Pain is a symptom caused by injuries to various tissues (nociceptive pain), as well as injuries directly to the nervous system (neuropathic pain). When pain, for a variety of reasons, persists for longer than 3 months, it is considered chronic pain. Chronic pain is a serious medical condition and public health concern. Treatment can be costly, but the loss of mobility, independence and the ability to work is an even greater impact to patients, family and other caregivers, and society. Various studies have estimated the prevalence of chronic pain to be approximately 30% of the population.
The global market for all pain therapeutics is worth over $40 billion (IMS World Review, 2011). Although many of these treatments, including NSAIDs and simple analgesics, are utilized for acute pain (less than 3 months), the market for chronic pain treatments is still upwards of $15 billion worldwide. Chief among these are the opioids, which constitute $12 billion globally, followed by a variety of anti-epileptics (e.g., pregabalin), anti-depressants (e.g., duloxetine), and topical anesthetics (e.g., lidocaine). Because of the large opportunity for chronic treatment, long-acting transdermal formulations have been a perfect fit for some patients. As of 2013, transdermal opioids – buprenorphine and fentanyl – account for about 1/3rd of all long-acting opioid prescriptions (IMS NPA Audit). Together with the third transdermal treatment for chronic pain – the 5% lidocaine patch (known as Lidoderm® in the United States) – these transdermal chronic pain treatments accounted for about $3 billion in 2013 sales in the United States.
Oxymorphone is an opioid that is around seven times more potent than morphine when taken orally. However, the relative potency of oxymorphone increases significantly when given by other routes of administration, because the drug has very low oral absorption (10%). The high potency, low oral bioavailability and longer half-life compared to other opioids make it a suitable candidate for transdermal delivery. As an analgesic, oxymorphone was first patented in 1959. Originally, it was delivered intravenously and used mostly in hospitals. In both short- and long-acting tablet forms, it has been marketed by Endo Pharmaceuticals under the brand name Opana® since 2006, with a crush resistant form registered in 2011. The current market for oxymorphone is around $600 million in tablet form in the United States (IMS Health).
Phosphagenics first began investigating the preclinical value of a TPM®/Oxymorphone patch in 2012. Oxymorphone was selected because of its high potency, low oral bioavailability and longer half-life compared to other opioids. By the end of 2012, a transdermal matrix patch suitable for the clinic was developed, and a single-dose Phase 1 trial was undertaken in early 2013. Results indicated that oxymorphone had been delivered continuously for 72 hours and that safety was not an issue. Following some formulation and design improvements, a multi-dose Phase 1 trial was conducted in September 2013. The results, announced in October 2013, were outstanding and beyond our expectations.(see chart below):
- all subjects achieved plasma levels, on the first patch application, well in excess of the level considered to be therapeutic in the first rotation;
- with each rotation, plasma levels increased, and over each subsequent 72 hour period, therapeutic levels were comfortably maintained;
- some subjects achieved plasma levels equivalent to the highest doses of Opana® ER (40mg).
TPM®/Oxymorphone Patch – Multiple Dose Phase 1 Study Results
In August 2014, Phosphagenics announced the results from an additional Phase 1 clinical trial, which confirmed results from the previous study. The mean oxymorphone delivery profile and PK parameters were similar to those obtained in prior studies, with all subjects showing oxymorphone plasma levels in the therapeutic range. At this point, the TPM®/Oxymorphone Patch has proven reproducible across two separate manufacturing and clinical campaigns; the total number of subjects exposed to the patch is now 27.
The TPM®/Oxymorphone patch product is currently being finalised by tesa Labtec GmbH. tesa was instrumental in completing the composition of the TPM®/Oxycodone patch product, and have been engaged to provide similar support for the oxymorphone program.
Oxycodone is an opioid that is more potent than morphine, and demonstrates fewer adverse effects in patients. Consequentially, it has become a leading pain management drug for the treatment of moderate to severe pain. Currently, it is administered in tablet or intravenous form. Oxycodone, as a pure analgesic or in combination with other drugs (such as acetaminophen) generate revenues in excess of $4 billion per year, with Oxycontin alone posting sales of approximately $2.5 billion in 2013 (IMS Health).
Phosphagenics has conducted six clinical studies since 2009 on a TPM®/Oxycodone formulation, with successful results.
The first study, an open-label Repeat Insult Patch Test (RIPT) evaluated the skin response of 50 healthy human participants with induction and challenge phases. The study showed that no significant erythema or sensitization were observed.
The second study was the first to examine the safety and tolerability of a prototype transdermal TPM®/Oxycodone Patch. Healthy subjects received a 3-day application of the prototype transdermal patch or a single dose of oral oxycodone. Results demonstrated that the prototype TPM®/Oxycodone Patch could deliver oxycodone in a sustained manner for the full three days of patch application – a world first.
The third study was an open label, single center, repeat dose application PK study in 20 healthy volunteers conducted at the Royal Adelaide Hospital. Its primary objective was to compare the delivery profiles of two transdermal patch candidates containing TPM®, a matrix and a reservoir system, following daily application over a 10-day period. The study revealed that daily application of the TPM®/Oxycodone Patch delivered therapeutic bloodstream levels of oxycodone in a reproducible, consistent and sustained manner, again with no irritation observed.
