that's a punchy target imho zombynation imho but of course it could happen.. all depends what the can resurrect out of those poor/very poor phase 3 trail results going forward.. I don't have a clue about that but Pharma Giles and snark hunter seem to very usefully have good knowledge here .. Immu have a decent amount of cash in the bank still which is very important.. and the product is safe and some trial users want to keep using it... so still reasonable hope of upside from here imho..
(I've only got a smallish position left here now but will hold and watch on for weeks/months I expect.. have brought my average price down meaningfully to 40p at least...bought and sold a bunch around time of recent news/collapse but selling plenty thru the 30's is now looking premature...even including recent pullback from late 40's , north of 50p in coming weeks seems very possible ...)
well at least it bounced decently this late morning and early afternoon.. allowed trading out of a hole - as I fortunately, in the end, somewhat did - and helps buy and holders too.. some excellent posting from Pharma Giles here, thanks.. but post of the day for me by a big margin is snark-hunter, thanks factorially: one minute after reading I bought a bunch more here ( sold plenty of them this arbo granted ) Many twists and turns still to come here I expect.. good luck to all fellows holders..
Many thanks Pharma Giles. Have been reading your comments about P3 and found them very helpful. So much so that my investment in IMM was sold a while ago (had 40K at one stage) It was all too good to be true, sadly. TM's comments rang a bell too - of AZM not that I can remember that debacle too clearly, but it rand the wrong tune to me. Your comments rang true throughout, and many thanks.
With close to 50m shares traded today compared to 140m in issue
a spate of holdings RNSs ( or maybe just one) should start to appear
in the next few days
Someone( or a number of parties) has picked up a major stake in Immupharma on the cheap particularly given that the trial results may not be that bad after all imho
Reducing the placebo response rate is an art in any clinical trial.... I should point out it's my job to know much more about drug development than any small company..
If IMM are reading this my suggestion would be to present the Week 12
response rates - if they also show a superior effect to placebo then undertake a sustained response/remission analysis. The eligibility criteria of SLEDA>6 for inclusion will only help drive out the delta (difference between active and placebo) for the induction phase of the study at week 12 (see my previous post on induction vs maintenance) but will have little influence on the maintenance phase.. When you go out to Week 52, with your primary time-point, the baseline disease activity has less influence on driving out the delta, as a subjects disease activity 1 year ago is too far in the past, and will naturally change as part of the normal fluctuation of the disease over the longer term..
The analysis I would recommend (assuming week 12 was good) is to look at the proportion of patients in response at both Week 12 AND Week 52 (i.e. combined response rate for a single responder analysis). This will drive down the placebo response more so than the active (if superiority was also seen at week 12)..
If positive you will still be able to use the data to support an NDA for a long-term label claim, but naturally will need another study with this as your endpoint (in patients with anti-dsDNA autoantibodies).. it may allow less patients to be needed for the next study though..
Good luck and would like to see some good out of this... all is not lost here...
Todays results which failed to show a statistically significant improvement are very disappointing and the market has reacted but I think current market value is an over-reaction. The facts are that the drug is safe and improves the life of Lupuzor sufferers.
In the fullness of time will recover due to a better realisation of the following:
- Lupuzor did achieve 7.9% uplift over standard treatments but not proven beyond statistical doubt.
- The effectiveness among the 153 patients that got to the end of the course of treatment was 68.8%, which was 9.6% above standard treatment but no statistical significance test yet available.
- In a specific sub group there is a 14% uplift, very close to the statistical significance test, and of these 8% went into remission whereas non in control group did.
- No patients had any side effects whereas standard treatment includes steroids, anti-malarials, and other drugs which all have side effects, some very severe, over the longer term
- The detailed results have yet to be produced and discussed with the FDA
- The open label extension completes in October which may add further support for Lupuzors efficacy without further trials and a deal
- Lupuzor appears to have general effects against auto-immune and even chronic inflammatory indications and pre-clinical evidence supports the molecule's use in: Neuropsychiatric lupus (NPSLE); Gougerot-Sjögren Syndrome (GSS); Guillain-Barré Syndrome; Chronic Inflammatory Demyelinating Polyneuropathy; Arthritis; Crohn's Disease and Asthma. All of these are commercially attractive and large markets
Key are the discussions with FDA which is moving to a more patient centred approach to drug approvals; the drug is safe and does improve the life of Lupuzor sufferers.
