Xiaflex

[newguy]

There is a UK clinical trial for Xiaflex starting next month: http://www.peyronies-disease.co.uk/2011/01/xiaflex-trials-uk.html  I have no idea how many people they are looking for, or if they have already filled the places, but I thought this might be of interest to people here!! Thanks.

[BSSS]

Since I just started as a participant in the third phase of the Peyronie's trial I did some layman's research on the mechanical side of Xiaflex and came across the following info on a Dupuytren's link:

"Xiaflex contains purified collagenase clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria. Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits. Injection of Xiaflex into a Dupuytren's cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord"

It is fascinating to me that the drug - an enzyme made up of protein - is taken from a fermenting bacteria? Anyone know what happens when collagen is hydrolyzed? Evidently the matter changes form....maybe has a lot to do with all the following discoloration and swelling as well after an injection.

When I wikied it I even saw a refernce to gas gangrene....lol..I'm starting to think of the old axiom 'curiosity killed the cat' but can't help but be curious about the drug and what kind of reaction could possibly be going on in there if I receive the real thing. Oh well...back to the (drawing boards) search engines for more info! Hoping the cat has a few lives left!

BSSS
 

[BSSS]

BTW,

If some of you kind gentlemen that are trained medically would tell me what happens to the collagen once treated/injected I'd be grateful.

I'd like to know what actually happens to the collagen, and how the body rids itself of what part of it is dissolved or whatever, if in fact it does.

Thanks!
BSSS

[ComeBacKid]

This question has been discussed widely, I thought the collagen is just dissolved?  However then, wouldn't that tissue need to be replaced?  Or perhaps it is just formatted into new flexible tissue.  Maybe Tim could weigh in on this or someone in the trials could ask their doctor this question and report back for us!

Comebackid

[MikeSmith0]

This question has been discussed widely, I thought the collagen is just dissolved?  However then, wouldn't that tissue need to be replaced?  Or perhaps it is just formatted into new flexible tissue.  Maybe Tim could weigh in on this or someone in the trials could ask their doctor this question and report back for us!

Comebackid

I haven't even gotten a good answer to this.  I've asked - nobody seems to know.  In dupuytren's contracture, all you "need" is to dissolve the cord...and that's all that happens.  The enzyme is supposed to break the large, inflexible collagen structures down into tiny molecules that just get taken back in the bloodstream.  In Peyronies Disease, depending on the severity, once the plaques are dissolved, there needs to be rebuilding with normal / healthy collagen (my understanding is that some scars can be "released" in surgery - to reduce tension - but others require grafting due to the invasiveness into the tunica - so this varies).  Although some guys simply have the scar tissue sitting far enough "above" normal tunica (which i think is rare and unlikely - it's very intertwined) that dissolving the scar reduces the curve and improves everything...I think most are going to have a more complex situation.

I would not be surprised if xiaflex could lead to a worse hinge effect... if the scar tissue is causing the curve AND providing support - dissolving it could make the hinge worse if there is little normal tunica to support an erection.  I don't think we'll have good answers to any of this for years - many many guys have to try xiaflex in many situations (many of which are excluded from the study).  Nothing is out there to rebuild elastin or to encourage healthy collagen reformation.  Will the body do it on its own?  Maybe.  Who knows.  Will it work for everyone?  We've already heard from phase 2 people (not on placebo) that it won't... though there's not a lot of detail - just that it didn't reduce the curve.  This time, with 4 cycles instead of 3 - it might work a little better - and they measure the study subjects for 1 year after injection 1... so they are looking to see the body's response...at least in these "ideal" 200 cases that are going through it now.  So, the answer to this might be known in another 8 months or so.  

I don't have much faith the body will do anything to repair the area normally... given that it didn't repair the "microtrauma" right the first time.

[ComeBacKid]

I'm convinced it could alter the cells, I know with pentox my penis has become much more soft and flexible, doens't feel like a cast is on it when its flaccid, George is good at explaining the immune system and how pentox effects it and keeps it from attacking ones self.  If my penis can be made flexible again xiaflex could do the same thing.  This is pretty amazing stuff, and def. should keep people hopeful.  

