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Last comments received and responses posted - Feb 15.
Reverse splitting, stock consolidation – good idea or bad?
Before attempting to answer that question, some history might be in order.
For those too young to have been around or too old to remember, MSHL came out of a need to focus market attention on Novogen’s cancer technology. Cancer drug development is an expensive business, and with a family of drugs coming through the system, we were only too aware of the series of capital raisings ahead of us in the absence of a licence deal. And yet the story of phenoxodiol and its stable-mates continued to get lost in everything else that Novogen was doing with men and women’s health supplements, cosmetic preparations, drugs for heart disease and inflammatory bowel diseases, and wound care. The fact that a proportion of money managers that we were speaking to thought that phenoxodiol came from red clover only served to emphasise that our message was not cutting through.
We were faced with a problem …. the story was too big, too diverse and too fragmented. For a Company with an emerging world-wide profile as a health supplement supplier, attempting to re-engineer itself as a major new force in cancer drug technology was a significant hurdle. I was only too aware of this, as being chairman and the face of MSHL, I was charged with doing the road-shows.
So was born the idea of quarantining the cancer technology from the rest of Novogen. If investors wanted a bit of a play in everything, then Novogen was the opportunity. If their interest or investment strategy was more focused on cancer biotech, then MSHL was the vehicle.
MSHL was Chris Naughton’s brain-child. My opinion of the merits of the concept is not important, because it is a fait accompli and we now deal with the consequences. Suffice to say however that there was a deal of caution expressed at the concept by the market at MSHL’s initial public offering. Nevertheless, the offering was successful and I think that the market eventually was split between those who agreed with the Company and saw merit in the concept, and those that didn’t but accepted the inevitability of the situation and the opportunity it presented.
That’s the background…….now to where we find ourselves today. Retaining a listing has to be the priority, so there wouldn’t appear to be much of an alternative to a reverse split. Whether a 1 for 10 is appropriate or excessive, I will leave to people more familiar with market dynamics than me to comment on. The one big unknown in all of this is whether a major announcement is due or possible in the near future, at which point all of this speculation and discussion will get lost in the mist and we will be feting Company management.
But let’s be cautious….let’s assume that we are going to have to be patient a bit longer for the good news. In that case I have a couple of thoughts on the subject.
The first thought is that even if you accept that the original idea of creating MSHL was sound, the inescapable truth is that the execution was severely wanting. MSHL share price is where it is today because it never got the necessary horsepower put behind it. I would stake the MHSL technology and opportunity against any other cancer biotech in the world, and on that basis, MSHL should have had a similar market trajectory and profile to a company like Genentech in its formative years. It didn’t because MSHL was run as an empty shell. Who was going to take seriously a company that didn’t have a dedicated office, least of all in the country where it was listed? A company with no employees, no local contact point, and an annual PR budget that most biotech companies would spend on coffee supplies for the boardroom. A company that regarded its Annual Stockholder’s meetings as interruptions that needed to be got through, rather than as an opportunity to showcase the Company’s technology to the world.
There is nothing like putting your balls on the line to get an idea off the ground. Among other things, it gives you a deep insight into what you need to do to make things happen, it develops a great sense of urgency, and it instils in you a deep sense of responsibility to thousands of shareholders who have put their money and faith in you. A CEO and a Board of Directors who have never gone through that, inevitably are going to have a different view of the world. MSHL paid the price for that particular view of the world. [Paying directors in share options rather than cash would go some way to changing that world view.]
The reverse split will go ahead because the major shareholder (Novogen) wants it to. But unless the lessons of the past have been learnt, nothing (short of a major positive announcement) will prevent the share price declining again. It is to be hoped that the incoming CEO will have the wit and experience to correct the problem, because I am afraid that I just don’t see the current management having the necessary dedication to change.
My second thought has to do with the overall direction of the group. MSHL was created to house a part of Novogen’s technology opportunity. That part has now become almost the whole, and it is difficult to see any of the mothballed Novogen programs being reactivated anytime soon. Success with any of the anti-cancer drugs would give the entire isoflavonoid drug program an enormous credibility boost and almost certainly renew interest by the industry in the cardiovascular and anti-inflammatory drug programs, but it is hard to escape the conclusion that the group focus now and for the foreseeable future is on cancer. Which immediately questions the rationale for having two listed companies. I hope the incoming CEO gives this matter some thought as well.
A final thought. The Remuneration Committee. A club of executive and non-executive directors who decide each other’s salaries and entitlements….all completely above-board, independent , Chinese walls etc. A bit like politicians deciding on their own salaries. But why not try something totally radical and have remuneration decided by the people who actually own the company ….the shareholders. Three or four shareholders could be elected each year…I am sure we could find some who would do it for nothing.
Russ says:
Dr Kelly,
In your reply to Jonathan, you say you “hope” the company takes into consideration the secondary and tertiary endpoints and not just the PFS.
Wouldn’t this be an obvious step to take considering all the time and money spent?
You would expect every angle to be covered and all opportunities garnered to get the best result possible for cancer sufferers and shareholders alike. It’s not like “we’ll do another trial next week and check that possibility then”.
Thanks Russ
gkelly says:
A formal analysis obviously would encompass all three levels of endpoints. However, the Company last year was talking about conducting an ‘informal’ analysis only because of the premature end to the study. Fortunately, commonsense intervened and their most recent announcement was along the lines that they had decided against unblinding the data and were continuing with plans to analyse the blinded data. That announcement, however, only made reference to PFS. It is entirely possible that that was just shorthand for ‘a full analysis’, and I sincerely hope so. There may well be some jewels in the secondary and tertiary endpoints that could easily win the day.
jonathan says:
Graham, thank you very much for staying involved. I am still not 100% satisfied by your answer to my question about the company almost persuing a “lessor” review. Clearly they were about to risk blowing the integrity of their data, and then decided not to at the very last minute. ( See below).
