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This is what makes the technology so difficult which is what Dr. Seymour acknowledges.
Other posts by Nanopatent have provided more details. I haven't had time to read the source material, but I think it was cathepsin that was involved in removing the glycan caps.
In theory, adding cathepsin mimics to the 'Cide in addition to NPC1 mimic ligands could overcome that difficulty.
I would think that is why Dr. Diwan created multiple candidates for initial in vivo efficacy screening. Unfortunately, these same efficacy screens in vitro did not point to the lower efficacy they saw in vivo in the previous USAMRID testing of EbolaCide1.
I am not sure how they overcome that - maybe the in vitro efficacy results can be quantified and ranked?
Diabolical Southpaw, daBoze, dougwur, Larson1 and L Vus,
I am feeling much the same about the company as all of you. The technological promise and initial results may be great, but can management and their technical personnel successfully pull together the science, apply the technology and the lead the business forward in a reasonable amount of time?
I have less than 10% of the amount in NNVC that I had this spring - counting on being able to jump back in when (or if) they can make meaningful progress.
I would have even less without the uncertain odds of getting an Ebola partnership going forward with USAMRID or another agency if the crisis continues to worsen.
The lack of PHE announcements in particular is disturbing to me. MERS and H7N9 were supposed to be tested. Without management communication we can only speculate that maybe it did not go well.
I am looking to buy at lower prices and sell some or all on pops until management gets better at communicating and executing.
I may be incorrect wrt ZMapp GLP Tox testing based on your reference, Changes. It was my impression that there was GLP Regulatory Tox Safety testing done. This seems to say they were just starting it - either for the portion on large animals or for all of it.
The drug had never before been tried in people, though it and some predecessor drugs had been tested in monkeys, showing some effectiveness. Mapp was only now gearing up to start the larger animal toxicity studies typically needed before testing it in humans, with an eye to doing the first human safety studies in healthy volunteers next year. For that reason there were very few doses available when the Ebola outbreak started.
VIII. Human Safety Information
The Animal Rule neither replaces the need, nor establishes special requirements, for an adequate
human safety database for drug development. The expectation is that drugs “will be evaluated
for safety under preexisting requirements for establishing the safety of new drug and biological
products.”84 FDA anticipates that the nonclinical and clinical safety development programs will
proceed in a manner similar to that of drugs developed under traditional regulatory pathways.
Some of the general principles include the following:
- Nonclinical toxicology, safety pharmacology, and PK studies should provide adequate safety data to support the initiation of human trials.
- Risk-benefit assessment and ethical considerations must guide the design of human trials at each phase of development.85 The regulatory and ethical complexities of establishing the necessary safety database should be discussed with the review division, preferably early in the drug development program.
I agree the Maximum Feasible Dose should be enough. To me it does not make sense that you need to go beyond that to find toxic or even lethal doses.
When the toxic or lethal effects are not due to your drug but due to side effects like electrolyte imbalances such as water poisoning, that just doesn't make sense.
Some FDA CDER guidance states that MFD is enough, but others still hold to the older (and in my opinion outdated) requirements for lethality findings.
As for PEG, I am not worried about it alone. You have to drink something like 2 gallons of the stuff before you get a colonoscopy. It alone is not a concern.
But there are potential issues with competitive inhibition (FluCide sialic acid shouldn't be a problem, but EbolaCide NPC1 is more complicated).
And low potential risks for the micelle structure. The micelle is composed of PEG plus pendant fatty acids. PEG macromolecules are stable, nontoxic and safe, but PEG interspersed with fatty acids may not be as stable and may result in breakdown before excretion. The glycol monomers liberated from PEG would not be safe.
I do not consider these to be high or even moderate risks. But they do need to be tested properly to be proven out - in GLP Regulatory Toxicity and Safety studies - and submitted for independent review.
All other companies' drugs that have been used (ZMapp) or likely have been used (TKM-Ebola) or likely will be used (GSK-vaccine) have been through or plan to go through these most basic, fundamental tests.
This is why efficacy testing alone is not enough. Safety testing is also needed. We can't risk killing more people than we can help.
If EbolaCide tests in BSL-4 facility and if found to be highly efficient, why not employ it right away to fight Ebola? How far did Zmapp go, in meeting goals according to FDA regulations, before it was employed in the US and in Liberia, Africa?
Such a partnership is likely required for progress on EbolaCide2, Nanopatent - although there may be a long shot backdoor per Leifsmith's hope for personal use by individual health care workers prior to traveling to Africa.
USAMRID and NIH would be ideal to enable following the regulatory required path to use of EbolaCide2:
Even in vitro efficacy testing requires a BSL4 facility.
And animal efficacy with primates requires further controls in a BSL4 facility.
And agreement on even the potential for abbreviated GLP animal Tox testing will need agreement by government agencies.
In this case, the hopes for emergency use of EbolaCide2 and the share price changes will go hand-in-hand.
A partnership announcement should result in a sharp pop in SP.
OTH no partnership announcements will continue the recent SP range and likely drift lower.
Right - I'm waiting for PR or filing to confirm this.
If it is a done deal, I haven't seen that. But I also saw that there is an ongoing audit to determine the actual cost of the facility and a commitment to buy it at the actual cost without markup.
This is a step in the right direction for removing one of the conflicts of interest between NNVC and Theracour. I will be happy to see it finalized.
A company putting out a product is fine.
People doing their own research, making their own decisions and using it for their own uses is fine.
A company misleading people with false or unsupported claims about health benefits without independent review is not fine.
Very simplistic and I am sure some isolated exceptions, but basically where I come down on the issue.
I think we both agree on the first 2 points regarding personal freedoms.
Where I think we disagree is on the last point. I don't want so much biased noise in the marketplace by companies with vested interests in profit that it is difficult for people to make their own unbiased, informed choices.
That is, in my opinion, where regulatory authority is helpful and necessary - even if not always perfect. Your example of the legal challenge on folic acid claims is a great example where we need to hold our regulatory bodies accountable. You are right that this reversal of the regulatory decision has been a benefit to society to prevent spinal defects.
