Inovio Zika Phase 1 Clinical Trial Design Superior To NIH Zika Phase 1 Clinical Trial Design

Summary

• Inovio has a chance at addressing the Zika problem (protecting pregnant mothers) whereas NIH does not.
• Taxpayers will waste $2 billion or more on the NIH solution which is not effective.
• I novio was first to human trials with a superior product using electroporation for lower expense and highlights the unlocked value in the platform which can be extended to other candidates.

Need For Effective Vaccination of Pregnant Mothers Against Zika Virus

As of August 13th, 2016 there have been 1872 confirmed cases of congenital syndrome associated with the Zika virus ( table 1), many of which have been of the form of microcephaly (babies born with unusually small head circumference). The numbers of Zika cases are growing rapidly worldwide during the summer seasons of peak activity of the Aedes aegypti mosquito. For pregnant mothers in affected countries there is concern for the new born babies and people demand action.

Early Vaccine Trials for Zika - Inovio (INO) Solution Superior to NIH Solution

There are two early Zika vaccine candidates in phase 1 clinical trials. And while both candidates look similar on the surface (both use plasmid DNA to target the premembrane and envelope regions of Zika) the solutions are vastly different upon a more detailed look.

Highlights on the difference between the two early Zika vaccine approaches follow which clearly show that the Inovio solution is superior:

Inovio Pharmaceuticals solution to Zika vaccine:

• From clinic to phase 1 safety data in 12 months [ 9 minutes 21 seconds in this video]
• Cost of clinic to phase 1 safety data per one estimate:$300,000[ 49 minutes 33 seconds in this video]
• Peak immune response and days to peak: 40,000 end point titers at day 30 [ slide 9, bottom right]
• A "very good" immune response (15,000 end point titers) at day 20 [ slide 9, bottom right]
• Possible (?) ability to protect mothers in pregnancy - needs to be proven
• If proven to protect mothers in pregnancy the amount of vaccine needed to be produced to protect those mothers would be low in comparison to the NIH approach
• Uses electroporation delivery techniques for faster uptake of vaccine and therefore faster immunogenicity (able to protect pregnant mothers faster)
• Uses intradermal delivery to the surface of the skin (punctures the skin but just barely). Next gen device won't need to even puncture the skin
• Microneedles to access skin tissue
• Potential for 1 dose for protection(needs to be evaluated if 1 dose will do it - see discussion below)
• Requires only 1 or 2 milligrams ( about the size of a grain of sand) for dose size - small amount of vaccine to produce
• Leverages technology from the father of DNA vaccines Dr. David B. Weiner from the Wistar Institute. The platform and technology is an evolution and optimization of research from Dr. Weiner over a span of 30 years.
• Leverages infectious disease expert and scientist of the year Dr. Gary Kobinger from Laval University

NIH solution to Zika vaccine:

• NIH Zika vaccine is based on the same design as the NIH West Nile vaccine except for delivery device (West Nile used Bioject 2000, Zika uses Pharmajet). There is not much difference between those delivery devices in terms of technology. The data represented below is based on real results from the West Nile data which should be very close to real results for the NIH Zika phase 1 clinical trial.
• From clinic to phase 1 safety data in roughly 18 months (18 months is "estimated" due to the slower rates of immunogenicity for the NIH approach)
• Cost of clinic to phase 1 safety data:$2 billion or more(for reasons explained in this article)
• Peak immune response and days to peak: 10,000 end point titers at day 100[ figure 2 NIH West Nile vaccine data]
• No good immune response prior to day 100 [ figure 2 NIH West Nile vaccine data]
• NO PROTECTION to pregnant mothers. Requires "women of child bearing age" to ALL be vaccinated
• Since ALL women of child bearing age would need to be vaccinated the amount of vaccines produced by the NIH would be much higher than that of the Inovio approach
• Slow immunogenicity (100 days) due to no delivery technique to get DNA in to the cells other than to "overwhelm" the cells with vaccine. [ figure 2 NIH West Nile vaccine data]
• No electroporation is used. Further, no technology is used for efficient uptake of the DNA in to the cell tissue.
• Requires a shot in the arm because the amount of vaccine required by the NIH is too large to use an intradermal approach. This is a side effect of the NIH not having the ability to use an efficient means for uptake of the DNA vaccine whereas Inovio can use smaller doses due to use of electroporation
• No needles required (uses Pharmajet device which uses a spring loaded delivery mechanism)
• Requires 2 or 3 doses for protection spaced a minimum of 56 days apart (8 weeks) or maximally 20 weeks apart (140 days). The reason for this long period is explained below.
• Requires 1 milliliter of vaccine (about the size of half a spoonful). This is a LOT of DNA plasmids to produce compared to the Inovio approach.
• Part of the reason why the NIH solution costs so much is that the NIH is new to the plasmid DNA technology and they are "fishing" for ways to proceed with the technology. Whereas Inovio has 30 years experience with the father of DNA vaccines the NIH have only one study to my knowledge (West Nile vaccine) and are therefore with little expertise on this vaccine type. It is suggested that the NIH partner with Inovio for future vaccine candidates rather than compete against Inovio if the NIH wishes to continue to pursue this path of vaccine solution.