Fortunately the company has £10m in the bank, and has several other oncology and diabetes drugs in the pipeline, and 2 drugs platforms, which may be of interest to pharmaceutical companies in any deal which I suspect will be forthcoming but not at the stellar valuations we were hoping for.
Statements from company:
Whilst we are disappointed at the high response in the placebo plus standard of care group that resulted in statistical significance not being reached between the two treatment groups, we believe Lupuzor has the potential to bring a much needed safe treatment to the millions of Lupus sufferers around the world.
top line results provide evidence for the continued investigation into the development and commercialisation of Lupuzor. It thinks the drug has the potential to offer patients and physicians a much needed effective and safe treatment for lupus.
ImmuPharma is in ongoing discussions with a number of larger pharmaceutical companies, it added.
The results of this study will now be shared with those potential commercial partners. There can be no certainty as to the outcome or timing of these discussions.
Unfortunately the study was underpowered... Just to put in context if the 7.9% was a true treatment difference, between active and placebo, you would have needed 1678 patients in the study (839 per group) to see the difference statistically, based on a 90% power... 200 was always optimistic (others may use a different term!)...
It's now all about digging into the data and finding the subgroups that responded best. The study was really only a Phase II and will now be treated as such. It will be up to IMM to convince any would-be partner that the positive subgroups are not cherry picked, and are truly likely to respond better in any future study... It will be tough but do-able, if IMM haven't lost too much credibility..
My hope is this hasn't put investors off investing in pharma/biotech (we need your money for research). This study was always, on probability, likely to fail to reach statistical significance (see my previous posts) and run by a team that didn't appear to have sufficient experience in drug development... I also think some of the analysts/brokers should be hanging their heads in shame with their ridiculous/unfounded predictions..
I'm truly sorry if genuine investors have lost a lot of money here. I hoped my posts would balance out the misleading comments provided by IMM, and the rampers..
awful news and truly enormous fall this morning.. commiserations to all including myself.. fortunately I'd sold a lot of my position down over previous months but the few thousand shares I have left are decimated... sit, watch and hope that something can be resurrected from the ashes is all I can now do I guess....incredible fall this morning mind.. but it's a one trick pony and I guess that's why..I have thought about topping up a little in low 20's p as a punt but have not so far..
Must confess I thought the results would be out this morning. As way of insight the company are only expecting/reporting top-line results at this moment in time. This typically includes the results for the primary endpoint and key secondarys. As the data is limited to the key endpoints its straightforward to interpret. Deeper analysis comes later when the full data set is available, and you can dig deeper into the results/subgroups (so in a couple of months). The results are usually provided in SAS table format, as a PDF and very easy to read. As the ITT has 100 patients on active, and 100 patients on placebo it makes it even easier to see response rates (%s = the numerator in each group ) then you look at the p-value to see if it reached statistical significance (p = <0.05). As this has been deemed a Phase III, by the company, it makes the outcome black or white either the study reached statistical significance for its primary endpoint, at week 52, in the Intention to Treat (ITT) population, or it didnt i.e. its pass or fail based on this.. Phase II has a little more flexibility about its overall interpretation (as its exploratory, rather than pivotal). As a note most pharma companies Ive worked with would have run the IMM Phase III study as a Phase II, it would be deemed too risky to run as a Phase III (see my previous posts). I understand Cephalon pushed IMM back on calling its study a Phase III and subsequently ran as a Phase II.
In a nutshell the results should be instantly interpretable as for a Phase III theyre based on the primary endpoint/timepoint (one key table).. hopefully no delays..