But I don't want to throw away our regulatory system. I want to improve it.
That is not what I said nor implied.
There is a big difference between calm, reasoned people with resources and time to make good decisions...
vs.
Thousands of horribly sick patients with a 50/50 chance of living in the present epidemic being given an informed consent form for some new treatment being able to read the small print stating whether there is even any independently reviewed animal safety and efficacy data let alone any Phase I human safety data.
The latter is not ethical. The patients are under duress. Their families are under duress. And the health care workers are under duress without also having to take on the added burdens of informed consent forms and treatments that don't even have the minimum levels of safety and efficacy testing.
I anticipate NNVC doing the in vitro efficacy testing, initial in vivo efficacy testing and at least a minimum amount of GLP Toxicity and Safety testing - at least - before they get to a point where they would make a call to use EbolaCide2.
This is not something they can or should shove into people before they have a minimum of evidence it can do some good. They do NOT have that yet.
I wouldn't be so dismissive of false hope. There are numerous examples of it harming patients - the most notorious being shysters in Mexico who got cancer patients to abandon their chemotherapy to travel to Mexico to get "treatments" with worthless Laetrile.
Really sorry to hear about your friend, Leif. On this point you and I agree. Your friend should be able to do what she feels best for her own health.
While I don't have all the details, a company is supposed to be able to sell a nutraceutical under the GRAS (generally regarded as safe). What they cannot do is promote its actual or potential health benefits unless they have evidence that has been submitted to FDA to support such claims.
It really shouldn't have had to come to this (and won't solve the larger issue), but I think your friend does have the option to contact FDA directly to request compassionate use. I do not know exactly how this works, but at least she has another path.
Again, this is a very unsatisfying option considering the larger issues, but it may help your friend.
Why Ben and Jerry's Chocolate Chip Cookie Dough Ice Cream of course!
My google search made me smile:
Hospital Uses Ben & Jerry's Secret Ebola Cure
On a more serious note, I know he had the typical supporting care (IV fluids, nutrition, electrolytes, etc).
Also, Dr. Sacra received at least 2 blood transfusions from Dr. Brantley (first American patient from the present epidemic). The remaining antibodies of previous victims can be used to provide passive antibody resistance to the infected patient.
I haven't seen that the experimental drug he received has been identified publicly. I am waiting on this as well.
Yeah, I was hoping for more ADIF discussion. Nanopatent was kind enough to reply, both times. Maybe Big Kahuna or someone else has more information.
ADIF is a bit of a black box to me. That may be intentional and needed - maybe due to proprietary and potential security concerns.
I can be corrected on this, but my understanding from putting together various pieces (I haven't done a recent review, so this may be a little rough):
Dr. Diwan has scoured the literature to put together a comprehensive electronic library of potential ligands to mimic cellular entities necessary for viral interaction/entry/infection.
A physical library of many of those ligands is or has been stockpiled.
A physical stockpile of nano micelles is or will be also available.
The ligands can be attached to the nano micelles in various combinations to provide various alternative nanoviricides (this is where the licensing/IP issues may come into play).
These nanoviricide candidates can then be tested in short order against field-collected samples to select for greatest efficacy. That candidate can then be produced in in small batches initially and then scaled up to larger batches.
I don't think they have all these pieces in place - particularly the scale up part. Not much evidence that it is not a "pipe dream" as you say, but that may not be forthcoming as I stated earlier. It is at least theoretically possible as I understand it.
But aside from proof of concept and readiness, my concerns are with the IP. NNVC holds licensing rights to nanoviricides to treat a limited number of very specific viruses.
If NNVC presumably holds the IP rights to ADIF (which seems implied by their Annual and Quarterly Reports), shouldn't they also hold the rights to all prospective candidates and the lead candidates generated with ADIF?
But that would seem to go against the limited licensing from Theracour.
It would seem this is another conflict of interest if it turns out that drug candidates that NNVC generates through ADIF are still covered by Theracour's IP. They would have to negotiate terms of licensing which would add delays to what is supposed to be a rapid response technology. Or worse, NNVC would provide candidates with their ADIF to which they had no IP rights to the benefit of Theracour - either for their own separate development efforts or at least the strengthening their negotiating position for licensing back to NNVC.
Goodness, No! Provide people with better options - and kick NNVC into gear to do the necessary work to become one of those better options.
Mapp had at least already done their animal GLP Tox Safety and Efficacy testing.
Tekmira, too and they also started Phase I clinicals with people.
BioCryst, Newlink and GSK are all doing the work to get to animal and Phase I safety.
I want NNVC there with EbolaCide, too. But FluCide is first to not miss that opportunity and EbolaCide needs as many resources as possible after that to put them in a position to help. Other treatments are further in development and will be used first. We need to put ourselves in a position to be a fast follower to be there should there still be a need.
But bottom line: They need to do the work and GET IT DONE!
In response to:
So, just let them die while Rome burns?
This is a different issue and one where I agree with you, Leif.
As a personal choice, a sick individual (or anyone) should be able to do what they feel is best for them - it is their body and it is their life.
But that is different than giving free rein to for-profit enterprises to "offer" their medicines with the imprimatur of authenticity giving potentially false hope to individuals who are desperate and have limited education and sophistication to inform their choices.
I agree you and I should have the choice to use EbolaCide2 for ourselves by asking for it directly - and for anyone else to ask for it directly. But we have the ability to compare the options. We know or can find out what all the options are, how far along each are in development, how solid is the evidence.
A similar, disturbing incident where we can both probably agree with the right to free choice is the one where Chimerix/FDA at first refused, then relented to provide access to life-saving treatment for kids.
Link: FDA, Drug Companies Struggle with Compassionate Use Requests
A national publicity campaign recently succeeded in obtaining early access to an experimental treatment for a seriously ill child, touching off a broader discussion of compassionate use policies and their impact on drug development and approval.
