Infergen/Actimmune/ribavirin trials for PEG nonresponders

[MKAndrew]

I got lucky.  I was invited to a dinner in NYC put on by InterMune, the makers of Infergen and Actimmune (gamma interferon).  The speaker was Dr. Larry Blatt, who helped invent the Infergen molecule.  Because of the astonishing potential of their early trials (65% EVR), they're going to do a full-scale trial that includes ribavirn, for an entire 48 weeks, geared toward PEG nonresponders.  The best part - NO PLACEBO.  Everyone gets a potential SVR dose of all drugs.  There is growing evidence that ribavirin may play an important role in the early phase of treatment.

This info has not yet been announced on InterMune's website, and probably won't be for a while.  I'm hoping I'll also find out recruitment info early too, so I'm building a list of people who have not responded to PEG who may be interested in participating in this trial.

You can get the details at:

http://www.mkandrew.com

[cuteus]

you are a blessing with your input.  I took trigonometry in HS, long time ago, never took calculus, it will take a while to get into math again. I will some day.  TY again for the links.

[GreatBird]

Thanks for the link on the HCV documentary. I bookmarked it.

[willing]

nice summary. You probably have to dig through the lab's fine print to see how the coefficient of variation changes with range, but 39% seems huge! Reconciling that level of noise with strong "no EVR->no SVR" predictability is a problem. Since the EVR studies don't publish the actual vl drop distributions generous rounding seems like a reasonable way to go (ie, assume you got a 2log drop for anything over 1.5).

[willing]

glad you like the idea. I have no idea how the legal side of the medical-release forms plays out for an org of this sort but will try to investigate and report back.

log(374000)-log(5700)=5.57-3.75=1.82. Fluctuations from test to test are test-specific, so you have to dig up their specs, but across tests they seem to come in under 1 log unit (<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12809843">see</a>). If  making a tx decision, I wouldn't base it on falling .18 log units short...

[cuteus]

since you are around, and you are a math wiz...I wanted to know what log drop it was when vl goes from 374,000 to 5700 at 12wks? I believe the 2log would have been 3740, what is the margin of error?  I hope you can enlighten me.  

TY

[jg2001]

I'm sorry to hear that you relapsed.  I followed your diary when I was first diagnosed...I'll tell ya what, you made me laugh and that link to your song...I can't right now remember the name of it...was something else.  Like I said, I'm sorry ou relasped, but your humor is...well...let me put it this way, I love a warped sense of humor!

[cuteus]

What an awesome idea, a national pt registry so stats like mine can be accessed by any researcher. can you imagine all the pharmaceuticals playing together nicely?
What a task to achieve, but how priceless the data could be.  The general population not on clinical trials also included in stats.  Even better if all hcv infected with all alt tx or lack of also registered.  

I have a dream....

[willing]

Hi Scott - I agree with you completely: warts and all, combo tx is the best medicine we've got and I'm very grateful to have been one of the lucky few who had access it. Navigating uncertainty is definitely  one of the challenges of this disease and, as you point out, one doesn't have to go very far to get to the edge of what's currently known.
Our decisions aren't made any easier by incomplete studies. For example, regarding the value of extended tx, it may well be true that more than 48-weeks has value, particularly for late-responders, but IMHO the patient data to support this is not in yet. In the two studies you cited above, the Drusano one is based on extrapolating 48-week results (no patient actually did more than 48) and the Brouwer one is a publication of a 96-97 study  that's been around for a while as an abstract. While interesting, it doesn't compare 12 vs 18 months, which is the main question for 1s!(though a 15% response rate at 18 months is better than the 28% reported by <a href="http://www.hivandhepatitis.com/2003icr/38easl/docs/032103b.html">Balan</a>).

One thought I've been mulling over for a while is that a voluntary patient registry, whereby patients provide access to their records to  a central clearinghouse, would supply much more data. To maintain credibility, the records would need to be screened by a nurse/pa volunteer and there's the costs of hosting the database, maintaining privacy, etc. For example, discounting the applicability to the US population of studies like <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14996350">Kasahara ety al</a>, which showed a huge difference in mortality rate for those who benefit from SVR, would be a lot harder in the presence of a large-scale patient registry.

