Ben Richardson, CEO at SulNOx, confident they can cost-effectively decarbonise commercial shipping. Watch the video here.
Phil G. You're welcome. Well, like you, I think we have got a first sight of the news but the exciting part or, the full importance of it, will be revealed in the presentation.
My main question is whether we can expect continuation of MRx0518 monotherapy trials into Phase II. I'm hoping that we have seen enough evidence to justify MRx0518 as a (potential) standalone therapy.
Agreed. In a nutshell, the monotherapy results show that the immune system gets activated to fight cancer - that would firm up its position as ideal combination candidate for Keytruda or other drugs. I suspect that the presentation will substantiate that with more numbers. Some 98 genes are involved in this activation apparently!
There is talk about huge confidence to carry on. Recruitment of patients for part B is taking place. However, RNS got lost in the vaccine panic. Tomorrow and Wednesday should be different though.
Pete,
I think at this stage we can talk more about targets re the "control rate" rather than statistically meaningful results as the sample is too small. Unless, the improvement is observed on an overwhelmingly high percentage of patients, in which case statistics would come into it. Just for the sake of an example, if 42% was observed for the control rate (like in the case of combination therapy), the chances of that occurring as a matter of a coincidence would be far too small.
Now, can't see why we wouldn't have the same target as in the case of the combination therapy i.e. 10% or better for the control rate. I'm hoping that we would comfortably exceed that even with monotherapy ...
If so and we see comparable success in the case of monotherapy, then it can mean we / 4D are in the DRIVING SEAT going forward!
The title of the presentation suggests that the early data from MRx0518 as monotherapy have gone beyond than just establishing its safety:
"Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumors"
The key words being "emerging evidence of immune modulation" would imply that there has been some activation or enhancement or / and regulation of the immune system in fighting cancer. However, let's see the full presentation or even the summary before jumping to conclusions.
The title of the upcoming presentation gives some hint about any (early) data that may be presented to back it up:
"Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumours" ...
"emerging evidence of immune modulation" being the key words. So clearly we are not only talking about safety but we must have seen some early data that suggests efficiency. It may be through activation or enhancement of the immune system in fighting cancer. However, let's see the full presentation before jumping to conclusions.
... the SP trendline should be an upward one. There has been some long and hard consolidation process creating a solid basis at little above the 100p mark. Such consolidation has been taking place at various stages, and especially after we saw the SP settling following the five-fold rise from 35p in early Q3 or the four-fold from the 40-50p range where it stayed for some time.
Of course an upward trend is dependent on news but progress on the various fronts should take place at an accelerated pace compared to the 2014-2019 period. Hence, there should be no shortage of news but patience is also needed as we are talking about a pharma company. Progress need not only in the R&D arena: I'd expect further commercial milestones to be achieved in the next say 12 months.
Oncology will be the main driver of valuation and as early indications could have hardly been better so far, the company is communicating that in an increasingly forthright way. IBS drug will be the second hopeful project and whose trial helps maintain investment interest by filling in the time gaps.
I'm expecting and hoping for an unequivocally strong announcement on oncology in Q4 2020 (similar to the one we had in Q3) that should create a new base for the share price off to start 2021 in the right footing. The level of this new baseline is a function of a number of variables and ultimately, it is not that important as I think most investors are convinced by the 4D story and are aiming high... in the short to medium term i.e. 12 - 24 months.
The dark horse is the Covid-19 trial and as I've said before it is only on the off-chance that something will come out of that. Having said that, reading between the lines from company's own announcements or interviews, we can be cautiously positive on the asthma trial "...4d pharma was able to quickly instigage a clinical trial in covid-19 based on our detailed understanding of our asthma program." ... I like the words "detailed understanding"
Whereas nothing can be taken for granted at this stage, a diversified R&D portfolio underlied by a development platform that is unique to 4D and whose value seems to be recognised by a global market player, the risk/return prospects look very attractive indeed.
