Roundtable Discussion; The Future of Mineral Sands. Watch the video here.
Other than the shenanigans going on with Teva, and some of the other major generic companies - I can't see any reason for the latest dip on AIM. SP on Dhaka has held up well, no recent -ve news, and very much doubt BXP are involved with any of the alleged price fixings associated with Teva et al.. The buys today are mainly mine, into my ISA, Long term hold but I'd expect recovery this year..
Prior to a Type A meeting the company submits a “meeting package” also known as a “briefing book”. This is often anything from 30 to 150 pages long. The package gives background information relevant to the issue (iclaprim on the liver) . The package will include everything from pre-clinical tox through to effects in different populations [e.g. elderly, or patients with pre-existing liver issues). Any new information may be supplementary to the NDA but often is just the result of a deeper dive into the data the company already has from its pre-existing development program. In the package the company adds a serious of Q’s they want the FDA to address. The company details its position on each Q’s and typically ends the Q with “…… does the FDA agree?” The Q’s should really follow a logical stepwise approach to get an answer on the bigger issue. A day or 2 before the 3rd of May meeting MTFB would have received a response to their Q’s from the FDA. Some would say “Yes, the FDA agrees” and others would start “No, the FDA does not agree – followed by the FDA’s reason”. Typically only the Q’s the FDA say “NO” to get discussed in more detail at the meeting (often with a few rapidly produced slides from the company).
Following the meeting the company usually has a good grip of the FDA’s stance. The minutes shouldn’t raise anything fundamentally different to that which was discussed (although can have some post-meeting notes).
Others on this board will know more about the background/issues here, I’ve only recently taken a small punt on MTFB – but as I understand it MTFB saw some transient rises in LFT’s (notably the transaminases). This doesn’t sound overly worrying so wonder what the FDA have seen differently? The raised LFT’s, presented in the public domain, are at 3xULN. This can happen by chance so FDA will probably also have looked at the rates of 10xULN. I haven’t seen any data on this (may have been none of course) but 10xULN rarely happens by chance. Also if the company are arguing benefits in a specific population (i.e. those with renal impairment where Vancomycin may carry a warning) the FDA will look at these patients in more detail to make sure Iclaprim doesn’t have a greater effect on their liver (I’ve not looked into the metabolism or excretion of Iclaprim - but if excreted by kidney could raise the question).
We don’t have enough information in the public domain, but the liver effects sound transient so I would expect, on probability, the company will soon announce their planned timing for a resubmission (supported by an enhanced risk minimisation/management plan). I’m hoping the SP will move north when a resubmission date is provided by MTFB – but who knows?
It will be interesting see if we get a reason behind the recent rise - wonder whether this is following further analysis of a P3 study that really shouldn’t have failed (given a Birch SLIT P3 study, using the same trial design, showed a highly statistical difference against placebo).
SCIT is considered = or better than SLIT [Cochrane review]) - so still confused as to how the study didn't clearly demonstrate a difference over placebo??
Their current NAV has increased to 71 Taka per share - which equates to 65p per AIM share, by my calculation
Wasn't really expecting the trial results in this RNS but at least we have a little more clarity.. Still blinded and sounds like a CRO issue (although was expecting the company to point to a collating data delay). All will be revealed this month. - they may be collating birch pollen data to help results?
"PQ Birch Phase III trial will read out before the end of Q1 2019. The delay has been caused by a longer than expected time needed by the Group's trial service providers to audit, review and consolidate data from the field trial. Allergy Therapeutics remains blinded to the data package and management looks forward to receiving the data.
Not so sure johntay - Dupilumab, is a monoclonal antibody for the eczema. Side effects include allergic reactions, cold sores, and inflammation of the cornea.. I can't see it receiving traction for pollen induced allergies (unless accompanied by severe asthma maybe?) - could be wrong of course but it was rejected by NICE based on costs - if I recall?
https://www.ncbi.nlm.nih.gov/pubmed/30005097
https://www.tandfonline.com/doi/abs/10.1080/13543784.2019.1582640?journalCode=ieid20
If you can't download the full paper - the expert opinion concludes
Ridinilazole is a novel antibiotic with ideal properties for the
treatment of CDI. Namely, it has a very narrow spectrum of
activity that causes minimal killing of the host microbiota while
displaying potent activity against clinical strains of C. difficile. It
is non-absorbable providing large concentrations to the colon
when delivered orally. Given that it is not absorbed systemically,
it is expected that ridinilazole should have a favorable safety
profile including a lack of drug interactions and systemic toxicities;
results that have been confirmed to date. Given the
promising results from the phase II clinical trial, ridinilazole
may be able to lower the risk for CDI recurrence thus improving
sustained clinical response rates; a current unmet medical need.