As 7-year-old cancer patient Josh Hardy gained relief from a life-threatening infection following a bone marrow transplant thanks to Chimerix’s promising new antiviral drug brincidofovir, hundreds of patients turned to the Internet and social media to intensify pressure for similar compassionate access. The trend demonstrates the need for sponsors, health professionals and government regulators to find new ways to handle these difficult requests, while also supporting clinical research and biomedical R&D.
The "Right to Try Act"—the very first to pass in the U.S.—was signed into law by Colorado's governor after passing the state legislature unanimously. Similar bills are coming up for approval in Arizona, Louisiana, and Missouri. Each bill would allow patients, in partnership with their physicians, to request experimental medications that are still being tested.
If I were dying of Ebola and you were to tell me of bare minimum safety tests needed before I will be permitted to try EbolaCide here's what would happen: if I were in a state to be civil I would thank you and tell you that I'm going to use the EbolaCide, if not, I'd just tell you to go to hell and use the EbolaCide.
I believe that the most profoundly unethical thing that can be done is to deprive people of the freedom to work with their own chosen advisors and make medical decisions without the "help" of an authority willing to use physical violence against me and those offering to help me.
If the Ebola patients in Liberia are likely to die, I don't see the necessity to do animal studies. Man is an animal. A dying man is an apt test subject. Enough bureaucratic nonsense.
The letter of the law loses force in a real catastrophe. "Do it and apologize later" people come to the fore.
I would say yes - EbolaCide could qualify for Orphan Drug Status in US and OUS. For US early development, granting of OD status, full development, approval and commercialization/use would result in a Priority Review Voucher.
So a ways to go, since they haven't even applied for Orphan Drug Status for EbolaCide.
There are varying estimates of worth (like anything, it depends on the buyers' motivations and competition).
Earlier this year, Biomarin sold a PRV to Regeneron for $67.5 million, I think.
Dr. Seymour made an interesting comment in the R&R conference talk about whether EbolaCide will pass FluCide in importance.
So - just speculating - there may be a possibility that NNVC puts EbolaCide into the Regulatory Toxicity studies before FluCide.
Food for thought.
And once EbolaCide is found to be effective in animals, the FDA animal rule, the WHO, the NIH cannot deny us entry to Clinical Trials, first for safety in humans. How long will that take??? A couple of weeks! Remember, we are low toxicity EbolaCide!!! Then straight to hospitals
VIII. Human Safety Information
1316 The Animal Rule neither replaces the need, nor establishes special requirements, for an adequate
1317 human safety database for drug development. The expectation is that drugs “will be evaluated
1318 for safety under preexisting requirements for establishing the safety of new drug and biological
1319 products.”84 FDA anticipates that the nonclinical and clinical safety development programs will
1320 proceed in a manner similar to that of drugs developed under traditional regulatory pathways.
1321 Some of the general principles include the following:
- Nonclinical toxicology, safety pharmacology, and PK studies should provide adequate safety data to support the initiation of human trials.
- Risk-benefit assessment and ethical considerations must guide the design of human trials at each phase of development.85 The regulatory and ethical complexities of establishing the necessary safety database should be discussed with the review division, preferably early in the drug development program.
Don't have your sources, but my prediction is a variation on your theme.
I am anticipating we get more clarity in the 10K filing toward the end of September.
They will say they are pursuing both opportunities for EbolaCide and FluCide (and DengueCide) and have the resources to do all.
Speculating on what they won't put in the 10K is timelines (if so, I am not happy about this as a shareholder). For timelines, I think we will have to guess. They need to validate production of FluCide in the new facilities which - if it takes about 3 months - puts them toward the end of this year. Then production for Tox with Batch Release and Characterization about another 3-4 months which is about March/April 2015 for FluCide GLP Regulatory Tox start.
For EbolaCide, timing is anyone's guess. But to your point, Rawnoc, the proof of concept testing and agreements for testing will keep up PRs to keep stockholders from totally revolting during that time.
I am looking to buy some stock back in the low $3 range - maybe I'll buy some from Dougwur who said he'll sell then. The stock risk gets lower the lower the price you buy it (like Dr. Kaz) . And it is the only way I'll buy over the short term because I believe it will be maybe 2016 before we get to clinical studies (like Diabolical Southpaw and Arch). I can earn more money elsewhere while I wait (like NoRetreat - although I am ultimately more optimistic about the company's prospects).
NNVC DOES have promise, but it will take patience and I am not sure where ultimate price support lies while we wait.
To close on a humanitarian note, NanoPatent's recent post excerpting from the latest reports from Africa is absolutely heartbreaking. I really wish NNVC could go faster and I am hoping the new facility will help. Let's spend some of the money now to get the right people to make progress on all fronts in the multiple facilities - FluCide, DengueCide and EbolaCide!
[Rawnoc:] My sources say Flucide Tox has taken a back seat. They're all over Ebola now. Flucide is on the back burner.
They will be using the new facility for Tox materials, which will ultimately make production faster, but will make the start anyone's guess. It's all about EBOLA now.
They claim the there will be Ebola testing before year's end, and are hoping that this will squelch the bag holders from demanding flucide Tox.
"We would be foolish and irresponsible if we didn't take advantage of this huge opportunity all the media attention will bring us."
And then, next March when there is still no news, they will say they are starting Flucide Tox up again. Had to stop production to accommodate the Ebola opportunity, but now they're back to producing Flucide and as soon as they have enough material they will send it to BASi.
Forget flucide for the foreseeable future.
Unlikely EbolaCide use this epidemic, but potential opportunities for partnerships or PRV.
FluCide is still most important. Period. Full Stop.
I still think FluCide is more important to saving lives than EbolaCide. And more important to getting product available on the market to help many more people and save many more lives.
But I think it is important to discuss EbolaCide as I think the discussion here has lacked coverage of some important points. (I am reposting this with updates.)