Clearly the Inovio approach is superior to the NIH approach but what is Congress led ("led" being the key word) to believe?

When the Zika epidemic had a recognized impact by the CDC in early 2016 Congress asked that the director of NIAID/NIH, Dr. Anthony Fauci, provide testimony regarding the Zika outbreak. Dr. Anthony Fauci testified a total of 7 times with Congress and during those 7 speeches Dr. Anthony Fauci presented the NIH solution for Zika to Congress but never once mentioned what other companies or organizations were doing to fight the Zika virus. During the same period of time Congress would not listen to testimony regarding Zika from any other source than Dr. Anthony Fauci. This was the first warning sign that something was wrong. How could we permit the NIH which is a national health entity to be biased towards its own solutions to Zika when not allowing for an unbiased representation of other solutions to Zika such as Inovio's? And how could Congress trust that funds would go to the right places if they only heard testimony from one person?

NIH Should Think Before It Spends Taxpayer Money

Between March, 2016 and August 2016 Dr. Anthony Fauci spent a total of $222 million for use by the NIH to fight Zika. During this time Dr. Anthony Fauci ran out of money so he raided emergency funds earmarked towards other health issues such as malaria, universal flu, and tuberculosis during which those latter 3 programs suffered from lack of funds. To be clear that $222 million spent by the NIH only covered a 5 month period which means that an entire year of NIH activity would cost close to a half billion dollars which is a significant amount of money. Dr. Anthony Fauci knew that he was running out of funds and so he asked Congress to pass a Zika Response Appropriations Act (H.R. 5243) which would grant the NIH an additional $230 million in funds. Meanwhile Dr. Fauci has admitted that the Zika vaccine would take about 3 years to show whether or not it will work and at the same time another unspecified amount of time to get the vaccine approved and distributed. At the burn rate of a half billion dollars per year and 3 years plus an extra year for approval and distribution the NIH is going to spend roughly $2 billion on the low end of the spectrum for a Zika solution.

$2 Billion (or more) Gets a Good Solution from the NIH Right? Wrong...

For $2 billion one would assume that you are getting a good product. But it turns out that is NOT the case. The reason that we know that the NIH is not producing a good product is due to it being based on an NIH west nile study from 2011 which has real data. In that study it shows in figure 2 that in order to receive maximum immune response the patient has to wait a total of 100 days. 100 days is a long time to get a protective immune response after a shot (longer than an entire trimester of pregnancy). So if you are a woman in your first trimester and you have Zika the NIH shot will not provide protection until part way thru the second trimester due to the 100 days it takes to offer protection. And the main driver for getting a Zika vaccine quickly is to protect pregnant women which the NIH solution cannot accomplish.

Inovio Has the Better Solution

The immune response in figure 2 of the NIH solution shows that even at maximum protection from the NIH solution it is only 1/4th the immune response of competitors at Inovio [ slide 9, bottom right]. Specifically the Inovio immune response at day 20 is already 150% of the immune response at day 100 for the NIH vaccine and by day 30 the Inovio immune response is 400% (or 4 times) better than the immune response at day 100 for the NIH vaccine ( reference slide 9, bottom right 40,000 end point titers at day 30 for Inovio intradermal EP versus 10,000 end point titers at day 100 for NIH).

