Highly Touted Anti-Herpesvirus Drug Tanks (or Why Doctors Should Follow Trial Protocols)

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Hopes (and Stock Valuations) Tumble As New Herpesvirus Drug Tanks

Brincidofovir, better known to many in the chronic fatigue syndrome (ME/CFS) community as CMX001 tanked in its large Phase III trial. To say such a result was unexpected would be understating things. A lipid forumulated version of Vistide, Brincidofovir, demolished other anti-herpesvirus drugs in laboratory studies. They suggested that Brincidofovir should not only be considerably more powerful than other antivirals but that should cause many fewer side effects.

[fright]
In-vitro-efficacy-Brincidofovir.jpg
[/fright]ME/CFS patients and doctors hoped the days of very long duration, expensive, high dose antiviral regimens to treat simmering herpesvirus infections might be over. With the company expressing interest in ME/CFS patients with documented herpesvirus infections some hoped an ME/CFS/herpesvirus trial might be next.

It's not to be so - at least not yet. The drug managed to meet one important endpoint: it did dramatically reduce the frequency of cytomegalovirus infections in transplant patients when they were on the drug.

Shortly after the transplant patients went off the drug, though, their rates of CMV infections soared. By the end of the trial no difference in CMV infections was found between the brincidofovir treated patients and the controls. When that result was announced Chimerix's stock price dropped eighty percent.

Did Doctors Unknowingly Sabotage the Trial?

All may not be lost. Chimerix researchers found that the increased infections occurred in patients treated with steroids for diarrhea. Suspecting the diarrhea was caused by a potentially fatal outcome called graft versus host disease (GHVD), the doctors hit the patients with immune suppressing steroids which resulted in increased rates of infection.

[fright]
blue-bacteria.jpg
[/fright]Diarrhea, however, is also a known side effect of brincidofovir which can be managed by pausing the dose. Chimerix officials belief the doctors in the study mistook a side effect of brincidofovir for GHVD. The fact that eight times as many corticosteroids were given in the Brincidofovir arm as in the control arm suggested Chimerix was right. Chimerix noted that patients given a temporary pause in treatment - as suggested in the treatment guidelines - did not end up with higher frequencies of CMV infection.

Ultimately some doctors inability to follow the study protocols not only may have ruined an enormously expensive study (450 transplant patients) and prevented a good drug from getting to the market but may have also killed some of the patients in the study. Oddly, brincidofovir, may have doubly improved its worth as it was able to keep CMV under control even as some patients were bring given immune suppressing drugs. Once brincidofovir was discontinued, however, the CMV infections - some of which were fatal - showed up in spades.

Back to the Drawing Board

Hopes for the drug remain high, but Chimerix immediately stopped all Phase III trials and went back to the drawing board with some Phase II trials. The HHV-6 Foundation reported that Chimerix is developing an IV form of the drug which should eliminate problems with diarrhea and more trials are expected this year. Hopefully only time and money has been lost.

The HHV-6 Foundation also noted that the earlier introduction of this drug in the Phase III trial compared to the Phase II trial could have played a role. Other trials suggest that early introduction of antivirals may, in some cases, impair a developing immune response and result in a higher frequency of later infections.

It's also possible that longer drug treatment regimens may be helpful. The Foundation pointed to a valganciclovir trial which found dramatically lower rates of infections in transplant patients receiving the drug for a year vs three months.

The Foundation reported that two other new anti-herpes virus drugs are currently either in Phase I or II clinical trials
 
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Cort

Founder of Health Rising and Phoenix Rising
Staff member
Well this sucks. No cure for us @Strike me lucky
Hopefully its just a roadblock. I suspect it is actually; the drug has done too well in other studies not to make it through at some point. It does push FDA approval back though...

I imagine the Chimerix is kicking itself for not making it very, very clear to doctors that the diarrhea it may cause was not the result of GHRD or whatever it was.
 

Who Me?

Well-Known Member
I hope it's just a bump in the road but yet another drug that could help us is now delayed.
 
Just wondering ......
Are Brincidofovi and CMX001 the two latest names for ME/CFS?
This disease?/disorder?/ whatever it is, has ruined my life since 1990 and has taken the best years of my life away from me. I continue to hope and pray that a cure, or even an effective treatment will be discovered.
Thanks so much for all that you do for those of us that suffer from this nightmare, Cort!
 

lisapetrison

Active Member
I wonder what percentage of the people in the trial were living in blatantly moldy homes. Nothing works right when people are under that much immune stress.
 

Carollynn

Active Member
I can't believe these researchers put the patients on steroids. Powerful TNF-a-blockers, they can wake up viruses! This is a portion of an article that I found in my search for relief from chronic shingles on top of ME/CFS (with elevated EBV and HHV6). Subsequent papers go into this, but for now this is what I can find to be able to share quickly:

From Immunotherapy
Anti-TNF-α Agents in the Treatment of Immune-mediated Inflammatory Diseases: Mechanisms of Action and Pitfalls
Léia CR Silva; Luciena CM Ortigosa; Gil Benard

Posted: 12/20/2010; Immunotherapy. 2010;2(6):817-833. © 2010 Future Medicine Ltd.