”After consideration of regulatory advice provided to the Board, it was decided to preserve the integrity of the study for regulatory review and not perform any endpoint analysis prior to database lock. The OVATURE protocol specifies that tumor response analysis be performed on independent Tumor Response Evaluation Committee assessment of radiological evidence, and this cannot be performed until after database lock has been achieved. The Board has decided to avoid potentially compromising the data from the OVATURE trial by completing an analysis of the primary efficacy endpoint of progression free survival based on assessments of radiological scans by site personnel, which have not been verified by the independent Tumor Response Evaluation Committee.”
Your answer to someone else’s question has brought another to mind. You refer to a “minimum sample size” of 400, then 190, and that the trial now unfortunately contains only 140 patients. I don’t understand the idea of a minimum sample size of 400, or 190, if the FDA, based on the language in the SPA, was prepared to grant approval of phenoxodiol based on only 95 “events”. I have been assuming that the trial can easily produce 95 events from 140 participants ..?
THANKS Graham,
gkelly says:
Jonathan
The second question is the easier, so I will do that first. The different sets of patient numbers are confusing. I apologise if I am going over well-covered ground here, but just to allay any confusion….
The FDA and our consultant statisticians collectively determined that we needed to recruit a total of 470 patients (allowing for a 25% drop-out rate) in order for the difference between the two treatment groups to achieve a particular level of significance when the trial ended. That pertained to the analysis of all primary, secondary and tertiary end-points. The original figure was 470 patients, later reduced with the approval of the FDA to 340 patients. I don’t know what lay behind this reduction, but assume that it represented some relaxation of the stringency of the statistical package.
Because OVATURE was being conducted under an SPA, the Company has the opportunity to achieve marketing approval before the trial is finished. By ‘finished’ I mean when all patients have been recruited and a certain length of time has passed for follow-up. Under an SPA, approval can be granted without having to wait for the study to finish and is based on an approximately mid-way, interim analysis. The original target figure for that interim analysis was 195 events, reduced later to 95 events. An ‘event’ covers a wide range of outcomes including disease progression, withdrawal for drug toxicity or disease complications, or death.
I would imagine that there are at least 95 ‘clean’ events out of a total of 142 patients. So that particular goal-line almost certainly has been crossed. Leaving aside the critical issue of whether the statistical target will also be met, the terms of the SPA dictate that the study needs to be fully recruited (that is, all 340 patients), before an interim analysis can be conducted. Clearly that is not possible in this case with the closure of recruitment, and so that is where discussions with the FDA would need to have taken place, and I can’t believe that they haven’t.
As to your main question. I am not sure whether I can change your mind on this one, but I will try. You have experienced the roller-coaster ride that has been NVGN for almost as long as me. You have seen indicated time-lines come and go unachieved, and so I understand your displeasure. Nevertheless, I urge you to keep an open mind on this matter.
I may be misinterpreting your point, but if I was to paraphrase you based on your previous email, it is that the Company is nervous about failure and is seeking to extend the review process in order to buy time. That viewpoint could quite easily be put to bed by NVGN and MEI running an effective IR program. But we won’t go there again…
In the same way that I don’t believe that the moon landing actually took place in a Los Angeles warehouse, I think this is what is behind the latest announcement:
(i) When the Company decided to cease any further recruitment early last year, they decided to un-blind the study. I think their midset at that time was, why bother spending any more time or money on cleaning up the data to the nth degree? Why not salvage what data we have (and this would largely be efficacy and safety data) and use it to licence phenoxodiol? That would leave us free and cashed up to pursue triphendiol, NV-128 and the rest of the anti-cancer pipeline.
(ii) At some point, wiser and cooler heads fortunately prevailed and they decided to continue with an analysis of the final data in the hope of still presenting it to the FDA. I think that this is the critical (and positive) message in this recent announcement. Irrespective of whether they are aware of the efficacy data, they must believe that FDA approval is still possible technically. That advice might eb coming from the Company’s regulatory consultants in Washington, but I suspect that it is the FDA themselves that have so advised them. I emphasise that Ihave no inside information on this aspect (or any other for that matter), but this seems to me to be the most likely scenario.
(iii) That meant that any notion of un-blinding the data and subjecting it to analysis was binned. So the data-cleaning process was continued with the aim of achieving database lock.
(iv) Filling missing data points and getting signatures on forms is one thing, but the single largest potential weak spot in a study such as this is the diagnosis of disease progression. Different interpretations can be put on CT-scans (is that a new tumor or just a lymph node?; has the longest diameter of a tumour been measured?; is that a scar or a collapsed tumor mass on the liver, or a new tumour?). Then there will be patients who came off study because their health deteriorated and their CA125 levels rose, but who didn’t have a CT-scan until after they ceased treatment. At what point are these cases determined to have progressed? The role of the Tumor Response Evaluation Committee is to remove any questions over this critical point. And in order to avoid any accusations of bias or re-writing history after the event, Step 1 is that the database be locked. Step 2 is that the TREC do their job. Step 3 is that the statisticians then do their job.
I am delighted that they are taking this step. I could not believe the earlier plan of un-blinding the data as that would have destroyed any prospect of marketing approval based on this data. My residual concern is that the Company is still only talking about analysing the data for the primary end-point which I hope is wrong, because to do so and neglect the secondary and tertiary end-pointes would be an extraordinarily foolish act.
The course of events from this point is essentially out of the hands of the Company and in the hands of professionals (eg. TREC and regulatory consultants), so I am confident that with them guiding it, and with the good-will and support of the FDA that I know exists from personal experience, that we are well and truly on track. If it means waiting another 3-4 months, then so be it. The prize is worth the wait.
john Says:
Graham,
I have a few questions/comments re OVATURE that I would love your response to. It is my hope that management has somewhere gotten some encouragement either from some anecdotal evidence that they bumped into…or the FDA…that has persuaded them to go with the TREC review. What I don’t understand is why they even considered going about the review in any lessor way in the first place. At the Dec NVGN meeting in NYC Alan Husband answered a question of mine by saying “the FDA has not told us that our SPA has been invalidated”. How could he have said that while preparing to review patient performance in a manner that was contrary to trial protocol..?