[willing]

as best I can tell, the origin of "12-week rule" goes back at least to the Neumann, Perelson <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9756471">Science,'98</a> paper that first characterized HCV viral kinetics and weighs in with a whopping 379 citations. By adapting a simple mathematical model for viral replication and fitting it to observed data the authors provided estimates of virion half-life and production which have remained largely unchanged. A key finding was that rapid decline in viral load is predictive of the effectiveness of ifn therapy. This finding has been confirmed over and again. One of the most influential studies is the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12939591">Davis , et al</a> paper that retrospectively analyzed the Manns peg-intron data. From Tables 1 of that paper, of 511 patients on a peg+800mg  regime 131 did not have a 2 log drop by week 12 and of those <em>none</em> reached SVR. From Table 4, of 188 patients on a peg+10.6mg/kg regime, 45 did not reach a 2-log drop by week 12 and again none reached SVR. The predictive value of early viral response has been reinforced in other ways. Neumann's <a href="http://www.natap.org/2003/AASLD/day3_2.htm">presentation</a> at last Oct's AASLD showed that, at the cost of 3-5 VL tests during the first 4 weeks, you could obtain the same strong negative predictive forecast ("it's not going to work") by week 4.  Many strains of HCV are simply unfazed by IFN (see <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11952150">He and Katze</a> or <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12734407">Pavio and Lai</a> and there doesn't seem to be any data that suggests such strains will succumb to longer therapy.

The question of when riba works its <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14988824">magic</a> doesn't seem to have much of an aswer yet. Though there's evidence that <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15057741">later (post 20)</a> dosage reductions (of ifn and riba) don't affect outcome, if your goal is SVR rather than fibrosis reduction, I haven't seen any studies that confirm you can drop the riba before the ifn.

[thanbey]

There will be a documentary airing on PBS this fall. It has been in the works for about two years.

It is being made by the people who produce "The Infinite Mind."

<a href="http://www.lcmedia.com/hepcfilm.htm">PBS's HepC Documentary</a>

Many local PBS stations have done programs on hepatitis C. Most concentrate only on the treatments, but this looks at the history, the industry and advocacy.

Should be interesting.

thanbey

[honey1616]

I'm so glad to see you have joined us and offering so much great information!  I have never seen you before but you have probably been around longer then me as I just came to this forum early December.  Thanks for posting your website and I am currently reading that also!

[GreatBird]

I can't find it airing here where I live. I haven't seen much coverage of HCV on PBS, which is disappointing. :(

Oh well.

[MKAndrew]

The PBS show is called "Informed Choices," or something like that.  It has played mostly on the Eastern seaboard, as far as I know.  It probably sounds odd for me to say this, but I don't keep track of stuff like that.  Besides my own silly blog, I'm also vice president of the Hepatitis C Association and a published novelist and I do the occasional topic-based stand up comedy.  I mean, it's not like I'm famous or anything.  I just get invited for interviews & stuff.  I do them, but for the PBS show, I had to borrow a tape from HCA's president because I kept missing it on television.

Mainly, I'm more interested when I'm not speaking, because there are so many great minds out there much smarter than mine.  I always consider it much more of a privilege to get invited to an important event.  The last person I want to listen to is me, because I don't learn a damn thing listening to myself talk.

[GreatBird]

>>I recently did a PBS show with Dr. Carroll Leevy.<<

Do tell. Was it a local show? Or something being produced for national air...and when, if so.

Grazi.

[MKAndrew]

Sorry - forgot to mention.  High iron levels and treatment.  I read a study that suggested that elevated iron levels don't affect SVR.  However, the study I read was conducted with SVR patients who were checked for high iron levels.  Based on that kind of data, we still don't know whether or not high iron impedes the effect of interferon.  I'm not doing phlebotomy for the sake of IFN therapy, but to save the rest of my organs from early destruction.  Hemochromatosis is known to cause diabetes, and I'm diabetic.  Diabetes (insulin resistance) is a known treatment negative.

[MKAndrew]

At InterMune's presentation, Dr. Lawrence Blatt said he believed that ribavirin has done pretty much what it's going to do by week 24.

[MKAndrew]

Hemochromatosis:  When I was first diagnosed with liver "something" back in 1986, my doctor said I was binding iron.  However, he ruled out hereditary hemochromatosis because nobody else in my family had the disease.  My curent physician calls my problem "secondary hemochromatosis."  Weekly phlebotomy of 550 Ml has been extremely effective in lowering my ferritin, transferrin, total iron binding capacity, and my iron levels are now within normal range.

Individualizing treatment: Dr. Robert Gish was the first guy I know to measure success by IFN sensitivity on a broad scale.  He's at California Pacific, UCSF, and Nevada.  Mark Sulkowski of Johns Hopkins may have been the first guy to double Peg-Intron.  Cecil made it popular.  Sulkowski is probably more revered.  Lots of heavy hitters out there are ignoring FDA recommended protocol and proving that novel therapies work for a significant number of nonresponders.  One of the big things emerging is extended dosing for genotype 1.  I recently read a statistical evaluation suggesting that geno-1s should treat for an additional 36 weeks after testing undetectable, regardless of when it occurs in treatment.