Good posts WW - as you say all about the results and so you think the market's built a second study into the SP? My thoughts were it hadn't but was glad to get another balanced opinion.
Re: predicting a study outcome based on blinded data - yes it's pretty near impossible to say which way efficacy will go when the data is still blinded. I learnt this early on in my career. I wasn't sure if TM was suggesting otherwise - apologies to him if he wasn't..
...just to add, i take your point about overconfidence prior to unblinding. But if a drug were to demonstrate a highly positive result, in the way imm hope and expect, then one indication is likely to be a positive trial response of the nature they are describing re extension etc. It is difficult to envisage a situation where a very high number on the active respond, in addition to a typical response to those on placebo, and there be no visible indication of this prior to unblinding. They need to see safety, a positive trial response, and a relatively low placebo response to get an outstanding result - so far, they have two out of three.. fingers crossed, ww
PG - i think the need for a second trial will be dependent on the result. Many are hoping that the result reflects the promise shown in (most of the) previous trials. But In terms of the impact on the shares - any positive efficacy signal will likely have a projected response. The reason being that it will demonstrate the value of the platform - if it works in a hard to treat area then it will likely have broad applicability. P140
is safe, has a unique moa, could be used in combination, is easy to administer, cheap to manufacture - it is likely to seed a series of late clinical stage assets in valuable indications. Thats the hope anyway - we still need that result
Hi WW - Quite typical for the FDA to ask for 2 Phase IIIs, often theyll run in parallel. The rationale for 2 Phase III studies is that the active can still win by chance in a small study (i.e. still reach statistical significance) so the FDA like to fully reassure themselves with a second study, supporting the same trends. Youre right though that the other option could have been to do a much larger single study and look for consistent trends in the subgroups, by geographic region etc. This link to the FDA guidance on when a single study is acceptable may help?
The safety profile sounds good on what we know. Patient numbers on long-term (1 year) treatment are still quite small, to support a long-term label, but still possible (if the FDA have agreed ?). The extension study will help but they may want different patients hence the 2nd Phase III? Whether they can use the Cephalon 200 patient study may be tricky. Placebo worked better than active in this study (40% vs 34% SRI response rates, at week 24, respectively). If they argue trehalose may have countered the P140 effect in this study, for efficacy, then the same could ring true for safety?
Just my thoughts but I was interested to know if the market was accepting of the 2nd Phase III study? I'm guessing not though?
PG - thanks for your thoughts. The request for 2 identical trials seems unusual though. Is it? What purpose can there be in having two identical and consecutive trials (rather than one larger study) if the possibility of making a decision after the first study doesnt exist? Presumably it will have been clear to the FDA that if a positive trial result is achieved first time round then pressure will mount to pass the product - and perhaps rightly so. Safety has been proven across multiple trials - this phase 3, cephalon phase 3, phase 2b, phase 2, and hopefully in the extension study, strengthened by the point that the active molecule Is dosed at very low levels. Be interested in your thoughts on the above. Thanks, ww
CJ - time will tell but the SPA clearly states IMM need 2 phase III studies of 200 patients each.
Under the new SPA, the necessary number of patients for the phase III programme has been reduced to 2 studies with 200 patients each.
- I haven't seen anything different from the FDA. I'm probably not so inclined to believe the company I'm afraid. I was around when Tim McC was CEO of Alizyme - it was shamelessly ramped and luckily I got out before they crashed. Others weren't so lucky.
Not long now and as we know all depends on the results
the company have already stated that the safety profile of Lupuzor is benign based on previous studies so the FDA were ok with the small number of patients in phase 3. The company have also stated that there will be no need for a further study if the agreed phase 3 primary end points are met, as this is in the public domain I'm inclined to believe the company. The're currently enrolling for an open label study anyway. Hope this helps.
