I think maybe Accaeric you might be misunderstanding the...

I think maybe Accaeric you might be misunderstanding the statement from the FDA that there are no safety or efficacy issues.

What this means is that the FDA are agreeing that the studies that have been conducted are adequate and well controlled. But there is a big difference between saying this and thinking that QRX has provided the substantial evidence required for approval of MoxDuo.

Lets take efficacy to start with.

QRX themselves are no longer making the claim that MoxDou shows superiority over and above it component parts. This is reflected in the slide in the latest capital raising presentation where the claims for MoxDou are made.

In terms of efficacy the claim is: “Efficacy: Comparable analgesic efficacy to equivalent doses of morphine or oxycodone”

The key word here is “comparable” – not superior. The reason for this is that there is no evidence for a MoxDou “synergy” in terms of analgesic effect. And one bit of good evidence (from study 002) that there isn’t any additional efficacy benefit.

In the key efficacy study (Study 008) MoxDou 12/8 (morphine equivalent dose: MED= 24) was compared with its component parts morphine 12 (MED=12) and oxycodone 8mg (MED=12). With the finding that there was a strong analgesic advantage for MoxDou.

In theory this study should have satisfied the efficacy combination rule in the first NDA application. But it didn’t – the NDA was rejected. The reason is because the finding is a nonsense. Of-course there would be a strong analgesic advantage for MoxDou 12/8 over it component parts because twice the morphine equivalent dose (MED) was being administered.

The issue is what would happen if MoxDou was compared with its MED of morphine and oxycodone. Well just this was tested in study 002 when MoxDou 12/8 was compared to its morphine equivalent dose (MED) of morphine and oxycodone. With the finding that there was no difference in analgesic effect. Goodnight superior efficacy claim.

And so the first NDA application was rejected simply because although the studies are adequate and well controlled they just don’t show what combination studies are supposed to show. And this has occurred simply because for the first time you are combining two two immediate-release opioids.

If you wanted to test the synergy argument you would run a non-inferiority trial. Lets say you think that morphine / oxycodone when combined are twice as effective than morphine and oxycodone individually. Simply test MoxDou at 6/4 (MED = 12) against morphine 24mg (MED=24) and against oxycodone 16mg (MED=24) in a non-inferiority trial. If no difference in analgesic effect is found you then have your superior efficacy claim supported. But this hasn’t been done and is unlikely to be done.

Which is why safety and side effects are where the focus is. From the slide presentation the claims for safety and side effects are as follows:

Safety: Decreased risk of experiencing severe oxygen desaturation events compared to equi-analgesic doses of either morphine or oxycodone.

Side Effects: Reduction in risk/occurrence of clinically significant opioid - related side effects, such as nausea, vomiting, dizziness, somnolence, pruritus, and respiratory depression compared to equivalent doses of morphine and oxycodone

There are two main studies relating to safety and side effects.

In study 008 MoxDou 12/8 (MED=24) was compared with morphine 12mg (MED=12) and oxycodone 8 (MED=12). As noted earlier there because the double MED there was strong analegis advantage for MoxDou. And despite effectively double the MED the differences between adverse effects and respiratory events were not statically significant.

In effect this is arguing from the null. You didn’t find a difference so one doesn’t exist. The trouble with this argument is that it is unlikely that the study would have been sensitive enough to detect a true difference even if it was there. To actually show equivalence would require demonstrating that the 95% confidence interval for the difference between the arms was also small – and this requires a much larger sample size than is needed when testing efficacy in a superiority trial (as 008 was).

It is because of this weakness for safety and side effects in study 008 that Study 002 was necessary.

When it was initiated in early 2011 the purpose of Study 002 was to support European approval and a safety update in the US to gain labelling advantages (ie stronger claims about safety advantages) for Moxdou.

It is pretty obvious that it was never intended that Study 002 would be critical FDA approval and the design (at least initially) doesn’t appear to have been discussed or agreed with the FDA. The reason for this was because at that time it was assumed that the superior efficacy argument would win the day for approval.

