

> Trophos compound

> collection. The molecule has a cholesterol-like

> structure and displays

> remarkable neuroprotective properties both in vitro

> and in vivo. It

> was discovered thanks to the original

> high-throughput screening

> platform using primary motor neurons that Trophos

> developed to

> support its drug discovery strategy. TRO19622 is as

> effective as a

> cocktail of three neurotrophic factors in keeping

> motor neurons alive

> in culture. TRO19622 also improves survival of

> striatal neurons in a

> cell-based model of Huntington's disease and

> displays anti-apoptotic

> properties for other types of primary neurons. In

> vivo, TRO19622 is

> active in several preclinical models of

> neurodegenerative disease.

>

> TRO19622 has satisfactorily completed preclinical

> evaluation involving

> cardiovascular, CNS, respiratory and immune system

> safety studies. It

> also shows no mutagenic potential and is not toxic

> in vivo at drug

> concentrations >50 times the expected therapeutic

> level for four

> weeks. An oral formulation has been developed for

> clinical trials.

>

> TRO19622 has successfully completed Phase I clinical

> trials. These

> were conducted in France and involved single and

> multiple dose studies

> on healthy adult subjects. TRO19622 was demonstrated

> to: i) be well

> tolerated; ii) have achieved the predicted effective

> clinical dose via

> the oral route and, iii) have an excellent safety

> profile.

>

> TRO19622 is now in Phase Ib clinical trials. These

> studies will insure

> there is no interaction between TRO19622 and

> riluzole, the only

> approved drug for the treatment of ALS, and evaluate

> the

> pharmacokinetics and tolerance for one month in ALS

> patients. These

> trials pave the way to start an 18 month pivotal

> Phase II/III clinical

> trial of TRO19622 as an add-on to riluzole in ALS

> patients in Q4 2006.

> The trial will be conducted in the USA and Europe. A

> Phase Ib study in

> juvenile SMA patients is also anticipated to start

> by the end of 2006,

> with support from the AFM [a French patient

> association].

>

> HOW DOES TROPHOS BENEFIT FROM ORPHAN DRUG STATUS?

> TRO19622 has been granted orphan drug designation

> status for the

> treatment of ALS in the USA, and for the treatment

> of SMA in the EU.

> This status allows Trophos the opportunity to

> benefit from the advice

> of regulatory authorities in order to design the

> clinical trials, and

> thereafter seek " fast track " review by both the FDA

> and the EMEA.

>

> WHEN WILL TRO19622 BE AVAILABLE TO PATIENTS?

> Trophos is actively developing TRO19622 to treat

> patients with the

> motor neuron diseases ALS and SMA. TRO19622 has

> successfully completed

> Phase I clinical studies and is currently being

> evaluated for its

> tolerance and safety in Phase Ib studies involving

> ALS patients. These

> studies pave the way for the initiation of a pivotal

> Phase II/III

> clinical trial in ALS patients in Q4, 2006. In the

> meantime, Trophos

> is working with paediatric neurologists and the AFM

> to develop

> protocols for clinical trials in juvenile SMA

> patients. Assuming the

> continued success of the ALS and SMA clinical

> trials, and regulatory

> approvals, TRO19622 may be available by 2010.

> ------

>

>

> Tokyo, Japan

>

__________________________________________________

[Guest guest]

Mitch;

Just to reiterate: The drug has not yet been tested on ALS or SMA

patients. The Phase 1 trial was purely to check safety and was

conducted on healthy subjects, so it could not have produced any

therapeutic benefits. That's why there is no mention of improved

function or anything like that.

The " success " they have had is: (1) preventing cell death in cellular

models of neurodegenerative disease and (2) showing that the drug is

well tolerated and safe in people without ALS or SMA. The Phase 1b

trials will test the safety of the drug in people with ALS and SMA

(ALS first, SMA hopefully by the end of the year). It sounds like

those are going to be very short trials (one month), so I doubt there

would be any therapeutic benefit seen in them either. If the drug is

to show therapeutic benefit, it will be in the Phase II/III trials

following the Phase 1b trials.

I have to say I'm impressed with their information disclosure. I wish

every company/project would release such detailed information. Also, I

like the fact that they kept their word about the Phase 1 trial: they

said it would last a year, and sure enough one year later they

announced the results. OK, so it was a trial with healthy patients,

but it's still a sign of efficiency. Compare that with the CARNI-VAL

trial - the Phase I trial finished 9 months ago and all we have heard

is vague comments about " encouraging results " and " some functional

improvement " . Most of the information has come from parents of

participating children. Where is the official announcement about

exactly how much improvement was seen, at what dosage, at what age

etc. etc.?