118p? Surely that price doesn't do the company justice even at this stage :-)
So following the merger news which was based on a share price of 110p, we have seen a rise of the low (intra-day) point compared to the pre-RNS period. So with the market-wide dramatic falls we saw the SP hit c.103p yesterday. Assuming such rise of the low point of c.15%, we can be forgiven for expecting to see an upward trend as we get into November and get closer and closer to news.
It s one of the rare occasions whereby shorts are (almost) welcome! Being confident about the share price, even in the short term, I see the shorts serving the purpose of facilitating situations of share squeeze...after all, rns are due either imminently or at least in q4.
With the elephant in the room i.e. imminent funding need, sorted (which the company wasn't going to leave it till last minute), the ADRs as some kind of a predecessor to US listing and some further Q4 news coming... what could stop further rises? Oh I forgot those shorts which one can even hear or smell the burning smell as they close.
Delighted to see the SP rise so far ... Of all the funding scenaria I was thinking of, a merger was certainly a surprise!
Thank you noix - so no separate part II trial as we'll have part B of phase I/II.
Therefore, effectively in part A of phase I/II, we got, as an additional bonus to confirmation of tolerance, a glimpse into the likely EFFICACY of MRx0518/Keyruda that is going to be properly assessed as part B.
So what can we hope, in terms of further news for 2020 re oncology?
- either a firm-up of the positive developments compared to the August progress report re the 12 patients (completion of part A) plus of-course any progress news re the commencement of part B.
- also looking at the August presentation we have the neoadjuvant part A results in 2020! It will be extremely interesting to see whether we get the same hint on efficacy from MRx0518 alone as we got from the combination treatment.
Just to clarify one sentence in my earlier post "Whilst part phase I/II, part B results (very likely to be successful) will also give a boost, they will probably send the SP higher than recent highs (i.e. 170p). " the reference was to the next single result within part B ... (as opposed to all the endpoints within part B oncology).
Also, I've been assuming so far that phase II would follow phase I/II in the case of oncology after completion of part B. However, I suspect that the term phase I/II means that phases I & II have been combined into one...
In other words, there may not be a phase II as such. In that case, part B should involve recruitment of more patients and optimisation of the dose and, when completed in 36-48 months (?), it will have practically determined the success (or not) of the treatment.
Oncology is the main play as different posters are remarking. The company staff were most excited or optimistic about that programme according to one of the CEO interviews a few months ago - I recall he said that they were having such conversations over a beer. That was even before the recent success with part A of phase I/II trial. When (and if) oncology continues to show further signs of success into phase II endpoints, (such endpoints commencing in H2 2021 I'd assume), the value of the company should rise significantly and can easily end up in the billions (in a 18 to 36 month horizon?).
Whilst part phase I/II, part B results (very likely to be successful) will also give a boost, they will probably send the SP higher than recent highs (i.e. 170p).
Nonetheless, the beauty in the case of 4D is the platform: talking about other SP catalysts ... having got the information from RNS/presentation/ responses from company, I am now convinced in my own mind that the IBS results were positive enough for all avenues to be open (be they related to commercial licensing or further development by the company or both).
Covid-19 success would be on the off-chance (in my view) but hope we hear soon about the asthma programme. Let's not forget the "top-secret" vaccines collaboration with Merck though we could do with some kind of update even in general terms. Finally, "watch this space" i.e. pre-clinical efforts on neurodegeneration which should lead to clinical trials in the not too distant future.
And one more thing: having the SP hovering around 100p is not ideal but, at the same time, it's not a bad new base whilst we expect the news / share price catalysts be they short, medium or long term ones.
(Post to be seen in conjunction with one just posted)
"Hi,
FAS is the Full Analysis Set, all subjects randomized in the study
EEAS is the Efficacy Evaluable Analysis Set, which includes all the FAS patients who completed the full 8-week treatment period without major protocol violations deemed to impact the assessment of efficacy; these patients were excluded in an blinded review i.e. before anyone knew if these patients had received Blautix or placebo.