Unfortunately I see no validity to your point (c) in your note. This company is desperate to make something out of this trial, so extra effort now, as they are running out of funds, does not impress me. Without good data in its best form, they are nearly sunk.
Here is my fear…management caught wind of the fact that fewer patients were being found to have good PFS times than they would have expected at the site level, which caused them to decide to switch to the TREC route in desperate hope of finding a more generous referee.
Would love to know what you think. Thanks Graham.
gkelly Says:
I share your frustration. But in looking to explain our frustration, I think there is danger in misinterpreting what is happening here. In no particular order, I make the following points. Some of these go beyond your enquiry, but I am taking this opportunity to try and put down on paper a comprehensive view of this matter.
(i) I am the first to criticise both Boards for their lack of IR skills, but I certainly do not question the scientific integrity of the Boards. I have full confidence in Professors Paul Nestel and Bryan Williams in particular in ensuring scrupulous adherence to scientific protocol and to good corporate governance. Professor Nestel has broad experience in the conduct of clinical studies and was an advisor to a number of major pharma companies. I have no doubt that these two eminent scientists will ensure that good clinical study practice is followed without fear or favour.
(ii) I really don’t think that the Company has that much more idea of the outcome of this study than those shareholders who, by extraordinary detective work, have managed to winkle out the data that has led to the crude analyses that have been floating around on the message boards. If most of the data remains blinded to the Company, which it should be if they are adhering to the study protocol, then they really are left pondering the available data with little more understanding than the rest of us. That is as it should be until data lock has occurred.
(iii) My information is that a significant number of patients experienced disease progression within 4-6 weeks, which fits in with the advice originally proffered by our consultants that we would see little or no tumour response in the control arm. A smaller proportion of patients appear to have remained on study for considerably longer than this. I would like to think that these latter patients would mostly be in the PXD arm, but only time will reveal that.
(iv) The emphasis in all the discussions about the trial outcomes has focused entirely on PFS. That is not surprising given that it is the primary end-point, but we should not lose sight of the fact that secondary, and even tertiary, end-points have relevance with the FDA. I have a feeling that overall survival might emerge as the most pertinent end-point, given the lower sample size. The significant tumour responses that we saw in the earlier Phase 2 study at Yale, where previous PXD therapy yielded responses to subsequent taxane salvage therapy, gives me hope that any marginal response to PXD + carbo in OVATURE, might reasonably be expected to deliver slower disease progression following the use of salvage therapy. I sincerely hope that the Company has instructed its statisticians to analyse all end-points – anything less would be negligent.
(v) My understanding is that the outstanding data matters that need cleaning up are not associated with tumour response or clinical status, but are relatively minor issues. Nevertheless, until they are attended to, the data cannot be locked.
(vi) It is my understanding that the SPA is neither active nor extinguished. It is ‘suspended’, which you would expect given that the study was terminated early. This means that the Company is free to go back to the FDA once they have the final analyses for further discussions.
(vii) The Company employs a high profile Washington law firm that provides regulatory advice based on a close working relationship with the FDA. If they have advised the Company to pursue the latest course of action, then it is for good reason and based on that advice only.
(viii) I don’t understand your comment about pursuing a ‘lessor’ review process in the first instance. From what I can see, the trial has followed the original proscribed course, particularly now that we are at the back end, where vigilance is everything. An inappropriate step at this point could prove disastrous. I was told when we first designed OVATURE that we were going to lengths in terms of vigilance that were not usual. I knew at the time that because we were going into an area not previously trod with chemo-sensitisation that we had to go the extra yards. I think that you are just seeing that come to fruition now.
(ix) The introduction of a TREC at this point is not something new. This group was always going to be the final arbiter of the all-important scan outcomes. I don’t know if they have detected any discrepancies between site review and independent review or are concerned to ensure that there are none, but it would be prudent to cover this off.
(x) I totally reject your final comment about the Company changing course at this late stage out of desperation. They are doing nothing more than following the advice of independent advisors who have everything to lose by playing with the normal rules of engagement.
(xi) I am not an apologist for the Company. No-one knows better then me the strengths and weaknesses of the two Boards and executive. And while it appears that mistakes have been made (the appointment of a particular CRO being a prime one), we need to bear in mind that this study has attempted to do something entirely novel and highly challenging. It was the needs of the FDA that made it more challenging than originally hoped for, so I would hope that this will be taken into account in the final analysis.
- Philip Says:
January 20th, 2010 at 6:35 am eDr. Kelly, in Chapter 18 of your book, you mention “Interestingly, mention was made of advice from the IDMC on the ‘disposition’ of remaining patients, which essentially means that if the IDMC is satisfied that the clinical benefit of the drug has been established, then they have the power to recommend to the Sponsor that all remaining patients on study should be put onto the phenoxodiol treatment arm. Again, we have not been informed of that advice.”Am I to understand from this statement that to the best of your knowledge the IMDC offered advice to the Sponsor, but you simply aren’t aware of the specifics of this advice?Or am I to understand that the IMDC did not advise that the remaining patients be placed on the PXD arm? - gkelly Says:
January 20th, 2010 at 8:26 am ePhilipThank you for the opportunity to clarify this comment. I have been asked by some correspondents about the phrase ‘disposition of patients’, mentioned by the Company in an earlier press release in connection with IDMC advice. I was trying to explain what this could have meant in the context of the role of the IDMC.Mention is made in two separate press releases of the IDMC reviewing safety and efficacy data over the course of 2008. Efficacy data review is a normal process for the IDMC in order to assess at a relatively early point the ethics of continuing with the study. If it is clear that it would be futile to continue because the statistical end-point will never be reached irrespective of the size of the study, then the IDMC is obliged to advise the Sponsor accordingly. At the other end of the spectrum, if the drug is providing an obvious clinical benefit, the IDMC has the power to so advise the Sponsor on the grounds that it is unethical to continue to consign half of the patients to an inferior treatment. The Phase 2 data involving Gleevec would be a case in point for this latter scenario. The middle ground is that a clinical benefit is apparent, but that the trial should continue to full enrollment to allow it to meet its statistical goals.We can only assume from the press releases that the IDMC did in fact review the ethical data on at least 2 occasions. I have no idea what their conclusion or advice was on either occasion, but I think we would be safe in assuming that the fact that the study was allowed to continue suggests at the very least that the study had not crossed a futility line. The middle ground scenario mentioned above seems the most likely option, and I take that as a positive.
