Oxford Pharm Gp Share Discussion Threads

[timbo003] 03/2/2015 09:21

Had a chance to have a more detailed look at the last RNS

It looks like the naproxyn trial will be running slightly ahead of the ibuprofen trial, so I checked the clintrials . gov web site for details:



There's the old "failed" ibuprofen study using version 1 of OXP001, still no results reported, they need to speed up a bit on that.

Then there's an extremely brief outline of the proposed Naproxyn study using OXP005, they will have to expand on that before they commence, in its current form they don't even state the size of the dose. They state that they have topline PK in Q1, in which case they need to get a move on.

Worth noting, that even if they can overcome the reduced bioavailability (seen in the first OXP001 study), it does not follow that they will get good endoscopy results, as extent (and speed) of absorption will be directly correlated to extent of gastric damage/irritation.

No sign yet of the second OXP001 (ibuprofen study) on the Clin trials web site, so they need to get motoring on that one too if they are to meet their timings.

[timbo003] 30/1/2015 08:00

Not a good update:

* Revenues from Calcium business falling

* No real mention of the statin projects, so have they dropped that particular white elephant?




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[timbo003] 20/1/2015 07:51

It looks like they are intending to do the ibuprofen study and the naproxen study in parallel, which seems a bit reckless, given that both products have the same inherent problems:

* If you show reduced gastric irritancy in fasted volunteers, you will do so as a result of reducing the rate and extent of absorption, so the product will not be bioequivalent (and not be as effective as an analgesic) as demonstatrated in the first unsuccessful study with OXP001

* Even if you do show reduced irritancy in fasted volunteers, it is most unlikely that you will show a reduced irritancy in an actual use study in patients when the patients will take food with the medication. All NSAID labels state take with food (less chance of gastric irritation), the food effect will completely overwhelm any effect from the buffering in the OXP formulations, so you would expect to see no difference in the OXP formula and the controls.



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[gnnmartin] 09/1/2015 00:03

I'm pleased but surprised at the rise. I didn't think there was much risk they couldn't produce a version of XPZero that would give a fast release. The good news will come when they can show it acts as fast as straight Ibuprofin while still causing reduced gastric damage.
Nigel Martin

[andrbea] 08/1/2015 11:57

If one of the major pharmas snaps them up this year it could be in royalties / milestone payments on future sales. The potential gastric-safe market worldwide is gigantic IMO. Surprised that the 19% rise today isn't more like 100%, as they enter the finishing straight (hopefully) of the research.

[kloos2] 08/1/2015 09:28

Nice to see the share price respond positively to the news.

[timbo003] 08/1/2015 07:46

Update on OXP001 today

They state:

The Company has now successfully optimised both the active pharmaceutical ingredient (API) and the formulation, developing an immediate release product that achieves comparable in vitro drug release to the Ibuprofen reference

So as predicted, they had to do somewhat more than just improve the disintegration time (which they had previously inferred), they have had to change the API. This will almost certainly mean that they have changed the ratio of Al/Mg Hydroxide : ibuprofen (see post 485 above), which will account for the delay.

Still, at least they are now on the right track. It remains to be seen whether this new formulation has both the same GI benefits as their previous failed formulation whilst achieving bioequivalence with the reference.

If they are clever designing the next POC study they could certainly increase their chances a tad. They should just go for very infrequent sampling points for blood draws, that way they will increase their chances of achieving bioequivalence, also maybe administer with a bit of food (as per current label for the reference product) rather than used fasted volunteers again, that would probably help achieving bioequivalence, but it would also make the reference product "safer" at the same time, thus making it more difficult to show a clinical meaningful difference between OXP001 and the reference.




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[timbo003] 15/9/2014 12:00

Regarding today’s RNS: I think OXP need to sort out what’s gone wrong with their “safer” ibuprofen formulation before they start spending serious money on the Naproxen formula.

Just to reiterate what I have stated before: improving the disintegration time for OXP001 is a complete red herring. The product will already have had a fast acceptable disintegration time, otherwise it would not have been deemed suitable for the previous study, no one would run a bioequivalence study with a sub optimal product vs a fast release control (Brufen tablets in this case).

The most likely reason for the failure of the previous study was because there was incomplete release of the ibuprofen from the Aluminium Magnesium hydroxide complex (which has nothing to do with tablet disintegration time).

