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Ovidius - I take your view on this. When you get a response from the government that cites a "paucity of data" regarding information they specifically asked for, you (PVCT management) have dropped the ball. They should have recognized this before they submitted and either gotten the data they needed or worked with the FDA to get agreement to accept the concept that no tumors means no symptoms.
It will be interesting to see if there is a Plan B.
OK, they didn't "demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints." Seems odd, since PV-10 destroys/shrinks tumors better than anything else available. FDA wanted to see evidenoe of "clinical benefit (e.g., pain, infection, significant bleeding)". PVCT didn't have it. I think both PVCT and the FDA share some blame.
I work as an environmental consultant, and interact with regulators regularly. We apply for permits and go back and forth until the regulators are satisfied. Sometimes we convince them to accept our way, sometimes we do things their way. It's a process.
Wachter explained that they knew they didn't have good information on clinical benefit. The data wasn't collected during the Phase II. Someone should have realized that this would be an issue, and they either should have decided to get the data before submitting, or continue to talk to the FDA about the alternate idea that tumor ablation = clinical benefit. Wachter seemed to think the FDA accept this idea, but obviously they didn't. This looks like a big misjudgement on PVCT's part.
OTOH, the FDA doesn't seemed to have grasped the difference between evaluating systemic versus intralesional drugs. They should be more flexible in accepting end points that fit PV-10, particularly visual evidence that the tumors are gone, so any pain, etc. is also gone, even if an acceptable method of measuring it wasn't used. The FDA could be more open-minded on what constitutes clinical benefit.
More discussion between the two would have helped.
They went from a meeting in December to guidance in January to submittal in March and rejection in May. The glimmer of hope is that it is very clear what PVCT needs to do. I hope they can design a study and get it in front of the FDA quickly. They can re-apply as soon as they get the necessary data. Time and money should take care of that. In the meantime, I hope management works to clean up their image and restore credibility. They are definitely losing the PR battle.
Key point being missed (or deliberately ignored) is that the BTD application is not just based on the 28 patients who had all tumors injected, but also an additional 26 patients who had 1 or 2 tumors left uninjected to study the bystander effect per the article. That's a total of 54 patients.
The trial had limitations on the number of tumors that could be treated. When approved, all injectable tumors will be treated, so the subgroups are more representative of how PV-10 will actually be used.
New article on PVCT website from cCancer. Nice summary of the recent presentations and ASCO abstracts.
http://ecancer.org/news/5688-pv-10-data-for-break-through-therapy-designation-application-highlighted-by-asco.php
If you want to get to the meat of the data, here it is:
"Results showed that for 28 patients who had all their existing melanoma lesions injected with PV-10 (i.e. had no uninjected lesions) the overall response rate was 71% (CI 51-87%) with 50% achieving a complete response (CI 31-69%).
In a second analysis when these 28 patients who had all their lesions injected were considered together with a group of 26 patients who had up to two lesions left untreated (to investigate bystander effects) a complete response was achieved in 232 of the 363 injected lesions (64%).
Furthermore, the abstract showed that in the combined analysis 121 lesions required a single injection for complete response, 84 required two injections, 22 required three injections and five required four injections.
Of the 28 uninjected bystander lesions 10 achieved complete response."
These are the facts. Unlike most of what was spewed out today.
Vorlon - I've seen 2031 before, but I don't know what it is based on. If you saw my other post, my brief research came up with a different date. Do you know how 2031 is arrived at?
Unfortunately, by taking the time to prepare the post, I missed the best buying opportunity.
Go to the PVCT website under the clinical trials section and all the patents are listed. How long is a patent in force? For 20 years after the initial filing. (http://community.freepatentsonline.com/wiki/when-does-a-patent-expire)
Look at the list of patents. At the bottom are the oldest. Click on some of the oldest ones and they were filed in 1996, so they will expire soon. Tragedy? No. These are not for the use of PV-10 as a treatment for cancer.