40 patients from the FAS were excluded in the EEAS
Having completed the full treatment period and without major protocol violations deemed to impact assessment of efficacy, clearly the EEAS is the more representative of the true activity of the drug. FAS is required to be reported as per the trial’s protocol
Hope that answers your query. "
When looking at the numbers in the presentation (as opposed to the RNS), it seemed to me that TWO groups (not ONE) i.e. IBS-C and the aggregate of IBS-C + IBS-D had achieved statistical signifiance at P=0.1, in other words 90% confidence that 4D's drug was superior to placebo by the difference stated. In the case of IBS-C statistical significance was borderline whereas the aggregate group comfortably passed . However, at first sight, that seemed to be at odds with the RNS so I wanted to check my understanding was right: posting the answer from 4D on Friday as others may find it as helpful as I did.
RESPONSE FROM 4D:
"When the Phase II trial was designed the statistical analysis plan was based on 1-sided Pearson chi-squared test (don’t mean to overload you with statistical jargon, just for completeness) at a significance level of 0.1. Some retail investors have expressed some confusion about the 0.1 significance, as many are used to seeing 0.05, however this is not uncommon for this kind of signal finding Phase II trial.
So, in the IBS-C EEAS group Blautix vs placebo was statistically significant at p=0.097, i.e. <0.1. And yes the IBS-C/D combined group EEAS at p=0.037 comfortably met our pre-defined 0.1 significance level, as well as the conventional wisdom if you will of 0.05.
To reiterate two important points. Firstly, the IBS-C patients are the same as those in the IBS-C/D combined group, and analysis of statistical significance is heavily impacted by sample size."
Secondly, this was a Phase II trial to generate a signal and additional clinical data to guide Phase III, and not a pivotal trial which is ‘make or break’ on 0.05 statistical significance, though we are of course even more encouraged having met this. While p values are an important aspect of interpreting scientific data, in this relatively small clinical trial (compared to pivotal IBS trials) we believe the key and most clinically relevant figure is the relative response rate compared to placebo. For the IBS-C FAS this was 25%/17.1% = 1.46 = 46% over placebo; for IBS-C/D combined FAS 24.1%/17.5% = 1.38 = 38% over placebo; in both EEAS groups the effect size over placebo was enhanced. This we believe is a clear and positive outcome, particularly in IBS where the margins for currently available therapies vs placebo are not dissimilar (and sometimes smaller).
Hope that has clarified your query, thanks for getting in touch"
PS. Another post will follow soon clarifying the FAS, EEAS definitions and why RNS seemed to me initially to be at odds with presentation (they were not as it turns out).
Agreed, I was impressed with the response which has made me even more positive about the prospects of the company.
Clearly Blautix was much more of a success than most people realised. Why the fall? I can only guess but I'd say a lot of people misunderstood or didn't want to fully understand the results (e.g. some of the larger investors)... then herd mentality finished the "job".
Also, the company has to sort out its funding plans sooner or later. However, as money is to be well spent and for very specific purposes that shouldn't impact (much) on the share price. Ultimately, it may even help it once plans get firmed up. One could look at Synairgen or Scancell. They've raised very significant amounts in the last few days and look at the impact on price.
Synairgen is an interesting example: the SP rose dramatically only to fall by 50% from peak prices (260p to 130p approx if I recall well) and once confidence about the fundraising was coming back, it started regaining its strength very significantly.
Looking forward to further news.