The reference to ‘disposition of patients’ could mean a number of things, from recommending that patients be moved from their current treatment arm, to unblinding the study and informing patients as to their current treatment. I would expect the Company to have informed us publicy if any such event had occurred. It didn’t, so make of that what you will.
The public analyses being done by people a lot smarter than me and being speculated on, points to just a small difference (if any) between the mean PFS values for the two treatment arms. That is hardly surprising. PXD was never going to put cancers of this ilk into long-term remission. We were looking for just a small delay in disease progression as clear evidence of a chemo-sensitising effect. As I have explained in the Phenoxodiol book, the projected median PFS outcomes were highly conservative. If the median PFS for the control arm is closer to 14 weeks (as I suspect it will be), then that will not have to be extended by all that much in order for the study to achieve its goal. By way of example of this, you only need to look at the Phase 3 docetaxel study in late-stage prostate cancer patients carried out some years ago. Median survival times (the primary end-point) for the control arm (mitoxantrone + prednisone) and test arm (docetaxel + prednisone) were 16.4 and 18.9 months respectively. That was enough for the the FDA to approve the drug’s use back in 2004.
The other aspect of this matter that needs to be kept in mind is that drugs have been approved in the past on secondary and even tertiary end-points. The focus on PFS in this case may be misleading. The continuance of 25 patients on the study during 2009 suggests the possibility that OS might well come into play.
- Jan Says:
January 20th, 2010 at 10:44 am eDr. Kelly.Prof. Alan Husband clarified that on 4/15/2009 there were only 2 patients on the study so this disposition of the patients is not an important issue. If someone relistens to the presentation he gave on 11/3/2009, this point is quite clear. A lot of people, including I, missed this because I think we didnt think that the recruitment to the trial slowed down this much to have only 2 patients on the study when the trial cancelled. I think we all assumed that 2 and 47 patients are for the patients on 11/3/2009.This indicates that most of the recruitment happened earlier in the trial and not much can be said about the PFS differences using publicly available data. (I think).However, if most of the recruitment happened early in the trial, than there is a good chance that OS numbers will be quite good (this is based on 49 patients still being followed for median OS on 4/15/2009). This is easier to estimate and is independent of the PFS values.One explanation, which is the most fascinating, is what you wrote in ch18 of your book:In ch18 of your book, you wrote:
Ten patients at the end of the study (that is, who had shown disease progression) were given salvage therapy comprising a taxane. Eight of these 10 patients showed an objective tumour response (partial or complete response) including 4 who had been classified as taxane-resistant or taxane–refractory.–
i.e., phenoxodiol might be continuing to work well after the patients stop taking it. This affects the OS of the salvage therapy causing high median OS even if the PFS values of the pdx arm are in the 16-24weeks. - gkelly Says:
January 20th, 2010 at 4:04 pm eJanI agree. I think that we need to consider the possibility that the secondary end-point (OS) might be more meaningful than PFS.
November 6th, 2009 at 10:23 am
Gentlemen
I didn’t attend this year’s AGM. I will see about next year.
It is hard for me to comment on the AGM given that I wasn’t there and I have had only one feedback from someone who was there. But that feedback wasn’t particularly complimentary of the Board, or the Chairman in particular. Hopefully the Wellcome trilogy (Chairman, CEO, CFO) have got the message that their performance is under question.
I do wonder however when I see comments such as that in the Chairman’s address about phenoxodiol being a promising therapy for certain haematological diseases. As I have pointed out many times, any drug that needs to be deconjugated by glucuronidase or sulfatase is not going to be effective against non-solid tumors. If the Company has worked out a way to put phenoxodiol into the bloodstream without it being conjugated, then Johnston’s remark is valid. But if not, then phenoxodiol remains a potentially wonderful opportunity for solid tumors only. If the Company has a different view of this, I look forward to be re-educated.
The only other bit of interesting news is that the SPA for the OVATURE trial has not been withdrawn. That fits in with my belief that a positive outcome from that trial retains the possibility of FDA approval despite its premature closure.
Graham Kelly
December 2nd, 2009 at 7:43 am
Joe
I intended this site to be a forum for comments, questions etc. I can only respond when others post something, and this has been the first post for quite a few weeks. In the meantime, I haven’t been idle. I have been completing a book on the history of phenoxodiol with a view to puting it on the site for download. I was going to wait until I finished it, but instead I will put up the chapters completed to date and add as I go along. Give me a day or two to do this.
Re the departure of Chris Naughton. It came as much as a surprise to me as I guess it did to most people. I appointed Chris back in about 1997. He came with a significant background in the pharma industry, plus a strong financial background, and I was more than happy to pass the reins of management over to him. He proved to be a competent and financially prudent manager, and I still believe he would have been the right person to manage the Company’s growth once it achieves its first FDA approval.
Financial and business competency ar one thing… style is another. I learnt very early on that asking people to invest their hard-earned dollars in your idea and trusting you do the best with that investment requires a high level of respect for the investor. That respect means maintaining a good level of communication and information flow and reassurance. There is a line that a CEO of a public company needs to tread along carefully in that respect, but a competent CEO should be able to do that and keep both market regulators and shareholders happy. Chris’s style and personality was such, that irrespective of whether it was real or imagined, it failed to show reassure shareholders that they had his respect. It was a painful thing for me to watch the alienation of shareholders that followed over the years after the efforts I had gone to to build trust in the Company.
