Daclatatasvir & Sofosbuvir

[Quest5245]

Let's end the lack of cooperation between Gilead and Bistol Myers and get these two drugs on the maket to the people who need them.  The only way we can do that is through our White House Petition.  Pleas sign at www.hepc-cured.org we on have until 3/20/13 to get 100,000 signatures to have the white house intervene.  Please have your friends, relative, neighbors sign and add it to their face book and twitter... we need to end this deadly disease now. 4 million in US have this disease, 170 million world wide, hepc killmore people today than AIDS, a 1000 people a day die waiting for a cure.  Take action now---sign the petition.  Thank you

[Quest5245]

I am not sure how this site works but the drugs we need to cure hepatitis c is daclatasvir and sofosbuvir.

[hrsepwrguy]

http://www.medhelp.org/posts/Hepatitis-Social/Could-we-all-sign-this-petition-for-the-The-Whitehouse-to-get-Gilead-on-the-move/show/1908083

http://www.medhelp.org/posts/Hepatitis-Social/Sign-petition-to-put-pressure-on/show/1722631#post_8817062

http://www.medhelp.org/posts/Hepatitis-Social/Do-you-know-about-this/show/1904195

[can-do-man]

Maybe Medhelp can just start a forum for nothing but this, this is getting unreal folks.

[rivll]

I have always supported the petition but I am confused by a few things and I will not pass this new petition onto friends and family until these questions are answered.
Gilead is currently testing Sofosbuvir with their own GS5885. It looks promising. Bristol Myers also have some promising drugs in the works.
They are all working on this at a furious pace (yeah, maybe for profit, but so what? We still benefit).
It seems rather naive to expect that because Sofosbuvir and Daclatasvir are a cure for many, that we will expect Pharma to drop everything else and proceed with our drugs of choice even if a million people sign the petition.
If there was nothing else in the mix, I would be more supportive of this push, but Gilead and the others are working on it.
How do you suppose we could persuade them to switch gears, when 1. it may not be a cure for all and 2. They already may have a comparable drug
to Daclatasvir?

[Willy50]

I was an earlier supporter of the concept of promoting the continuation of the collaboration.  That made sense in March and April of 2012.

The goal in my mind was the most rapid passage of the most efficacious treatment.  My fear was that Gilead would not be able to rapidly move approval forward, and in the worst case scenario, the trials would have to be replicated or that the compound GS5885 would not be as powerful as Daclatasvir.

As it turned out, Gilead WAS able to fast rack the approval of a combination using 7997 & 5885.  Phase 3 trials with this combination started dosing in Oct or November 2012, and NDA approval is expected in 2014.  It wasn't a seamless transition, but I don't think one could argue there was much more than a 6 month delay.

In terms of efficacy, I have not seen any data which supports that one compound or the other, either GS 5885 or Daclatasvir works better with 7997 (sofosbuvir) better or worse; they seem to be equivalent.  I am unaware of any proof (yet presented) stating that Daclatasvir would be superior to 5885.

At present, there is probably more evidence which now exists that supports the safety and effectiveness of the two Gilead drugs in combination, than 7997 in combination with Daclatasvir.  If this is true, the finish line is closer with the 2 Gilead drugs in combination than with a Gilead/Bristol collaboration.
(please correct me if I am wrong)

I greatly admire the earnest attempts to move this forward, but each month that 7997 & 5885 moves closer to approval and each month that 7997 & Daclatasvir does, the compelling need for the collaboration diminishes. (IMHO)

It is another question entirely whether ......no matter how many signatures are collected...... whether you can force a collaboration between corporations, any more that you can enact legislation to force people to marry, no matter how good the intentions are or how good the outcome might be.

best,
willy

[Quest5245]

Gilead's sofosbuvir & 5885 are only achieving sucess with the use of ribavirin.  Ribavirin is just as toxic as interferon.  I don't know about you, but I do not want to take toxic drugs that and still do not cure the hep c and lead to "other" life long health problems because of using a toxic drug.  The only 24 week trial that attained 100% SVR without toxic drugs is when daclatasvir and sofosbuvir were combined.