I agree though no one has given a good explanation on exactly how xiaflex works and what happens to the bad tissue, does it dissolve, change into healthy tissue, or a little of both?

Comebackid

[jw1441]

I asked an eminent urologist last week if he was optimistic about Xiaflex.

He said he is much more optimistic about (Xiaflex + traction).  Apparently Dupytrens patients use a splint.  

[MikeSmith0]

I asked an eminent urologist last week if he was optimistic about Xiaflex.

He said he is much more optimistic about (Xiaflex + traction).  Apparently Dupytrens patients use a splint.

i agree.  even in the study they have us doing "modeling" - which is nowhere as strong as traction and only for a few minutes.  traction would be better.  i just have not had any positive effects of traction, particularly on girth.  

[chefcasey]

Has anybody ever tried traction after xiaflex?  I think one of the dangers of xiaflex is that it can possibly give you a thinner tunica, so I don't know if you'd want to strap yourself in for 4 hours a day.  I think traction made a couple dents even larger, which sucks because i really felt like it was giving me back some stability and straightness.  I don't think I'll try it again unless I'm truly stable in Peyronies Disease.

[MikeSmith0]

Has anybody ever tried traction after xiaflex?

you are not allowed to for now

they just want to have you stretch it for a few min a day.

[ComeBacKid]

Chefcasey,

Your observation is wise, until someone can explain to me exactly what xiaflex is doing and what happens to the tissue, I would not combine xiaflex and traction, I would do xiaflex and give it a few weeks off.  People get to excited and want to swing for the fence with a full cure all at once, take it slow, and see what works, we got plenty of time, don't panic.

Comebackid

[Mathewfamily]

I don't know about traction while on the Xiaflex trial.  I am still sore and it has been three weeks since the shots.  When you do the modeling it makes it sore, I couldn't imagine having it pulled all the time.  No Thank You.

[fubar]

Has anybody in the xiaflex study noticed any improvement in their flaccid state.? Also I do not know if guys were excluded from the study because of hourglass or hinging .Have not read the criteria in sometime. If not excluded have you noticed any improvement with those issuses?


Fubar

[Humorous3]

Has anybody in the xiaflex study noticed any improvement in their flaccid state.? Also I do not know if guys were excluded from the study because of hourglass or hinging .Have not read the criteria in sometime. If not excluded have you noticed any improvement with those issuses?


Fubar

Fubar,

Reference your hourglass question, here is the link to the study criteria.  Look at item 6 under Exclusion criteria.  

http://www.clinicaltrials.gov/ct2/show/study/NCT01221597?term=peyronie%27s&show_xprt=Y&show_locs=Y

Concerning improvement in the flaccid state, I finally noticed some and I'm almost at the end of Phase 3/beginning of Phase 4.  It's hard to describe but it seems to be denser/has more substance/more body.  I hope this helps.  

Humorous

[BSSS]

Has anybody in the xiaflex study noticed any improvement in their flaccid state.? Also I do not know if guys were excluded from the study because of hourglass or hinging .Have not read the criteria in sometime. If not excluded have you noticed any improvement with those issuses?


Fubar

not yet.....I've been through the first series of injections.  I also didn't notice much if any change erect.  I don't have a compass to measure angle, but at first glance it appears about the same.
I definitely do not have the hinge effect although I was concerned about modeling the first few days.

[BSSS]

all you guys in the phase III trial might want to ask your clinic about the 'open label' follow up if you receive the placebo in phase III.  From the looks of it Auxillium is currently recruiting 250 subjects by invitation only to participate in the open label study and the one they are recruiting for now is only open to the phase II participants it appears. The open label part currently being recruited for ends 03-2012.  I have no idea if Auxillium intends to do anymore open label studies, but it might be worth asking about....esp if you think you are currently receiving the placebo.