There are two ways to get around this problem, either co-administer the OXP001 with copious amounts of competing anions which will displace the ibuprofen from the Al/Mg Hydroxide (food should do it), or reduce the ratio of Al/Mg Hydroxide : ibuprofen in the formulation, which will help shift the equilibrium towards the release of free ibuprofen. The downside to either of these approaches is that they will increase the risk of reducing the gastro protective properties of the formulation.

Naproxen has similar physico chemico properties to ibuprofen, with similar pKa (circa 4-5) and logP (circa 3 – 4) values. Therefore I would expect the Naproxen formulation to have similar problems to the ibuprofen formula with respect to its binding and release characteistics from the Mg/AL hydroxide complex and therefore similar problems, i.e. incomplete release in vivo and lower extent of absorption (AUC)

I see from the OXP web site that they have modified the project timeline table, there are now less projects included in the table, they have lost their internal “oxp” project numbers and the there are no dates specified for any of the projects:




Compare and contrast with project pipeline timeline used previously up until a month or so ago:







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[gnnmartin] 08/7/2014 11:25

I'm curious. In the last month around 15% of the shares have been traded, in chunks of up to 4.5% (on June 30). I had expected an RNS by now.
Nigel Martin

[timbo003] 17/6/2014 07:38

They should stick to what they are good at:



This is clearly good news for them, there are no commercial numbers, but the taste masked calcium technology is clearly commercially viable and they should be concentrating on a global roll-out, rather than wasting time and money on pipe dreams like OXP001.



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[timbo003] 03/6/2014 12:57

I have been thinking about what would I do in their situation.

The data they have on reduction of lesions and improvement in Lanza score would be impressive, if it were not for the fact that OXP001 was not bioequivalent to the control.

Why is it not bioequivalent?
It is not bioequivalent because not all of the ibuprofen is released from the salt complex in vivo and it probably ends up in the faeces.

How could they make it bioequivalent?
They could repeat the study in the fed state (rather than the fasted state), we often adopted a protocol which required dosing 2 hours after a standard meal (simulated actual use). There are several advantages for doing this, not least (in this case) there will be far more gastric and intestinal juices flowing around, these contain hydrogen, potassium and sodium ions which are necessary to displace the ibuprofen from the Magnesium Aluminium complex salt. Once it is displaced it can be absorbed and so the amount absorbed should be the same as a conventional tablet (circa 100%).

The potential drawback to this approach, is that the gastric intestinal damage from both formulations will be considerably reduced, so they may no longer be able to detect a difference between OXP001 and Brufen tablets wrt Lanza scores and other safety indicating parameters.

Even if this approach didn't get them out of the hole they are in for OXP001, it could provide a solution for the two taste masked developments, OXP002 and OXP008 where no safety claims are envisaged. Perhaps shareholders should suggest it to OXP management, or at least draw their attention to this thread.


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[gnnmartin] 02/6/2014 16:32

Tim, thanks. And thanks for the links.

[timbo003] 02/6/2014 15:47

Nigel, Thanks for that.

I suspect the tablet disintegration time (and more importantly dissolution time) will already have been reasonably fast, otherwise the OXP001 tablet would not have been progressed to the clinic. In fact all tablets tested will need to disintegrate within 15 minutes in order to comply with pharmacopoeial requirements.

The disintegration test/spec employed for conventional tablets can be found here on these two links:




There is some OXP001 dissolution data here (slide 5):

The dissolution looks fast, although there are no details of the method.

I suspect the problem is that neither the disintegration test, or more importantly the dissolution test are predictive of what happens in vivo (this is a very common problem). What they need is a validated in vitro / in vivo correlation. They don't have one of those, so what ever they come up with next time, with their minor formulation change, they will not have any idea of how in will perform in vivo, it will just be a stab in the dark.

We spent years developing a validated an in vitro / in vivo test for paracetamol dosage forms, it is not a simple task, that is for sure, the end result wasn't perfect by any means, although it did the job.



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[gnnmartin] 02/6/2014 12:32

Tim, I appreciate as ever your bearish view on OXP, but feel that OXP go some way to addressing your criticism in the final paragraph (copied below), so the RSN is perhaps less spun than your post suggests.