2006/2/21, <mongomustgolf@...>:

> :

>

> Thanks for posting the update. I'm curious as to what

> " success " they've seen with ALS & SMA. One would have

> to assume that aside from safety being measured and

> seen as tolerable during the Phase 1, the researchers

> would have to see some positive clinical or functional

> benefit from the use of the Trophos drug to move on to

> 1b for ALS & begin Phase 1 for SMA.

>

> Their earlier FAQ section listed maintaining strength,

> etc. along with regaining lost strength/function as

> possible benefits - are they seeing this

> preliminarilly? I don't see why the

> makers/researchers couldn't be more blunt/open about

> their early results - its not like

> non-trial-participants can go out and trial this

> medication on their own (its not an approved drug for

> anything yet it seems).

>

> Oh well, I suppose one needs to be patient. Pretty

> cool, nonetheless, that a private company is driving

> research for therapeutic treatments as well as private

> charities & government funded efforts. I have a

> changing attitude torward the French as a

> result-Yay-Go France-Hooray for France (actually

> -hooray for Trophos, Go Trophos!)...Mitch

>

[Guest guest]

Mitch:

That's a very good point. I hadn't thought about the impact of

revealing results on recruitment for the next stage. The problem is,

particularly in the Internet age, information will find its way to

people who want to know, so there's an argument that they may as well

make sure the information coming out is accurate and official.

I could understand if they had a blanket ban on revealing any results.

What I find frustrating is that the CARNIVAL investigators keep

revealing little snippets of information, but without going into

detail. For example, at the FSMA conference Dr. Swoboda mentioned

improvements of 14 or 15 points on the Hammersmith Scale for some

younger kids, which is a HUGE increase, equivalent to passing several

physical development milestones. But she didn't say if that was a

common result, or if just one kid improved that much and all the

others barely changed (in which case it probably wasn't the VPA that

caused it), or if half the kids improved a lot and half didn't improve

at all, or whatever.

The SMA trial for the Trophos drug will also be " Phase 1b " (ie. a

study purely to check safety/tolerability, but on subjects who have

the condition in question). I find it encouraging that they even

mentioned a date. They didn't have to do that, so it makes me think

they must be pretty confident that this thing is going to work.

Fingers crossed...

2006/2/23, <mongomustgolf@...>:

> :

>

> I'm with you regarding the official results of the

> CarniVal Trial - only, the Phase 1 (which my son was

> part of) - was performed under the same guise as the

> Trophos with so-called " healthy " subjects - for SAFETY

> purposes to test for tolerability. The efficacy

> results for the Carni-Val trial are being tested

> during the Phase 2. The investigators made the main

> goal - testing for safety/tolerability - very clear to

> participants at the outstart.

>

> Another key difference between CarniVal and Trophos

> is, of course, funding. The CarniVal trials is being

> funded, for the most part, by a private charity -

> through much hard earned charity funding efforts of

> families, friends, kids, adults with SMA. Trophos - a

> private company - is apparently receiving most of its

> funding through investors.

>

> The reasons, I believe, the investigators are somewhat

> mum on the preliminary results (even with the

> participants to some degree) - is to allow for

> effective recruiting and enrollment of the Phase 2.

> Since Valproic Acid & Carnitine are both FDA

> ( & whatever else international regulatory agencies) -

> Doctors can and do prescribe " off-label " usage of

> these drugs for their own patients to trial. I know

> this to be true and factual - as several kids & adults

> with SMA in the Cleveland, Ohio area alone, trialed

> VPA off-label - I don't know the ones that did, but,

> it did happen, happens now, and will continue to

> happen. We all want " Lorenzo's Oil " and we all want

> it yesterday (I'm one of 'em). I believe one of the

> big concerns of the VPA investigators is being able to

> enroll enough inviduals to obtain significant

> information to allow for FDA approval, etc.

>

> I look forward to the Ib results with ALS & Phase I

> for SMA of Trophos. Hopefully it helps as it seems it

> might. Go Trophos GO! Also, hopefully it proves so

> beneficial - that it receives approval well before

> 2010.