Of course, I could be reading it all wrong, but the info I saw was on the govtrials website.

http://www.clinicaltrials.gov/ct2/show/NCT01243411?cond=%22Peyronie%27s+Disease%22&rank=4

BSSS

[Humorous3]

Has anybody in the xiaflex study noticed any improvement in their flaccid state.? Also I do not know if guys were excluded from the study because of hourglass or hinging .Have not read the criteria in sometime. If not excluded have you noticed any improvement with those issuses?

Fubar

Fubar,

I actually have some "official" results concerning improvement in the flaccid state.  At the end of Cycle 3 measurements (18 weeks), my length has increased by 2cm, which is about 13/16th inch.  (You can see my complete post in the Topic: Thread for Guys in Xiaflex Trial - Currently or Previously.

Humorous

[Ben]

good grief that is really a good new !! have you seen an improvement on erected state, or the gain is just in the flacid state ?

[fubar]

Humorous3

Yes I have read your other post ,awesome news! I wonder if they would continue injections after the study if you continue to improve.Or if they say that's it your done.Or the drug has run its course and would provide no more benefit.Man the question's go on forever.

Fubar

[MUSICMAN]

If your improvement reaches 15 deg. or less bend they stop your study.

[fubar]

Musicman

Thanks for your pm. I see your point many would be pleased at that point.If one having a 90 degree bend went to 15 yes I'm sure that person would be overwhelmed with joy ,I would also.The fact that they would cut me off after being their test Guinea pig would make me want to dot someones eye.

If I had a great improvement I would want them to go on treating me until it seemed it no longer had a positive effect.Putting your penis on the line for them so they can get wealthy? Should warrant ongoing treatment.

Fubar

[ronners]

Fubar,

Let's not forget that these trials are voluntary ... at the risk of sounding like I'm defending big, heartless biotech companies, people who have signed up know the risks and they know about the trial protoculs ... maybe there is good reason not to go beyond four treatment cycles -  the previous trial only went to three ...

[BSSS]

Has anybody in the xiaflex study noticed any improvement in their flaccid state.? Also I do not know if guys were excluded from the study because of hourglass or hinging .Have not read the criteria in sometime. If not excluded have you noticed any improvement with those issuses?


Fubar

not yet.....I've been through the first series of injections.  I also didn't notice much if any change erect.  I don't have a compass to measure angle, but at first glance it appears about the same.
I definitely do not have the hinge effect although I was concerned about modeling the first few days.

I do want to follow up this post with some notice of a change.  I've seen some difference in my angle when erect.  I didn't at first but the angle is less sharp, or more gradually curved.  I really couldn't put a number on it at this point and the info is anecdotal of course, but none the less encouraging. I did round one of injections several weeks ago and have been pretty good about remembering the modeling.

BSSS

[lespleen]

is xiaflex intended as a treatment option for guys who present with no detectable scar via ultrasound , no curve per se, but rather inflammation and indurations?

[MikeSmith0]

is xiaflex intended as a treatment option for guys who present with no detectable scar via ultrasound , no curve per se, but rather inflammation and indurations?

There has to be a palpable plaque to inject it into.  It is not intended to be injected diffusely.

[lespleen]

so it can't be injected where there's an induration and localized pain but no plaque?

[MikeSmith0]

so it can't be injected where there's an induration and localized pain but no plaque?

The substance is meant to eat through collagen based scar tissue... so i'm not sure you'd want it injected just anywhere... it could harm the tunica itself if it is just randomly injected.  Maybe in the future, guidelines for people with diffuse scarring will be developed but as of now, it's not for that purpose.  

[ComeBacKid]

So if it eats the plaque or scar tissue, what fills that void once that tissue is gone?  Does new tissue regenerate?  Otherwise you would lose mass and size.  The real question is what about someone who has scar tissue mixed in with healthy tissue, can the xiaflex differentiate and leave the healthy tissue alone or does it just eat up anything in its way.  If this is the case like Mike believes, then you would want to map out where the scar tissue and plaque is ahead of time with a doppler ultra sound and other tools and inject xiaflex in a targeted way.

Comebackid

[shrout]

Comeback, this sentence referring to Xiaflex is taken from the website of Mr. David Ralph, one of the UK's top Peyronies specialists ...