IMO (not a patent expert) the 2 key patents are the 2 newest ones. 8,530,675 is the synthesis patent - it was filed in 2010. 8,557,298 is the latest describing the use of PV-10 - it was filed in 2007. So they are good until at least 2026. And they can always file additional applications as they find new uses.
It took me about 5 minutes of Googling to find this information. I googled "when do patents expire" to find out how long they last. If everyone would take a deep breath now and then and do a little digging, you will find that, while there is a grain of truth to the "facts" that AF and others put out, they have no relevance to the prospects of approval or bringing PV-10 to market. If you think management and the SAB members are as stupid as AF does (or is), then you shouldn't be here.
He exercised options at 0.95. That's what the code "M" on the form means. It may seem backwards, but this type of transaction is listed as disposed "D" on the form. He did not sell stock, he "disposed" of the options, which means he got the 25,000 shares.
It's explained (poorly) here:
http://wiki.fool.com/Form_4
Look at the explanation for Table II, box 5. If he was being granted options, it would be listed as acquired "A".
Sympton control - this was cited in the Jan. 24 PR about the FDA meeting:
"The Agency agreed with Provectus that treatment of cutaneous and subcutaneous tumors in patients with locally advanced cutaneous melanoma (i.e., recurrent, in-transit or satellite melanoma that has not yet spread from the skin to distant sites) could provide clinical benefit to such patients, particularly if the measured objective responses in patients' disease correlated to a demonstrated treatment effect on one or more symptoms of their disease (e.g., pain, infection or significant bleeding).
The Agency agreed to work with Provectus to quantify symptom control in this patient population
In reference to discussions on the potential for breakthrough therapy designation, "FDA advised Provectus to provide objective response rates with adequate information to evaluate the symptomatic treatment effects (e.g. pain, infection, bleeding) in patients presenting with locally advanced cutaneous melanoma who received PV-10 to all lesions."
In yesterday's PR:
Dr. Agarwala said, "The high rate of symptom control in refractory patients with disease limited to the skin, manifested in CR of all monitored disease after minimal intervention, is the basis for a pending breakthrough therapy designation application for PV-10.
This sounds like PVCT was able to give the FDA what they wanted - correlation of objective response with symptom control. Interesting that Dr. Agarwala stated the connection - more powerful that way.
Thefamilyman - the compassionate use protocol is regulated by the FDA as a clinical trial (http://clinicaltrials.gov/ct2/show?term=Provectus&rank=9), so Agarwala is correct, although it would have been nice if he had mentioned the CUP.
Good article - interview w/ Dr. Agarwala. Picked this up on the Investor Village board.
http://www.thelifesciencesreport.com/pub/na/new-melanoma-therapies-are-ready-for-primetime-sanjiv-agarwala
Summary of current melanoma treatments and investigational drugs, including PV-10.
Ipilimumab (Yervoy) may have some additional serious side effects. Found this information via a post by "Boomertree2" on the Silicon Investor board (http://www.siliconinvestor.com/readmsg.aspx?msgid=29513455). The post includes this link (http://jco.ascopubs.org/content/early/2014/04/28/JCO.2013.51.1683) to an article in the Journal of Clinical Oncology. Here is a quote from the introduction:
"Ipilimumab improved overall survival for patients with melanoma compared with an experimental vaccine in previously treated patients and in combination with dacarbazine in the first-line setting.4,6 However, the immune activation caused by ipilimumab may also result in potentially severe autoimmune toxicity, most commonly involving the GI tract, liver, skin, and endocrine system.7 With increased clinical use, more rare adverse effects are emerging. To our knowledge, no cases of ipilimumab-induced myasthenia gravis have been reported in the medical literature to date. We describe two such cases below."
Yervoy was one of the reasons Adam F called PV-10 obsolete (even though Phase 3 trials are still underway).
ASCO has a policy that "embargoes" the abstracts and data. This sums it up:
"For a study to be eligible for acceptance into the ASCO Annual Meeting, information contained in the abstract, as well as additional data and information to be presented about the study at the ASCO Annual Meeting, must not be disclosed before the findings have been publicly released in conjunction with the ASCO Annual Meeting."
