Article on the Likelyhood of anti-LSD1 Antivirals soon

[StayingUpbeat]

ANTIVIRALS ON THE HORIZON

In summary, a novel paradigm is emerging in the antiviral therapy of latent infections. It may be

possible to use epigenetic modulators to maintain latent viral genomes in a repressed state, preventing the periodic recurrence of disease. Current clinical trials of LSD1 inhibitors and data accumulating on the effects of LSD1 inhibitors on HSV-1/2 reactivation in animal models hint that the potential of epigenetic regulators of viral latency may soon become clear.

(Starts on Page 15)

http://c.ymcdn.com/sites/www.isar-icar.com/resource/resmgr/docs/isar_news_24-2_dec-1-2014.pdf

Basically an extension of the research done on the use of MAOI's to prevent reactivation of HSV from latency. GSK currently has an orally administered LSD1 inhibitor in clinical trials for Acute Myeloid Leukemia. The author states that it will be a logical next step to test it's ability to suppress HSV.

Since GSK's drug irreversibly changes cells ability to express LSD1 it may end up working as a permanent solution.

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[Gothic Beauty]

Like how soon?

[StayingUpbeat]

Like how soon?

It was an op-ed piece by someone not associated with GSK so there are no timelines that can specifically be inferred. The drug itself is in human trials already so the point of the op-ed is that, with regard to herpes, assuming there are no adverse events for AML, there's nothing really stopping GSK from doing a human clinical trial for HSV.

This should all be kept in the context of the fact that GSK's LSD1 drug is only in Phase I clinical trials. There are at least a few years before there is enough data to know if its even safe enough to be a cancer treatment much less a herpes treatment. My complete guess would be about 5 years.

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[dont quit!]

would that medication be PO or in daily pill form? I know MAOI, have a lot of side effects. You would need to change up, a lot of your diet, particularly sodium. Interesting article, anything to keep from spreading the virus to others.

[StayingUpbeat]

The mechanism was discovered via the MAOIs but is not based on the MAOIs. It was known that the MAOIs (as a side effect) inhibit an enzyme called Lysine Specific Demethylaze (though not very well). In the process of figuring out if this was useful it was discovered that this enzyme is necessary for HSV reactivation.

Ssince it is also necessary for development of blood stem cells into lukemic blasts GSK developed a highly specific, orally available, LSD1 inhibitor. The side effect (and diet restriction) profile is yet unknown but should be different from the MAOIs (though who knows if that means better).

The really interesting aspect is that the drug doesn't specifically target the virus but a host process. I don't claim to fully understand epigenetics but it sounds like the concept for this drug is that it irreversibly blocks cellular production of LSD1 preventing detachment of a key methyl group from a specific gene in HSV leaving the gene unable to activate.

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[dont quit!]

That sounds really good. Hopefully it proves to be safe and passes clinicals that it is currently in. The more options the better!

[dont quit!]

Would that fall under the cure or suppressive category?

[StayingUpbeat]

Would that fall under the cure or suppressive category?

Hard to say exactly what the effect of this one would be. If the neurons can never again produce LSD1 I would think that would be pretty permanent. On the other hand it seems like that could be bad if LSD1 is necessary for replication of something like white blood cells.

Someone who understands epigenetics would have to chime in and make a prediction on this one I quite simply tap out.

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[StayingUpbeat]

Like how soon?

So... "market" is an interesting concept for this one. Since the drug is already in human clinical trials for another condition (A Phase I Study for GSK2879552 for AML) it could be FDA approved in just a few years. That would mean a doctor who is sufficiently adventurous could prescribe it off-label at that time.

This is the same concept that can be applied to brincidofovir, which, though still suppressive could be a game-changer when coupled with existing antivirals. It should be available as a general prescription as early as 2017. There is sufficient evidence that it will be highly effective against HSV and work synergisticly with current antivirals (CMX001 Potentiates the Efficacy of Acyclovir in Herpes Simplex Virus Infections). Getting it prescribed (and covered by insurance) should be a matter of walking into the right doctor's office and convincing him/her that: a. Your not getting sufficient relief from current antivirals and b. you will be helped by the drug.

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[dont quit!]

Hard to say exactly what the effect of this one would be. If the neurons can never again produce LSD1 I would think that would be pretty permanent. On the other hand it seems like that could be bad if LSD1 is necessary for replication of something like white blood cells.