"The hope with peyronie's is that the tissue itself changes in composition and regains some of its former qualities (elastisity etc)."

http://www.peyronies-disease.co.uk/2009/09/xiaflex-for-peyronies-disease.html

So rather than "eating" plaque and leaving a void, he's suggesting Xiaflex might, and I guess we have to realise there's still plenty of uncertainty,  be capable of changing the composition of plaque, potentially breaking down the networks of collagen and fibrin and restoring the tissue to something closer to it's original state.

He does say however that the results of the xiaflex trials so far are "not exactly mind blowing".  

[Worried Guy]

The results are "not exactly mind blowing" were the words I believe of the website owner and not David Ralph.  However, I see your point that a 25% improvement depends on how bad you are to start.  Some of the guys I've been following seem to be getting 5 degree reductions with each cycle. That means 4 cycles and I would be fixed.  I can see it helping some guys very much. I was private messaging a guy recently who has had some pretty good results.  So much so that he is worried he may have improved so greatly that he can't carry on with the trial.

[ronners]

Worried Guy is right - this is not a quote from David Ralph but from the website owner ... the website owner is also referring to the previous sets of trials and not phase 3 which is happening at the moment (much larger with different amounts of cycles) as this was posted in 2009 ... this is old news! Incidentally David Ralph and his team are running the UK Phase 3 trials at the moment ...

[shrout]

Worried Guy/ronners, you've both concentrated on the last sentence of my post, which I added as an afterthought.  I agree it's out of date and not by David Ralph, so probably a bit misleading. Apologies for that. Great to hear positive stories coming from the trials btw Worried Guy.

My main point was to draw Comeback kid's attention to the statement which implies that xiaflex doesn't "eat" plaque and leave a void, but changes it's composition to something with hopefully more elastic properties. I don't know who's actually making this statement, but as it's on Mr. Ralph's Peyronies site I assume it comes with his approval.

Is this also out of date? What's the current consensus on how xiaflex acts on Peyronies plaque at the cellular level? Is collagen and fibrin actually broken down and re-absorbed by the body, or changed to something else? If so, what? I see some folks have had a go at speculating, but no-one seems quite sure.  

[Worried Guy]

Shrout, I agree it would be good to know for sure what actually happens to the tissue.  They must know as they would have tested it on tissue in a lab.  

Shrout, this is not David Ralph's website but the website of a member on here.  He occasionally gets emails from David Ralph's secretary but David does not instruct him what to put on here. His secretary was asking if he knew of any men who would want to participate on the trial.

[MikeSmith0]

The best way to understand the controversy is to follow Gelbard's work, in my opinion.  Also, remember there are several collagenase enymes in the body - and it is not entirely clear what Gelbard was studying vs. what Auxilium is running in trials - though they are obviously very similar.  

"Collagenase causes extensive  dissolution in vitro of  the  tissue  comprising   Peyronie's  plaques,  as  well  as  normal   tunica  albuginea.  There   are  factors which may ovvercome thi slack of selectivity and permit its clinical  us e  in the treatment  o f  Peyronies Disease." - Gelbard, 1982

Gelbard subsequently patented the use of  purified clostridial collagenase for Peyronies Disease in 1982.  His patent is very complex, but it appears he might find some selectivity by the collagenase enzyme (for the plaque vs. the tunica) under certain circumstances.  Here is how he describes treated plauque:

"Treated plaque showed widespread fraying and dispersal of collagen bundles compared to the dense compact collagen seen in untreated tissue....very little diffusion and spreading occur from the site of initial enzyme deposition....elastic tissue is preserved, which may be particularly important in treating Peyronies Disease..."

In 1985, Gelbard has some success, but has a setback with a patient with a corporeal rupture
http://www.ncbi.nlm.nih.gov/pubmed/2991611


Gelbard, 1993 reverses his opinion on the negative effects of collagenase from his clinical trial:
http://www.ncbi.nlm.nih.gov/pubmed/8417217


I don't know if Gelbard was using what Auxilium is using...two other patents have been filed since his patent.