I do not want to wait while a cure exists now.  Nor do I or want anyone else to continue to be used as laboratory animals while a drug company wants to put profits before patients.

Gilead refuses to cooperate with Bistol Myer so they can get the entire Hep c market, Gilead 5885 is having, at best, poor results  unless the RVB is added to the mix.

[Quest5245]

Willy,

Gilead is only having any sucess with sofosbuvir and 5885 if they combine it with ribavirin.  A toxic drug.  Nothing has attatined the 24 week, 100%, non toxic cure except daclatasvir when combined with sofosbuvir.  Gilead is trying real hard to bury that results.  If a trial only results in 60% to 80% SVR..........it isn't a cure!  Especially when they can only get that results if they use ribavirin in the mix, a toxic drug that has horrible side effects and leads to other life long health problems from its use.  

[dointime]

Both the Gilead 7977 and the BMS daclatasvir look good enough to get approval in other combos eventually.  So won't doctors then be able to cherry pick them and write their own off-label combo?  That is unless 7977 is only issued in the form of a combination pill.  

dointime

[Willy50]

First off, to dointime.  Since sofosbuvir has been in trials for treating geno 2's and 3's with ribavirin it will seek approval for the same and will likely be approved as such.  This means that the pill.....7977/sofosbuvir should be available by itself.  Once approved......daclatasvir should also be available in separate pill form.

It is another question whether a doctor would prescribe either off label, or whether insurance would pay.  I'm all for the safest, strongest treatment coming out sooner.  I'm just not aware of how companies can be "made" to collaborate and pay for trials against their corporate will.  The mechanics looks possible until prescribing and paying comes into the equation.

Next.... Quest......  Thank you for your reply.  There exists an issue; we don't have all the data. I believe that the data exists, but I do not believe either of us has a large enough number of responses (successes, failures, response rates when compared to staging,  genotype, geno subspecies and il-28 genetic marker to make broad claims. You *could* be right, but what trials, what numbers are you basing your claims on?

You are extrapolating success, but with very few numbers. (I think)

Back in Oct/Nov 2012 Vertex started ION-1 for naives. 200 people, 50 per cohort, 7977 & 5885 with and without Riba for 12 weeks, and the same with and without riba for 24 weeks.
The second part of that trial is about to commence.  Now that the 2 -12 week arms are done, and will very soon have their 4 week EOT PCR's we will have the results of a 12 week trial of 7977 & 5885, both with and without riba.  Presumably a SVR-4 will be highly predictive of success.
600 more trial particuipants will start in cohorts designed around the success of the first cohort design.  
In a matter of a few weeks we will see what Gilead is betting on.  If you are correct, you may see trial design of 12 weeks of 7977 + 5885 + Riba. (or if it is a real failure it may be 24 week duration) If you see them drop riba and go with 12 weeks of treatment we may infer that you are incorrect; that they CAN treat people for 12 weeks without riba.

You can also note that Gilead is doing a trial (lonestar)....has added a trial..... a small one in which small groups will treat w/ 7977 & 5885 for 8 weeks.  I think it will be about 25 per arm, in this case about 25 people on 7977/5885/RBV and the same size group w/ the 2 compounds but NO RBV.  I infer from this that they have indeed had success treating without the combination of the two drugs without riba.  I mean.....if they had failure w. the 2 drugs without riba in 24 and 12 week......why would they try a trial for 8 weeks?  I do not claim to know or possess the facts.  Which trials are you suggesting prove that they need RBV to treat successfully?
I am inferring they have had success.

I have an open mind about this, but I admit being cynical that someone can force the drug companies to collaborate.