Its possible IMM originally planned to use the Cephalon Study C33457/2047 as the second 200 patient study maybe? The issue however is the SRI response rate at week 24 in this study was 34% on active vs 40% on placebo. The pdf study report (which can be found by putting Study C33457/2047 report into google states
Efficacy Results: The SRI at week 24 did not show a statistically significant difference between the CEP-33457 and placebo treatment groups in either the full analysis set or the completer analysis set. Active drug was numerically superior to placebo only at the 8-week time point. Also, none of the secondary or exploratory efficacy variables showed statistically significant differences between the CEP-33457 and placebo treatment groups, except for some isolated cases at specific time points. These isolated numerical differences with small nominal p-values were not considered clinically meaningful.
The company thus cant use this as their second 200 patient study, and will have to justify the failure of the study to the FDA. Theyre case is that it was the use of the glucose trehalose as an excipient, rather than the sugar mannitol. However trehalose orally is given at doses of 70-100g, in some studies, and so whether 0.05g sub cut once every 4 weeks, really was the cause of the study failure is a big question. Cephalon didnt buy it and evaluated trehalose before they started the trial..
All leads to the need for a second Phase III and Im certainly not buying any of the companys arguments for a single study Been in this industry far too long for that and its the heads of the divisions who dictate how much data they want (not the new head of the FDA)..
By the way when someone suggests their confident about any study outcome when the studys still blinded be careful. Theres an amateur mistake here (and been there) - you believe the patients who have done well must have been on active, and those who didnt do so well must have been on placebo but when you come to un-blind (and in IMMs study will be un-blinded on the 6th of April) theres often a higher placebo rate than expected and frequently doesnt pan out the way you thought. If someone was to know something before un-blinding it would mean the blind had been compromised and guess what yes the FDA will pick it up and ask big questions
Actually SPA's are as much about agreeing primary endpoints, and time-points, to support a label claim - it's by no means a slam-dunk. Regarding subject #s to demonstrate efficacy (not safety) this is up to the company to decide based on their stats and assumptions. If they've underpowered the study then it's their issue.. The FDA will comment on subject # from a safety standpoint though..
Your assessment is not quite accurate, IMM have a 'Special Protocol Agreement' that states as long as the phase 3 trial is carried out in accordance with the agreement and the results are sufficient to meet the targets they will grant the drug a licence.
Seems to be a fair bit of movement, given the study is still blinded until the 6th of April..
Regarding the 2nd Phase III - nothing appears to have changed since the IMM announcement on 12th August 2013 which states the FDA has agreed Under the new SPA, the necessary number of patients for the phase III programme has been reduced to 2 studies with 200 patients each. hxxp://www.immupharma.co.uk/fda-grants-immupharma-ammended-spa-lupuzor-phase-iii-company-progresses-development-activities/
Although Lupuzor has Fast track status this does not mean less data is required to satisfy the FDA. There are 2 main FDA regulatory pathways 1) the Regular Approval pathway and 2) Accelerated Approval pathway. These pathways are very different. Lupuzor is going down the Regular Approval pathway not the accelerated route. Fast track, which Lupuzor has, allows more frequent visits with FDA, rolling submissions, slightly faster review, but still means you go down the Regular Approval pathway, as with most new drug applications. The regular approval pathway means demonstrating a clinical benefit and typically requires 2 phase III studies. Occasionally the FDA may allow one (see FDA guidance on when a single study is acceptable hxxps://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4227B1-02-02-FDA-Appendix1.pdf but this is not normal (unless there is significant supporting or bridging data e.g. in other indications). Benlysta submitted 2 clinical studies involving 1,684 patients, and then further data was submitted for the approval of their SC formulation in July 2017. There is no indication that the FDA have said they will accept a single 200 patient phase III, and if its not in writing then its not agreed.
Lupuzor does not have Accelerated approval status, which would allow a single study based on a validated surrogate endpoint, followed by a verification study once the drug is approved. No drugs in Lupus are going down the accelerated approval route (as far as I know) as theres no validated surrogate as highlighted by the FDA guidance on developing treatments for Lupus.