Someone who understands epigenetics would have to chime in and make a prediction on this one I quite simply tap out.

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does sound complicated, but if all WBC's were disabled than this drug would not in production at all. LSD1 is probably only produced in immature bands, not healthy normal WBCs. But that is just my guess. But this medication concept sounds good.

[vzhe]

[uSER=39398]@StayingUpbeat[/uSER]: That's interesting. I made a fairly comprehensive infection risk spreadsheet at one point.

In my models intercourse with a person who has a >82% reduction of shedding is statistically safer than sex with an untested person.

The best possible shedding reduction right now is 48% from ACV based drugs.

If a vaccines gave us a reduction of at least 50% in shedding rate that is cumulative with ACV, this still wouldn't be enough to be a functional cure (e.g. less risk of transmission than with an untested person). But if CMX001 or any other compound could reduce shedding by another cumulative 50%, we'd be at 87% reduction in shedding, which would be decisively a functional cure in my models.

It's important to note that the only compound that has achieved that on its own before is pritelivir with its 90% reduction in shedding (definitely a functional cure).

[sickornotsick]

Do you know if this would be a daily therapy like valtrex?

The mechanism was discovered via the MAOIs but is not based on the MAOIs. It was known that the MAOIs (as a side effect) inhibit an enzyme called Lysine Specific Demethylaze (though not very well). In the process of figuring out if this was useful it was discovered that this enzyme is necessary for HSV reactivation.

Ssince it is also necessary for development of blood stem cells into lukemic blasts GSK developed a highly specific, orally available, LSD1 inhibitor. The side effect (and diet restriction) profile is yet unknown but should be different from the MAOIs (though who knows if that means better).

The really interesting aspect is that the drug doesn't specifically target the virus but a host process. I don't claim to fully understand epigenetics but it sounds like the concept for this drug is that it irreversibly blocks cellular production of LSD1 preventing detachment of a key methyl group from a specific gene in HSV leaving the gene unable to activate.

---

The mechanism was discovered via the MAOIs but is not based on the MAOIs. It was known that the MAOIs (as a side effect) inhibit an enzyme called Lysine Specific Demethylaze (though not very well). In the process of figuring out if this was useful it was discovered that this enzyme is necessary for HSV reactivation.

Ssince it is also necessary for development of blood stem cells into lukemic blasts GSK developed a highly specific, orally available, LSD1 inhibitor. The side effect (and diet restriction) profile is yet unknown but should be different from the MAOIs (though who knows if that means better).

The really interesting aspect is that the drug doesn't specifically target the virus but a host process. I don't claim to fully understand epigenetics but it sounds like the concept for this drug is that it irreversibly blocks cellular production of LSD1 preventing detachment of a key methyl group from a specific gene in HSV leaving the gene unable to activate.

---

[sickornotsick]

Do you know if this would be a daily therapy like valtrex?

The mechanism was discovered via the MAOIs but is not based on the MAOIs. It was known that the MAOIs (as a side effect) inhibit an enzyme called Lysine Specific Demethylaze (though not very well). In the process of figuring out if this was useful it was discovered that this enzyme is necessary for HSV reactivation.

Ssince it is also necessary for development of blood stem cells into lukemic blasts GSK developed a highly specific, orally available, LSD1 inhibitor. The side effect (and diet restriction) profile is yet unknown but should be different from the MAOIs (though who knows if that means better).

The really interesting aspect is that the drug doesn't specifically target the virus but a host process. I don't claim to fully understand epigenetics but it sounds like the concept for this drug is that it irreversibly blocks cellular production of LSD1 preventing detachment of a key methyl group from a specific gene in HSV leaving the gene unable to activate.

---

The mechanism was discovered via the MAOIs but is not based on the MAOIs. It was known that the MAOIs (as a side effect) inhibit an enzyme called Lysine Specific Demethylaze (though not very well). In the process of figuring out if this was useful it was discovered that this enzyme is necessary for HSV reactivation.

Ssince it is also necessary for development of blood stem cells into lukemic blasts GSK developed a highly specific, orally available, LSD1 inhibitor. The side effect (and diet restriction) profile is yet unknown but should be different from the MAOIs (though who knows if that means better).