Ebola is horrible. Given the known choices out there now, if - God forbid - any of my family were stricken with this horrible disease, I would choose EbolaCide2.
By the way, I am not a healthcare provider but a scientist - and a realist.
One of the reasons I am disappointed/frustrated with NNVC is that they didn't take a more aggressive approach to get started with GLP Regulatory Tox with material available.
If they had animal safety data on multiple species with FluCide - even in part - along with the existing moderate efficacy in vivo for EbolaCide1, they would have a better shot at at least using EbolaCide1 in the present epidemic.
At present, as a US Company, they don't even have drug product that would meet US law regarding requirements for export per 21 CFR 312:110 as enforced through the FDA.
As such, they need extraordinary exceptions - any one of the following:
1. FDA exercise of enforcement discretion (essentially such an Ebola threat without other medicines that they decide to not enforce present laws - a very high bar).
2. Partnership or sponsorship by CDC, NIH or maybe USAMRID, that would be able to export under their research authority (a huge risk opening up government agencies to domestic and foreign criticism in the absence of a very desperate situation with no better alternatives).
So from the standpoint of humanity - as much as I would like to see EbolaCide1 or 2 used in the present epidemic, it is just not likely to happen unless things get horribly bad and failure of alternative treatments that will get the first shots based on more safety and efficacy data.
And from the standpoint of financial opportunity - I have a responsibility to invest where I can get the best return. Right now, that is more so in BIB, XPH, and RXL broad ETFs than in NNVC.
And I feel responsible not to snow people over with long shots and hyped hope (re: EbolaCides for the present epidemic). EbolaCide use now is possible, but extremely improbable.
KMBJN, Competitive Inhibition is a good discussion to have again for those new to the board. Thanks for including the link to the earlier discussion.
LINK to Robi-Post 71984
The above linked post was one of my first posts on this board and I was a bit surprised not to see any consideration of even potential safety issues (at least since the time I started reading posts here).
I didn't (and still don't) consider competitive inhibition to be a likely problem with FluCide and probably not likely for other 'Cides (although we may need more information on the ligands for the others). KMBJN, you and Dr. Kaz have just posted some good points regarding this.
It is interesting to look back at Zincfinger's reply. Unlike recently, at the time he was very dismissive of the potential safety issues with competitive inhibition. (He now doesn't even refer to it by its technically correct terminology (competitive inhibition) for some unknown reason.)
LINK to Zinc Post 75002
Zinc quote:
Competitive inhibition is NOT a problem!:
{A}ttachment will occur ON THE DRUG and not on cells, but Nanoviricides have many receptors (most cells only have a few of any particular receptor) so they're not going to be significantly clogged up with ligands (and the animal trials have clearly ruled that OUT as a problem.
The nanocides will initially cause a relative deficiency of the ligands: some of them will be bound to the drug and thus not interacting with cells). BUT the body has regulatory mechanisms that adjust the level of such things as needed. As the number of ligands attaching to cells drops due to some being attached to the drug, the regulatory mechanism will up production of the ligands until a proper number is attaching to cells again. This also was ruled out as a potential problem for the drug by the previous animal tests.
The importance of the previous animal tests here is that they have demonstrated that ligands attaching to the drug are not a problem for the drug (because it has so many recptors) and also that the initial reduction in ligands due to some attaching to the drug (soon corrected by up regulation of production of the ligand to compensate) is also not a problem.
If either of those two things was a problem it would have shown up in the animal tests. With 100% of drug treated animals surviving after 21 days a dose that killed ALL control animals in five days and ALL animals treated with the current best therapy in seven days it is very clear that neither of those causes any serous problem.
Any problem that arises in human trials would have to be due to some interaction DIFFERENT in humans and animals. The interaction between the virus and the drug is EXACTLY THE SAME so there's no room for a new problem there.
IF any problem were to arise it would be due to 1) the deficiency in the ligands caused by some of them attaching to the drug *OR* 2) some problem with breakdown and elimination of the drug (because those are the only ways the drug is going to interact with the human host.
1 is unlikely to cause any problems because normal regulation should quickly compensate for the receptors that get attached to the drug.
2 is very unlikely to cause any problem: PEG is widely used in drugs and foods and has shown no signs of problems. Other components of the drug break down into naturally occuring biochemicals
So IMHO it's reasonable to say that the odds of problems due to ligands binding to the receptors on the drug are very small. IF they were going to happen they should have happened in the animal trials
FluCide is most important. Period. Full Stop. GLP Regulatory Tox and Safety testing on FluCide is needed now.
EbolaCide2 may be important - if and only if they can work on it without impacting FluCide. It could provide an important proof of concept.
However, we should be aware of the following. FDA and other countries' regulations on compassionate and emergency use generally require data from GLP Regulatory Tox on multiple species of animals with PK/ADME to determine the safe and effective dosing - at a minimum. NNVC HAS NOT done this yet for even FluCide, let alone EbolaCide2 (although EC2 may potentially leverage some of FluCide data when that is done).
Maybe the situation gets desperate enough in some countries to allow use of medicines with less safety data - but that is a very long shot.
More importantly, however, EbolaCide2 could also provide another source of funds (GAs, NGAs, industry partners) to further work on Ebola and Marburg and other filoviruses that do have larger markets and may qualify for Orphan Drug status with the possibility of Priority Review Vouchers that could be worth tens to hundreds of millions of dollars to NNVC from big pharma companies.
One other possibility - share price run up for NNVC over the sensationalistic coverage of the disease with progress on EbolaCide2. However much of this would likely be from weak hands and may not result in much sustainable price increase.
Lousy Engineer quote:
Don't know why everyone is fixated on Ebolacide- the reality is there's not much money to be made from Ebola.
Time waits for no one - not even NNVC.
I want to see NNVC succeed like most everyone else, but the biggest risk I see is competition. Not circumvention of patents, but other aggressive companies beating NNVC to market with other technologies.
The markets for the 'Cides are huge but how much will be left if NNVC doesn't pick up the pace?