I can only speculate on the reasons behind his departure. I suspect that certain major shareholders made their feelings known either via voting or more directly. There is also the matter of the upcoming Annual Shareholders Meeting of MEI, and my guess is that there may have been warnings of some dissent heading that way.
The one thing I am fairly certain of is that this has nothing to do with OVATURE. I am told that his departure has been brewing since the Novogen AGM six weeks ago, so I am certain that it simply boils down to shareholder dissatisfaction.
If this is a case of restoring public confidence in the Company and its management and direction, then my personal view as a shareholder is that the job is only half done with the departure of Chris. What the Company and its shareholders deserve is a Board (and Chairman in particular) that is prepared to engage with shareholders, not treat them as incidental nuisances to be faced once a year.
I used to think that the technology was such that the Company would prevail despite the current Board, not because of it. The technology is even stronger than it used to be, but my view now is that it and its shareholders deserve a better deal.
GRAHAM KELLY
January 11th, 2010 at 9:03 pm
Hi Dr. Kelly
Okay, I read your latest post and have some “far out” questions regarding Phenoxodiol and Novogen, I just thought I’d throw some at you even though you may think some are silly.
Q1) Given we don’t know the best way to use Phenoxodiol (prior to chemo, or during chemo) why try a trial which staggers the phenoxodiol. We know the half life of phenoxodiol, we know the half life of chemo. So why not start with Phenoxodiol for a week, wait till it’s out of the patients system, then start chemo for a week with no phenoxodiol, then start phenoxodiol for a week, then start chemo + phenoxodiol for a week and so on.
Q2) If you had to guess a probability of success for the OVATURE trial (success in terms of a p-value less than 5%), what would it be and why. Do you think current management were responsible for the delays.
Q3) Why doesn’t Novogen look at combining their own drugs, for example doing a trial where patients take chemo + Phenoxodiol for a week, next week chemo + Triphendiol, following week chemo + NV128, following week all three drugs and chemo and so on.
Q4) Why doesn’t Novogen take-over MSHL while the MSHL price is low. Surely it’s an ideal time to consolidate and remove the risk of MSHL delisting?
Q5) Novogen entered a cosmetic collaboration some time back with an unknown party. Do you think they are still working together, I presume with compounds like NV07a?
January 12th, 2010 at 10:06 am
Eddie
All good questions.
Q1. The question of the temporal use of PXD with other drugs is a vexed one. As I have tried to make clear on the website, the way that PXD is interacting with various drugs almost certainly varies from drug to drug. I even suspect that there might well be differences with the one drug depending on whether you are using PXD to reverse chemo-resistance or to enhance chemo-sensitivity (where there is no chemo-resistance). I know that sounds incredibly vague and sufficatingly complex, but it really isn’t. It’s just a matter of the Company and clinicians accepting that one size doesn’t fit all, and then working diligently through each drug combination. At the moment there are really only two combinations in play – taxanes and platinums – and the evidence looks fairly clear to me on each. If I was receiving PXD + cisplatin, I would use the two drugs concurrently …. that is, stay on PXD continuously and use cisplatin in the normal weekly way. If I was receiving PXD + docetaxel, I would use the two drugs on a staggered basis…..that is, PXD for 3 weeks, then a week’s washout and then dose with docetaxel. The current PXD + docetaxel trial at Yale being conducted in conjunction with Sanofi-Aventis started life as a concurrent treatment schedule. I sought to have it changed to a staggered treatment schedule, but was unsuccessful. I don’t know if that recommendation was accepted eventually.
Q2. This is a tough one to answer. The original statistical plan was done on a best-guess basis of what we expected to see. The clinical advisory panel (comprising about 12 of the world’s foremost gynecological cancer specialists) was unanimous in their prediction that virtually all patients receiving carboplatin + placebo would progress within 4 months. The question then became, how much delay in progression would the FDA accept as being clinically meaningful, and how many patients would be needed to demonstrate that effect? Our advice was that a 2-month delay in disease progression would be acceptable, and on that basis the study sample size was determined to be over 400 patients. This was the advice of the FDA statisticians. The minimum sample size subsequently was reduced to about 190, presumably because the FDA relaxed the stringency of the statistics.
To get back to your question, I remain confident that PXD is capable of meeting the challenge we set it originally. The issue now, however, is whether it can achieve that outcome on the basis of data from only two-thirds (140) of the adjusted minimal sample size (190). That is a line-ball call.
On the issue of taking responsibility for delays, the slow patient recruitment is the major factor, and that is a direct function of the FDA’s insistence on having a PXD + placebo arm as the comparator arm. If we had been allowed to run with PXD + carboplatin versus any combination of 5 standard drugs as originally proposed, I think that the study would have been fully recruited some time ago. That is no-one’s fault …. just a legacy of the regulatory system that we have inherited.
Where management can take some responsibility is in the appointment of the original CRO. The big-is-beautiful view of service providers was contrary to my advice and we paid the price.
Q3. What a perceptive question. Yes, that is what should be happening and almost certainly will one day. The different mechanisms of action of the three drugs, and in particular their involvement in the different death receptor families, points to the benefit of multiple therapy.
Q4. Another even more perceptive question. The original rationale behind the formation of MEI (as tenuous as it was) has now evaporated. I can see no sound argument for the retention of the two companies. Novogen should re-absorb MEI, relocate its primary listing to NASDAQ, appoint a US Board of Directors and a President/Chairman who speaks with a strong New York accent and who is prepared to communicate freely with shareholders.