On that note...... have you noticed that Vertex has a new shared compound als2200?  It's pretty similar to 7977.  7 day monotherapy, 4.5 log drop mean in 5 days and 4/8 were below level of quantification.  This would be an excellent possible collaboration w/ Bristol..... Vertex had the shared rights to it and have shopped it around, but for whatever reason it appeared that Bristol is not collaborating. I believe they have worked out an agreement w/ 1 or 2 other companies, but not Bristol.

Check this out;
http://www.natap.org/2012/EASL/EASL_24.htm

I don't claim to know the answers, but until I am shown more data I am of a mind that I cannot influence these companies and I am not certain that what they are pursuing is inherently worse that the 7977 and Daclatasvir collaboration.

And yes..... in a better & more perfect world they might have continued the collaboration.  When they paid 11 billion for the compound (7997) it almost made a collaboration impossible.  : (

willy

[Willy50]

5th paragraph starts out;
"
Back in Oct/Nov 2012 Vertex started ION-1 for naives."

should read Gilead instead of Vertex
==========
also
http://www.gilead.com/pr_1771657

[can-do-man]

Looks like you are right dointime.

In addition, he said, both daclatasvir and sofosbuvir are likely to be approved soon, with an indication for therapy in combination with the standard HCV drugs, pegylated interferon and ribavirin.

There would then be nothing to stop doctors from using them together off-label, while avoiding the other two, which are associated with a host of adverse effects.

http://hepatitiscnewdrugs.blogspot.ca/2012/11/daclatasvir-and-sofosbuvir-promising.html

[Quest5245]

Once Gilead combines it sofosbuvir with its 5885 the doctors can not, as you mention, using them (sofosbuvir and daclatasvir) together off-label.  You will not have that right.  You will have to use Gilead's combo and doctors will not be allowed to give you Gilead's combo and daclatasiv.  They only reached the non toxic successful cure rate with only two drugs....sofosbuvir and daclatasvir.  As to date Gilead has not attented the success it did when these two drugs were combined.  We keep repeatig the same thing over and over..

[hrsepwrguy]

"In addition, he said, both daclatasvir and sofosbuvir are likely to be approved soon, with an indication for therapy in combination with the standard HCV drugs, pegylated interferon and ribavirin"

Meaning the compounds in question will be available in stand alone form
----------------------------------------------------------------------------------------

"There would then be nothing to stop doctors from using them together off-label, while avoiding the other two"

Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration.[1] In the United States, the Food and Drug Administration Center for Drug Evaluation and Research (CDER) reviews a company's New Drug Application (NDA) for data from clinical trials to see if the results support the drug for a specific use or indication.[2] If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route of administration, and other information to be included on the drug's label. More detail is included in the drug's package insert.

The FDA approves a drug for prescription use, and continues to regulate the pharmaceutical industry's promotional practices for that drug through the work of the Office of Prescription Drug Promotion (OPDP, formerly the Division for Drug Marketing, Advertisement and Communication (DDMAC).[3] The FDA does not have the legal authority to regulate the practice of the medicine, and the physician may prescribe a drug off-label. Contrary to popular notion, it is legal in the United States and in many other countries to use drugs off-label, including controlled substances such as opiates. Actiq, for example, is commonly prescribed off-label even though it is a Schedule II controlled substance. While it would be legal for a physician to independently decide to prescribe a drug such as Actiq off-label, it is illegal for the company to promote off-label uses to prescribers. In fact, Cephalon, the maker of Actiq, was fined for illegal promotion of the drug in September 2008.[4] Under the Food, Drug, and Cosmetic Act (FDAC) at U.S.C. 21 §§301-97, manufacturers are prohibited from directly marketing a drug for a use other than the FDA approved indication. The Food and Drug Administration Modernization Act of 1997 created an exception to the prohibition of off-label marketing. Manufacturers are now able to provide medical practitioners with publications on off-label uses of a drug, in response to an unsolicited request.[5] In 2004, the federal government and whistleblower David Franklin reached a $430 million settlement in Franklin v. Parke-Davis to resolve claims that Warner-Lambert engaged in off-label promotion of Neurontin in violation of the Federal Food, Drug, and Cosmetic Act (FDCA) and the False Claims Act. At the time, the settlement was one of the largest recoveries against a pharmaceutical company in U.S. history, and the first off-label promotion settlement in U.S. history.[6]

http://en.wikipedia.org/wiki/Off-label_use

[can-do-man]