"The pharmacokinetic data showed a different drug release profile for OXP001 compared to the Ibuprofen reference, including slower drug release and some OXP001 subjects showing lower bioavailability. However, analysis of the data from this study shows no relationship between the drug release profile and the amount of gastric irritation. Specifically there is no correlation between the standard pharmacokinetic parameters tested - peak plasma concentration, area under the concentration-time curve, time to peak plasma concentration and concentration half-life - and gastric irritation and analysis of the comparable subgroup confirm the positive effect of the OXP technology on gastric irritation compared to Ibuprofen. Based on in-vitro testing, the pharmacokinetic behaviour of OXP001 is believed to be due to slow tablet disintegration. Accordingly, Oxford Pharmascience is initiating tablet optimisation work to ensure bioequivalence to the reference Brufen 400mg tablet. The Company will be validating an optimised tablet via a further pharmacokinetic and gastric irritation study, expected to conclude in the coming months, before proceeding to larger scale pivotal trials in line with previous guidance."

Nigel Martin

[timbo003] 02/6/2014 10:11

Even given a fair wind from here, OXO001 and OXP002 (and OXP008) will now be delayed (my guestimate 12 months) and more studies required. Therefore in order to execute the current plan, more funds will presumably be required.

The extent of absorption is reduced (unacceptable from a regulatory perspective), they are silent on rate of absorption, but I expect that this will be lower too.

Even if they could get the extent of absorption up to within the 80 - 120 limits, then I suspect rate of absorption will still be compromised. That may not be a big issue for OXP001, but it would be a very big issue for OXP002 (and OXP008), where speed of onset is an essential feature.

Let's now see how far things slip given this disappointment, here is their last timeline which now needs updating:




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[timbo003] 02/6/2014 08:15

What ever the eventual outcome, one thing is for sure:

I do not believe they will be able to progress OXP001 or OXP002 without reformulation work and at least one additional PK study to try to resolve the bioequivalence issue. Therefore timelines will be put back around 12 months (conservative guestimate) for both projects.


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[timbo003] 02/6/2014 07:52

That's a lot of positive spin on a very ambiguous result

My comments:

1. Reduction in lesions is impressive

2. The products are not bioequivalent, that is a potential show stopper.

3. Less systemic exposure to ibuprofen = less side effects = less efficacy

4. There is way too much spin saying it will only need a minor adjustment in the formulation to rectify this, a minor adjustment may not do it, a minor
adjustment may over do it and they loose the beneficial safety effect.

5. Extent of absorption is compromised, what about rate of absorption?

6. This is not good news for the taste masked development OXO002

7. This study is with fasted volunteers, label says take with food, food will have a buffering/protective effect. Pivotal clinicals will need to be with food in patients. What will happen then?




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[typhoon] 15/5/2014 09:26

Article on statins ..... might be beneficial to OXP

[timbo003] 03/5/2014 19:28

bamboo

It is almost certainly Invesco who reduced (presumably down zero). Neil Woodford made the original investment whilst at Invesco and ended up with just under 30%.



Presumably he must still be a believer and he has arranged for the shares to be transferred to his new fund.



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[bamboo2] 03/5/2014 13:44

I guess there will be a corresponding rns to say who has sold or reduced?
If ORA/R Griffiths is still a holder it could be him.

[fillipe] 02/5/2014 19:36

Today, 1632hrs.
Nil to 29.26%....Woodford Investment Mgt. That's quite some news!

f

[johnwise] 30/4/2014 07:19

Oxford Pharmascience Group PLC Appointment of CRO for Safestat pilot study

RNS Number : 8433F

Date : 30/04/2014

Oxford Pharmascience progresses towards clinical proof of concept study with its OXP003 Safestat(TM) atorvastatin product and appoints Quotient Clinical to undertake its early clinical development program

[timbo003] 17/4/2014 09:42

I've now had a chance to have a quick look at the recently published patent application concerning the OXP002, OXP008 and OXP001 projects (taste masked ibuprofen and reduced GI toxicity ibuprofen projects).

As mentioned in my previous post, PCT Patent application WO2014053822, assigned to OXP (which appears to concern the technology), published on April 10th 2014, see link to the application on the espacenet web site:


The international search report at the end of the application (see pages 29 – 31) refers to a number of documents, all designated with an "x", this can sometimes mean bad news as "Category "X" is applicable where a document is such that when taken alone, a claimed invention cannot be considered novel or cannot be considered to involve an inventive step."

