REMOXY, page-5

The rejection of REMOXY by the FDA certainly appears unfounded and unjust. One respected medical journalist expressed disbelief at the FDA’s decision, describing it as “anti-opioid madness”. On the face of it, Pain Therapeutics appears to have been hard done by.

One might conclude that, in this era of the “War on Opioids, an intransigent FDA will refuse to approve any new opioid product, no matter how effective its tamper-proof features are. But I think that other aspects of the REMOXY case need to be considered before reaching that conclusion.

The first aspect to consider is that this was not REMOXY’s first rejection by the FDA. In fact, it was the fourth, with REMOXY's first FDA rejection occurring well before the “War on Opioids” was declared. Furthermore, this decade of rejections for Pain Therapeutics has occurred while outspoken CEO/Founder/ President/Chairman and entrepreneurial award winner, Remi Barbier, has been at the helm. Barbier and the FDA should, by now, be well acquainted. REMOXY received its first CRL (rejection) in 2008. The FDA wanted additional non-clinical data. After NDA resubmission, another CRL was received in 2011. This time, the FDA had a number of concerns, including CMC issues. After a third submission, another CRL was issued in 2016, with the FDA determining that additional actions and data were still required, including abuse-deterrence studies. The latest and probably last CRL for REMOXY came in August last year. Despite Pain Therapeutics providing the requested abuse-deterrence studies, the FDA rejected its novel oxycodone capsule because of concerns about potential abuse.

It is therefore clear that all of the FDA’s rejections of REMOXY over the years can’t be blamed on a difference of opinion on abuse-deterrence. Wherever the truth lies in this particular case, there would seem to be a long history of unfortunate miscommunication between this Company and the FDA. And the “miscommunication” hasn’t just been with the FDA. After REMOXY’s second rejection by the FDA, Pain Therapeutics was hit with a securities fraud class action by investors for allegedly concealing certain information regarding the REMOXY FDA-approval process. It was further alleged that Pain Therapeutics filed the second NDA for REMOXY despite knowing that it would also be rejected by the FDA due to then-unresolved problems with the product.

Also, Pain Therapeutics shares further history with the FDA. In 2016, along with Durect Corporation, the licensor of REMOXY’s abuse-deterrent technology, Pain Therapeutics was issued with a warning letter from the FDA regarding false and misleading advertising in website promotion of REMOXY. The FDA took exception to statements about REMOXY on the websites being presented as established facts. These included claims that REMOXY was long-acting and tamper-resistant, when this had not yet been determined by the FDA. The FDA was also concerned that it wasn't clear from the information presented on the websites that REMOXY had not yet been approved for sale by the FDA.

In its latest rejection of REMOXY last year, the FDA argued that the benefits of the drug outweighed the risks. In the words of one of the Panel, who voted against approval

I applaud the sponsor for being innovative and taking a step in the right direction but ultimately, when I'm balancing the risk-benefit and the availability of some similar options that are currently on the market compared with the possible public health impact, for me it was a no.

In my opinion, the section that I have underlined goes to the heart of why, despite impressive abuse-deterrence studies, two separate panels of the FDA emphatically rejected approval of REMOXY.

In his statement made last November about the FDA’s consideration of new opioids, FDA Commissioner, Scott Gottlieb, outlined the questions that the FDA is asking when evaluating any proposed new opioid. One of these questions is “Does the approval of an additional opioid drug create added risks for diversion, accidental overdose, abuse and misuse, or other concerns?” The FDA’s answer will likely be “Yes” for any new opioid, despite the strength of any abuse-deterrent features. It is therefore the answer to the next question which is crucial

If the approval of an additional opioid will create such added risks, will the new drug provide sufficient clinical differentiation that can benefit certain groups of patients, or offer other important clinical benefit, such that the benefits to patients of introducing the additional opioid outweigh the risks?

REMOXY, in my opinion, doesn’t offer clinical differentiation from drugs that have already been approved. By my count there have already been five abuse-deterrent, oral oxycodone products approved by the FDA. All use different tamper-proof/abuse-deterrent features.

The relevant question here is, what does the rejection of REMOXY mean for the future of Phosphagenics’ TPM opioid patches?

Firstly, I think it’s important to note that the FDA hasn’t stopped approving new opioids. Since abuse-deterrent OxyContin was first approved in 2013, the FDA has approved multiple new opioids. These include Targiniq ER (oxycodone/naloxone), Embeda (morphine/naltrexone) and Hysingla ER (hydrocodone) in 2014, MorphaBond ER (morphine sulfate) and Xtampza ER (oxycodone) in 2015, Troxyca ER (oxycodone/naltrexone) in 2016, RoxyBond (oxycodone IR), Vantrela ER (hydrocodone) and Arymo ER (morphine sulfate) in 2017 and Dsuvia (sufentanil IR) in 2018.

Secondly, as well as having the obvious advantages of transdermal v. oral opioids, both TPM opioid patches are differentiated from existing approved opioid patches (fentanyl and buprenorphine). Compared with the fentanyl patch, the TPM/Oxymorphone patch may address a broader patient population (beyond opioid- experienced patients), it may be less abusable, it is likely to have less residual drug and may potentially have formal abuse-deterrent claims. Compared with the buprenorphine patch, it is expected that the oxymorphone patch will provide better pain management and less potential cardiac issues. Also, as the buprenorphine patch is not preferred because of its weekly dosing regime, poor patch adhesion and very high levels of dermal irritation, it is expected that the TPM/Oxymorphone patch will outperform it on these issues. Finally, in a chronic pain management regime that utilises the other opioid patches, the fact that oxymorphone is a different molecule adds a valuable addition to an opioid rotation program.

Therefore, there is a positive outlook for Phosphagenics’ TPM opioid patches, based on the fact that the FDA is still approving new opioids and that the TPM patches may provide differentiation/added benefits beyond existing options.

More of a concern, in my opinion, is the trend of drug sponsors voluntarily withdrawing their opioid products from the market. Six of the opioids approved in recent years and mentioned above have since been discontinued. Although drug sponsors have provided little explanation, my guess is that growing litigation against opioid manufacturers is largely responsible. Therefore, it may take a contrarian to see opportunity in a market with declining competition….