(Let alone all the lethal cases of Flu that could be prevented - saving lives!)
See below for an example of the mindset needed. Admittedly GSK has many more resources to throw at Ebola, but the aggressive mindset of successful companies large and especially small is universal.
We have the money! Let's get after it to get into GLP Regulatory Tox and Clinical Trials! Be creative, work with regulators, bring in the best consultants, hire the best talent, hire more people and buy more equipment for other 'Cides so it doesn't impact FluCide for Tox, expedite with cash whatever is needed to get it done!
- Dec 2013 Presentation by Dr. Seymour - stretch goal of Q1 2014 for GLP Tox
- May 2, 2014 email from Dr. Seymour to Forzanano Post 89375 - Start GLP Tox? This quarter (Q2).
- Now? Is decision now to build drug product for GLP Tox in new plant or continuing in old plant? Either way, what is the status?
Shareholders deserve:
1. Better Communication
2. Better Projections (there is NO TOX START DATE SET in PRs, 10Ks or 10Qs at this time, and that needs to change!)
3. Better Adherence to projected critical path timelines.
Look at the contrast below ...
LINK to Fierce Biotech with images: The Ebola vaccine game plan takes shape as GSK, agencies hit the gas
The Ebola vaccine game plan takes shape as GSK, agencies hit the gas
August 28, 2014 | By John Carroll
When GlaxoSmithKline ($GSK) bought out Okairos last year for $325 million, the platform vaccine technology it acquired was focused on a slate of early-stage development programs covering a range of targets like hepatitis C, malaria and tuberculosis. But in recent weeks the international frenzy over a serious outbreak of Ebola in West Africa has pushed that program to center stage. And today the pharma giant--one of the world's top vaccine players--has joined hands with a global consortium of agencies, nonprofits and investigators to compress a years-long development effort into a matter of weeks as the outbreak worsens.
Initially, GSK officials had sounded distinctly skeptical about whether the vaccine could be ready in time to help contain the outbreak. But this morning there was a distinct can-do attitude in its approach to the crisis.
Using a $4 million grant, Oxford's Adrian Hill will launch a Phase I safety test in about two weeks, once it locks up the necessary paperwork. Hill's study in volunteers will take place alongside separate trials at the National Institute of Allergy and Infectious Diseases in the U.S. And after it's been run through small studies on the healthy volunteers, a green light from regulators would allow investigators to immediately broaden the work to an at-risk population in Gambia and Mali to evaluate whether or not it can contain the virus.
While investigators are testing the vaccine in volunteers, GSK plans to simultaneously ramp up production of 10,000 doses, prepping for a quick vaccination campaign.
If all goes well, GSK says the early-stage study can be wrapped in 3 months--virtual light speed in the pharma industry.
The consortium is gambling on next-gen vaccine technology that was spun out of Merck back in 2007. Inspired by the research of Okairos founder Riccardo Cortese, investigators have been using deactivated chimp viruses to deliver genetic material to cells, triggering a powerful CD8 T cell response--an immune response that can be directed squarely at an invader like Ebola. Most of the attention for Okairos, a 2012 Fierce 15 winner, had been focused on its hepatitis C vaccine work.
The lightning quick effort comes as the WHO notes that the number of people afflicted with the deadly Ebola virus could triple in coming months, noting that 40% of all reported cases have occurred in the past three weeks. The epidemic could ultimately hit more than 20,000 people as health officials try to end the outbreak in the next 6 to 9 months.
GSK R&D chief Moncef Slaoui sounded a note of cautious optimism in his statement.
"Today's announcement shows how private and public partners can pull together to respond to this critical public health emergency," said Slaoui. "Developing a new vaccine is complex with no guarantees of success and it's still early days for our Ebola vaccine candidate. But we are encouraged by progress so far and will do the best we can, along with WHO and our partners, to speed up development and explore ways in which the vaccine could contribute to the control of this or future Ebola outbreaks."
Presumably, Dr. Diwan has completed the work to redesign ligands and made EbolaCide2 on a lab scale for initial testing. Still, I couldn't help thinking how the computer simulation approach of Dr. Diwan and human gamification approach of the U Wash Inst for Protein Design could be nicely complementary leading to 'Cides with ever greater efficacy.
The following is an interesting article from The Seattle Times:
LINK: Gamers helping UW in Ebola research
Images are only available at the link.
Originally published August 25, 2014 at 9:28 PM | Page modified August 26, 2014 at 2:41 PM
Gamers helping UW in Ebola research
Players of the online computer game Foldit are helping University of Washington researchers in their search for a cure for the Ebola virus.
By Katherine Long
Seattle Times higher education reporter
Months before the recent Ebola outbreak erupted in Western Africa, killing more than a thousand people, scientists at the University of Washington’s Institute for Protein Design were looking for a way to stop the deadly virus.
For inspiration, they turned to an unlikely source: gamers.
Specifically, they asked thousands of computer-game enthusiasts worldwide to tackle an Ebola puzzle on the interactive game Foldit, a 6-year-old project that encourages people to solve puzzles for science.
Some of those solutions were so promising that researchers have started to investigate them.
The collaborative work between scientists and game players could as easily be a dead end as a breakthrough. But one thing is clear: The three-dimensional insights by Foldit players helped jump-start an effort to design proteins that could one day help neutralize the deadly disease.
“We actually noticed that the scientists don’t know where to start” when beginning to design a protein to counter Ebola, said Zoran Popovic, director of the Center for Game Science at the UW, which runs Foldit. “What Foldit is doing is creating three, four, five possible places to start from.”
Designing proteins from scratch in the laboratory to block emerging diseases is a new idea, more science fiction than reality. Scientists think it could one day be used to quickly create treatments for dangerous new diseases, or even block old ones, such as influenza.
Six months ago — by coincidence, around the time the current Ebola virus outbreak was identified in southeastern Guinea — biochemistry senior fellow Vikram Mulligan, with the UW’s Institute for Protein Design, put up an Ebola puzzle on Foldit.