Q5. NV07a was/is a great product. A chemical with an ability to promote repair of sun-induced tissue damage and having an anti-wrinkle effect, always seemed to me to be as close to the cosmetic Holy Grail as it was possible to get. I don’t know where the various collaborations stand on that project, but I would be very surprised if they are ongoing after 6-7 years. There is a couple of reasons that I can think of for this. The first has to do with regulatory difficulties of getting a drug approved for cosmetic use. I don’t think there were insurmountable hurdles there, but I recall that it was an issue for cosmetic companies that caused them some concern. The second reason has to do with a lack of understanding about the biology of isoflavonoid compounds. These compounds are very small molecules and fat-soluble, so they go through the skin very well (much like cortisone will when applied as a cream). That means that they act both locally (on the skin where applied) as well as systemically (on skin and other tissue distant from the point of application). Systemic action is the basis of nicotine patches and contraceptive creams. If you were to set up a study looking at the effect of NV07a on skin function, then you couldn’t compare it to a placebo within the one individual. If NV07a was applied to one side of the body and a placebo cream to the other side, you would not expect to see any difference because of the systemic potential of the compound. The only way to compare would be to use test product in one individual and control product in another individual. Guess which approach the brilliant people who planned and conducted these studies used with the inevitable outcome.
Sadly, I think the reality is that the NV07 project, along with the anti-inflammatory and cardiovascular projects will be moth-balled indefinitely. If and when Novogen is consumed by a larger company, I would anticipate their re-emergence. But as long as Novogen goes it alone, it seems far more sensible to focus on its cancer drug opportunities.
January 13th, 2010 at 8:56 am
Dr. Kelly: Thank you very much for answering questions about Phenoxodiol. I have two questions about the OVATURE trial.
1. Is the patient population in this trial different from the patient population in the Phase 2 trial? Has there been advances that would change the 28-40 weeks expected median OS for the control arm?
2. Can you talk about the specific requirements of the SPA signed with the FDA? (e.g., is it 50% improvement over the control arm? Any requirement for the OS? If yes, HR? p? ). I’m suprised to see that PFS (not the OS) is the primary end point.
Thank you very much
January 13th, 2010 at 10:16 am
Jan
The main difference between the patients populations in the Phase 2 and 3 trials was the degree of platinum-resistance. In both studies the patients were platinum-refractory (that is, they had all shown disease progression during the previous platinum line of therapy). The difference lay in the interval between the previous line of platinum therapy and the platinum re-challenge. In the Phase 2 study, there was no restriction on the length of that interval and no restriction of the use of any other therapies in the intervening period. In OVATURE, the platinum-free interval was strictly no greater than 6 months, and no other intervening therapies were permitted. I explain this in greater detail in Chapter 18 of the phenoxodiol book that should be posted within a few days, so I would suggest waiting for that if you are interested in such details. For the moment, however, when we analysed the Phase 2 data and focused on that sub-set of patients where the platinum-free interval was no greater than 6 months, we achieved partial responses and stabilised disease with PXD + carboplatin therapy in two-thirds of the patients. That was the basis of our projections of the mean progression-free survival (PFS) outcomes in the control and test arms of OVATURE for the purpose of the statistical plan.
The only potential change that I am aware of in relation to the overall survival (OS) of platinum-refractory patients is in the more recent use of dose-dense platinum therapy, that is, the use of weekly platinum therapy versus the standard 3-weekly dosing schedule where the total amount of platinum delivered over each 3 week period is greater with the weekly dosing schedule. From what I can understand, there is not unversal agreement on the benefit of dose-dense platinum therapy, but in any case, for the OVATURE study, the 3-weekly dosing schedule was used throughout.
You would need to speak to the Company in relation to the specific details of the SPA. However, what I can say is that it was the FDA that proposed that PFS be the primary end-point and OS a secondary end-point. I can also say that we took a deliberately conservative view of the mean PFS outcomes for the purpose of the statistical plan, such as the mean PFS for the control arm being set at 5 months, when all clinical advise was that almost all control patients would have had disease progression by the second scheduled scan at 4 months.
January 13th, 2010 at 10:40 pm
Dr.Kelly,
Regarding the OVATURE trial, assuming a successful outcome, would you expect the results to be released and then a submission for approval to the FDA to be lodged or a direct lodgement for consideration for approval?
What is the “correct order” for next steps of progression from where we are now to approval ?(assuming good results)
What’s your ” best guess ” as to when results may be released? (I know your crystal ball must be nearly wornout but your thoughts are greatly appreciated,)
January 14th, 2010 at 4:22 am
Dr. Kelly. Thank you very much for answering my questions.
I’m looking forward to reading your next chapter.
Two more questions:
Do you know if cross-over was allowed?
Can you clarify the term “no other intervening therapies were permitted”? I assume if the patient does not respond (especially if she is in the control arm), she can get/switch to alternative (3rd and 4th line) therapies (such as dose-dense therapies). These patients would still affect the OS and HR.
I have additional follow up questions to see if we can deduce any information of the 47 patients still on the study but I think they can wait for ch18 as I dont want to take too much of your time.
Thank you very much
January 14th, 2010 at 9:05 am
Russ
The Company is obliged to release the OVATURE data as soon as it has it. The latest indication seems to be that that will be in a month or two. What happens to it after that, assuming a positive outcome is anyone’s guess. I am not privy to the latest discussions between the Company and the FDA in relation to the SPA. The FDA has shown commendable flexibility in recent years over pivotal trial data where there is significant clinical need, so I would not rule out some form of conditional approval in the event that all parties agree that the drug provided a clinical benefit without side-effects. On the question of side-effects, one other issue that has been rather lost in the mix is the possibility that PXD might actually protect patients from cisplatin-induced neurotoxicity. The lab evidence for that possibility was published recently, so it might become a factor in FDA thinking.
If the data did meet SPA requirements, then the FDA has 3 months under the terms of the SPA to review the data and respond to it. That time frame would almost certainly expand somewhat to allow a fullsome look at the data, following which the Company would need to lodge its manufacturing package. Going on behind the scenes has been an enormous (both in terms of personnel and money) project aimed at establishing the manufacturing credentials of the drug. For example, companies need to show that they have been able to manufacture to appropriate standards 10% of the anticipated batch size. So, if you predict that you will be making drug in 1 tonne batches, then you need to have produced 100 kg batch sizes. Given how far down that track Novogen was when I left the company, I can’t see that being a delaying factor.