However, in this case one of the category X citations is EP1341556, which is assigned to ISIS Innovation (i.e. Oxford University) and it turns out that this has been granted in Europe


It looks to me, as if EP1341556 has fairly broad claims, which cover most of the formulations that OXP are contemplating for ibuprofen and other NSAIDs. Bearing in mind, we know from slide 5 in Marello's presentation, that OXP are relying on inlicenced technology from the University of Oxford for OXP001 and OXP002, it looks like this Oxford University patent is that inlicenced technology. Therefore, even if OXP's recent patent application WO2014053822, is totally dominated by EP131556 (which it appears to be), or it is deemed to be non-inventive and therefore not patentable due to the prior art (which it may very well be), OXP should still have good protection, providing they have the correct arrangements in place with the University of Oxford, who appear to own the technology.

If I were a shareholder, I would now be asking for further details about the licencing agreement with Oxford University, for example: Is it on an exclusive basis? What is the duration of the arrangement? What milestone payments are payable to the University? What are the royalties payable to the University? All these would have a huge impact on OXP earnings, if OXP002 and/or OXP008 were ever commercialised.

Likewise, I would also be asking the same questions regarding the University of Queensland arrangements (referred to in slide 5). In addition, I would be asking for information about that technical aspects of the University of Queensland technology, in particular, information on patents and published papers etc.



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[timbo003] 13/4/2014 23:50

I will add a bit of meat to the bones of my brief account (above) of the Proactive Investor event last Thursday (see link to slide set used for the presentation):


Marcello took his full allocation of 30 minutes for his presentation, so there was no time for questions at the end, which was a bit of a shame. Notable nuggets were as follows:

Slide 5 on OXP zero (safer NSAIDS) states "Patented technology from Oxford University, University of Queensland, In-house" i.e. three different proprietary technologies spanning the range of products they would like to launch. Marcello did remark that the in house technology referred to in the slide, was a patent application that was due to publish imminently , as I alluded to in post number 327 of this thread:


We were not told any details of the technology, other than it was a novel salt. However, since the meeting, I have had another look on the various patent web sites and low and behold, the application did publish at the end of last week (April 10th)


We now therefore know, exactly what the technology is all about, i.e. the ibuprofen salt of mixed Aluminium and Magnesium hydroxides. I will attempt to critically appraise this later in the week, if I have time, but for now, I will comment of the remaining slides, in light of this information.

Slide 6, 7 and 8 looked reasonable regarding the current market size and potential for a new entrant offering safer NSAIDs and statins.

The narrative around slides 10 and 11 was useful, as it set out the current situation and how the 2 taste masked developments (suspension and gummy) could impact the market. I do think that Marcello may be underestimating the risks involved with this taste masking development. If the ibuprofen is completely taste masked, it could be too tightly bound as the salt, resulting in either incomplete release (a show stopper), or delayed release (possible impact on speed claims), but in the absence of a predictive in vitro release test (i.e. a validated in vitro / in vivo correlation), it is not possible to say with any certainty what the outcome will be for the pivotal studies. Given that the safe ibuprofen (OXP001) and taste masked ibuprofen (OXP002 and OXP008) are essentially the same thing, the ongoing study on OXP001 may give a good steer (assuming they are conducting PK studies with the endoscopy work).

I was not impressed with slide 12, the putative mode of action (or lack of it in this case), is just plain wrong, as I have explained quite a few times already, earlier in this thread.

Slide 13 (Safestat) is outright speculation. The colonic delivery system employed is fine and I have little doubt that OXP will be able to deliver Atorvastatin to the colon, using the UCL delivery system, without changing the drug. However, it is pure, groundless speculation to suggest that it will have any clinical benefit over a conventional statin tablet. The active moieties following statin dosing are metabolites, the metabolites are also responsible for the side effects. Therefore why should reducing presystemic metabolism, have any clinical benefit?

Slide 14 is interesting, as it enables investors to see what the analysts are getting spoon fed, regarding possible sales in the future. I have no doubt that they then fail to apply the appropriate risk adjustment to the estimated sales figures, which is why we have seen such fanciful estimates regarding the future value of the company.

The bullet stating "GI Safer Aspirin for CVD could double this" assumes that even if the technology were to work for ibuprofen (which it won't) , it would also work for aspirin. It definitely would not work for aspirin. Aspirin (acetylsalicylic acid) is rather unstable, for example:

If you employed the procedure described in the examples given in the patent application, but substituted aspirin for ibuprofen, or tried to formulate aspirin as an aqueous suspension, you would end up with zero aspirin and a lot of degradation products.



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