The really interesting aspect is that the drug doesn't specifically target the virus but a host process. I don't claim to fully understand epigenetics but it sounds like the concept for this drug is that it irreversibly blocks cellular production of LSD1 preventing detachment of a key methyl group from a specific gene in HSV leaving the gene unable to activate.

---

[dont quit!]

[uSER=39398]@StayingUpbeat[/uSER]: That's interesting. I made a fairly comprehensive infection risk spreadsheet at one point.

In my models intercourse with a person who has a >82% reduction of shedding is statistically safer than sex with an untested person.

The best possible shedding reduction right now is 48% from ACV based drugs.

If a vaccines gave us a reduction of at least 50% in shedding rate that is cumulative with ACV, this still wouldn't be enough to be a functional cure (e.g. less risk of transmission than with an untested person). But if CMX001 or any other compound could reduce shedding by another cumulative 50%, we'd be at 87% reduction in shedding, which would be decisively a functional cure in my models.

It's important to note that the only compound that has achieved that on its own before is pritelivir with its 90% reduction in shedding (definitely a functional cure).

Sorry for my ignorance but how are you coming up with figures? Gen vaccine reduces rates by 55% and with a cumulative effect of acyclovir we would possibly be at 75-85%.

[vzhe]

100% initial risk. Daily Valacyclovor reduces by 48% (http://www.nejm.org/doi/full/10.1056/NEJMoa035144).

GEN-003 claims 52% reduction (http://www.genocea.com/assets/Wald-IDSA-2014-10-oct.pdf at one specific dose, at 2 months, but not at 6 months - so I doubt they can really achieve that).

100% reduced by 48%:

1 - ( 1 * .48 ) = 52% Remaining risk after Valacyclovir once daily.

52% further reduced by GEN-003 55% shedding reduction at 2 month mark:

.52 - ( .52 * .52) = 23.39% Remaining risk after both GEN-003 at 2 month mark and Valacyclovir once daily

Total Risk reduction: 1 - (.52 - (.52 * .52)) = 75.04%

The combination would be 75.04% comulative reduction in shedding. Not good enough.

I've calculated the annual infection risk for being with one or more untested partners at 0.483% for males and 0.878% for females. This is based on a whole array of assumptions and data that are beyond scope for this post. But based on my model the risk of transmission during 10 years of sex with untested, unaware or lying partners in the US is 9.14% for females and 4.93% for males.

For comparison the 10-year risk with an infected partner and only condom use is 62.8% for a female, and 28.0% for a male. A year is defined by an average of 49 sexual contacts as per the valacyclovir study, which also cites the actual underlying risk as increasing at 0.35 per 1000 sexual contacts.

Those numbers might seem high, but they have to be high or the virus would not sustain a reservoir in around 20% of the population with demographical numbers that grow by about 10% per decade of sexually active life.. (https://en.wikipedia.org/wiki/Epidemiology_of_herpes_simplex). The reason someone isn't affected is essentially statistical luck. Back to the data.

To achieve an equivalent transmission rate as with untested partners - e.g. the inflection point where it becomes safer to have sex with someone infected under treatment, than with a random person met at a club, we'd have to reduce shedding by 82% or more. 90% would be a functional cure because risk would be lower than with a random person. This is assuming a uniform distribution of risk. Certain events that temporarily weaken the immune system might change this equation. E.g. not having sex while having a cold might be a good idea, but the general point is sound.

To achieve such a high shedding reduction of at least 82%, a vaccine that works perfectly cumulative (assumption) with once daily valacyclovir would have to reduce shedding by at least 66%.

Looking at the data I doubt GEN-003 will achieve that. The 52% they have is very shaky and holds true only for two months after the final shot and then drops off quickly all the way to 40% at the 6 month mark and 8% at the 12 month mark.

There's a chance that Dr. Halford's vaccine might do better, both because it elicits a stronger immune response, and because it can achieve a more sustained immune response. If it can achieve a sustained 66% reduction it would be good enough. If it can achieve a lower but sustained reduction, it might still be suitable for a functional cure combination therapy with one more agent.

Looking at all that I conclude that a live attenuated vaccine is probably our best shot (ha!) for baseline treatment, and that in combination with pharmaceutical agents it might actually get us to a functional cure.

[dont quit!]

100% initial risk. Daily Valacyclovor reduces by 48% (http://www.nejm.org/doi/full/10.1056/NEJMoa035144).

