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That is correct. Nice to have an update. Phase 1 should be done by end of Feb or beginning Mar. Hopefully they expedite the report and FDA doesn't have to see Phase 2 data until IDE submission. This would save time.
From the last PR:
After three (3) years of effort, Vivos Inc. was provided the opportunity to deliver a presentation to the Mars Veterinary Health Pet Cancer Care Alliance. This Alliance is an advisory board to over 3000 clinics across the world.
We used our contacts to put the word out in Los Angeles that we can treat celebrity pets with cancerous tumors.
Our rabbits are currently enjoying the state of the art facilities at JHU. We all wish them well!
https://researchanimalresources.jhu.edu/
If you add the opportunities for combination therapies to the already large number of tumor types that can be potentially treated with Radiogel, the sky is the limit !
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407252/
We will not approve anything less than 100% containment of negativity assessed by state of the art methodology !!!
IDE submission is most likely end of Q2 or Q3. Technically, the clinical trial can start as soon as the IDE is approved, assuming the IRB approves the protocol before then and patients are ready to be recruited. On one of my projects the first patient was dosed 2 weeks after IND approval.
Contrary to what some may say RDGL is now in a great position. In the words of one of the most successful heads of research in big pharma, "Drug discovery/development in a bloody business. It's hard". I know medicinal chemists with 30+ years of experience that have never worked on a single compound that made it to market approval. I have a client who started on a device in 2008 and they are still not in the clinic. Dr K is not perfect but nevertheless did a great job getting us to where we are.
The FDA has suggested the EFS and we are now one preclinical study away from the IDE submission. They want to see Radiogel going into patients as much as we do. Safety is paramount to them so the containment study will help defining the top radioactive dose that can be administered. It is highly unlikely they will request another study.
For an EFS, the device does not have to be in its final form:
https://www.fda.gov/medical-devices/investigational-device-exemption-ide/early-feasibility-studies-efs-program
Yes, they have the rabbits. In the best case scenario they have propagated the original VX-2 tumor cells and have fresh cells available to inoculate study rabbits for Phase 1. Count 3-4 weeks for tumor growth and 2 weeks for containment study so Phase 1 data could be available end of Feb. Starting with cryopreserved cells would add ~3 weeks to the timeline.
Phase 2 appears to have been added to the protocol later. Not sure whether the FDA requested it since it is not a containment study. It's definitely a nice to have.
Another fact: Nobody on this board knows exactly what the FDA requested other than it is related to tumor containment. We only know roughly the study RDGL proposed to address the question and that it was accepted by the FDA. Everything else is speculation.
Fun facts:
The limit of detection of Y90 by PET is 1 MBq/mL (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726297/).
The limit of detection of Y90 by liquid scintillation counting is ~ 0.1-1x10-6 MBq/mL, depending on the tissue processing protocol (https://www.unitjuggler.com/convert-decay-from-dpm-to-MBq.html).
Question: Which method is more sensitive to quantitatively determine Y90 distribution to major organs?
More on Dr Fisher can be found here: https://versantphysics.com/drfisher/
His scientific and professional accomplishments are outstanding. Anybody questioning his credentials or any of his published work should contact him and give him the opportunity to answer or rebut directly.
Even after nearly 50 years of research in the field and 100+ papers, Dr Fisher apparently needs to be educated!
Somebody on this board keeps calling Dr Fisher and RDGL "positron deniers" and criticizes them for not using PET to assess containment. The paper below once again proves him wrong.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044762/
Extremely difficult, apparently...
The small fraction of Y90 that decays to an excited Zr90* which in turn decays by emitting gamma radiation does not make Y90 a direct gamma emitter.
Y90 -> Zr90 + Zr90* + beta
Zr90* -> gamma
Yittrium-90, a pure beta-emitter? Really? I wonder where they got that from?
The update mentioned:
"Johns Hopkins received the rabbits for our VX-2/Rabbit Animal Study and now has let them acclimate for the required two weeks."
Now, if they meant:
"Johns Hopkins received the rabbits for our VX-2/Rabbit Animal Study and now has TO let them acclimate for the required two weeks."
Then inoculation can't start for another 2 weeks.
In today's PR you will read that the rabbits have been acclimatized (2 weeks) and are thus ready to be inoculated. It's all in JHU's hands now.
There are 2 major unknowns that will influence the timelines:
1. Will they need 2 rounds of inoculations per phase? (i.e. one set of donor rabbits and one set of recipient rabbit to get enough rabbits for each study - starting from cryopreserved VX-2 cells the yield is ~33%, from fresh cells ~88% - it is possible that JHU propagated the initial rabbit inoculated to avoid starting from scratch, unfortunately we don't know)
2. Are Phase 1 and Phase 2 run sequentially or in parallel?
Assuming a worst case where they need the 2 rounds of inoculation for each phase and the studies are run in sequence, JHU will need ~ 5 months.
And how many approved oncology drugs are 100% safe? I have been involved in INDs where the therapeutic index was close to zero... And they were still approved. It's all about risk/benefits.
The rabbit test(s) will take some time if Phase 1 and Phase 2 are run in sequence.
IDE submission will likely be in 3Q and first patient enrolled in 4Q.
Indeed, a very good PR. Only those who have never developed any drug/device would think otherwise.
It also shows that, unlike the claims of some, RDGL has been busy on multiple fronts. The stage is now set for a very exciting year ahead!
We don't have cryopreserved rabbits but cryopreserved VX-2 cells. A big difference!
Rabbits have been ordered. They may have been delivered this week or will likely arrive next week. Acclimatization is rarely longer than 1 week so Phase 1 will start soon.