Mulligan could have written a computer algorithm from scratch to find weaknesses in the Ebola virus protein, or he could have adapted an already-written algorithm. Instead, he opted to try to use the expertise of Foldit players.
He asked them to identify possible entry points in the virus that could be used to “gum up the Ebola machinery,” jamming the virus’ ability to replicate and sicken humans.
If a protein could be designed to stick to the virus, altering or disrupting its function, that protein could be made into a treatment.
For several weeks, about 500 of the more than 300,000 registered Foldit players tried their hand at the Ebola puzzle, looking for a place where a short chain of amino acids could fit into the virus.
Foldit players manipulated protein models online, taking advantage of human puzzle-solving intuition. They used their cursors to move, bend and twist color-coded protein chains.
And several players came up with top-scoring solutions — “hot spots,” or places where a protein could bind to the virus.
“It turned out human intuition could solve this problem very, very well,” Mulligan said.
Now, Mulligan and other UW researchers are using the results in the lab, designing peptides that could eventually become the basis of an Ebola-fighting drug.
Mulligan emphasized that the lab is not using live Ebola cultures. The UW lab is using an Ebola protein that cannot replicate itself, nor can it infect humans. It is made with a harmless strain of bacteria using recombinant DNA technology, and the peptides are made with yeast, using genetic-engineering techniques.
The two are mixed together to see which peptides specifically stick to the Ebola protein. If some promising candidates result from the work, the results could be given to outside collaborators who work with live Ebola virus strains.
Researchers at the Institute for Protein Design hope that one day, treatments for emerging diseases will be designed in weeks or months — by researchers using computer algorithms to design specific proteins. “The hope is we’ll have a very rapid pipeline one day, from disease threat to candidate treatment,” Mulligan said.
That comes back to the Foldit players. How important are they?
Even a small protein can fold into a tremendous number of different shapes, and knowing the structure of a protein is the key to understanding how it works. As it turns out, “humans can think in 3-D much more easily than computers can,” said Brian Koepnick, a graduate student at the Institute for Protein Design who worked on the Ebola puzzle.
Human Foldit players seem to be better than computers at finding things like virus hot spots, Koepnick said. And researchers may be able to teach those human strategies to computers, making protein-folding solutions even faster and more efficient.
Vijay Pande, a professor of chemistry at Stanford University and director of the Pande Lab, is skeptical about the contribution human gamers can make.
“In this particular case, it seems to me that computation (not gamers) would be more successful” at designing a drug, Pande said by email.
His lab has used computational methods to recombine existing drugs into a potential Ebola treatment. A company, Globavir Biosciences, plans to develop the drug and seek approval for it.
The drug does not use human-designed proteins, and Pande said repurposed drugs are easier to administer and manufacture. “From a drug-design perspective, there are numerous benefits to the repurposing drug strategy, especially when we need to move quickly,” he said.
The UW’s Institute for Protein Design points to some successes, Mulligan said, including a protein that effectively binds some of the peptides in wheat gluten that cause irritation in those who suffer from celiac disease. The drug is going into clinical trials.
And the lab has also designed a protein that protected mice against a lethal dose of the influenza virus. Foldit players contributed to that research, which is still in the early stages.
Protein design is “science fiction now, but we hope it will be science fact one day,” Mulligan said.
Katherine Long: 206-464-2219 or klong@seattletimes.com. On Twitter @katherinelong
That is amazing! And truly a blessing for your father, you and your family.
It is what I hope for NNVC - to relieve suffering and save lives. Everything points in the right direction for nanoviricides - efficacy in vitro, in animals and method of action that is not dependent on host so highly likely efficacy in people - and safety in countless animals to date.
Like you, I also really like the continuing potential of biotech in general for helping a growing and aging world of people. I believe enough to steadily hold the volatile BIB.
Let's hope these breakthrough developments continue for us as we age and for our families. This is truly a great time we live in.
You're a good egg Forzanano! And I was really happy to see when you posted on the father's recovering.
Important new report on site of TOX manufacture from web search (Google: "Flucide Program").
If the source's statement can be believed, he received an email from Dr. Seymour with this information: the Flucide materials for GLP Regulatory Tox are going to be made in the new facility. He posted this on Aug. 25.
If true, I would think this pushes the start of Tox toward the end of this year or early next year. I am figuring about 9mo to 1 year to report Tox results and another 3-6mo or so to file a CTN/CTX with Australia TGA and EC/IRBs. So maybe Q1-Q3, 2016 to start FluCide clinical trials.
I have come to believe this was going to happen anyway (at least use of supplemental FluCide from the new facility - see my previous posts) based on conservative approach of NNVC management and sensitivity of CDER in FDA for similar clinical manufacture in particular for nano materials. Note that NNVC plans to leverage the Australian Phase I/IIb clinical studies for the FDA IND submission.
I have already greatly reduced my NNVC stock holdings waiting for a lower share price due to extended timelines. I am holding a little in case there are bounces in SP on potential announcements on Ebola partnerships or other Ebola developments. Just a long road here. I am not abandoning NNVC, but I am making much better returns short-term elsewhere. I am fine with the potential risk of losing a bit of any upswing in SP. I balance that with opportunity cost of tying up too much in NNVC now and the hope of buying at lower share price.
Msg 1660 of 1687 at 8/25/2014 2:42:21 PM by S_Colton
FluCide Program
I just got word back from ES that, although the old plan was to make tox study FluCide in the old facility, the new 5x quantity requirement has made the old facility a limitation. They’re moving in this week to Shelton, and the output of tox material should go up by a large multiple.
Zinc was right...the company is relying on the new facility to be up and going to expedite FluCide tox testing.
Expect an update in the forthcoming 10K. I don't know when that will come out, but last year (according the NNVC's website) it came out on 10/1...so five weeks?
Thanks, Nanopatent. If anything else on ADIF Patents, IP, licensing turns up, it would be great to know.
