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"You should read Toca results" <-- This is my favorite quote. Any other words of wisdom?
So 83% = 100%. And =< 5 cm is the same as no limit. Got it. Thanks.
Look at all of Celldex's CRs in phase 2. Better than VB-111, right?
http://ir.celldex.com/releasedetail.cfm?ReleaseID=809242
You can laugh all you want. Last I checked I don't think VB-111 limit tumor size to =< 5 cm.
No worries. Many analyst are like you: drawing false conclusions from different data types.
Toca did limit tumor to =< 5 cm (slides 11 and 13). If their phase 3 criteria is different (celldex) then that would be a huge red flag.
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Toca and VB-111 have different mechanisms for attacking the cancer cells. One tries to starve the tumor while the other one tags it so it can be detected (and killed). Both seem effective but neither is highly effective.
Perhaps (and this is my hope) they complement each other and be more effective together? I would love to see a trial with Toca and VBL -- once both are approved (knock on wood) -- with Avastin out of the way.
To answer your question, I see Avastin as more of a 'competitor' to VB-111 than Toca. rGBM patients jump from one treatment to the next and take a 'cocktail' approach so Toca getting approved doesn't hurt VB-111, imo.
You can find Toca's latest presentation here: http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Tocagen is actually not very supportive of Avastin:
http://tocagen.com/impact-avastin-bevacizumab-clinical-trial-eligibility/
You're comparing apples to oranges. Tocagen's data is from recurrent HGG. VBL is recurrent GBM (grade 4).
I haven't seen the details of the CRs for Tocagen but yes, the reported results look very good. It looks like the FDA has seen something that it liked -- very much.
I would compare VBL against other rGBM treatments only.
Still a limit, right?
It looks like they limit the tumor size: "Does the patient have either (1) a single, enhancing tumor recurrence/progression that is ≤ 8 cm in greatest dimension."
https://clinicaltrials.gov/ct2/show/NCT01985256?term=tocagen&rank=4
AdamF seems to like TOCA:
Adam Feuerstein?
@adamfeuerstein
$TOCA — Is this negative stock move bc of the Toca 511/FC data update, or bc lack of near-term catalyst? Strange (to me.)
"The sponsor has provided preliminary clinical data that demonstrate that treatment improved survival in recurrent platinum-resistant patients. An indirect comparison was conducted to show that the survival benefit compared favourably with the survival observed with authorised products. The Committee considered that this constitutes a clinically relevant advantage.
A positive opinion for ofranergene obadenovec, for treatment of ovarian cancer, was adopted by consensus."
The last part is also a nice read.
My take away is that a medical committee reviewed the data and found it compelling enough to grant orphan status.
Here is the background for the COMP coordinator:
http://www.ema.europa.eu/docs/en_GB/document_library/contacts/bdaum_CV.pdf
The committee consists of medical professionals with similar backgrounds. Their vote, imo, is significant because in order to get the designation, they get an up close view of all the data and immediate answers to any question that they may have.
Ovarian orphan news came out last week, if you knew where to look.
This was published last week:
http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/10/WC500236838.pdf
search for "envigo" which is consulting for VBL
You can say everything is nonsense since nothing has improved OS.
pro's and con's of SPA. It seems like most of the con's are in the process of obtaining a SPA and operating under it - stuff that I (and I would guess most other investors) don't care about. Once the trial is under a SPA, then it's mostly beneficial if one's goal is to get the drug approved.
https://camargopharma.com/2017/04/special-protocol-assessment-important-drug-development-program/
Phase success and LOA for drugs receiving a FDA SPA or orphan drug designation
http://www.nature.com/nbt/journal/v32/n1/fig_tab/nbt.2786_T9.html#t9-fn4
extremist .. here is a good place to start: http://ir.vblrx.com/static-files/9b1c10ac-65b5-4867-9100-0c25ab7a1a9c
In the presentation, check out slides 6 and 33.