GEN-003 claims 52% reduction (http://www.genocea.com/assets/Wald-IDSA-2014-10-oct.pdf at one specific dose, at 2 months, but not at 6 months - so I doubt they can really achieve that).

100% reduced by 48%:

1 - ( 1 * .48 ) = 52% Remaining risk after Valacyclovir once daily.

52% further reduced by GEN-003 55% shedding reduction at 2 month mark:

.52 - ( .52 * .52) = 23.39% Remaining risk after both GEN-003 at 2 month mark and Valacyclovir once daily

Total Risk reduction: 1 - (.52 - (.52 * .52)) = 75.04%

The combination would be 75.04% comulative reduction in shedding. Not good enough.

I've calculated the annual infection risk for being with one or more untested partners at 0.483% for males and 0.878% for females. This is based on a whole array of assumptions and data that are beyond scope for this post. But based on my model the risk of transmission during 10 years of sex with untested, unaware or lying partners in the US is 9.14% for females and 4.93% for males.

For comparison the 10-year risk with an infected partner and only condom use is 62.8% for a female, and 28.0% for a male. A year is defined by an average of 49 sexual contacts as per the valacyclovir study, which also cites the actual underlying risk as increasing at 0.35 per 1000 sexual contacts.

Those numbers might seem high, but they have to be high or the virus would not sustain a reservoir in around 20% of the population with demographical numbers that grow by about 10% per decade of sexually active life.. (https://en.wikipedia.org/wiki/Epidemiology_of_herpes_simplex). The reason someone isn't affected is essentially statistical luck. Back to the data.

To achieve an equivalent transmission rate as with untested partners - e.g. the inflection point where it becomes safer to have sex with someone infected under treatment, than with a random person met at a club, we'd have to reduce shedding by 82% or more. 90% would be a functional cure because risk would be lower than with a random person. This is assuming a uniform distribution of risk. Certain events that temporarily weaken the immune system might change this equation. E.g. not having sex while having a cold might be a good idea, but the general point is sound.

To achieve such a high shedding reduction of at least 82%, a vaccine that works perfectly cumulative (assumption) with once daily valacyclovir would have to reduce shedding by at least 66%.

Looking at the data I doubt GEN-003 will achieve that. The 52% they have is very shaky and only after 2 months after the final shot and then drops off quickly all the way to 40% at the 6 month mark and 8% at the 12 month mark.

There's a chance that Dr. Halford's vaccine might do better, both because it elicits a stronger immune response, and because it can achieve a more sustained immune response. If it can achieve a sustained 66% reduction it would be good enough. If it can achieve a lower but sustained reduction, it might still be suitable for a functional cure combination therapy with one more agent.

Looking at all that I conclude that a live attenuated vaccine is probably our best shot (ha!) for baseline treatment, and that in combination with pharmaceutical agents it might actually get us to a functional cure.

I see. Thank you for explanation. As an FYI, Genocea has updated vaccine statistics. They ended up @ 55% reduction in shedding. Basically the same.

[vzhe]

Interesting, do you have a link to that?

And yeah, it doesn't really change the numbers enough to make a difference.

[vzhe]

I found this:

"During the 28-day observation period immediately after completion of dosing, the best dose of 60 µg per protein / 75 µg of Matrix-M2TM adjuvant demonstrated a highly statistically significant 55% reduction from baseline in the viral shedding rate, the primary endpoint of the trial and a measure of anti-viral activity"

The 52% were at 2 months. The 55% were at 1 month. I don't think that's an actual improvement but just speaks to the fact that in both cases the 6 months were at 40% and 12 months at 8%. It probably still helped their stock.

If they did an 80% reduction I'd be up for doing boosters every 6 months, but at barely 40% after 6 months, which probably drop even faster if you take ACV at the same time, this doesn't seem that great of a deal.

My guess is, this is probably as good as we'll ever get from protein subunit vaccines, and I doubt that's good enough for a prophylactic either. That leaves ACAM (which would be the first replication deficient vaccine to ever work), Admedus (which would be one of the first DNA vaccines to ever work), and Dr. Halford's vaccine which almost certainly works (it's a live vaccine - we know they work), especially as a prophylactic.

Is there any way in which we can support Dr. Halford?

[dont quit!]