In vitro, I think AUX collagenase was shown to dissolve the plaque of peyronie's in greater quantities than the tunica albuginea.  Why this would be is unknown and makes no theoretical sense.  I don't have the reference to the paper (or i might just not be remembering it right).  I know there is research where they took peyronie's plaques from surgical patients, cut them up, and then exposed them to xiaflex.  I THINK Xiaflex reacted more with the plaque - possibly because it had more collagen or that enzyme had a greater affinity for disorganized collagen which comprises the plaque.  It did not affect elastin.  In vivo, 0.58 mg is a very small dose, so the dissolved collagen should just be broken into smaller pieces that can be dislodged and absorbed by the body.  

[ComeBacKid]

Thanks for that reply, I see that, from what I've heard on here, the results don't sound exactly mind blowing, but the dosage level might be a little low, perhaps a different injection method or more of the xiaflex may work better.  Eventually this company will have to put up a product or go bankrupt, unless they are selling other things that do work.

Comebackid

[Worried Guy]

I thought the same as you until I started to speak to people who are either on the current trial or have been in the past.  People seem to be making real progress.  Check out the UK Xiaflex page.  WFX has gone from 30 degrees down to 18 in just one cycle.  In the UK VED study it took guys months to achieve those gains yet 2 (admittedly painful injections and modelling) and the same can apparently be gained.  One of the guys on the study with a severe curvature improved by 25 degrees in one cycle. Another man from a previous cycle has improved "more than he could ever have imagined".  If Xiaflex does not work it will be at least a decade or two before we see anything else.  I'm growing more positive about it.  Many guys who have had it are not publically posting on here. No bad side effects have yet to be reported other than moderate swelling.  I don't think Pfizer will go bankrupt if it never went to market.  Some drugs are never passed it's just part of R&D.

[newguy]

I thought the same as you until I started to speak to people who are either on the current trial or have been in the past.  People seem to be making real progress.  Check out the UK Xiaflex page.  WFX has gone from 30 degrees down to 18 in just one cycle.  In the UK VED study it took guys months to achieve those gains yet 2 (admittedly painful injections and modelling) and the same can apparently be gained.  One of the guys on the study with a severe curvature improved by 25 degrees in one cycle. Another man from a previous cycle has improved "more than he could ever have imagined".  If Xiaflex does not work it will be at least a decade or two before we see anything else.  I'm growing more positive about it.  Many guys who have had it are not publically posting on here. No bad side effects have yet to be reported other than moderate swelling.  I don't think Pfizer will go bankrupt if it never went to market.  Some drugs are never passed it's just part of R&D.

That really is an impressive improvement. I guess the one question is, as the tissue heals will the improvement remain? If the answer is yes, then this is certainly an exciting and very quick improvement. With other treatments being utilised afterwards, that 18 degrees can probably be improved even more. With peyronie's there doesn't appear to be a ciure as such, but anything that results in imporvements like this is something that could potetnially be of benefut to many thousands of men!  

[MikeSmith0]

I guess the one question is, as the tissue heals will the improvement remain?

i asked a doctor this question.  he said it will only remain with traction in his opinion...with duputreyn's - they have to wear a special glove to keep the fingers extended.  In my opinion, you need traction AND pharmaceutical assistance.   if the penis is allowed to go back to it's flaccid, bunched up state - the scar has no reason not to form again.  keeping it stretched, regularly, while the scar is gone - WHILE inhibiting TGF b1 and increasing Nitric Oxide will make it harder for the scar to reform - maybe.  this is just theory...but I think this is the key.  a 1 pronged approach doesn't usually work in complex conditions.  And Peyronies Disease is more than complex...it's been an unsolved mystery for 250+ years.

also, they need to inject full plaques in multiple locations.  in the trial- they are just injecting a tiny amount in 1 tiny spot.  some people need more than this and in more locations.  xiaflex in multiple locations + traction + pentox + cialis will probably be the closest thing to a nonsurgical cure, if not better than surgery altogether.  who knows how long u will need to stay on pentox and cialis... but this is of course just my opinion on the matter.  I'd imagine the VED helping things too.