"Study data also suggest that VB-111 may induce an immuno-therapeutic effect. Of the 46 patients who received VB-111, 25 patients experienced a fever post-dosing of VB-111 at least once, while 21 patients did not. Feverish patients demonstrated increased overall survival of 16 months, compared to non-feverish patients, who had a median overall survival of 8.5 months (p=0.03). This correlation between clinical efficacy and fever suggests that VB-111 may induce an immune response in patients and supports a role of the immune system as part of VB-111’s mechanism of action. "
At a high level, the fever suggests the activation of the innate immune system (the body detects foreign microorganisms), which heats up the body as a first line of defense. This then recruits/activates the adaptive immune system, which is more specific (and more potent). Evidence of cytotoxic CD8 T-cells and apoptotic cancer cells suggest that the adaptive immune system was present at the tumor site.
These fever responses were seen in rGBM and prOC (and I would guess Thyroid as well) patient populations treated with VB-111. I don't think the determination is final but it has the FDA and the medical community very curious/excited about what's going on with VB-111.
Oren ... the way I understand mOS and 12-mo survival is as follows. VB-111's 12-month overall survival is 57% and its median OS is 59 weeks (over 12 months). This is why I was confused why you predict that mOS would be OK but the 12-month survival would be extraordinary.
Can you explain how mOS will just be OK but 12-month OS will be extraordinary?
I'm assuming that "OK" = lower than phase 2, and "extraordinary" = much much better than phase 2. Correct?
My take on this is that the FDA wouldn't allow them to move to phase 3 if they found evidence of data tampering. Companies can find other ways to make the data favorable (through using the inclusion/exclusion criteria) in phase 2 but that comes back to bite them in phase 3.
If twitter/internet experts can see the change in data I'm sure the FDA, with the data right in front of them, can see the change. VB-111 is a fast-track / orphan drug. Wouldn't surprise me if the FDA requested and approved the change.
Chardan Inaugural Gene Therapy Conference
Repeated many things:
- Didn't select for patients
- Effective with rGBM, prOC and Thyroid
- rGBM patient with 2 recurrences in complete response since 2013
Evidence of immune component due to immune reaction. Expect separation between two arms to be later. It takes time for immune system to activate - delay about 100 days.
DSMC decision based on safety and survival. Not allowed to stop trial early for efficacy because it's a single trial looking at survival under SPA. FDA agreed to put drug on the market based on SPA and they don't want to cut it any shorter.
Company is blinded but not patients and doctors.
Past approvals had 15-20% responders. Takes time to analyze final data.
Company *thinks* the data will be positive so they're building the new manufacturing facilities ($7 million).
If tumor is completely non-angiogenic, VB-111 has very little chance to work. Needs some angiogenisis to bring CD8 cell, immune system kicks in. Combining checkpoint inhibitor (won't work with limited mutations or immune system present ) with VB-111 (will bring CD8 cells into the tumor) will give checkpoint inhibitor better chance to work.
I totally understand his MO. He is a "click whore" who writes click-bait material. The more clicks = more $$$ for him. That's why he goes out of his way to over-dramatize events.
He is also a manipulator, who uses his blind followers to manipulate the stock of a company.
"Shortened FDA Advisory Panel Is Bad Omen for Puma Bio's Controversial Breast Cancer Drug" -- Fraudstein, 4-18-17
This is what Fraudstein said about PBYI on 4-18-17. PBYI's stock price was $36.85. It fell to $29.00 on 5-8-17. On the day of the FDA panel, 5-24-17, (positive outcome for PBYI) the stock jumped to $74.95. It is now trading at $121. So yes, I hope Fraudstein did short the stock. I just feel back for all those people that blindly followed him and his "advice".
https://www.thestreet.com/story/14091093/1/shortened-fda-advisory-panel-is-bad-omen-for-puma-bio-s-controversial-breast-cancer-drug.html
Fraudstein has been wrong on other biotechs. I hope he got burned on all of them.
The back story is the failed IPO. The fraudstein is (wrongly) blaming it on the CEO .. (fraudstein has an unhealthy dislike for Israeli biotechs). But if he did his research he would know, "The IPO in August was canceled because one investor, US venture capital fund Keffi Group, headed by founder Jide Zeitlin, did not deliver its money at the closing."
