Driven to shed light on why Phosphagenics has chosen postherpetic neuralgia as the indication for its topical oxycodone trial and why it was decided to run the topical oxycodone Phase 2 trial ahead of that of the company's lead product, transdermal oxymorphone, I’ve been continuing to look for answers. Finally, by using the jigsaw piece of Lyrica, I think I have found them.
This week, Pfizer released its Q2 2014 results. Sales of Pfizer’s Lyrica rose 16% in the quarter to $1.32 billion. (1) This means that ten years after first being approved by the FDA for the treatment of postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), Pfizer’s top-selling drug is now on track to book over US$5 billion in annual sales. (2)
Lyrica holds patient-share leadership in PHN therapies in the world’s major markets. (3) However Lyrica’s stratospheric sales figures owe relatively little to its status as the lead treatment for PHN - less than 600,000 people across seven major markets were said to be affected by PHN in 2011. (3) Rather, PHN has been used by Pfizer (and several other pharmas) as a gateway indication into the lucrative broader neuropathic pain market. Relatively high patient responsiveness to treatment compared with other neuropathic pain populations and relative ease of diagnosis are said to be key reasons for the selection of PHN as the neuropathic pain indication tested in clinical trials.(3) Pfizer has then used its approvals for PHN and PDN as the launching pad for Lyrica's wider commercial success by obtaining approvals for the drug in treating other types of pain, such as fibromyalgia (approved 2007) and neuropathic pain associated with spinal cord injury (approved 2012). (4)
Notwithstanding Lyrica’s approval for additional indications, its explosive sales growth owes much to Pfizer’s extensive use of off-label promotion. Pfizer has twice been found guilty of promoting Lyrica for multiple types of pain (other than PHN and PDN), including other forms of neuropathic pain, chronic pain, migraine and perioperative pain. In 2009 Pfizer was ordered to pay US$2.3 billion for off-label promotion of Lyrica and three other drugs. (5) The company was fined again in 2012, this time just $43 million, for the illegal promotion of Lyrica and the antibiotic Zyvox. (6) Despite the penalties for its misdemeanours, Pfizer clearly remains comfortably ahead in the game.
Lyrica’s relevance to Phosphagenics lies in its position as the market-share leader in PHN therapies. Later this year, Phosphagenics will commence a Phase 2 trial in the use of a TPM/topical oxycodone patch for the treatment of PHN. Most importantly for Phosphagenics, the TPM topical patch will need to demonstrate that it can effectively reduce pain intensity. Surveyed U.S. and European neurologists agree that reduction in pain intensity is the attribute that most influences their decisions regarding prescribing in PHN. Furthermore, it is also agreed that greater reduction in pain intensity is one of the most important unmet needs in PHN. (7)
Prescribers and key opinion leaders believe that there are no superior alternatives to Lyrica either currently available or on the horizon. Surveyed US neurologists say that Lyrica is their prescription choice for 40% of their PHN patients and opinion leaders hold the view that no current or emerging therapies hold significant advantage over Lyrica in reducing pain intensity.(7) Nevertheless, it seems to be agreed that current treatments, including Lyrica, leave an unmet need. A Decision Resources report on PHN therapies concluded that a sizeable opportunity exists for any therapy that can effectively reduce pain intensity and/or achieve meaningful pain reduction in a greater percentage of patients while offering a safety and tolerability profile equal to or better than that of current therapies.(3)
In order to form an opinion on TPM/topical oxycodone’s chances of bettering Lyrica on pain intensity reduction and safety and tolerability, Lyrica’s effectiveness on these attributes needs first to be considered. Thus the question is – just how effective is Lyrica at reducing PHN pain intensity and how safe and tolerable is it?
In the clinical trials upon which Lyrica’s approval was based, it was demonstrated that pregabalin (Lyrica) significantly reduced the pain of PHN compared with placebo. Because pregabalin's clinical trials for PHN were conducted more than a decade ago and the drug has been the subject of numerous studies since, more clinical evidence is now available. A shortcut review published in the Emergency Medicine Journal in 2012, which scanned 48 papers, concluded that pregabalin does not seem to decrease the intensity of acute herpetic pain nor does it decrease the incidence of PHN. (8) A Clinical Evidence Synopsis published this month in The Journal of the American Medical Association found that, compared with placebo, pregabalin was associated with only a modest increase in the number of patients experiencing meaningful pain reduction from PHN.(9) At best, it would seem that Lyrica is only modestly effective at reducing the pain intensity of PHN.