Even though the pharmaceutical companies are preaching standard everything to the rank and file gastros, these same companies are funding small studies with heavyweight hepatologists.  I recently did a PBS show with Dr. Carroll Leevy.  I found out that he will be presenting the results of his own small study with alfa-gamma-riba at the DDW in May, so we may hear some more encouraging information.  So far, nobody is leaking anything about his study - not even Intermune.

[MKAndrew]

You're right about Schiffman, but I generally present stripped-down versions of this stuff, because unlike avid researhers like yourself, most people don't want to wade through the entire process of how things come to be in the hepC community.  This may well be a flawed approach but that's me.  Flawed.  

There are mucho hepC websites full of clinical studies.  I get email from people who read these things and don't understand medical terminology.  I watch people get really excited when the pharmaceutical companies do press releases on the web during big liver meetings because they can't actually present their material at the liver meeting because whatever they're pushing to make their stocks go up is not allowed on the floor of these conventions because it ain't approved by the FDA yet.  It's considered "selling."  But - it's all over the internet, and people who rely on the online hepC forums find themselves bombarded with press releases disguised as clinical studies.  Or they'll post a novel study done by a couple of post-graduate students who need to get published.

Naturally, pharmaceutical companies need a recognized MD to aid them in establishing dosing guidelines, etc.  I would have liked to have been at the meeting when Dr. Whoever recommended 3 miu of Intron-A three times a week.  Serious underdosing and trillions of molecule-specific quasispecies resulted, but the aim of every pharmaceutical company is always the same: Acceptable benefit with the least risk.  Schiffman did analysis for Roche for the Pegasys FDA hearings.  His recommendations are based on 180 mcg QW for 48 weeks of therapy.  Since that time, numerous studies have emerged challenging the 12-week predictor, and the dosage, and the duration of treatment, but the bottom line is this: Roche sales reps are telling your doctors to use the 12-week predictor model, even though they know that IFN-sensitivity is the new emerging model.  This is what I mean when I say, "Roche established the 12-week predictor model."  So I'm not arguing with you.  You're absolutely correct.  Schiffman derived the algorithm for Roche.  I apologize for not being more specific.

[layla]

I would like your opinion on this (if you don't mind): I have seen there is some growing evidence ribavirin is important in early tx but what about after that? How important is it for the rest of tx and what about extended tx? I am on 72 weeks tx and wonder how important the riba is after a certain point, (my sx are ok so I can do it but wonder how much one needs it.) I see others who are on only peg on the extention or very reduced riba.
It's nice to see you hear. I've met you elsewhere before and respect your opinion (as many do). LL

[thanbey]

A 2 log or greater drop in viral load is also associated with response. Otherwise, the chances of SVR are about 3% or less.

We now find those who are obese are unlikely to respond, either.

That's what the doctors, drug companies, the
FDA and the NIH, and most knowledgeable advocates say.


Take your arguments up with the doctors and researchers. They are the experts.

thanbey

[thanbey]

Take it up with Dr. Schiffman.

[thanbey]

The 12 week algorithm was developed by Mitchell Schiffman   not Roche Pharmaceuticals. It was based on his data finding that the response rate for those who do not see an undetected result at 12 weeks is 3%.

The thread below was closed so I post it here.

thanbey

[grouchyOldGuy]

Hey miles.....you mentioned hemocromatotis as a being ruled out in your iron man column as a hereditary factor? Are you thinking that HCV can mutate the genes, mimicking Hereditary Hemocromatosis causing the high Ferritin and Iron...or is the HCV inflamation causing it? you had a 4 k count wow....mine has always been high it is 1500 now...I've asked many but they don't wanna try phlebotomy to get it down even to see if it will make me feel better overall, my bloodwork is good and will support it but they say no. You mentioned Gish somewhere in your writing, was that Dr.Gish from UCSF?... I was seeing him in 93 and his current partner said there is no proof that lower iron responds better to treatment ...I disagreed but couldn't really find a good enough study to show her and she was pretty set in her ways. I have recently gone to UCSD and am waiting for a hepatolgist and a biopsy...the new GP I got there has e-mailed the hepatoligist I'm waiting to see to ask if a phlebotomy is a good idea. How did you get them to give you one? Did you feel better after you did phlebotomy and the iron was normal? I have one of the HH mutated genes H63D and they called me a carrier is that associated with higher iron? Lots of questions sorry but not to many docs wanna talk about this and give me the look...heh do you think it's worth the trouble or know of a good study I can show them? thanks miles and let me know pal....

[Xenigma]

Hey Miles
That's great news.
I'm gonna head over to your site and check out
the details. I'm glad to see you here! Just want to tell
you again how much I enjoy your website and thanks again
for all the laughs!
Enigma