Link to the full policy: http://am.asco.org/confidentiality-policy
Per the Form D, Rule 506b exemption applies.
Rule 506(b) exempts an issuer of securities from registration under the Securities Act for offerings of an unlimited size. To qualify for the exemption, the securities may only be offered and sold to accredited investors and up to 35 non-accredited investors who meet certain sophistication requirements (such as being officers or directors of the company selling securities). Under Rule 506(b), the issuer may not engage in general solicitation of the offer and must have a reasonable belief that the purchasers are accredited investors or sophisticated, non-accredited investors.
Sales started on April 2. About 2/3 of the %5 million have been sold as of the time of filing.
New Moffitt article (http://ecancer.org/news/5569-pv-10-decreases-melanoma-cells-in-tumours.php). Link provided by Investor Village poster Wile_E_Coyote.
It's a followup to the Moffitt presentation at AARC, so most of the information is already known. However, this quote stood out:
"The studies showed that immunohistochemical staining of biopsy specimens for mel A (an immunohistochemical marker of melanoma viability) demonstrated the complete disappearance of viable melanoma cells in both the injected and bystander tumours. "
When they said earlier that there were no viable tumor cells after 7-10 days, I thought they meant the injected tumors. Turns out the bystanders were gone, too.
Well worth reading.
Found this video by Dr. Andtbacka from the Hemonc conference dated today (http://video.healio.com/video/Trial-updates-on-injectable-onc;HematologyOncology). No mention of PV-10. Still don't know what was presented there. There was a PR after the AARC conference, nothing now. Was expecting....something.
Sorry about the link. I was going thru the videos on the Hemonc website looking for any mention of PV-10 from last weekend's conference and got off track. Still, the videos that have been posted in the last few days don't say anything about PV-10. Maybe Dr. Andtbacka's most recent talk will get posted soon.
I don't understand the rest of your post, however. Data from the Phase II patients who got all tumors treated was presented last year, and Moffitt has published a paper and data was presented at the recent AACR conference.
Video of Dr. Andtbacka's presentation at Hemonc.
http://www.healio.com/hematology-oncology/hemonc-today-melanoma/current-status-of-injectable-therapy
New post in the blog (http://provectuspharmaceuticalsinc.blogspot.com/p/blog-news-items.html) quotes that PV-10 would be an "integral part" of the presentation. It's in there, but is by no means highlighted. The data discussed is the original Phase II data. Nothing from the subset that got all tumors treated, nor any update on the Moffitt study.
Merrick Ross and Agarwala were there, too, but I don't see any other substantive mentions of PV-10. Rather disappointing.
Another "news" "Expected best-in-class clinical benefit (March 18, 2014)", a follow-up to the last blog post. This is fascinating stuff.
New "News" item in the Blog. Analysis of the sorafenib fail.
http://provectuspharmaceuticalsinc.blogspot.com/p/blog-news-items.html
This is very good news. In retrospect, it shouldn't be a surprise. This is from the abstract: "In murine models of breast cancer and melanoma, we have shown that IL injection of PV-10 (10% RB in saline solution) leads to ablation of injected tumors and regression of non-injected bystander tumors. In these models, increased anti-tumor T cell responses were measured, supporting the induction of systemic anti-tumor immunity after tumor ablation with PV-10. In our ongoing phase I clinical trial exploring melanoma regression in patients...".
Moffitt worked with breast cancer cells in the pre-clinical part of the study, where the results where the same as with melanoma cells. But they only studied melanoma in Phase 1 (human) portion, and that is what most of the discussion was about. Now we know why they did the preliminary breast cancer work. (I wonder why liver wasn't included, too.)
Great to have people out there connecting the dots.
There are no papers or presentations of the Phase 1 breast cancer data listed on PVCT's website. This is the only discussion about it that I can find, also from the website: "In October 2008, the Phase 1 study was completed successfully. 12 subjects received IL PV-10 treatment. Treatment was well tolerated in all subjects, with no evidence of systemic or serious local side effects. Several subjects exhibited evidence of efficacy, including tumor ablation or shrinkage."