The other major goals of PHN treatment are to improve patient physical functioning and quality of life. The most commonly reported side effects of Lyrica which can affect more than 10% of patients, include dizziness, sleepiness, swelling of hands and feet, balance and coordination problems, fatigue, dry mouth, weight gain, tremor, blurred vision and double vision. (10) Online patient reviews suggest a significant level of dissatisfaction with the drug (11,12) It seems fair to conclude that Lyrica's side effects preclude a significant number of users from experiencing improved physical functioning or quality of life.
TPM/oxycodone’s success at reducing pain intensity won't be known until the completion of Phase 2 trials. However, an IAH/POH trial of the patch on racehorses hints at its potential effectiveness. Six horses exhibiting shinbone soreness were treated with the patch for 10 consecutive days. Treatment with the topical patch was found to be highly effective. All of the horses demonstrated complete pain resolution. Five of the horses were pain-free within 24 hours and the sixth horse within 48 hours. (13) (In comparison, it has been found that patients who do respond to pregabalin usually achieve a statistically significant reduction of pain associated with PHN by the end of 2 days of treatment.) (14)
The likelihood of the TPM/oxycodone patch improving patent functioning and quality of life is much more certain, as the advantages of topical over oral therapies are already well accepted. An article on the neuropathic pain of postherpetic neuralgia which was featured in Pain Medicine News notes that oral therapies for PHN such as Lyrica inevitably compare poorly with topical therapies in improving patient quality of life. Topical analgesics are favoured for their excellent side-effect profiles and end-organ safety as well as practical advantages for the patient. Topical therapy is also considered to have the potential to simplify and reduce systemic analgesic use and its associated titration,side effects and complexity.(15)
Therefore, the question of why Phosphagenics chose to test the TPM/oxycodone topical patch for the treatment of PHN pain has been answered for me. My other question was, why hold the topical patch trial before the Phase 2 trial of POH's lead product, the transdermal oxymorphone patch?
I've come to the conclusion that this decision has been made for strategic reasons related to licensing deal negotiations for the oxymorphone patch. I am assuming that it’s already accepted that the oxymorphone patch is effective and I am also assuming that both Endo and Pfizer will already have some level of interest in the transdermal oxymorphone patch. Endo's likely interest relates to its extended-release oxymorphone product, Opana. Sales of its No. 2 sales product, Opana, have been hit by generic competition. Sales declined by more than 40% from 2011 to 2013 and are further threatened by abuse-deterrent oxymorphone products in development.(16) Meanwhile, Pfizer, the global leader in pain therapies (mainly due to sales of Lyrica), is looking to build strength in the area of chronic nociceptive pain. It is seeking to partner on suitable therapies in that area, including improved opioids with fewer side effects, novel abuse-resistant formulations and approaches to address over-consumption.(17) It will be keen to relieve Purdue of some of its $2.8 billion annual sales of OxyContin.
I am further assuming that both companies will also have interest if the topical oxycodone patch is proven efficacious for a neuropathic pain indication in Phase 2 trials. Endo will be extremely pressured to recapture the sales that it enjoyed with Lidoderm, its No. 1 sales product prior to the entry of generic competition last year. Sales have already plummeted to approximately 10% of sales at peak. (18) In Pfizer’s case, it has fought hard to withstand multiple generic patent challenges and appeals with respect to its neuropathic pain blockbuster Lyrica. (19) The company will be anxious to protect the $5 billion it stands to make from the drug each year until patent expiry in 2018. One can be certain that it will already be making plans for the period beyond.
That’s why I think Phosphagenics chose to complete the topical oxycodone trial first. Having the flexibility of two proven effective, highly valuable products at the bargaining table, one for nociceptive and the other for neuropathic pain, could seriously raise the stakes.
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