The basic idea of Study 002 was to show a reduction of adverse events including nausea, vomiting and dizziness and changes in respiratory function in patients with moderate to severe postoperative compared with equi-analgesic doses of either morphine or oxycodone. To enable this comparison the three arms of the trial comprised: MoxDuo 12/8 (MED=24) morphine 24mg (MED=24) oxycodone 16mg (MED=24).

From the initial analyses there seemed to be a respiratory advantage of Moxduo when analysed for AUC of blood oxygen desaturations compared with oxycodone but not morphine. The AUC outcome reflects both severity and duration of respiratory impairment.

And the weakness of this measure is that to some extent the duration of events is driven by the investigators (staff were told to intervene when these events occurred). As it turned out patients in MoxDuo group did in fact experience events of shorter duration indicating that staff intervened more quickly. As a consequence, analysed in this way, the finding is not all that strong.

With respect to the secondary outcomes it was noted that for nausea new FDA rules required the administration of anti-nausea medication only to patients that vomited (unlike previous Moxdou studies) which made interpretation of the results difficult. But there did appear to be an advantage over oxycodone.

The company itself (at the time) was not particularly upbeat about these results, noting that further studies would be required in order to sustain an improved labelling claim.

“The main objective of the study was met, with valuable information gained that will allow the design of future studies aimed at securing a comparative label claim for the respiratory advantages of MoxDuo IR.”

So all up not a great study – which at that time had the aim of simply helping with a labeling claim after approval. Now unfortunately it is front and centre in terms of the FDA approval. And this is clearly not where the company had hoped to be at this point.

The original analyses from Study 002 have been updated, presumably following advice from the FDA. The updated analyses move away from AUC of blood oxygen desaturations and focus more on the incidence or probability of having am oxygen desaturation event. These results are also presented in the capital raising investor update.

In summary. The incidence of is better for MoxDuo compared with oxycodone. But there are no statistically significant differences between MoxDou and morphine in terms of incidence of xxx. In addition there were no statistically significant differences between MoxDou and Morphine and Oxycodone for rate of serious oxygen desaturations.

Perhaps one weakness in everything that is being argued is that you are seeing a case made for benefit for MoxDou over oxycodone but not morphine. And so you begin to wonder whether this is dependent on the 1.5 factor that is used to convert to MED. It is known that the conversion factor varies between people, patient groups, settings, different type of pain. Suggesting that any advantage might be very context dependent.

But generally the results for safety in my mind are just not that compelling. Clearly the existing combination rule processes have not been appropriate for this particular type of combination of drugs. And this has surprised the company – but in some ways it should have always known that a combination product that comprises two components that are very similar – immediate release opiods was a very different kettle of fish compared with existing combination products.

But as a result the trial strategy has been at cross purposes with what now will be critical to the approval decision. You get the impression the FDA put the whole thing in the “too hard basket” and has preferred just to let an independent panel of experts look at the whole thing.

And although they will present their own position the highly variable panel process will feature highly in the decision – particularly around how to view combinations of opiods in this specific context.

As noted in the agenda for the (now cancelled) Advisory Panel meeting:

“The committee will discuss the safety and efficacy for the new drug application (NDA) 203077, proposed trade name MOXDUO (morphine sulfate and oxycodone hydrochloride) capsules, submitted by QRxPharma Inc., for the proposed indication of management of moderate to severe acute pain where the use of an opioid analgesic is appropriate. This product represents the first drug combination consisting of two immediate-release opioids.”

But overall (and contrary to opinion here) I would rate the probability of approval as quite low. Having said this I would rate the probability of the sp rising between now and May as very high. This is because of the considerable amount of sophisticated money that entered QRX at 60 cents in the capital raising wanting to exit their positions, in profit, before the FDA decision is made. As such I think QRX represents an excellent buy early, sell before decision type of play.

All imo – Southoz