As the importance of CDI recurrence continues to be appreciated,
ridinilazole should become a first-line agent due to its antirecurrence
properties. Due to all of these reasons, the results
from the planned phase III study are eagerly anticipated.
Funding
This paper was not funded.
As per RNS on the 16th of Jan - PQ Birch Phase III trial will be announced in Q1 2019. - also states "We see momentum in the business and look forward to updating the market at our interim results"
Interim (half year) results are due 6th of March. The trial results will more than likely be in a separate RNS to the interims though - but who knows.. Maybe the company will update us on their progress e.g. when database lock is planned.
On probability the trial results RNS should contain the words "highly statistically significant" but we'll see - nothing is certain when it comes to trialling drugs
interesting I can buy at 14.31 and sell at 14.32 through my ii account (on preview tests that is)
I see a few 100k and 250k share sells over the past couple of days... is this likely to be spread betting companies selling for their shorters? Small volumes so I guess there wouldn't be a short squeeze when the results are announced, but welcome thoughts from people who know more about these things than me..
Good to see the growing media attention around the need for new, narrow spectrum, antibiotics. Destiny Pharmas SP seems to be benefiting (unfortunately I don't hold any). Hopefully SUMM can market themselves a little better and attract some media attention too..Investment will come once there's a clearer way forward on how the health authorities/governments will pay for the end product. I think that came across in last night's program and made it very clear that we're up a certain creek without a paddle unless we increase investment now and make changes to the way we pay for them... SUMM does seem like an attractive buying opportunity for any big pharma wishing to get into, or expand, their presence in the antibiotic arena (even as a PR exercise, given the growing media attention).. Just a matter of patience - unfortunately no pill for that!
For some reason Post 2 excludes all the key text - I've therefore posted the full text on the ii site - link below and much easier to read than the posts below (for those interested of course)..
https://www.ii.co.uk/discussion/t/pqbirch301-outcome/1146910
Will try again for Post 2
From the data available, in the public domain, the likely placebo CSMS will be around 1.5 (range 1.3 – 1.7). This sounds low but is an accurate estimate from what we know. In order for the PQBirch301 trial to reach a successful outcome, we need to see at least an 18- 20% reduction from this placebo score. Assuming 1.5 as the placebo response, we would need our active arm to be 20% improvement from placebo. The P2 program however did use the total symptom score (TSS), and used a conjunctival provocation test (CPT). It’s worth noting that the symptom component of the CSMS is likely to be the main driver for the actual total score. If we consider the 1.5 for placebo roughly 0.9 will be from symptoms vs 0.6 from the medication component (again based on information in the public domain and these are rough estimates).
If we consider some of the potential issues (e.g. insufficient birch pollen – which could mean no symptoms in the placebo group) AGY could use a modified ITT as their primary population for analysis (also known as mITT or mFAS) i.e exclude patients from the primary analysis set who were exposed to <80 grains/m3 per 24 hours in any week for example, They can’t change their primary and secondary endpoints but can adapt their primary population for analysis (must be predefined in the SAP), and as long as they do this before unblinding If they don’t pre-define as a mFAS it simply becomes a subgroup analysis of the full FAS. The may wish to do something like this if new information has come to light during the study, or at least prior to database lock (unblinding).
Hope the top-line summary is helpful but like I say by all accounts, and based on probability, this specific trial should yield a successful outcome given the drug has a well proven mechanism of action, and a decent P2 program to establish dose and efficacy. Unlike other studies the trial design doesn’t look like it will throw up too many hurdles either.
Good luck and time will tell of course..
From the data available, in the public domain, the likely placebo CSMS will be around 1.5 (range 1.3 – 1.7). This sounds low but is an accurate estimate from what we know. In order for the PQBirch301 trial to reach a successful outcome, we need to see at least an 18- 20% reduction from this placebo score. Assuming 1.5 as the placebo response, we would need our active arm to be 20% improvement from placebo. The P2 program however did use the total symptom score (TSS), and used a conjunctival provocation test (CPT). It’s worth noting that the symptom component of the CSMS is likely to be the main driver for the actual total score. If we consider the 1.5 for placebo roughly 0.9 will be from symptoms vs 0.6 from the medication component (again based on information in the public domain and these are rough estimates).
If we consider some of the potential issues (e.g. insufficient birch pollen – which could mean no symptoms in the placebo group) AGY could use a modified ITT as their primary population for analysis (also known as mITT or mFAS) i.e exclude patients from the primary analysis set who were exposed to <80 grains/m3 per 24 hours in any week for example, They can’t change their primary and secondary endpoints but can adapt their primary population for analysis (must be predefined in the SAP), and as long as they do this before unblinding If they don’t pre-define as a mFAS it simply becomes a subgroup analysis of the full FAS. The may wish to do something like this if new information has come to light during the study, or at least prior to database lock (unblinding).