>

> Mitch

>

[Guest guest]

Sure sounds promising. I think if I was a doctor who'd just done a

trial in which kids with a previously untreatable disorder seemed to

partially recover their strength, I'd be shouting it from the

rooftops, so I have to admire their restraint in keeping so quiet.

Our daughter Alice is one and a half, probably a mid-range Type 2,

though the diagnosis has got worse each time a doctor has had a guess

(which has really helped to soften the blow!). In Japan there is no

rule with VPA about being over the age of 2, but we've decided to lay

off it until she passes that milestone, just in case. With bureaucracy

moving at a snail's pace, a CARNI-VAL trial is planned for a few

years' time over here, but it's available off-label and, as you say,

everyone wants Lorenzo's Oil. We'd happily take part in a trial, but

waiting a matter of years just doesn't make sense.

Tokyo

2006/2/23, <mongomustgolf@...>:

> :

>

> Purely as hearsay from other parents with kids in the

> study - most of the participants showed some

> significant improvement on the hammersmith - some more

> than others. Those that showed the most, tended to be

> younger (under 5) - and of the intermediate type.

> Bryce - who'd just turned 4 before starting with the

> medication showed significant improvement clinically -

> CMAP score increased over 25% & MUNE - increased

> slightly & stabilized - but showed little to no

> improvement in the hammersmith (which was due in part

> that he just about maxed out the score from the

> beginning - thus a more advanced test - modified for

> Type 3's is in effect for the Phase 2, I believe).

>

> One or two of the kids (both older I believe) - gained

> excessive weight due to the medication that offset any

> benefit they may have been receiving. Aside from

> that, it is my understanding that all others seemed to

> receive some level of benefit (but again, this is just

> hearsay). BUT, there's the whole moving target thing

> going on as well - kids from age 3 to 5 (SMA or not)

> are learning how to do things & do things better - so,

> I'd think, in measuring functionality of a child 6

> months prior to receiving the medication - say at age

> 3 & 1/2 - and then again at the conclusion - a year &

> half later - at age 5 - well, obviously some of the

> apparent improvement has to do somewhat with just

> growing older, wiser, etc. Bigger to me, are

> indications of no decline. It sure seems to have

> helped Bryce - that's all I can really say for

> certain.

>

> But hell, I'm not a doctor - so what do I know?

>

> Hopefully things become much clearer in the near

> future - and fingers are definitely crossed! Mitch

>

> --- Senior <jsenior@...> wrote:

>

> > Mitch:

> > That's a very good point. I hadn't thought about the

> > impact of

> > revealing results on recruitment for the next stage.

> > The problem is,

> > particularly in the Internet age, information will

> > find its way to

> > people who want to know, so there's an argument that

> > they may as well

> > make sure the information coming out is accurate and

> > official.

> >

> > I could understand if they had a blanket ban on

> > revealing any results.

> > What I find frustrating is that the CARNIVAL

> > investigators keep

> > revealing little snippets of information, but

> > without going into

> > detail. For example, at the FSMA conference Dr.

> > Swoboda mentioned

> > improvements of 14 or 15 points on the Hammersmith

> > Scale for some

> > younger kids, which is a HUGE increase, equivalent

> > to passing several

> > physical development milestones. But she didn't say

> > if that was a

> > common result, or if just one kid improved that much

> > and all the

> > others barely changed (in which case it probably

> > wasn't the VPA that

> > caused it), or if half the kids improved a lot and

> > half didn't improve

> > at all, or whatever.

> >

> > The SMA trial for the Trophos drug will also be

> > " Phase 1b " (ie. a

> > study purely to check safety/tolerability, but on

> > subjects who have

> > the condition in question). I find it encouraging

> > that they even

> > mentioned a date. They didn't have to do that, so it

> > makes me think

> > they must be pretty confident that this thing is

> > going to work.

> > Fingers crossed...

> >

> >

> >

> >

> >

> > 2006/2/23,

> > <mongomustgolf@...>:

> > > :

> > >

> > > I'm with you regarding the official results of

> > the

> > > CarniVal Trial - only, the Phase 1 (which my son

> > was

> > > part of) - was performed under the same guise as

> > the

> > > Trophos with so-called " healthy " subjects - for

> > SAFETY

> > > purposes to test for tolerability. The efficacy

> > > results for the Carni-Val trial are being tested

> > > during the Phase 2. The investigators made the

> > main

> > > goal - testing for safety/tolerability - very

> > clear to

> > > participants at the outstart.