Viral diseases are not uncommon among patients on anti-TNF therapy, with herpes zoster being one of the most frequent.[100] A recent paper was unable to define the true effect of TNF inhibitors on manifestations of herpes zoster,[101] while another showed an increased incidence (3%) in the population studied.[102] Cases of recurrent varicella,[103] disseminated cutaneous lesions caused by type I herpes virus[104] and lymphoproliferation by Epstein–Barr virus[105] have also been reported. Hepatitis B reactivation can occur,[106] although an association with anti-TNFs in patients with viral hepatites remains controversial, since it is currently used for patients with hepatitis B, but not for those with hepatitis C.[83] Conflicting data exist regarding the beneficial and untoward effects of TNF-α antagonists in HIV-infected patients. Thus, the use of anti-TNFs in cases of HIV-positive patients is not recommended, although it has been used in a few cases with no obvious harmful effects.[83] A recent study reviewed the effect of these medications on the course of several viral infections, including hepatitis, AIDS, herpes, cytomegalovirus and varicella zoster.[107] These effects varied from occasionally predisposing to more severe infections (as in the case of cytomegalovirus and varicella zoster infections) to no clearly discernible effect (e.g., in hepatitis C and herpes infections). However, data regarding the effect of TNF inhibitors on the course of viral infections are mostly limited to case reports, thus further studies are warranted.

100. Nobile S, Catassi C, Felici L: Herpes zoster infection followed by Henoch–Schönlein purpura in a girl receiving infliximab for ulcerative colitis. J. Clin. Rheumatol. 15(2), 101 (2009); comment on: J. Clin. Rheumatol. 12(5), 249–251 (2006).
101. Strangfeld A, Listing J, Herzer P et al.: Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-α agents. JAMA 301(7), 737–744 (2009); comment on: JAMA 301(7), 774–775 (2009).
102. Wendling D, Streit G, Toussirot E, Prati C: Herpes zoster in patients taking TNF-α antagonists for chronic inflammatory joint disease. Joint Bone Spine 75(5), 540–543 (2008).
103. Domm S, Cinatl J, Mrowietz U: The impact of treatment with tumour necrosis factor-α antagonists on the course of chronic viral infections: a review of the literature. Br. J. Dermatol. 159(6), 1217–1228 (2008).
104. Becart S, Segaert S: Recurrent varicella in an adult psoriasis patient treated with etanercept. Dermatology 217(3), 260–261 (2008).
105. Justice EA, Khan SY, Logan S, Jobanputra P: Disseminated cutaneous herpes simplex virus-1 in a woman with rheumatoid arthritis receiving INFLIXIMAB: a case report. J. Med. Case Reports 2, 282 (2008).

http://www.medscape.com/viewarticle/734142
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I wonder what percentage of the people in the trial were living in blatantly moldy homes. Nothing works right when people are under that much immune stress.
Agreed...Or they were doing OK - they got hit by something - and now they're getting whacked by the mold in their homes as well.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I can't believe these researchers put the patients on steroids. Powerful TNF-a-blockers, they can wake up viruses! This is a portion of an article that I found in my search for relief from chronic shingles on top of ME/CFS (with elevated EBV and HHV6). Subsequent papers go into this, but for now this is what I can find to be able to share quickly:

From Immunotherapy
Anti-TNF-α Agents in the Treatment of Immune-mediated Inflammatory Diseases: Mechanisms of Action and Pitfalls
Léia CR Silva; Luciena CM Ortigosa; Gil Benard

Posted: 12/20/2010; Immunotherapy. 2010;2(6):817-833. © 2010 Future Medicine Ltd.

Viral diseases are not uncommon among patients on anti-TNF therapy, with herpes zoster being one of the most frequent.[100] A recent paper was unable to define the true effect of TNF inhibitors on manifestations of herpes zoster,[101] while another showed an increased incidence (3%) in the population studied.[102] Cases of recurrent varicella,[103] disseminated cutaneous lesions caused by type I herpes virus[104] and lymphoproliferation by Epstein–Barr virus[105] have also been reported. Hepatitis B reactivation can occur,[106] although an association with anti-TNFs in patients with viral hepatites remains controversial, since it is currently used for patients with hepatitis B, but not for those with hepatitis C.[83] Conflicting data exist regarding the beneficial and untoward effects of TNF-α antagonists in HIV-infected patients. Thus, the use of anti-TNFs in cases of HIV-positive patients is not recommended, although it has been used in a few cases with no obvious harmful effects.[83] A recent study reviewed the effect of these medications on the course of several viral infections, including hepatitis, AIDS, herpes, cytomegalovirus and varicella zoster.[107] These effects varied from occasionally predisposing to more severe infections (as in the case of cytomegalovirus and varicella zoster infections) to no clearly discernible effect (e.g., in hepatitis C and herpes infections). However, data regarding the effect of TNF inhibitors on the course of viral infections are mostly limited to case reports, thus further studies are warranted.

100. Nobile S, Catassi C, Felici L: Herpes zoster infection followed by Henoch–Schönlein purpura in a girl receiving infliximab for ulcerative colitis. J. Clin. Rheumatol. 15(2), 101 (2009); comment on: J. Clin. Rheumatol. 12(5), 249–251 (2006).
101. Strangfeld A, Listing J, Herzer P et al.: Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-α agents. JAMA 301(7), 737–744 (2009); comment on: JAMA 301(7), 774–775 (2009).
102. Wendling D, Streit G, Toussirot E, Prati C: Herpes zoster in patients taking TNF-α antagonists for chronic inflammatory joint disease. Joint Bone Spine 75(5), 540–543 (2008).
103. Domm S, Cinatl J, Mrowietz U: The impact of treatment with tumour necrosis factor-α antagonists on the course of chronic viral infections: a review of the literature. Br. J. Dermatol. 159(6), 1217–1228 (2008).
104. Becart S, Segaert S: Recurrent varicella in an adult psoriasis patient treated with etanercept. Dermatology 217(3), 260–261 (2008).
105. Justice EA, Khan SY, Logan S, Jobanputra P: Disseminated cutaneous herpes simplex virus-1 in a woman with rheumatoid arthritis receiving INFLIXIMAB: a case report. J. Med. Case Reports 2, 282 (2008).

http://www.medscape.com/viewarticle/734142
I'm really surprised there haven't been more studies on this. These drugs are used a lot.
 

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