That of course assumes that the SPA statistical needs are met. But given that the study has been terminated with only about two-thirds of the minimum amount of required data available for analysis, the more likely scenario is that the statistical outcome will fall short of the required level. Just how short then will determine how long (and if) the FDA would take to review the data.
January 14th, 2010 at 9:09 am
Jan
No, there was no cross-over allowed. Patients, once they progressed, were entitled to salvage therapy.
The reference to ‘no other intervening therapies’ was in relation to the absence of any chemotherapy prior to recruitment since the previous platinum challenge. That is, the platinum-free interval of no greater than 6 months extended to other forms of chemotherapy as well. That was part of the original study design, but it is entirely possible that the FDA allowed it to be relaxed when the study encountered recruitment difficulties.
January 15th, 2010 at 12:56 pm
Thank you very much for both your answers and the chapter 18 of your book.
Did a patient need to stay on the study for at least 2 cycles (8 weeks)? Or could the oncologist move her to salvage therapy without waiting for the scans?
I’m looking forward to the completion of the chapter and your book.
Thanks
January 16th, 2010 at 12:13 pm
Dr. Kelly. To give you a context to my last question, let me clarify that I’m trying to understand the meaning of the following terms in the following press release.
“disposition of subjects remaining in the OVATURE study”. Were the patients pulled off from the study? Would the doctors pull patients off the study just because the trial got terminated early?
“unblinded data from 117 subjects”. Does this mean 117 patients completed off the study and 25 were still on the study on 5/29/2009 receiving pdx/placebo?
http://www.novogen.com/news/news0501.cfm?mainsection=05&subsection=03&newsid=324
The IDMC reviewed available unblinded data from 117 subjects and noted that, at the time of termination of recruitment, 142 subjects had been randomised to the study.
The IDMC supported the Company’s decision to close the study to accrual, and, in a review of the available safety data, the IDMC confirmed that there were no safety concerns with phenoxodiol in these subjects. Consistent with the IDMC charter, the Company will convene an expert committee to review the IDMC recommendations including those with respect to the disposition of subjects remaining in the OVATURE study.
January 18th, 2010 at 6:05 pm
Jan
You probably need to contact the Company directly (Alan.Husband@novogen.com) if you want to get the answers directly from the horse’s mouth. But I am happy to try and answer your questions to the best of my ability.
It is difficult to see any patients being ‘pulled’ from the study. All that happened was that the Company announced an end to recruitment. The study still continued, first of all as long as patients remained on the study (for the primary end-point of PFS) and second for the secondary end-point of overall survival.
My interpretation of the 117 ‘unblinded’ patients is that 117 patients had finished the study and their data was cleaned and available to the IDMC for analysis. The remaining 25 patients were still on the study and would be until withdrawn and their data made available for analysis.
Graham Kelly
January 18th, 2010 at 9:07 pm
Hi Dr Kelly
Once again I feel compelled to check your website each night waiting for the next instalment in the Phenoxodiol story. Wouldn’t it be great if the OVATURE results were published at the same time you finished your book, after all the OVATURE results must be due around now.
From my understanding, it seems that Phenoxodiol works but we just don’t know how best to use it. Given it’s excellent safety profile, it seems likely that the FDA approve it if extended survival is proven.
A question, if Novogen was to gain approval following submission of their dossier, would their license partner continue to research how best to use the drug or do you think they would simply market the drug for Ovarian Cancer. Would doctors learn about it’s “off label” potential given it kills most cancers in the test tube?
And a final question, do you think that keeping Phenoxodiol at a steady state in the blood would have an improved efficacy over twice a week bolus injections? If the drug is not active in the blood (due to conjugation), surely it wouldn’t matter how frequently you take it as long as there is sufficient accumulation of drug in the tissue which has the ability to change Phenoxodiol back to an active form… the key would then be to assess what is the best concentration of phenoxodiol in certain tissues (cancer) to go with what doses of chemo… and also the order they would be taken.
January 22nd, 2010 at 9:14 am
Dr. Kelly. Can you comment on a question I asked before (probably you missed it)?
1. Did a patient need to stay on the OVATURE study for at least 2 cycles (8 weeks)? Or could the oncologist move her to salvage therapy without waiting for the scans? In your opinion, would this be considered a disease progression or drop out?
Also,
2. In addition to death of course, when would a patient would be stopped being followed up for survival? I think intent-to-treat analysis require the OS data from the drop outs as well. I might be mistaken though. I’m trying to get a sense if 47 patients being followed up include the drop-outs (if I’m not mistaken you estimated drop-out ratio to be as high as 25%).
I am already looking forward to the first chapter of your second book.
Thanks
January 22nd, 2010 at 4:30 pm
Jan
1. Scans were scheduled at the end of each 8 weeks, but could be done at any time if disease progression was suspected based on CA125 levels or clinical status. To be classified as disease progression, the patient would need to have a verifying scan…the final decision would be in the hands of the medical monitor, but I would think that without a scan, any removal from study treatment would be considered a drop-out.
The reasonable expectation is that all patients in the control arm (plus an unknown number in the PXD arm) will show no response to therapy and will experience disease progression from the time of entry to the study. CA125 levels could be expected to rise in a linear fashion, and disease symptoms could be expected to worsen. For the purpose of OVATURE, diagnosis of DP rests entirely on RECIST criteria, which is that the patient shows a minimum 25% increase in the diamater of major lesions and/or the development of new lesions. Obviously scanning is the only way that this can be verified.
I can imagine a scenario where the clinical evidence cleartly points to DP, and salvage therapy might be instigated before a scan could be scheduled, but I would think that that would be done on authority of the medical monitor and still constitute a DP.
By the by, in itself, a ‘drop out” need not be a negative in the sense that platinum toxicity could be a reason, for example, for drop-out, and the incidence of drop-out due to drug toxicity is a tertiary end-point. One of the overlooked potential outcomes of this study is that PXD will protect from platinum neurotoxicity. There are quite a few aspects to this study beyond that of the primary end-point that those of us who wait and watch need to bear in mind. OS, as you have pointed out previously, is another such aspect.