If one were to assume that the Zika NIH vaccines were to achieve a faster immune response than the West Nile NIH vaccine then that is also incorrect. Specifically, the documented NIH Zika trial has 4 arms to its trial with the very fastest most optimistic "arm" to the trial having its last "dose" being 8 weeks (56 days) past the initial dose whereas the worst case "arm" to the trial has the last "dose" being 20 weeks (140 days) past the initial dose. Even in the most optimistic case the NIH vaccine will take many more days past day 56 to ramp up to maximum immune response (certainly longer than 60 days) which is nearly an entire trimester of pregnancy. And in the worst case of 140 days for the last dose past the initial dose it would probably be close to 150 days for maximum immune response for the NIH Zika trial which is almost two full trimesters of pregnancy. In short, the baby that the mother is carrying is NOT protected from microcephaly in the NIH vaccine solution whereas with the Inovio vaccine solution there is "very good" protection available within 20 days and maximum protection available within 30 days of a single vaccination.

In short, Inovio has potential for offering a pregnant mother hope. Further data is needed to find out if 20 days is fast enough in the Inovio vaccine case to verify that hope. But Inovio offers hope whereas the NIH solution does not.

NIH admits it cannot protect pregnant mothers - But Inovio might

Dr. Anthony Fauci has admitted that the NIH Zika vaccine is not intended to protect mothers in their pregnancy with the NIH Zika solution. But even though he has stated it there are very likely only a handful of people that understand the significance of this fact. Specifically the time that a woman is most likely to want to be protected from Zika is when they are pregnant. And the NIH solution will not offer those women any help or assurances. Further, how difficult is it to get women of child bearing age (prior to pregnancy) to have 2 (or even 3) doses of NIH Zika vaccine prior to them reaching pregnancy? The answer to that question lies in looking at data from an unrelated vaccine for influenza where 38% of people did not receive even a single shot of the influenza vaccine in 2015. The percentage of people not receiving influenza vaccine would even be greater than 38% if they were required to have more than 1 shot as is the case in the proposed NIH Zika solution. It should be clear that the time at which people will get themselves vaccinated are at times when they feel like it will help them (such as being in pregnancy for Zika) and the NIH offers no help in those circumstances.

Inovio, on the other hand, could help pregnant mothers if the ramp up time on the immune response is fast enough during the first trimester (further data is needed to find out if 20 days for a "very good" immune response will do this or not).

Inovio is more efficient at number of doses that would need to be manufactured than NIH

As already mentioned, Inovio has the potential to only require 1 dose of Zika vaccine per person whereas the NIH vaccine requires 2 (or 3) doses per person. Further, Inovio has the potential of only needing to dose first trimester pregnant women which is a smaller population to dose than ALL women of child bearing age for the NIH solution.

Per one estimate one liter of manufactured DNA plasmids would produce up to 50 vaccine doses. We will use that optimistic estimate herein.

By the time that Zika vaccines will be available (in early 2020's) the number of women of reproductive age will be close to 1.8 billion [ slide 8]. Meanwhile the number of pregnant mothers per year is roughly 213 million per year.

This implies that Inovio would need 213 million doses per year to protect pregnant women (equivalent to 4.26 million liters of Zika vaccine per year or 8,250 five hundred liter fermenters).

This data further implies that the NIH would need (2 doses * 1.8 billion) = 3.6 billion doses total best case or roughly 72 million liters of Zika vaccine or 144,000 five hundred liter fermenters. In the worst case the NIH would need (3 doses * 1.8 billion) = 5.4 billion doses total worst case or roughly 108 million liters of Zika vaccine or 216,000 five hundred liter fermenters.

Clearly the Inovio solution offers a more reasonable ramp up for vaccine production than the NIH solution does. Even if the NIH solution is used at very high cost of development then we also must consider the high cost of production by the NIH solution compared with the Inovio solution which has a lower cost of production. Further, even though DNA vaccines offer many advantages over other vaccine types (such as no cold chain required, speed of creation, and repeatability of quality) there are difficulties in ramping up production to the scale that NIH would require which makes the Inovio scale up of production a more realistic scenario than the NIH solution.