As mentioned in my post below, on the 9th of Feb, I think the current Phase III study will struggle to hit statistical significance (as too few patients enrolled) but even if it did the FDA would still need enough information to support a detailed label claim (prescribing information for the physician - known as the Summary of Product Characteristics in Europe). The FDA will take the raw Phase III data generated by the company and do their own analysis. They will want to look at certain subgroups with different disease activity, or differing manifestations of the disease, and make sure it works in all the groups. This requires large subject numbers when the study population is as heterogeneous as it is in Lupus (800+ patients in each of the GSK studies). The FDA will also look at various groups by quartiles e.g. they will look at the effect size in the heaviest 25% of patients and compare to the lightest 25% of patients to make sure, with a fixed dosing regime, youre not giving too much to the lighter patients or too little to the heavier patients (especially given theres an unexplained dosing effect with Lupuzor). IMM will need to justify the dose and answer all the questions on this, as well as all the other questions the FDA will fire at them. Its brutal and if you dont have the data to support your answers it will be you need another study to answer them.
Safety is not a slam dunk either. Most of the unexpected serious side effects are uncommon i.e. effect less than 1 in a 100 patients, so very unlikely to be picked up in study with only 100 patients on active. Even common events (defined as between 1 in 10 and 1 in 100) are still not easy to pick up in 100 patients on active. As a rule you need significantly more patients than 100 in a study to see an event that affects 1 in a 100 patients..
and perhaps a pre cursur to the extent of volatility to come , especially when the final trial results RNS is released.. which should be sometime in the next 7.5 business days...
This is effectively a one trick pony and so I may well tank on bad results or explode upwards on good results..
Soa very dangerous stock right now... and my position here is a lot smaller than it once was.. I was tempted to buy some more around 100 p this morning but the volatility today and potentially going forward had me decide best hold off until that crucial RNS is released..
The fact we're this near the end of q1 - the promised RNS release Quarter - and still not having received the RNS is of course encouraging volatility..
I think the weakness stems from a number of unanswered questions, which may remain unanswered until the Phase III results are available.. In my research I had the Qs below.. I only have access to public domain data though..
1. Data supporting the primary at a week 52 endpoint?
I assume the long-term endpoint was to support a long term label claim with the FDA. SLE is a relapsing/remitting condition which means patients experience periods of flare and periods of remission (relatively quiescent disease periods). Trials in other immuno-inflammatory conditions e.g. Crohns disease (CD), generally separate studies into induction and/or maintenance studies. In an induction study patients with an active flare (moderately to severely active disease at baseline) are recruited with the aim to induce remission/or response in a relatively short time frame (6-12 weeks). In a "maintenance" study its about maintaining a patient in a quiescent disease state, typically over a one year period. In Crohns some drugs work well for induction (e.g. corticosteroids) but not so good for maintenance, and other drugs work well for maintenance (e.g. immunosuppressants such as azathioprine) but dont work so well for induction. The Phase IIb study with Lupuzor was an induction study (week 12), however as the Phase III study is evaluating subjects at week 52 it becomes an assessment of how well Lupuzor can maintain response. As far as I could see this is still an unknown for Lupuzor? The effect size seen in a 12 week induction study doesnt necessary reflect a week 52 time-point, which relies on inducing a response and then maintaining it for a further c40 weeks.
Its been stated by S Muller, that the precise mode of action of P140 peptide is not fully understood, but suggests it doesnt suppress the immune system. Most maintenance drugs I know do work by dampening the immune system to some extent, to prevent a flare (flare caused by increased immune-inflammatory activity). Although by not supressing the immune system this improves the safety profile, it raised questions for me about how well it will work as a maintenance therapy. I'm a little unusual in that actually I'd have been reassured by seeing side effects in the Phase III - as it would reassure me of the drugs activity.
There are also other questions such as tachyphylaxis (reduced response with time if a patient develops tolerance, so may need a higher dose).