IIRC, they injected tumors, then studied them after they were surgically removed. In other words, the women continued on with standard treatment, so there was no long-term follow-up.
The abstract was available earlier. This is the entire paper, published in the Feb. issue of the Journal of Surgical Oncology. First time that I know of that the entire article was made available to the public.
It's a review article, so there is nothing really new in it, but it's good to see a peer-reviewed paper from a prominent person at a respected institution.
New journal artice by Dr. Merrick Ross at MD Anderson. Link:
http://eorder.sheridan.com/3_0/app/orders/3442/article.php
BTD criteria - FDA guidance defining a breakthrough therapy. From the same guidance document cited in my previous post.
Qualifying Criteria: A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.
Emphasis is from the guidance document. The definition of "serious condition" is that same as used for expanded access, so PV-10 already meets it.
"Preliminary clinical evidence" is required to show "evidence of a treatment effect that would represent substantial improvement over available therapies for the treatment of a serious condition. Assessment of the treatment effect for the purposes of breakthrough therapy designation will be based on preliminary clinical evidence, which could include early clinical evidence of both clinical benefit and an effect on a mechanistic biomarker (generally derived from Phase 1 and 2 trials). Nonclinical information could support the clinical evidence of drug activity." This is just part of the discussion, but it points out that the nonclinical information being generated at Moffitt, for example, can be included in the application. Also, it is suggested that the new drug be studied alone and with the SOC. I can't evaluate if this has been done for melanoma (it's being tested in combination with radiation), but it is being done now for liver cancer.
"Demonstrate substantial improvement" - I don't have the expertise to make this judgement beyond the CR, PR and ORR percentages, which are impressive. The blogger and others are better equipped to provide in-depth analysis of clinical trial results and compare different therapies.
Approaches to demonstrating preliminary clinical evidence of substantial improvement include:
• The new drug reverses disease progression, in contrast to available therapies that only provide symptomatic improvement.
• The new drug has an important safety advantage that relates to serious adverse events compared to available therapies and has similar efficacy.
There are several other bullet points here, and these are suggested approaches that don't all have to be used. Management can use these 2 since PV-10 can reverse disease progression and has significant safety advantages over available therapies.
"Available therapies" - the new drug will be compared to the current SOC.
FDA will make a judgement call based on the contents of the application using these criteria. We can all make our own call by buying or selling. GLTA.
BTD Application - FDA guidance on what is needed. FDA guidance document can be found here:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf
When to apply: Although sponsors may request breakthrough therapy designation at the time of IND submission, or at any time afterward, they should not send breakthrough therapy designation requests until they have preliminary clinical evidence indicating that “the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints.” FDA expects that in most cases breakthrough therapy designation requests would be submitted as an amendment to the IND, but a sponsor could also submit its request with the original IND. Ideally, a breakthrough therapy designation request should be received by FDA no later than the end-of-Phase-2 meetings if any of the features of the designation are to be obtained. (So an application can be made based on Phase 1 data.)
Contents of the application: Breakthrough therapy designation requests should contain the following information (in most cases, this information could be captured in approximately 10 to 20 pages):
(There are a number of bullet items regarding contact info, indication covered, etc., but here is the meat of the application -)
A concise summary of information that supports the sponsor’s breakthrough therapy designation request for the indication being studied, including:
o The basis for considering the drug to be one intended to treat a serious condition
o The preliminary clinical evidence that the drug may demonstrate substantial improvement over available therapies. A sponsor should describe the preliminary clinical evidence, including, for example, justification for the clinical study endpoint used and a brief description of statistical analyses.
Note the use of the words concise and brief. FDA has to respond within 60 days, which is not policy but written into the legislation (we'll see if they meet the timeline).
Compassionate Use - Hi, new poster. Held the stock for many years. Question regarding CUP - only 3 sites in the US are listed as participating. Can a patient be treated at another location? How would a doctor get approval to do that?
Like many, I know at least 1 person who might benefit from PV-10, but transport to one of the approved CUP locations might not be possible.
Thx