Hope the top-line summary is helpful but like I say by all accounts, and based on probability, this specific trial should yield a successful outcome given the drug has a well proven mechanism of action, and a decent P2 program to establish dose and efficacy. Unlike other studies the trial design doesn’t look like it will throw up too many hurdles either.
Good luck and time will tell of course..
I’ll summarise but like I say the information is in the public domain, although not always easy to find if you don’t design clinical trials. Just to point out if you followed IMM last year, I posted why their Phase III trial would be very unlikely to hit statistical significance (link below). The numbers/assumptions all turned out to be accurate but just want to mention that with IMM (and most other P3 studies) the trial design was very different to PQBirch301, in that they used a “responder analysis”. This is where you define a “responder” based on a pre-defined, clinically meaningful, reduction from baseline in the score. You can then compare the proportion of responders on active vs placebo as your primary outcome measure – but dropouts can be an issue (if not accounted for – link below to my post).
https://www.ii.co.uk/discussion/t/why-raise-funds-now/1125612
Most modern P3 studies use this “responder” trial design but AGY can’t really do that here. Patients are likely to be asymptomatic at the start of the evaluation period - thus can’t be defined as a “responder” based on a predefined reduction from baseline (there are other ways but I won’t go into that here).
PQBirch301 is therefore somewhat old school in its design (but acceptable). They simply compare the mean combined symptom and medication score (CSMS) on placebo vs active, over the birch pollen season. This allows for a much great chance of reaching statistical significance, and gets over many of the hurdles I pointed out in my IMM posts.
The CSMS is the EAACI recommended endpoint for pivotal studies with allergens. Briefly, CSMS is the sum of daily symptom score (dSS) + daily medication score (dMS). dSS is comprised of six individual symptom scores: four nasal symptoms (itchy nose, sneezing, runny nose, blocked nose) and two ocular symptoms (itchy/red eyes, watery eyes), all rated on a scale of 0-3. The dSS can be calculated as a mean of all non-missing daily SS during the pollen season (range 0-18) divided by the number of individual symptoms (6 symptoms). This way the dSS can range from 0-3. The dMS is based on the following scores: 0 = no rescue medication,1 = antihistamines, 2 = nasal corticosteroids, 3 = oral corticosteroids, again calculated as the average of the daily MS during the pollen season. Consequently, the dMS has a range from 0-3. The CSMS, which is dSS + dMS, hence has a range from 0-6. The mean CSMS will most likely be calculated from the sum of all daily CSMS during the birch pollen season divided by the number of days in the birch pollen season. For assessment of efficacy, the respective mean CSMS of the active and placebo groups will be compared - Continued in next post due to character limit..
p.p.s - I take that back - I don't think anyone knows what's going on here!
p.s. that was the "political environment" in Bangladesh. Not the UK - I think we all know what's going on here!!
It's been interesting looking at BXP on the Dhaka. The SP always runs higher on this exchange but over the past 2 months the SP has increased by over 20%, while remained relatively static on AIM. The chart lines have historically run similar paths (albeit the line is always higher on the Dhaka) so wonder if we'll see a delayed uplift on AIM?
I looked at the Dhaka primarily to see what the recent reaction has been to the political environment. Looks like it's been very positive - and I accept they have a better insight than me!..
The interview with Matt Hancock on Peston last night was worth watching. Although Peston wanted to talk about Brexit Hancock made it very clear he was in Davos primarily to talk with world leaders about the growing/global need for new antimicrobials, to tackle resistance, and he wanted to talk about that.
I thought Hancock did more for SUMM than Glynn's interview the other day on proactive. Bit flat and he would have been better hammering home the message about the changing attitude of Governments and Health Authorities for reimbursing new/innovative antibiotics. Some links below on Scott Gottlieb from the FDA..
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm610503.htm
https://www.modernhealthcare.com/article/20180914/NEWS/180919913
The reality is reimbursement will have to change, and I'm personally invested here because I believe it will. Health Authorities know they will have to demonstrate to industry they are open for business, when it comes to antibiotics, and I'm sure we'll see more incentives during the time SUMM progress their Abx program through their pivotal trials..
I've finally finished analysing the probability of success for PQBirch301 and nice to see a Phase III, on AIM, that falls within the high likelihood of success range... If helpful I'll try to summarise in a later post why the research came to this conclusion (quite detailed) - that's if anyone is interested of course and all the information is in the public domain.
As a note the "sells" showing at 14.05 are all buys