How effective do you think Acam29, will be? It should produce a nice humoral response. Over or under 75% effectiveness? If it proves to be over, in your studies, that should be close to non transmission levels.

[vzhe]

Ok, so HSV-2 is a large virus, with many genes, which does not seem to have a dominant antigen. The largest protein represents maybe 7% of the genome. I think that's part of the reason why the protein subunit vaccines have been failing. Contrast this with HepB where a single protein (large surface antigen) represents maybe 32% of the genome, or HPV a tiny 8kb virus where just L1 reprents 19% of the genome, and where there are roughly 420 copies of L1/L2 per virus particle.

So clearly whole-virus vaccines are the way to go, and HSV-529 is a whole-virus vaccine.

But the second thing we can learn from protein subunit vaccines is this: The immunity they elicit fades extremely quickly. After 12 months there's only a 8% remaining immune response over baseline left.

Even if ACAM-529 were to temporarily elicit a strong immune response, can it sustain that elevated immune response? There's no answer until the trials return results, but there definitely is reason to be skeptical.

This is where a replication competent vaccine simply makes more sense: Maintain a slight reservoir of weakened antigens in the body, to sustain strong immunity over longer periods (years).

[dont quit!]

Nice info. Makes sense. Thanks. They should at least make his vaccine available to the infected. At the very least.

[throwawayday345]

So... "market" is an interesting concept for this one. Since the drug is already in human clinical trials for another condition (A Phase I Study for GSK2879552 for AML) it could be FDA approved in just a few years. That would mean a doctor who is sufficiently adventurous could prescribe it off-label at that time.

This is the same concept that can be applied to brincidofovir, which, though still suppressive could be a game-changer when coupled with existing antivirals. It should be available as a general prescription as early as 2017. There is sufficient evidence that it will be highly effective against HSV and work synergisticly with current antivirals (CMX001 Potentiates the Efficacy of Acyclovir in Herpes Simplex Virus Infections). Getting it prescribed (and covered by insurance) should be a matter of walking into the right doctor's office and convincing him/her that: a. Your not getting sufficient relief from current antivirals and b. you will be helped by the drug.

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Staying Upbeat, what's your take on this 8% reduction when it comes to GEN-003? I hadn't heard about this previously, you always seem to know what's up.

[StayingUpbeat]

Staying Upbeat, what's your take on this 8% reduction when it comes to GEN-003? I hadn't heard about this previously, you always seem to know what's up.

I believe [uSER=57117]@vzhe[/uSER] is talking about the data from the Phase I/IIa trial at 12 months: http://www.genocea.com/assets/Wald-IDSA-2014-10-oct.pdf

For the most effective dose the decrease in shedding at the 12 month mark was only 8%. The data at 12 months did not reach statistical relevance in the Phase I/IIa trial and they changed the dose+adjuvant mix for the full phase II so we'll have a much better idea what the true 12 month effect is from the data Genocea is scheduled to release in the fall.

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[Kurdt01]

For those of you more science minded which the last few posts seem to be...any theories on why GEN-003 would actually make things worse? and that it's not really getting better now 8 months after the 3rd shot?

[Curioso]

I'd be careful about permanently irreversibly changing the functioning of your cells in a fundamental way, just in case LSD-1 was useful for something? i.e. it has an evolutionary purpose?

Treating someone with a desperate drug for a terminal illness like leukemia is NOT the same thing as treating millions upon millions of people for a milder illness, if the side effects of the drug are serious. That's a fundamental, and that's why it would take a long time to get approval for prescribing this drug for a much milder and more prevalent illness, if it ever received approval.

Ppl seem to think any drug that demonstrates efficacy should therefore be readily available, as though toxic side effects don't and can't exist that could destroy your quality of life, or even destroy your life period. Similarly, a lot of vaccines seem to demonstrate a reasonably high number of serious adverse reactions, and, it is suspected, other longer term and more subtle immune system dysfunctions which are commonly not attributed to the vaccines which can be disabling or even lethal.

Similarly, I have doubts about the long term efficacy of the vaccine approach, any vaccine approach, apart from the many adverse reactions triggered by vaccines and their immune stimulating adjuvants, preservatives, excipients, etc. I'm not surprised we're seeing limited efficacy. In the end, any vaccine is simply encouraging your B-cells to make more of a certain immunoglobulin, pretty much.