2. In the Phase IIb study why should less frequent dosing perform better? Normally a higher dose is ruled out as a) its less well tolerated or b) it adds no additional benefit. In the initial Phase IIa 200ug given every 2 weeks performed well, and was taken forward to the Phase IIb but performed worse than 200ug every 4 weeks. I couldnt find an answer as to why, and S Muller quoted in another paper that in a dose-dependent manner, P140 peptide in saline provoked a downexpression of HLA molecules at the surface of B cells (as also found in MRL/lpr B cells) i.e. in mice the higher the P140 dose the better the effect (work by Page et al, annals rheum BMJ 2011). Without a scientific explanation for why a lower dose in man worked better in the IIb study a reader is left wondering whether the difference between the 2 doses is simply a chance effect, and the true response could equally be the response seen with the more frequent dosing?
3. Can trehalose have a systemic effect to inhibit P140 activity, when given in small doses, every 4 weeks,? Study C33457/2047 was undertaken by Cephalon on the back of the above Phase IIb study. Subject were treated for 24 weeks and results showed a placebo response rate at week 24 of 40% and an active (P140) response rate of 34%. The failure to show a positive difference in this trial was attributed to the excipient trehalose dihydrate, a disaccharide of glucose. A question arose to me as to whether trehalose dihydrate given in relatively small doses in man (circa 50mg) every
Interesting. I derisked some time back but keep a decent sized holding. I also expect a 2nd phase 3, and I've no idea how the market will react to that, although it's the most likely option. Key for me though is proof of concept as IF it does actually work, even at such low levels, then it opens up P140 with platform potential, so while the market might like it or not, anything other than a failure (ie no better than placebo) would be a win IMO.
Hi DD Id imagine IMM have the timeline for DBL pre-agreed with their Vendor (typically c4-6 weeks after last subject out). Normally DBL is a milestone that the clinical team work to (with the PIs and sign off as well), but maybe I can understand TCs reluctance to share the date . Agree with you about the speed to which the primary can be pulled following DBL.
However, I decided yesterday to sell my long held stock, (get the impression the market wont be so accepting of another Phase III as me) so my interest now is curiosity in results. Might buy back in after?
Hi, and yes but not often. Was alerted to it on twitter group. Good post by the way and agree once locked it could take seconds to the top line results, but as I suspect you have experience of, it's only once all the data is in that they can check any potential conflicts/issues with trial centres. Depending on the nature and number of these, it would delay the lock. Having said that, can't be long now.
I'm not on any of the other forums but had a look at LSE and ADVFN and some very good updates on last nights event.... Have to ignore the clinical interpretation by a lot of the rampers on ADVFN (they don't look like they've had any pharma experience) but some good snippets in-between the ramping posts..
Is anyone going to the investor meeting tonight? One question, if possible, would be the timeline for database lock (DBL) - this is the point at which you can unblind the data? If anyone can ask, that would be great, as were now over 5 weeks since last patient out, and 9 weeks since the last week 52 visit. The study would have used electronic data capture (eCRFs) and the data cleaned as the trial progressed, so database lock should have probably happened, especially as Simbec-Orion have an invested interest, and would have put their A team on the data management.
Although there will be literally 000s of pages for the full tables and listings, as this is Phase III there is one table that counts more than any other and thats the responder analysis for the primary endpoint at week 52 in the Full Analysis Set (ITT pop). To generate this table, following DBL, is very quick (could do same or next day if you really wanted to). It will take several weeks to generate the full tables and listing, analyse the subgroups, and write a report, but IMM should know now whether the trial has been successful.. Phase IIIs a bit more black and white than Phase II in as far as a definition of success goes at least.
I was hoping an RNS would be released ahead of todays meeting? I couldnt work out the purpose otherwise we know what Venture Life aims to talk about, but not IMM? The other indications are interesting, as is the size of the market, but in a nutshell we really need the Phase III topline result first I think
Presenting on the night will be;
Mr Tim McCarthy Chairman of Immupharma plc IMM.L (www.immupharma.co.uk). TPI acted as Placing agent in the recent £10m fundraise.
Mr Jerry Randall CEO of Venture Life Group plc VLG.L (www.venture-life.co.uk) TPI is joint broker to Venture Life and Jerry will be providing an update on recent developments and future plans for the company.
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