wigwammer
02 Apr 2018
Re: Has the market factored in the likel... 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. P140is 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. That’s the hope anyway - we still need that result
Pharma Giles
30 Mar 2018
Re: Has the market factored in the likel... Hi WW - Quite typical for the FDA to ask for 2 Phase IIIs, often they’ll 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. You’re 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? hxxps://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4227B1-02-02-FDA-Appendix1.pdfThe 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?
wigwammer
30 Mar 2018
Re: Has the market factored in the likel... 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 doesn’t 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
Pharma Giles
30 Mar 2018
Re: Has the market factored in the likel... 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 Happy Easter... and will look back in after DBL
corp jones
30 Mar 2018
Re: Has the market factored in the likel... Pharma, 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.
Pharma Giles
30 Mar 2018
Cephalon 200 patient study It’s 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 can’t use this as their second 200 patient study, and will have to justify the failure of the study to the FDA. They’re 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 didn’t buy it and evaluated trehalose before they started the trial.. All leads to the need for a second Phase III and I’m certainly not buying any of the company’s arguments for a single study… Been in this industry far too long for that and it’s the heads of the divisions who dictate how much data they want (not the new head of the FDA)..the way when someone suggests “their confident” about any study outcome when the study’s still blinded be careful. There’s an amateur mistake here (and been there) - you believe the patients who have done well must have been on active, and those who didn’t do so well must have been on placebo but when you come to un-blind (and in IMM’s study will be un-blinded on the 6th of April) there’s often a higher placebo rate than expected and frequently doesn’t 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…
Pharma Giles
30 Mar 2018
Re: Has the market factored in the likel... Hi CJThe SPA states 2 studies... of 200 patients..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..Hope that helps clarify
corp jones
29 Mar 2018
Re: Has the market factored in the likely ne... Pharma,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.
Pharma Giles
29 Mar 2018
Has the market factored in the likely need for another Phase III? 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 it’s not in writing then it’s 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 there’s 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, you’re not giving too much to the lighter patients or too little to the heavier patients (especially given there’s 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. It’s brutal and if you don’t 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..The study results are key
Pharma Giles
23 Mar 2018
Database Lock It would have been nice if the RNS could say why they missed the database lock (DBL) deadline. DBL is normally a pre-agreed date with the vendor (in this case Simbec-Orion). It's a hard deadline for the clinical and data management teams to work to, normally any slips are just by a day or 2.. For TM to be confident the results would be announced Q1 - DBL must have been planned for this week at the latest, given they're now saying 6th of April to get RNS out ~9 days later in mid April...Will look back in after Easter - good luck till the next RNS then..
Didledum
20 Mar 2018
Volatility I don't rule out shortselling
Nice to Michu
20 Mar 2018
Eye opening volatility here this morning 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..Good luck to all fellow holders !
Pharma Giles
05 Mar 2018
Re: Surprised by extent of recent weakness 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 Q’s 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. Crohn’s 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 it’s about maintaining a patient in a quiescent disease state, typically over a one year period. In Crohn’s 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 don’t 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 doesn’t necessary reflect a week 52 time-point, which relies on inducing a response and then maintaining it for a further c40 weeks.It’s been stated by S Muller, that “the precise mode of action of P140 peptide is not fully understood”, but suggests it doesn’t 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) it’s 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 couldn’t 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
oldjoe1
01 Mar 2018
Re: Surprised by extent of recent weakness IMM gone positive and on BIG buy volume V sell volume.Long may it last.Adding.
decision decision
28 Feb 2018
Re: Does anyone read this BB? 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.