The containment study is non-terminal for each time point (except the last one) so they need N=5-6 tumor bearing rabbits (I doubt the FDA asked for more). The big unknown is whether they will use rabbits inoculated with cryopreserved cells or rabbits inoculated with fresh cells. The latter will take 2 rounds of inoculation and an additional 3-4 weeks.
From the Nov 1st update:
"The FDA accepted the Risk Management Report. This analysis concluded that under the worst-case scenario of a missed injection, the dose to any significant organ was less than 1.4 Gy, which is insignificant."
A missed injection is like 100% leakage!!!!
I wish I had bought a lot more when it was ~2.5 cts.
Fasten your seatbelt. 2023 is going to be a fun ride and nickel days will be over soon!
Per the Nov update:
"We translated our animal test plan into the FDA GLP protocol. It is now divided into Phase 1 to determine biokinetics and Phase 2 to measure effectiveness. Johns Hopkins obtained the IACUC approval to initiate Phase 1 and is preparing an amendment to include the control group of rabbits for Phase 2"
One way to look at effectiveness is to measure tumor growth inhibition.
If they follow the same protocol as in the paper below there will be one set of donors rabbits followed by a second set of recipient rabbits used for the containment study (Phase 1). This would take ~ 3+3 weeks, plus 2 weeks (~4.5 Y-90 half-lives).
https://journals.lww.com/health-physics/_layouts/15/oaks.journals/downloadpdf.aspx?an=00004032-202105000-00003
Phase 2 (efficacy study) may take longer if they follow tumor growth for up to 28 days after treatment.
Where did you read this?
6.2
"2014 failed IDE application"
Wrong again. RDGL has never submitted an IDE before.
"A pre-submission meeting (Q140496) was held with the FDA on June 17, 2014, during which the FDA maintained that RadioGelâ„¢ should be considered a Class III device and therefore subject to pre-market approval. On December 29, 2014, the Company submitted a de novo petition for RadioGelâ„¢ (DEN140043)"
De novo petition and IDE are not the same thing. RDGL was trying to get market approval without having to go through the lengthy and costly IDE/Phase 1-3 path.
"He went into meeting resisting but prepared to surrender"
You are again changing your story...
There's nothing wrong with that. I have been on programs where we did not agree with the FDA. If it's ok for big pharma, it's ok for RDGL.
"Updates between first and 2nd meeting confirm MK knew FDA was suggesting more animal testing, and he was foolishly resisting that suggestion"
MK went into the second meeting with a draft rabbit study plan. So obviously he was not foolishly resisting.
You are misreading RDGL's statement:
"Vivos Inc. is pleased to announce that it has submitted the IDE, Investigational Device Exemption for The Early Feasibility Medical Device Study, First in Human Study for Y-90 RadioGel â„¢ , to the Food and Drug Administration as part of a pre-submission meeting process"
It is clear that they mean that submission of the IDE is part of the pre-submission meeting process. Not that the EFS is part of the pre-submission process.
So, my beef is with you.
"We now know this was the containment verification testing. MK foolishly resisted the suggestion"
Again, you're making assumptions to fit your narrative. The additional specific testing could be the sterilization validation runs on the particles referred to in the Nov update.
"My point was animal test plan hasn't started yet as of today's date"
Sorry, can't change your story every time you're caught!
"Submitting a draft IDE to FDA for comment under pre-submission discussion program isn't submitting a real IDE application for their consideration"
Of course not! But they have submitted a document which was reviewed.
"FDA will only consider Radiogel human trials when RDGL submits an IDE application"
FDA IS considering Radiogel for human trials and this is why they recommend the EFS!
"nobody knows the degree of Radiogel containment within a tumor"
That is incorrect. They have data in rabbits, cats, and dogs. Maybe not exactly what the FDA wants to see, but they have data.
"That's why FDA suggested the test"
Do you really know why the FDA suggested the test? Were you at the meeting?
"3rd meeting topic was animal test plan that hasn't even started yet!"
I am glad they didn't start the study without the FDA's ok. That would be dumb.
"RDGL hasn't even submitted an IDE application for FDA to consider"
RDGL submitted a draft IDE which the FDA reviewed and commented on.
"RDGL makes all kinds of bogus product attribute claims for present version of Radiogel without any data whatsoever to support those claims"
What kind of bogus attributes?
Summary from the 2nd meeting:
"The Vivos team felt that our meeting with the US FDA on 5/20/22 was a significant positive turning point in the FDA review process. We proposed an additional short-term animal test to prove beyond any doubt that RadioGelâ„¢ can deliver a precise dose of therapeutic radiation and does not migrate from the tumor site. We now have a clear path forward with the review team toward obtaining the IDE needed for the first in human clinical trials."
Where do you see resistance into 3rd meeting?
And nowhere was there a mention about data from previous vs current version as being an issue. You just made this up and keep repeating it. For an EFS the product does not have to be in its final form.
"always important to keep in mind why someone is asking for something" I couldn't agree more. You obviously don't know why the FDA is asking more data....
You forgot that the FDA already agreed that even if there was a miss-injection it wouldn't present a major risk. So obviously tumor containment does not have to be 100%.
" The FDA accepted the Risk Management Report. This analysis concluded that under the worst-case scenario of a missed injection, the dose to any significant organ was less than 1.4 Gy, which is insignificant. We also summarized the specific reasons that RadioGelâ„¢ is inherently safe. If the FDA accepts the draft meeting minutes, these safety conclusions will be in the permanent record and included in our application for the IDE for clinical testing."