Let's give an example. If you are a DNA vaccine manufacturer in the middle of phase 2 and you do not have efficacy data yet for Zika you would have two trains of thought. One train of thought would be that you would need 8,250 fermenters for Inovio (or 216,000 fermenters in the case of the NIH) to produce vaccine to the levels that the population demand. Whereas the other train of thought is that without efficacy data yet in hand do you go to the expense of buying that many fermenters right away in the event that the vaccine does not work?

The realistic answer to the example is somewhere in between. As a vaccine creator you need to fill initial demand which means that even without efficacy data in the middle of phase 2 you need to start planning for the big fermenters early. But at the same time you cannot purchase all 8,250 fermenters for Inovio (or 216,000 fermenters for the NIH) for vaccine production until you have proof that your vaccine actually works. So being in that position Inovio has the advantage for meeting consumer demand by not requiring as many doses to the population and therefore requiring fewer fermenters. One might argue that the NIH approach is more profitable because it requires more doses. But realistically the NIH is likely not going to be able to meet those profitability goals because the NIH will be unlikely to produce vaccine quick enough to meet the demand. Think about the floor space required in a manufacturing facility to store 216,000 fermenters - that is a very large manufacturing facility. And in the NIH solution that is likely to lead to shortages where people demand alternative solutions. Inovio is an alternative solution that would help meet demand quicker by utilizing only one dose per patient and requiring less manufacturing floor space (8,250 fermenters is large but doable).

Could we save taxpayers $2 billion or more by simply eliminating the NIH solution discussed in this article?

The answer should be yes. A simple analysis can cut out a lot of "fat" from the Zika budget. But the sad part is that the Congress is not asking the scientists to perform such analysis before they award funds and that is leading to waste. In the business world Dr. Anthony Fauci would fail because he is attempting to push four Zika vaccine candidates through because he can leverage bureaucratic contacts. A company leader, on the other hand, would have found the best one or two candidates out of the four possible candidates and focused limited resources accordingly. Per the information in this article it should be clear that the NIH solution to Zika should cut out the funding for the DNA clinical trial that they currently have in progress thereby saving taxpayer dollars on further waste.

Deep Dive Discussion on the Technical Tradeoffs between NIH vaccine and Inovio vaccine

Now let's further examine why the NIH vaccine is ineffective relative to the Inovio vaccine. First, the NIH Zika clinical trial injects half of a milliliter of vaccine in to the deltoid muscle of the arm. That is roughly the size of half of a spoonful of vaccine which if you think of all of the tiny DNA plasmids inside of that half of a spoonful it is a LOT of vaccine. It is almost an overwhelming amount of DNA plasmids when compared to the number of cells around the site of injection in to the deltoid. It is the NIH hope that enough of those DNA plasmids inside the injection make it in to cells to invoke an immune response against Zika. But the sad thing is that the NIH does not have the technology to get the DNA plasmids in to the cells of the deltoid muscle and so therefore the use of an "overwhelming amount of DNA" is their only hope for success. And in reality less than 1% of the actual vaccine makes it inside of the surrounding cells to get the NIH immune response. This is why the immune response from NIH is lower than the Inovio solution where the Inovio solution requires less vaccine due to Inovio having a more efficient means of getting DNA plasmids in to the cell tissue called electroporation.