2. A 25% drop-out rate was built into the study based on clinicians’ advice, but I am not aware of what the real-time experience was in this case. I think from memory that a line could be drawn under survival follow-up following withdrawal of the last patient from treatment. I am not sure about the nature of the 47 patients you mention, but I assume that it encompasses all patients who qualified for having an ‘event’ (for the purpose of analysis), which means ceasing study treatment for reasons related to either disease progression or drug toxicity.
January 23rd, 2010 at 1:04 pm
John
Have already posted my thoughts.
Graham
January 25th, 2010 at 1:44 am
Graham, thank you very much for staying involved. I am still not 100% satisfied by your answer to my question about the company almost persuing a “lessor” review. Clearly they were about to risk blowing the integrity of their data, and then decided not to at the very last minute. ( See below).
“After consideration of regulatory advice provided to the Board, it was decided to preserve the integrity of the study for regulatory review and not perform any endpoint analysis prior to database lock. The OVATURE protocol specifies that tumor response analysis be performed on independent Tumor Response Evaluation Committee assessment of radiological evidence, and this cannot be performed until after database lock has been achieved. The Board has decided to avoid potentially compromising the data from the OVATURE trial by completing an analysis of the primary efficacy endpoint of progression free survival based on assessments of radiological scans by site personnel, which have not been verified by the independent Tumor Response Evaluation Committee.”
Your answer to someone else’s question has brought another to mind. You refer to a “minimum sample size” of 400, then 190, and that the trial now unfortunately contains only 140 patients. I don’t understand the idea of a minimum sample size of 400, or 190, if the FDA, based on the language in the SPA, was prepared to grant approval of phenoxodiol based on only 95 “events”. I have been assuming that the trial can easily produce 95 events from 140 participants ..?
THANKS Graham,
Jon
January 25th, 2010 at 9:54 am
Jonathan
The second question is the easier, so I will do that first. The different sets of patient numbers are confusing. I apologise if I am going over well-covered ground here, but just to allay any confusion….
The FDA and our consultant statisticians collectively determined that we needed to recruit a total of 470 patients (allowing for a 25% drop-out rate) in order for the difference between the two treatment groups to achieve a particular level of significance when the trial ended. That pertained to the analysis of all primary, secondary and tertiary end-points. The original figure was 470 patients, later reduced with the approval of the FDA to 340 patients. I don’t know what lay behind this reduction, but assume that it represented some relaxation of the stringency of the statistical package.
Because OVATURE was being conducted under an SPA, the Company has the opportunity to achieve marketing approval before the trial is finished. By ‘finished’ I mean when all patients have been recruited and a certain length of time has passed for follow-up. Under an SPA, approval can be granted without having to wait for the study to finish and is based on an approximately mid-way, interim analysis. The original target figure for that interim analysis was 195 events, reduced later to 95 events. An ‘event’ covers a wide range of outcomes including disease progression, withdrawal for drug toxicity or disease complications, or death.
I would imagine that there are at least 95 ‘clean’ events out of a total of 142 patients. So that particular goal-line almost certainly has been crossed. Leaving aside the critical issue of whether the statistical target will also be met, the terms of the SPA dictate that the study needs to be fully recruited (that is, all 340 patients), before an interim analysis can be conducted. Clearly that is not possible in this case with the closure of recruitment, and so that is where discussions with the FDA would need to have taken place, and I can’t believe that they haven’t.
As to your main question. I am not sure whether I can change your mind on this one, but I will try. You have experienced the roller-coaster ride that has been NVGN for almost as long as me. You have seen indicated time-lines come and go unachieved, and so I understand your displeasure. Nevertheless, I urge you to keep an open mind on this matter.
I may be misinterpreting your point, but if I was to paraphrase you based on your previous email, it is that the Company is nervous about failure and is seeking to extend the review process in order to buy time. That viewpoint could quite easily be put to bed by NVGN and MEI running an effective IR program. But we won’t go there again…
In the same way that I don’t believe that the moon landing actually took place in a Los Angeles warehouse, I think this is what is behind the latest announcement:
(i) When the Company decided to cease any further recruitment early last year, they decided to un-blind the study. Not because they had any feel that the drug wasn’t working, but simply because at that point they thought that there was little or no prospect of gaining marketing approval. I imagine that they sought to salvage what they could in the hope that it would drive a licensing deal.
(ii) At some point, wiser heads fortunately prevailed (I sniff the input of the FDA and regulatory consultants here) and they decided to continue with an analysis of the final data in the hope of still presenting it to the FDA.
(iii) That meant that any notion of un-blinding the data and subjecting it to analysis was binned. The data-cleaning process was continued with the aim of achieving database lock.
(iv) Filling missing data points and getting signatures on forms is one thing, but the single largest potential weak spot in a study such as this is the diagnosis of disease progression. Different interpretations can be put on CT-scans (is that a new tumor or just a lymph node?; has the longest diameter of a tumour been measured?; is that a scar or a collapsed tumor mass on the liver, or a new tumour?). Then there will be patients who came off study because their health deteriorated and their CA125 levels rose, but who didn’t have a CT-scan until after they ceased treatment. At what point are these cases determined to have progressed? The role of the Tumor Response Evaluation Committee is to remove any questions over this critical point. And in order to avoid any accusations of bias or re-writing history after the event, Step 1 is that the data be locked. Step 2 is that the TREC do their job. Step 3 is that the statisticians do their job.
I am delighted that they are taking this step. I could not believe the earlier plan of un-blinding the data as that would have destroyed any prospect of marketing approval based on this data. My residual concern is that the Company is still only talking about analysing the data for the primary end-point which I hope is wrong, because to do so and neglect the secondary and tertiary end-pointes would be an extraordinarily foolish act.
The course of events from this point is essentially out of the hands of the Company and in the hands of professionals (eg. TREC and regulatory consultants), so I am confident that with them guiding it, and with the good-will and support of the FDA that I know exists from personal experience, that we are well and truly on track.