Quest you come here, slam members and mislead, I left the link that was in so please read. BTW that came from a well known Doctor not myself saying it. Unlike what you just posted to me.... Please take the time and research

[dointime]

"It is another question whether a doctor would prescribe either off label, or whether insurance would pay."

Willy50 - Yes, valid points.  I think we shall have to wait and see how the Gilead combo pill matches up to the combo with BMS.  If Gilead falls short then I think many doctors would be willing to get creative with their prescriptions.  Insurance companies might be stickier but just imagine the outcry if people were dying while the cure was already sitting on the shelves.  If the Gilead combo is that much worse then Gilead may even have to eat humble pie and go back to BMS with cap in hand.  Many outcomes are still possible, unfortunately taking even more time which many of us don't have.

I agree that we haven't got enough results yet to really know whether and in what circumstances ribavirin will be required with the Gilead combo pill.    

Hiya can-do-man and thanks for the link.  I am pleased to find out that there are others out there formulating a Plan B if Gilead drops the ball.  

dointime        

[Willy50]

I do not think that it is a shoo in that all doctors would simply write scripts off label.  I have seen some people who wanted low dose naltrexone, an approved drug, but they wanted it formulated so that they were taking something like 1/10th of a dose; no dice.

Here is a drug (naltrexone) that has been approved for many years, is safe and has no danger for abuse, but people still can't get doctors to write a script.

The summer that Incivek got approved many people got turned down by insurance companies..... for an approved drug.  There were a number of threads on this and people were just advised to insist, to put it in writing, to have the doctors call the companies, etc.  Insurance companies did not want to spend the extra $$$.  I think you can infer what many would say about coughing up and paying for not 1, but 2 premium priced drugs that are not FDA approved together.  
They will say; "NO".

So....to make it work, most of us need both; a willing doctor and a willing insurance company.  If you are lacking one you are probably out of luck.

I might venture a guess that the drug pricing could be such that the 7997 & 5885 combo might be "X price, and the single price of 7977 could be 5/8 or 3/4 price.  This would mean that if you had to order ala carte off of the menu buying 7997 and daclatasvir could end up costing you more money than the 7997&5885 combo; yet one more disincentive.

If you think that a company that spent over 11 billion for the drug before they spent a dime on trials is going to make it easy for Joe 6 pack to outwit them you may be in for a rude awakening when you try to outfox them.  

The trials at far from finished.  I hardly think it is safe to assert that 7997 and Daclatasvir are proven, or safe..... not in the numbers of results we have seen.  Nor is it safe to assume that 5885 and 7997 are any of the above; safe, efficacious or are guaranteed for approval.  Either drug combo could fail in some unforeseen way 5 foot before the finish line.  I don't expect it but  look at Incivek and Victrellis; they both have black box warnings now they didn't have when they were approved.  Look what happened to Bristol's 7997 replacement drug from Inhibitex;

http://www.pharmalot.com/2013/01/bristol-myers-tries-to-settle-hep-c-patient-claims/

I know that some of the info in these threads isn't super accurate, but the intentions are good and in a sense all they are asking for is some sort of consideration for using the 2 "best in class" drugs in combo.  If for some reason the drugs currently in trials were to fail I would imagine that any of us would welcome a back up plan.  I don't see how it could would work, but what if it was some sort of approval to use them off label, which as it sits now..... I find hard to envision it happening.

However........I remain dubious that the owners of the drugs will be swayed, or that government will intercede.

willy

[Willy50]

My above post was only partially directed to DT, but really it was mostly directed to "all" in the forum.

