This crosses over three recent threads so I thought it best to...

This crosses over three recent threads so I thought it best to use a new thread.

Following the Terumo update and the newsletter I sent a rather long list of questions to the company, with particular emphasis on the issue of Phosphagenics’ opioid patch size and why patch size became such a critical issue. As I found Ross Murdoch’s detailed response very helpful in improving my understanding, I have summarised it below. I will also work on a summary of today’s phone conference which I'll post later. I can assure you that the phone conference was merely polite and certainly not staged.

• You cannot simply increase the drug concentration in a matrix patch to increase the dose or the drug will become insoluble and crystallise out.  The way to increase the dose of a transdermal patch is to increase the size of it, while maintaining the same composition.

• There is not just one patch size for Durotep MT.  Like all opioid products, Durotep MT is offered in a range of dosage strengths.  Whereas an oral tablet can often just incorporate more drug in order to increase the dose, a transdermal patch is a finely tuned composition designed to maximise drug delivery per unit cm.  To double the dose of a patch, you either double the surface area of a single patch, or simply apply two separate patches.

• Durotep MT 16.8mg (42cm2 patch) is the highest dose in the Durotep MT range. The lowest dose patch, Durotep MT 2.1mg, measures 5.25cm2.  The subsequent doses measure 10.5cm2, 21cm2, 31.5cm2 and finally, 42cm2.  In Japan, this very high-dose patch is prescribed for opioid experienced, end of life cancer patients to manage their pain before death.  Even the smaller sized fentanyl patches can be lethal in opioid naïve patients.

  

• The three day Durotep MT is not the comparator of interest in Japan. Durotep MT has been surpassed by the once per day Fentos product.  Fentos comes in 5 different dosage strengths/sizes; 5cm2, 10cm2, 20cm2, 30cm2 and 40cm2.  Notably, the one day Fentos product is virtually the same size as the three day Durotep patch.  Both the one and three day products need to get to the same plasma concentrations to be equally analgesic, so they must be the same size (assuming they deliver drug at the same rate).  The three day product must just maintain this rate of delivery for a longer period. This can be managed one of two ways; either the three day patch is made thicker than the one day patch or the one day patch is very similar to the three day patch but it’s just removed earlier.  The latter would be a problem in the US, where residual drug can be an attractive target for drug abusers whereas opioid abuse is seen as less of a problem in Japan, so residual drug is of lesser concern.  Regardless, the one day patch is not one third the size of the three day patch.  This is true of marketed products as well as the Phosphagenics TPM/Oxymorphone patch.

• Patch size is only a small part of the equation.  The two main factors that govern patch size are rate of drug delivery and drug potency.  For example, morphine is 360 times more potent than aspirin; therefore, for an aspirin patch to be equipotent to a morphine patch, it would need to be 360 times larger or deliver 360 times more drug from the same surface area. Otherwise, at the same size and same rate of drug delivery, the aspirin patch would be 360 times weaker than the morphine patch.

• This is the challenge faced when using fentanyl as a comparator to oxymorphone.  Fentanyl is the strongest opioid currently available for humans and is regarded as being 50-100 times stronger than morphine. Fentanyl patches can only be prescribed to opioid experienced patients.  Oxymorphone is listed as 3-7 times stronger than morphine. For Terumo, it’s not simply about making a patch the same size as fentanyl. The challenge is making a patch similar in size to the fentanyl patch, that is as analgesic as the fentanyl patch, with a drug that is significantly less potent than fentanyl. It is not that the oxymorphone patch isn’t therapeutic; it’s just difficult to make it equipotent to the fentanyl product.

• Because of this, the company had always looked to position the transdermal oxymorphone patch principally as a competitor product to oral opioids.  It can claim the usual transdermal benefits over the oral opioids (morphine, oxycodone and oxymorphone) such as sustained release over several days, no breakthrough pain, reduced side effects, and it can also be prescribed to opioid naïve patients unable to yet receive the fentanyl patch. When first developing the oxymorphone patch, it was never intended to be positioned head-to-head with the fentanyl patch.

• The TPM/oxymorphone patch will be offered in a range of sizes – not simply one.  It cannot be commercialised as one size.  Based upon the Phase I clinical trials results on the TPM/oxymorphone patch, it might be hypothesised that an appropriate size range to offer could be 10cm2, 20cm2, 40cm2, 60cm2 and 80cm2.  This range of patch sizes was confirmed to be acceptable by a commissioned survey of US pain specialists in ~2012/2013.  However, the eventual commercial sizes would be confirmed only after efficacy studies (human clinical trials).

• By way of comparison, the Lidoderm patch measures 140cm2 and the label of that product states that up to three patches (420cm2) can be applied concurrently to manage pain.  This is because the active ingredient here (lidocaine) is much less potent.

• The way opioid titration works, opioid naïve patients would start on the smallest oxymorphone patch size, possibly a 10cm2 patch.  If this patch adequately manages their pain, they stay on this dose with the patch changed every 3 days.  If it doesn’t, they are titrated up to the next highest dose/larger patch.  This process continues until they reach the patch size that either works for them or they move onto a stronger treatment.  This is the same process used to titrate up oral opioids because everyone has a different sensitivity to pain and everyone has a different sensitivity to opioids.  For some patients with extreme levels of pain, the smallest oxymorphone patch size might be enough to manage their pain.  For others who report much milder pain, they may find that they require the largest patch size.  Everyone will respond differently as is completely normal in opioid therapy.

• The 40cm2 patch is a standard patch size that has been manufactured for use in Phosphagenics’ clinical trials and shown in annual report/publicity images, but there will likely be sizes smaller and larger than this, as previously explained.   Ross Murdoch is of the opinion that the improvements that have been made in the latest patch formulations consolidate the target size range (which has yet to be proved) and improve the stability and delivery characteristics. These are all essential components to developing a successful product.  

• It is untrue that the company has been systematically deceptive about patch sizes or patch efficacy or anything else for years. In the case of the patch, these accusations seem to result from a poor or selective understanding of the fundamental basics of pharmacology and transdermal drug delivery.