Nanopatent, licensing and ADIF rapid response technology question (Accurate Drug In Field TM):
You seem to have a good handle on NNVC IP rights and patents, so maybe you or someone else here can answer this.
Recently, re-reading some of the 10K and 10Q filings, I have noticed that while ADIF is listed prominently as an NNVC technology, there doesn't seem to be any discussion of licensing.
First, while various specific virus technologies are discussed as being licensed by NNVC from Theracour, I have not seen anything about a specific NNVC license or patents on the ADIF technology.
Since ADIF is and has been so prominently indicated in the filings, I would think NNVC would have everything lined up as to ownership or licensing. If so, great, but I would like to see the patent or license references if that is the case.
But second and more importantly, how are the rights and profits to be distributed between NNVC and Theracour if ADIF is used on a virus that is not licensed (yet, presumably?) to NNVC?
If NNVC has clear rights to ADIF, will they still have to negotiate with Theracour for the rights to design and manufacture the new drug - base micelle, ligands, combination?
Could this possibly delay the chance for rapid implementation of the rapid design capabilities of ADIF?
I may be wrong, but this looks to be another COI area that seems to need shoring up AFAIAC to spell out and protect NNVC shareholders (me).
I apologize for my previous curt replies, Bloomvest. Re-reading the Guidance Document you supplied from a layman's point of view, I can see why you are saying cGMP materials are required while others (including me) here have been saying cGMP is not required for Regulatory GLP Tox and Phase I clinical trials.
LINK: cGMP for Phase I Investigational Drugs
Generally, when industry refers to "cGMP compliance", they are referring to complete compliance to all the standards, including validations, warehousing, and very detailed requirements for CMC that apply to clinical Phase II/III/IIV and commercial product.
However, in this Guidance Document, FDA regularly refers to "adherence to cGMP" and "conformance with cGMP" and "compliance with cGMP" for the manufacture of Phase I clinical materials.
What might have been made more clear in this document is that FDA is referring to a subset of cGMP requirements that are required (and appropriate) for Phase I clinical materials (and associated preclinical materials e.g. Regulatory GLP Tox in the background and scope of the document at its beginning).
So you are right that there are cGMP requirements for manufacture of materials for the Regulatory GLP Tox studies. But we are also right that these are not generally recognized by industry as "cGMP compliant" which is commonly understood to be the full set of requirements for Clinical Phase II/III/IV and Commercial manufacturing.
So it will alway cause confusion to say "cGMP compliant materials" in relation to Regulatory GLP Tox or Phase I materials since the requirements are less than for the "cGMP compliant materials" required in later developmental stages. Better just to say something like "limited" or "partially" cGMP compliant materials for Tox and Phase I.
This distinction is perhaps most clear in the Code of Federal Regulations (CFR) which are the statutory legal requirements companies must follow for pharmaceuticals.
21 CFR part 211 are FDA regulations governing most GMP regulations as of 6/1/2013. When current industry practices are included, then they are referred to as current GMP or cGMP.
LINK: 21 CFR 211.
21 CFR part 210.2(c) covers applicability of the cGMP of part 211.
Note the second sentence in Red, Bold that says part 211 (largest portion of GMP) does not apply.
LINK: 21 CFR 210.2(c).
An investigational drug for use in a phase 1 study, as described in 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter. However, this exemption does not apply to an investigational drug for use in a phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study, as described in 312.21(b) and (c) of this chapter, or the drug has been lawfully marketed. If the investigational drug has been made available in a phase 2 or phase 3 study or the drug has been lawfully marketed, the drug for use in the phase 1 study must comply with part 211.
BACKGROUND
A. Statutory and Regulatory Requirements
Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B)) requires drugs, which include IND products, to comply with current good manufacturing practice.
Because certain requirements in part 211, which implement § 501(a)(2)(B) of the FD&C Act, were directed at the commercial manufacture of products typically characterized by large, repetitive, commercial batch production (e.g., those regulations that address validation of manufacturing processes (§ 211.110(a)), and warehousing (§ 211.142)), they may not be appropriate to the manufacture of most investigational drugs used for phase 1 clinical trials.
The 1991 guidance (reprinted in 1992) did not discuss all manufacturing situations, including, for example, small- or laboratory-scale manufacture of investigational products. In addition, the 1991 guidance did not address fully FDA’s expectation for an appropriate approach to manufacturing controls during different phases of investigational product development, which for most products includes a change in manufacturing scale.
This guidance describes an approach manufacturers may use to implement manufacturing controls that are appropriate for the phase 1 clinical trial stage of development. The approach described in this guidance reflects the fact that some manufacturing controls and the extent of manufacturing controls needed to achieve appropriate product quality differ not only between investigational and commercial manufacture, but also among the various phases of clinical trials.
This guidance applies to investigational new drug and biological products (including finished dosage forms used as placebos) intended for human use during phase 1 development that are subject to CGMP requirements of section 501(a)(2)(B) of the FD&C Act, and are excluded from complying with the CGMP regulations in 21 CFR part 211, by operation of 21 CFR 210.2(c).
I hadn't seen Puffer's thinking had changed, but thanks for the update, Sarbreur.
However, it doesn't change my thinking based on my reading of the risks involved with FDA accepting comparability of material produced in the existing lab with future clinical batches made in the new lab and the risk-averse nature of NNVC decisions to date.
They said scale up was "successful" in a December PR for the Annual Meeting - "the Company has successfully performed studies on the scale up of synthesis of FluCide."
This is a long time to be making materials even if it is in the old lab.
Besides, they already made a demonstration batch of the base viricide carrier at the Grand Opening of the new lab. Not much more (relatively) to do to add the ligands.
If they are so close, I would anticipate NNVC using material from the new lab to reduce the chance of rejection of comparability to clinical materials. As Dr. Seymour said, "There are no shortcuts. It must be done right the first time." Post 96884.