And if the name Jide Zeitlin / Keffi sounds familiar it's because he lost all his shares to Thai Lee for defaulting on his debt. Zeitlin is a sleazy investor and didn't have the money to deliver. I'm glad he is no longer one of the major shareholders.
http://www.globes.co.il/en/article-vbl-therapeutics-raises-40m-in-revived-nasdaq-ipo-1000975891
I'd be more concerned if there weren't any skeptics. Everyone should do their own research and make decisions accordingly.
Many of these "experts" recently said that VB-111 was going to report its interim data. This shows that they're lazy and didn't listen to the last conference call.
I am somewhat surprised that the stock price did not increase by more than 3-5% (it's at negative 0.8% as I type this). But for long-term investors, daily/weekly price movements is not a big deal.
DSMC final recommendation is great. Topline data is in a few months. Ph3 prOC and facilities will not significantly move the needle. It will be the topline data and perhaps, a partnership announcement (if positive). But ultimately it will be the topline data, which will (hopefully) lead to FDA approval.
Chardan Gene Therapy Conf on Tuesday, 10/10.
1) This is Chardan's inaugural conference.
2) Chardan has followed this company since 2015 and has always maintained a Buy recommendation (PT $20s)
3) Webcast: http://wsw.com/webcast/chard/vblt/ (1:45 pm ET)
This one, imo, is worth watching. Chardan is very familiar with VBL.
I have been on many boards and I must say, this one is one of the better ones; one of the more enjoyable ones. But you're right: we can always improve on being more civil and respectful.
thank you, wcopeland, for your (always) fair and balanced thoughts. I look forward to your contributions and (hopefully) our celebratory virtual high-fives if/when positive results are announced!
Some unusual (good) events so far for the VB-111 trial:
1) FDA encouraged/allowed ph3 to start before ph2 ended;
2) Recruiting was 5 months ahead of schedule; and
3) FDA allowed DSMC review and no interim.
None of these things change the mOS one way or another. On their own, we don't see each of these events happening often. But with this trial, all 3 have occurred.
VBL has limited resources so I don't see them having much influence over the FDA - compared to other biotechs - or focusing resources on making these events happen.
Item #1, the FDA must have seen something (durable responses?) that made them want to accelerate ph3. Hurry up and get this thing started!
Item #2, physicians and patients (who are much more savvy these days) drove this event, imo.
Item #3, again this is something the FDA allowed. I'm not so sure what it means .. perhaps the final data will reveal why this happened.
exactly, mantoo123. Making up info and claiming it's legit seems pretty desperate. If VB-111 improves mOS even by 10-20%, then that would be a major accomplishment.
I have a hard time understanding weak, fabricated info.
"The 105th event is irrelevant when it happened, who cares?
Based on the above the minimum composite rate reached so far is pretty solid, and if Avastin is behaving like historical (that is the only big assumption I am making), then VBL111 is already showing an improvement vs Avastin monotherapry. "
Who cares? LOL. Backtracking now are we ...? If your numbers are solid then you would know this. Interim was going to be a big event until the FDA canceled it. But for you, it's, "Who cares?" Keep making up these idiotic assumptions ... can't wait for when the final numbers come out.
By the way, hope you haven't mistaken VB-111 for VBL111. Being that you're experienced and all ...
Stop with the nonsense. I have not been paying attention? That's funny for a newbie to come here and say that.
You act as if your numbers are somehow solid, but they're not; they're assumptions. If you're not assuming then how many people were in each arm when recruiting was completed? If you're so certain tell me when did 105 events happen and what was the split between the 2 arms? When will 189 events happen and what will be the split between the 2 arms?
Spin it any way you want. There is no way your numbers are anywhere near solid.