> > >

> > > Another key difference between CarniVal and

> > Trophos

> > > is, of course, funding. The CarniVal trials is

> > being

> > > funded, for the most part, by a private charity -

> > > through much hard earned charity funding efforts

> > of

> > > families, friends, kids, adults with SMA.

> > Trophos - a

> > > private company - is apparently receiving most of

> > its

> > > funding through investors.

> > >

> > > The reasons, I believe, the investigators are

> > somewhat

> > > mum on the preliminary results (even with the

> > > participants to some degree) - is to allow for

> > > effective recruiting and enrollment of the Phase

> > 2.

> > > Since Valproic Acid & Carnitine are both FDA

> > > ( & whatever else international regulatory

> > agencies) -

> > > Doctors can and do prescribe " off-label " usage of

> > > these drugs for their own patients to trial. I

> > know

> > > this to be true and factual - as several kids &

> > adults

> > > with SMA in the Cleveland, Ohio area alone,

> > trialed

> > > VPA off-label - I don't know the ones that did,

> > but,

> > > it did happen, happens now, and will continue to

> > > happen. We all want " Lorenzo's Oil " and we all

> > want

> > > it yesterday (I'm one of 'em). I believe one of

> > the

> > > big concerns of the VPA investigators is being

> > able to

> > > enroll enough inviduals to obtain significant

> > > information to allow for FDA approval, etc.

> > >

> > > I look forward to the Ib results with ALS & Phase

> > I

> > > for SMA of Trophos. Hopefully it helps as it

> > seems it

> > > might. Go Trophos GO! Also, hopefully it proves

> > so

> > > beneficial - that it receives approval well

> > before

> > > 2010.

> > >

> > > Mitch

> > >

> >

>

>

> __________________________________________________

>

[Guest guest]

Kenya:

I fully respect your views, but we'll just have to agree to disagree.

We all have to make difficult decisions based on what we think is best

for our own kids - what's right for one family isn't necessarily right

for another. Please remember that I'm not in the US, so my daughter

does not have the option of taking part in a trial at the moment (and

perhaps not for a very long time). We have a great neurologist who we

trust completely, and when he initiates the CARNI-VAL treatment, it

will be with every possible precaution - regular blood tests,

check-ups, doses based on what is used for other conditions etc. We

know VPA is not a cure, but we also know that both researchers and

parents say it has most effect on children under 5. Do I wish that

wasn't so? Of course - what we all want is a treatment that improves

function whether you're 5 or 85 (and that's why the Trophos drug is

potentially exciting). But the best information available for VPA says

that if we wait several years for a trial to start, by that time our

daughter may be too old to get the full benefit. Any strength or

function that she has at 3 or 4 years old - even if she loses it later

on - will have a disproportionate benefit later in life in terms of

joints, bones, circulation, all kinds of stuff. That's why we feel

that waiting several years for a few bits of paperwork to be completed

is not the right choice for her.

Tokyo, Japan

2006/2/24, Kenya Birkle <smamom2three@...>:

> To me it does make sense to wait. As a mother of a child who was in the

> trail, I do know details about the trail. My son was in the part for the

> safety phase. With a drug like this, there are long term effects that are

> already know, this is not just any drug, it is used to treat migraines,

> siezures and mood disorders so the affect it has on SMA kids is very

> important to know.Yes we all want it now but it has already been stated that

> this is not a cure for SMA, they have never thought of it as that way, it is

> hopefully something that will slow down the " progression " With research they

> have found that there is more to SMA than just the lacking gene or mutation

> but other components as well, like a mitochondria issue. This trail is

> mainly funded by families and private groups, families have had to lobby the

> government in order to get funding for research. I respect your opinion and

> apprecaite that you are a very good conversationalist. It makes a better

> topic to discuss when parties are

> respectful.

>

> Kenya

>

[Guest guest]

Foul x 2 = 1 hour break for posting (rule #ID10T) using words longer

than 6 letters.

disproportionate - conversationalist

There is no right answer for everyone. The timing is right to try and

regain strength and red tape could mean years which could mean lots

of lost function. Could it be dangerous Yes.... But sometimes you

have to do what you have to do. I would take it today at 33 years old

if I could. I don't think anyone should be criticized for there

decision they make for there own child weather to try or not to try.

You have both oviously put a lot of thought into your decisions after

I sounded out all the big words in your post that was easy to see. I

wish you both the best of luck with your separate paths. I hope you

find something to work for you children and don't have to go all the

way to Czechoslovakia to find it. (13 letters is the best I could

come up with without using spell check.