[rivll]

Really good posts Willy and doin time/

[Quest5245]

Murphy: Hepatitis and the pharmacology of greed
Posted: February 25, 2013 - 10:35pm  |  Updated: February 26, 2013 - 12:06am

  Advertisement

By Mark E. Murphy
Murphy: Hepatitis and the pharmacology of greed
Savannah Now
Mark E. Murphy
February 26, 2013 12:06 AM EST
Copyright 2013 Savannah Now. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
I was eight years old, making rounds at the hospital with my father, when I first met the Yellow Man.

His eyes were an astonishing saffron color. His skin was also striking — an iridescent bilious hue.

My father sat poring over the Yellow Man’s voluminous chart in the nurses’ station, reading glasses perched on the end of his nose, while I tried my best to stay quiet.

Ultimately, I couldn’t.

“Why is he that color?” I asked my dad in a whisper.

“He has hepatitis,” my father said matter-of-factly, never looking up.

I nodded. I was fascinated. I even talked to my third-grade class about the Yellow Man later that week in Show and Tell. But I had no clue what my father was talking about when he told me that the Yellow Man had “hepatitis.”

Today, I do.

You see, I am a gastroenterologist. In my medical specialty, we deal with Yellow Men (and Yellow Women) just about every day. And many of them have various forms of hepatitis, or inflammation of the liver.

Some get it from alcohol; some, from medication. But an emerging variable in the growing liver disease population is hepatitis C — a viral illness that is now the leading cause for liver transplants in this country.

Over 170 million people worldwide have hepatitis C. More than 4 million of those people are in the United States. A lot of those folks acquired hepatitis C through blood transfusions (there was no blood test for the virus before 1989); some got it through IV drug use, or through tattoos and body piercings. A shocking 30 percent have no risk factors for it, and have no idea how they became infected.

So why is hepatitis C a problem?

Because it is a stealth epidemic.

You see, most people with this disease are not “yellow.” In fact, most of them have no symptoms at all. None, that is, until they develop cirrhosis and liver failure — or worse still, liver cancer. Hepatitis C is now the leading cause of liver cancer in the United States, and is the most rapidly increasing cause of cancer death in this country.

Hepatitis C kills more people every year than AIDS.

Let that sink in for a moment.

Traditionally, hepatitis C has been treated with a combination of an injectable drug called interferon and another orally-administered medicine called ribavirin. It’s a grueling regimen, resulting in nausea, malaise, weight loss, skin and hair changes, anemia, thyroid problems and depression in many patients.

Moreover, the cure rate (technically called “sustained virologic response,” or SVR) for this regimen is less than 40 percent after 48 weeks of treatment. Many people cannot complete the full course of therapy because of the horrendous side effects.

Now, to the punchline.

At a recent national medical meeting of liver specialists, Dr. Mark Sulkowski of Johns Hopkins University Medical Center described a Phase II research protocol using a combination of two new oral medications, daclatasvir and sofosbuvir. This medication combination has almost no side effects.

The gist of Dr. Sulkowski’s presentation is this: After a mere 12 weeks of treatment with this new regimen, the “cure” (SVR) rate for hepatitis C was an astonishing 93 percent.

When I read this, I literally stood up and whooped.

Hepatitis C patients have been waiting for a treatment regimen like daclatasvir and sofosbuvir for decades. It’s a true rarity in medicine — an honest-to-goodness game-changer, a phenomenally effective regimen for a serious, life-threatening disease that is also safe and well-tolerated.

The only problem? The two drugs are owned by different companies — daclatasvir is a Bristol-Myers-Squibb drug, while sofosbuvir is made by Gilead Sciences.

For reasons that are almost certainly financial in nature, Gilead has refused to do further work on this drug combination with Bristol-Myers Squibb, so there will be no further study of the regimen. With no Phase III trials, that means that the daclatasvir/sofosbuvir combination regimen will likely not be approved for use by the FDA.