========
staccani Saturday, 09/30/17 09:53:49 PM
Re: gr8db8 post# 1389
Post # 1391
If you still think that timing of recruiting (august 15 to nay 16 first 50 ca, june 16 to august 16 another ca 78 and Sept 16 to Nov 16 another ca 126 and dec 16 the last 2 patients ) is an assumption you have not Been paying attention. Also timing of events is not an assumption as we know we have not reached the 189th event yet
On its own it may be a minor risk, but when compounded with other assumptions -- timing of recruiting results, timing of events -- it becomes significant.
"Anyway the risk here is if avastin behaves significantly better than historical, so nothing is sure." Yes, this is the risk when making these types of analysis. Even if the recruiting numbers and events are accurately projected, not many know how much each arm contributed to these aggregate numbers.
Trial will be stopped if mOS improved by 50%+. Optune's trial was stopped with less significant improvement in mOS:
In the per-protocol population, patients treated with TTFields plus temozolomide demonstrated a statistically significant increase in OS, a powered secondary endpoint, compared to temozolomide alone (median OS 20.5 months versus 15.6 months, hazard ratio=0.64, p=0.0042). In the intent-to-treat population, the median OS was 19.6 months versus 16.6 months, respectively, hazard ratio=0.74 (p=0.0329).
http://www.businesswire.com/news/home/20151215005370/en/Journal-American-Medical-Association-JAMA-Publishes-Pivotal
In November 2014, the trial’s independent data monitoring committee concluded that the study met its endpoints at its pre-specified interim analysis of the first 315 patients with 18 months or more of follow-up. The committee recommended that the trial be terminated early for success and that all control patients be offered TTFields therapy even prior to progression.
http://www.businesswire.com/news/home/20151215005370/en/Journal-American-Medical-Association-JAMA-Publishes-Pivotal
Of particular interest was the decision not to include a sham device or placebo control in EF-14. The roundtable participants agreed that one the most common criticisms of the trial is the lack of a sham device or double-dummy design to control for potential placebo effects. Dr. Stupp reported that during the design phase, he and other trial participants agreed that it would not have been ethical or practical to include a sham device to control for possible placebo effects, given the burden of carrying a device which would have no potential for therapeutic benefit.
While the positive results associated with TTFields in EF-14 might be due to placebo effects, the panel agreed that seemed unlikely—particularly with respect to objective endpoints like OS which is a categorical event. Also, the magnitude of benefit observed with TTFields was robust (HRs of 0.69 and 0.75 for PFS and OS, respectively), typically beyond what one usually expects with a placebo effect.
A concern was also raised by the expert panel about the recommendation by the IDMC to terminate the trial and allow control patients to cross-over and receive TTFields based on the early interim analysis of the study data. Although this analysis was pre-specified, it occurred after only 50% of overall study events occurred. The roundtable attendees cited narrowing of the Kaplan-Meier curves noted with further follow-up of the study data presented at ASCO 2015, relative to the data presented approximately six months earlier, as a concern that the IDMC recommendation may have been premature, although the p values for both endpoints remained unchanged. The panel categorically supported continued and long term follow-up of all of the EF-14 trial participants, with a clear intent to track the percentage of control patients who cross over to start TTFields therapy following the IDMC recommendation and clarification of their outcome relative to the control patients who opted not to cross-over.
As a group, the roundtable participants agreed that the appropriately 3-month gain in the intent-to-treat (ITT) population for median PFS [7.1 months in the TTFields plus TMZ arm vs 4.0 months in the TMZ alone arm; 95%CI, HR, 0.62; p = 0.0013)]; and in that same ITT patient population, the median OS [19.6 months in the TTFields plus TMZ alone vs 16.6 months in the TMZ alone arm; 95%CI, HR, 0.744; p = 0.0038]; are in a range generally considered highly significant and clinically meaningful for cancer therapies (Fig. 2). When examined based on time of diagnosis (adding 4 months for completion of radiotherapy before randomization), the median PFS for patients treated with TTFields plus TMZ was 11.1 months and the median OS was 23.4 months. The participants also agreed that the improvement in 2-year survival rate with TTFields Therapy (43 vs. 29%) is notable, and likely to be considered clinically meaningful by the patient and his or her family.
http://www.sciencedirect.com/science/article/pii/S1040842817300070