Seriously please respect your opposing decisions that I am sure were

made with much thought. There is nothing worse than watching a child

suffer and feel helpless lets be thankfully we are the type of people

who recognize that and move on.

Terry

[Guest guest]

>

> Thank you for posting information on the Trophos Drug and it is

very encouraging. We had our son on the Hydroxyurea trial. He couldnt

fly to California after couple of months as he got weak afer a

hospitalization. We now have his neurologist near us prescribing the

drug and following the protocol. I cant say I have seen any big

improvements but he hasnt gotten any weaker and is fairly strong

compared to other Type 1 kids that I know of and have seen.

I am also encouraged by the work done by Oxford Biomedica and also the

work done in ESC. Please watch 60 minutes on Sunday 26th where they

are doing a segment on ESC. Dr Keirstaed is in it and he works with Dr

Kerr on applying ESC for SMA

Kavitha

[Guest guest]

Meg:

Trophos is a small company in France that is developing a drug

designed to prevent apoptosis (death) of motor neurons in ALS and SMA.

This press release has more info:

http://www.trophos.com/news/pr20060131.htm

They also have a detailed FAQ which I recommend (PDF file):

http://www.trophos.com/download/TrophosFaqs.pdf

They e-mailed me an updated FAQ which doesn't seem to have been

uploaded to their website yet, so here are the highlights:

------

WHAT IS TRO19622, HOW WAS IT DISCOVERED, WHAT IS ITS DEVELOPMENT STATUS?

TRO19622 is a new chemical entity derived from the Trophos compound

collection. The molecule has a cholesterol-like structure and displays

remarkable neuroprotective properties both in vitro and in vivo. It

was discovered thanks to the original high-throughput screening

platform using primary motor neurons that Trophos developed to

support its drug discovery strategy. TRO19622 is as effective as a

cocktail of three neurotrophic factors in keeping motor neurons alive

in culture. TRO19622 also improves survival of striatal neurons in a

cell-based model of Huntington's disease and displays anti-apoptotic

properties for other types of primary neurons. In vivo, TRO19622 is

active in several preclinical models of neurodegenerative disease.

TRO19622 has satisfactorily completed preclinical evaluation involving

cardiovascular, CNS, respiratory and immune system safety studies. It

also shows no mutagenic potential and is not toxic in vivo at drug

concentrations >50 times the expected therapeutic level for four

weeks. An oral formulation has been developed for clinical trials.

TRO19622 has successfully completed Phase I clinical trials. These

were conducted in France and involved single and multiple dose studies

on healthy adult subjects. TRO19622 was demonstrated to: i) be well

tolerated; ii) have achieved the predicted effective clinical dose via

the oral route and, iii) have an excellent safety profile.

TRO19622 is now in Phase Ib clinical trials. These studies will insure

there is no interaction between TRO19622 and riluzole, the only

approved drug for the treatment of ALS, and evaluate the

pharmacokinetics and tolerance for one month in ALS patients. These

trials pave the way to start an 18 month pivotal Phase II/III clinical

trial of TRO19622 as an add-on to riluzole in ALS patients in Q4 2006.

The trial will be conducted in the USA and Europe. A Phase Ib study in

juvenile SMA patients is also anticipated to start by the end of 2006,

with support from the AFM [a French patient association].

HOW DOES TROPHOS BENEFIT FROM ORPHAN DRUG STATUS?

TRO19622 has been granted orphan drug designation status for the

treatment of ALS in the USA, and for the treatment of SMA in the EU.

This status allows Trophos the opportunity to benefit from the advice

of regulatory authorities in order to design the clinical trials, and

thereafter seek " fast track " review by both the FDA and the EMEA.

WHEN WILL TRO19622 BE AVAILABLE TO PATIENTS?

Trophos is actively developing TRO19622 to treat patients with the

motor neuron diseases ALS and SMA. TRO19622 has successfully completed

Phase I clinical studies and is currently being evaluated for its

tolerance and safety in Phase Ib studies involving ALS patients. These

studies pave the way for the initiation of a pivotal Phase II/III

clinical trial in ALS patients in Q4, 2006. In the meantime, Trophos

is working with paediatric neurologists and the AFM to develop

protocols for clinical trials in juvenile SMA patients. Assuming the

continued success of the ALS and SMA clinical trials, and regulatory

approvals, TRO19622 may be available by 2010.

------

Tokyo, Japan