Gilead has issued no formal commentary about why it does not wish to pursue further development of the new regimen, although there is speculation that it is altering its focus to produce single-tablet combination regimens — a product line that has been highly successful for the company in the treatment of HIV.

In fact, Gilead is doing quite well financially. It is a company with over $4 billion in annual revenues and over 4,000 employees. Its average margin of profitability over the last five years has been a whopping 34 percent.

Moreover, the total return to its shareholders on Gilead’s stock has been nearly 95 percent over the past year.

Still, the salient question is this: Should Gilead Sciences’ profitability trump doing what is right?

Since Dr. Sulkowski’s data presentation at the AASLD meeting in Boston this past November, over 200,000 hepatitis C patients worldwide have died of complications of their disease. Meanwhile, Gilead, a tremendously profitable corporation, refuses to consider the development of a drug regimen that could have cured most of those individuals in the pursuit of even greater profits.

I find that unconscionable. In fact, I find it patently offensive.

In short, it’s just plain wrong.


Mark Murphy, M.D., is a Savannah physician and writer. ***@****




Comment

[Quest5245]

You stop misleading the people here.  I am not like you that have nothing else to do in their life except write lengthy, meaningless, nonsense.   Gilead combines sofosbuvir with 5885 and that is what they plan to do,.Gilead has no intention of just manuf. sofosbuvir by itself.  (where did you ever come up with that one) Gilead intends to make a combo pill of sofosbuvir and 5885 and  use ribavirn (a highly toxic durg) to treat Hep C people.  Bristol Myers will have no choice but to combine its daclatasvir with another drug and hopefully the will not require ribavirin to get any success Gilead must use ribavirin with there combo to get success..  Doctors will not be able to say ok, I will prescrib you sofosbuvir and daclatasvir because they will not be separate drugs(where ever did you get that from)....they will be combo pills.  Get it yet?  When sofosbuvir and daclatasvir were combined in the 24 weeks patients had SVR and no relapses to date in Hep C 1a.  We have many doctors backing us including Dr Mark Murphy. Who article I published before this post.  If it did not post then I would be glad to send it to your email for your review if you dare provide it.  The only two drugs together that cure without the use of toxic drugs is sofosburvir and daclatasvir.  If you still don't have it, the White House Petition   www.hepc-cured.org   Gilead is strickly putting profits before patients!

[rivll]

You make it sound like those 200,000 HCV patients worldwide would have been saved...when you know well had GS and BM cooperated and developed the drugs together those patients still wouldn't have had access.

The petition is fine, I signed it, but you need to be realistic. We are all disappointed that they will not work together but this is just beating one's head against the wall. There are other combinations in the works and even so, daclatasvir and sofosbuvir may end up available separately.
I do not disagree with you but I disagree with the frantic spin of your manner of persuasion.

[rivll]

I just read your 2nd post...unbelievable.
You just shot yourself in the foot.

[Quest5245]

Rivll,  Unless we get the cure here the rest of world doesn't stand a chance.  Yes there maybe "other things in pipeline" but why should be continue to used as laboratory animals when we have found a cure.  I have to say,  that when people decide to pick on a word  or two that may sound rash or out of sorts  to them or not acceptable to them......that is not the point here!.  We are dying from Hepatitis C, we are being given toxic drugs over and over again with horrible side effects, , people are dying every day waiting for a cure..  It would be nice if we all could see past our "hen picking"!  

[Willy50]

In answer to your question; how do you suppose that Gilead is going to treat genotype 2 and 3 patients when (as you maintain) they will only provide co-formulated 7977/5885 compounds in a single pill?

Answer; they are treating, currently in fda trial approval to treat g-2 and 3 with 7997/sofosbuvir and riba.  If you knew your subject you would know that.  They will not co-formulate it (w/5885) to treat genotypes 2 and 3.

Good luck with the endeavor.  

Willy