[Worried Guy]

Just a question!  why would the scar reform?  The injection breaks down collagen bonds!  I agree it would be a good idea to stretch and model the penis after an injection but I don't see why it would reform.

[bigk]

Just a question!  why would the scar reform?  The injection breaks down collagen bonds!  I agree it would be a good idea to stretch and model the penis after an injection but I don't see why it would reform.

Long term follow-up with previous studies have shown that the reoccurrance rate is fairly low.  But I don't know if they are using traction or not.

[MikeSmith0]

why would the scar reform?  

Well, why did it form in the first place?  Some of us have a weird healing process...and who knows how our bodies will interpret this kind of collagenase "injury" ... maybe it is a non-issue to the body, or maybe it is something that will trigger more inflammation, TGFb1, etc... i dont think anyone knows enough about scar tissue to answer this.  Also, we might have  a chronic problem. The woman on youtube with duputreyn's had a cord form 1 year after xiaflex.  it's probably not the "same" cord (no way to know) but Peyronies Disease could be a chronic thing that keeps creating scar tissue, for some of us.  For others, it might be a more simple injury plaque that can be dissolved and that's the end of it.

[pvpey]

Question, is using a VED a viable option to "traction"? Little off subject, but I was reading the regimens that some doctors are suggesting of meds and traction etc..

[newguy]

Question, is using a VED a viable option to "traction"? Little off subject, but I was reading the regimens that some doctors are suggesting of meds and traction etc..

VED doesn't seem quite so established with urologists for peyronie's disease treatment, but personally I'd certainly say that it's a viable option. It's popular here too, and there is good guidance from the likes of OldMan etc. I think the use of oral supplements, and a mechanical treatment (VED, traction) is the way to go. It seems that good progress can be made with both. If you find that one isn't for you, try the other. As long as you're doing something you're putting yourself in a good position.

[UK]

Found this that was published the other day, the interesting piece which I suspect will also apply to Peyronie's is this bit and it does read positive

"In tissue explant cultures treated with XIAPEX, enzymatic digestion was most rapid in the first four hours following injection, with nearly complete lysis of collagen occurring within 12 hours. Collagen lysis in these in vitro experiments was confined to the area and volume of the injection, with sharp demarcation between the affected and adjacent unaffected areas. The result in these in vitro experiments appears to be selective lysis of the structural collagen components of the Dupuytren's cord with sparing of arteries, nerves and capillaries following local injection.(3)"

http://www.prnewswire.com/news-releases/biospecifics-announces-positive-xiapex-data-presented-at-xvi-annual-federation-of-european-societies-for-surgery-of-the-hand-congress-122930178.html

[acetyl]

Does anyone know whether the Xiaflex (collagenase) treatments and subsequent "reshaping" have restored length as well as curvature in patients with Peyronies?

[acetyl]

Has anyone had Xiaflex treatments with Dr. Irwin Goldstein in San Diego?

[BSSS]

Does anyone know whether the Xiaflex (collagenase) treatments and subsequent "reshaping" have restored length as well as curvature in patients with Peyronies?

From what I know, that is one of the study outcomes, or at least I was told that.  Was also told I measured 2cm longer after a series of injections.

[SSmithe]

acetyl,
I have visited with Dr Goldstein, but not had any xiaflex injections.  He told me he was a test center for the drug.
I am curious as to what you think of Dr Goldstein.  He tried to talk me into something called penile revasculaization surgery for my ed.  He seemed a little too slick for me to trust him.
SSmithe

[Ben]

I've read article about penile revascularization. "They" take an arteria to link it with dorsal vein (which is called anamostose).
In the past it was called Virag V technique (named by R. Virag) but it seems that this technique is useless in cas of peyronie, and when it has some result they are not permanent.

[acetyl]

Thanks for the replies RE: Xiaflex for regaining length and responses to inquiry about Dr. Irwin Goldstein.  I'll post my impression after my consultation with him.