I think you are correct that NNVC is planning to deliver test materials to BASi in blended batches together upfront. The Annual Report stated they will be blending batches. But again, IMHO, that doesn't mean they won't add on blended batches from the new facility to study separately in parallel or blend those with the existing materials as a new/old blend, or other options to protect clinical comparability.
In all this I could be wrong. But it is my best guess based on all the available input.
Puffer's latest thinking on IV is that ALL of the material
for tox will come from the existing facility and that it will
ALL be delivered to BASi upfront. Apparently Diwan's preference
to do it that way. He thinks they will start tox by end of
next month and also thinks scale up in the existing facility
has already been accomplished. (I think there was a PR a few
months back already stating that scale up had been successfully
accomplished).
No, still not correct: GMP=cGMP. cGMP is the generally accepted usage, not GMP. Although GLP is generally accepted usage, not cGLP.
Bloomvest quote:
Notice I wrote "per GMP" I agree cGMP is not required.
P.S. You are also incorrect that the materials "need to be produced in the new facility per GMP".
The regulations are clear that cGMP is not required for Regulatory GLP Toxicity studies, although it is recommended.
I agree they likely supplement material for Regulatory GLP Tox studies from the existing lab with material from the new lab.
But they will NOT wait for cGMP certification from FDA. You might want to read those parts of the regs and the company's SEC filings more closely.
What makes sense is use cGMP-like material (before certification) with all the required CMC and documentation for the Reg GLP Tox study - as either supplemental or another arm of the study or possibly (although less likely IMHO) completely cGMP-like.
The letter from Dr. Seymour does leave open the door for your contention of using new material. It also continues to leave open the door for material from the existing lab.
But I agree it fits nicely with the theory that they will use new lab material in some way for Tox.
P.S. You are also incorrect that the materials "need to be produced in the new facility per GMP".
The regulations are clear that cGMP is not required for Regulatory GLP Toxicity studies, although it is recommended.
JG we probably agree on more than we disagree, just not on this point.
There was no communication from the company that I am aware of that the 2013 Tox commitment was GLP for Regulatory submission. This was when I first established a holding in the company, so I hadn't yet started saving links to information. So I don't have a reference (but I am willing to be proven wrong if one is found).
This is not the first time this board has missed the steps or requirements on the development path to Regulatory approval. One other, is the following quote from this FDA presentation:
Toxicology in Drug Development FDA Presentation
What Does FDA Expect in General Toxicology Studies?
- Formulation should be the same as the clinical formulation
What a crock! Frustration with delays and disappointment with ridiculously over-promising by management on timelines is not the same as agreeing with you that everything here is a scam.
They hit their timeline for Range Finding Toxicity in Q2 +/- 3mo last year (although yes, they very poorly didn't communicate the nonGLP nature of the study when they made the commitment.)
They have now committed to have scale up complete in 2014 in the March Shareholder Letter on their website - with completion of manufacture of materials and start of regulatory GLP Tox soon after. For me, they need to announce start of Reg GLP Tox in 2014, not just completion of scale up.
The communication mistakes (IMHO) that bother me the most are giving such clearly unrealistic stretch goals to get hopes up. First the Q1 Reg GLP Tox start goal at the LD Micro Conf in Late Dec 2013 and then the email posted here in early May stating start of Tox in Q2.
The company announced when the new lab building was delayed they decided to take a bit more risk (for ultimate comparability to future clinical material manufacturing - a real concern) and do the scale up and manufacturing in the old lab for Tox.
But, now the new lab is essentially ready for scale up as well. So my speculation is that they got risk averse and decided to have at least a portion of the Reg GLP Tox made in the new lab as well.
But (sarcasm) these complicated considerations of working on a new chemical entity (NCE) for an IND are too complex --
IT All MUST BE A SCAM!!!
(Yes, sarcasm)
Your "Fake Tox" post is plain wrong and twisted, confusing the issue.
See below. Later requirements for clinical trials DO NOT default to the same requirements for earlier Tox studies.
Just because stricter requirements apply to later studies does not mean those same requirements apply to the earlier studies.
Summary of Material Requirements for studies (from memory, but I think accurate):
1. Regulatory Toxicity Studies
- documented, well characterized test material that allows for comparison to clinical materials
- the minimum requirement for a GLP study - but not ever described by industry to my knowledge as "cGLP standard" - there is no "GLP standard" to meet in the guidances or standards).
- cGMP or cGMP-like with full CMC controls and descriptions of the manufacturing process and material properties is recommended, but NOT required.
2. Phase I Clinical Trials for both TGA (Australia) and FDA (US)
- cGMP-like materials are required for the study.
- Documentation showing the consistency and comparability of Tox materials used for preclinical testing to the Clinical materials planned for use in the clinical trial is required.
- cGMP materials are recommended.
- For Australia, either TGA or IRBs review and decide acceptability of all data (including comparability of materials, but also much more) prior to human use.
- For US, FDA makes the call.
3. Phase II, etc Clinical Trials for both TGA and FDA
- cGMP materials are required.
I hope the Bell-ringing on NYSE MKT gets good play tomorrow.
NNVC deserves the recognition for the progress to date. There is a great deal of promise in the technology and it deserves its day in animal studies and clinical trials.
I hope to see the fulfillment of that promise and take part in the resulting deserved rise in share price - even if my opinion is that it is just a bit further down the road than most supporters here seem to think.
If my supposition is correct, GLP TOX will not start until Q1 2015 and will not finish until Q4 2015.
This will also be about the time the new facility is able to start manufacturing cGMP-like materials at the same scale as the existing facility.
The new material could then be dovetailed in with the existing material and would be used to show comparable TOX results between manufacturing sites made with the same scale batches.
Then the next cGMP scale up for clinical studies would be shown to be comparable to the smaller cGMP-like scale for preclinical TOX - both made at the new facility.
I understand this is supposition on my part.
But it is consistent with what FDA likely wants to see for nano-medicines for which safety and consistency is considered to be highly dependent on repeatability and comparability of manufacturing and resulting material properties across sites and scales.