(iv) IBS-M is a poorly served market due to the nature of currently available therapies, which simply target the predominant symptom of constipation or diarrhoea. Clearly in IBS-M, in which patients fluctuate, you can see how prescribing a drug to address constipation is likely to exacerbate issues if and when a patient switches to having diarrhoea, and vice versa. 4D believe that our Phase II trial has shown that by demonstrating activity in IBS-C and IBS-D we would expect to be able to treat IBS-M. The results also strengthen our conviction in our hypothesis of IBS as a single condition (or at least spectrum) which is manifest with predominant symptoms of C or D. At this stage the potential to address IBS-M is an extrapolation yes, though a strongly support one, and something which would need to be investigated and tested further. Purely speculatively however, also consider the potential for a product approved for both IBS-C and IBS-D with an excellent safety profile to be prescribed ‘off label’ to patients with IBS-M who fluctuate between C and D
(iv) The Phase II results are a key milestone and catalyst for commercialisation efforts, supporting both progression to Phase III and our partnering conversations
Thank you for your continued support, and again for your patience. "
QUESTIONS PUT TO THE COMPANY:
(i) what were 4D's target improvement / response rates difference vs. placebo and absolute response rates? For example, in the case of the Phase I/II oncology trial we were aware of the 10% positive response rate target which was far exceeded by the 42% actual rate;
(ii) how important are the absolute response rates e.g. is a 24% response rate relevant for the combined group or is it mostly the 6%-7% difference from placebo that matters?
(iii) whereas having an overall statistically significant result without statistical significance in the underlying groups can be explained from a statistics point of view, what are implications in terms of commercialisation and phase III design?
(iv) the RNS stated that needs of the IBS-M group can be potentially addressed. How firm is that conclusion or is 4D making an extrapolation from the results that can be tested in phase III?
"Thanks for getting in touch and for your patience regarding our response. As I’m sure you can appreciate it has been a busy week on multiple fronts, and we wanted to provide accurate comprehensive responses to your pertinent questions.
(i) The idea of a ‘target response rate’ is not directly transferable from the oncology study to the IBS study. For example the 10% target for MRx0518 + Keytruda is a product of the particular patient population being addressed, the nature of the disease, and conversations with our partner Merck regarding, among other things, their expectations for Keytruda monotherapy in this particular patient population. Moreover, the Blautix Phase II trial was intended as a signal finding study – to generate the data to 1) support progression to Phase III, and 2) inform the design of a potential Phase III. We believe the trial very much met both these goals. We believe that in the case of IBS and this trial the most clinically relevant metric is relative response rate compared to placebo. With the above caveats, what we saw in the full analysis set was a relative response rate of (24.1%/17.5%=) 1.377 or 37.7% over placebo, and even greater in the efficacy evaluable analysis set. As described in the webinar this is comparable to (and superior to some) approved IBS products based on much larger studies of >1000 patients. Obviously Blautix is unique in that it is a single agent with comparable efficacy in both IBS subtypes
(ii) Believe this has been addressed above
(iii) We are very pleased to have achieved statistical significance in the combined group as we see Blautix as a treatment for both IBS subtypes. However, again, this was a signal finding Phase II intended to demonstrate a meaningful signal of clinical efficacy, rather than a pivotal Phase III trial which hinges on statistical significance. As you note, the statistical significance in the separate cohorts is in part a product of sample size – the ‘combined group’ are the same patients from the C and D cohorts, so the responses are the same, the larger sample size simply allows the statistical analysis to achieve significance. It is worth reiterating that in this study, in the full analysis set 76 IBS-C and 94 IBS-D patients received Blautix; this is a relatively small number compared to the comparator trials presented in the webinar, in which several hundred IBS-C or IBS-D patients received active drug"
REST OF REPLY CONTINUED IN NEXT POST TOGETHER WITH QUESTIONS
You can't really say it is more or less effective than other existing treatments before it has been launched as a product - let alone with Phase II hardly been completed.
arguably the main gap was on the way down from 170p closing on Tue to whatever it opened on Wed ... 160p? especially as news was positive so no reason for that. So question is how soon will it be filled.
Maybe, the famous FOMO factor is more relevant this weekend than last one ;-))