In order to understand why it takes the NIH solution so long (100 or so days) to get a maximum immune response we will use an analogy of a balloon. Think of a balloon that you blow up with air. You inflate it. Think of the outside of the balloon as being analogous to a cell membrane in the body and think of the air inside of the balloon as being analogous to DNA that you want inside the cell. The only difference is that in the case of the balloon the air wants "out" of the balloon whereas in the cell in the body the DNA wants "in" to the cell. Now think about ways in which to get the air (aka DNA) out of the balloon (in to the cell). Well, one way you can do it is to use a needle and pop the balloon. But that is kind of drastic because you would lose the balloon entirely. In a similar way if you turn up the voltage too much on the Inovio electroporation device it will "pop" the cell and the cell is no longer viable (this is called "necrosis" when it occurs for cells in the body that die due to electroporation). But what if you could speed up the amount of air that leaves the balloon by leaving tiny pin pricks over the balloon which are too small to make the balloon pop? In that way you can get the air out of the balloon and still leave the balloon externals "viable". In the same way, Inovio electroporation is designed to leave tiny pin prick holes in the outside of the cell but still leave the cell viable so that the DNA can get in. This allows for uptake of the DNA to occur quickly. Now in the NIH case they don't put any pin prick holes in the balloon. But the balloon can still deflate and it takes several weeks to do so. That is because the air eventually finds a way out of the balloon on its own thru probabilistic gas theory where the atoms continue to bounce around until they finally find a means to get out. In the same way the NIH approach uses probabilistic fluid theory for getting DNA in to a cell that doesn't have any major holes in it. The NIH approach takes time and the NIH approach also loses some DNA because it takes too long for the viable DNA to get in to the cell. So as a result the NIH immune response is muted compared to the Inovio electroporation approach. And the NIH Zika solution takes too much time to create a protective immune response.

Summary

The Inovio vaccine for phase 1 will go from the clinic to safety data in 12 months ( reference 9 minute 21 second mark) for some estimates as low as $300,000 ( reference 49 minute, 33 second mark). $300,000 is low partly due to GeneOne funding the R&D portion of the Inovio vaccine (partnerships help - hint to the NIH on how they can do better next time). But the $300,000 is also low due to Inovio, Wistar Institute, and Laval University (Dr. Kobinger) working together to provide low cost solutions via infectious disease platforms whereas the NIH is scrambling to answer the call for which the NIH has no answer. Further the Inovio solution has the potential of only requiring a single dose (NIH requires 2 or 3 doses) delivered to the surface of the skin (intradermal electroporation) with a dose size that is roughly the size of a grain of sand (1 milligram of vaccine) . That is the difference between an effective program (Inovio) and an ineffective program (NIH).

The NIH will spend $2 billion (on the low side estimate) for a Zika solution that will not achieve the goal of the vaccine (to protect pregnant mothers). And the NIH will have multiple cost overruns along the way. We know that there will be cost overruns for the NIH solution because its burn rate is about half a billion dollars per year and the current funding is only granting $34 million to the NIH to keep things going for a few weeks until Congress gets back from vacation .

Which one would you fund with taxpayer dollars?

1. The NIH spending $2 billion (low side estimate) for an ineffective Zika solution
2. $300,000 (as one estimate) for an effective (20 days or less for 150% protection and 30 days for 400% protection Zika vaccine from Inovio

As a taxpayer I choose option #2 and I think that option #1 is disgraceful. As taxpayers we should all be angry that option #1 is even being proposed.

As with any phase 1 clinical trial, the Zika phase 1 clinical trials are designed with small sample sizes and focused on safety as opposed to efficacy even though there may be some metrics collected during a phase 1 such as the endpoint titers which is a preliminary indicator of efficacy discussed in this article. Investors should be careful before making investment decisions in a company such as Inovio that has yet to prove efficacy with Zika in humans.

Other Zika solutions not yet in clinical trials or being evaluated (in the case of genetically modified mosquitoes)

There is a separate vaccine from BARDA which will need $342 million to fund Zika vaccine phase 1 which is more than a factor of 1000 more expensive than the Inovio vaccine solution.

Other Zika solutions are on the table such as genetically modified mosquitos from Intrexon (XON).

Vaccines from companies and institutions such as Bharat, Bio-Manguinhos, Butantan, US CDC, Hawaii Biotech, Inovio, Institut Pasteur, NewLink (NLNK), NIH, Novavax (NVAX), Replikins, Sanofi (SNY), Themis Bioscience, Valeva, CureVac, Geovax (GOVX), GSK, Institut Pasteur, Johnson & Johnson (JNJ), Merck (MRK), Oxford University, Pax Vax, Pfizer (PFE), Profectus Biosciences, Protein Sciences, Sementis, Sinergiu, and Takeda (OTCPK:TKPHF) are all preparing solutions to Zika.

Stocks: INO, XON, NLNK, NVAX, SNY, OTCQB:GOVX, GSK, JNJ, MRK, PFE, OTCPK:TKPHF