A fourth study, completed in October 2010, was led by Professor Guy Ludbrook at the Royal Adelaide Hospital. This milestone study was designed to compare various dosage regimes of the TPM®/Oxycodone Patch. Importantly, the study demonstrated that the extended dosing period of 14 days enabled steady state delivery of oxycodone into the bloodstream.
In November 2010, Phosphagenics announced signing a collaborative agreement with 3M for the optimization and development of a commercial scale-up manufacturing process. 3M’s expertise in drug delivery technologies assisted Phosphagenics to improve the delivery profile of the original patch prototype, which was confirmed in clinical studies conducted late 2011.
To further improve the patch, we engaged Labtec GmbH, an expert in the area of opioid patch technology. The new patch was completed in early 2013, and in May 2013 a single dose study was commenced. The trial results (see chart below) announced in July indicated that the TPM®/Oxycodone Patch could be suitable for treatment of peripheral neuropathic pain.
TPM®/Oxycodone Patch – Single Dose Phase 1 Study Results
Lidocaine is a well known topical local anesthetic used for a wide variety of conditions, including temporary relief of rashes, stings, sprains, strains, bites and burns. Lidocaine is sold in many forms. It is available as an ointment, jelly, patch or aerosol for topical use, as an oral solution, and as an injection for local anesthesia. The patch, commonly known as Lidoderm® in the USA, is approved for the treatment of post-herpetic neuralgia and had more than $1 billion in sales in 2013 (IMS Health). In addition to the patch, topical formulations account for an additional $1 billion+ in annual sales worldwide. Although widely used, lidocaine has poor penetration into the dermis, frequently rendering it largely ineffective.
Phosphagenics’ proven pharmaceutical delivery technology, TPM®, can be used as a targeted, localized delivery system, to increase the delivery of actives such as lidocaine to targeted areas while minimizing exposure to the rest of the body. Phosphagenics’ TPM®/Lidocaine Gel is capable of improving the penetration rate and delivery concentration of lidocaine while, importantly, limiting systemic exposure. Phosphagenics’ TPM®/Lidocaine Gel successfully completed a Phase 1 human clinical trial that demonstrated that Phosphagenics’ TPM® delivery system is able to increase both the depth of delivery of lidocaine (about 2- to 4- fold increase) and the amount of lidocaine delivered into the skin compared to Xylocaine®, a leading marketed 5% lidocaine gel (see chart below, left). Nevertheless, while absorption was increased, depth of delivery was well controlled using TPM®, such that the plasma lidocaine concentration did not increase (see chart below, right).
TPM®/Lidocaine Gel – Phase 1 Study Results
Diclofenac is a leading non steroidal anti-inflammatory drug (NSAID) widely used for sprains and strains. Voltaren®, which is manufactured by Novartis, is the market leader and is sold as oral and topical applications of diclofenac. In 2013, Voltaren® generated sales of approximately $400 million in the US and $800 million worldwide (IMS Health). Flector®, which is marketed by Pfizer, is the only transdermal NSAID patch product on the market in the United States; it contains diclofenac. Flector® generated US sales of about $160 million in 2013 (IMS Health).
Phosphagenics’ TPM® pharmaceutical delivery technology can be used as a targeted, localized delivery system, to increase the delivery of actives such as diclofenac to targeted areas, while minimizing exposure to the rest of the body. A Phase 1b human study was completed in 2009 and demonstrated that Phosphagenics’ TPM®/Diclofenac Gel results in more effective permeation of diclofenac into the skin than the currently available Voltaren® gel (see chart below). The study showed that dermal absorption of diclofenac was increased compared with Voltaren® gel (about 2 to 4 fold increase), while maintaining similar levels of systemic exposure (see chart below).
TPM®/Diclofenac Gel – Phase 1 Study Results
Ibuprofen is a leading non steroidal anti-inflammatory drug (NSAID) widely used for sprains and strains, and available both over-the-counter (OTC) and as a prescription (Rx) product in higher dosages. It is the 5th highest selling generic product worldwide, grossing about $2 billion per year (IMS Health, 2012). The leading OTC ibuprofen brand in the United States is Advil®, which generates more than $500 million in annual sales for Pfizer (Symphony IRI Group, Total US Multi Outlet, 2012). An ibuprofen gel or other topical formulation is not currently marketed in the United States (OTC or Rx), but can be found throughout the world, especially under the Nurofen® brand by Reckitt Benckiser.
Building on the expertise gained in formulating topical NSAIDs, in 2014, Phosphagenics took an early TPM®/Ibuprofen Gel into proof-of-concept in vitro formulation experiments. The percutaneous absorption of ibuprofen was first tested in two simple proof of concept solvent and gel formulations in the presence and absence of TPM® over 4 hours. TPM® increased the average percutaneous absorption of ibuprofen in both proof-of-concept dosage forms, with the cumulative amount of ibuprofen absorbed after 4 hours being 1.7-2.5-fold higher in the presence of TPM® when compared with negative controls.
Next, the percutaneous ibuprofen absorption was compared between the TPM®/Ibuprofen Gel (5% w/w ibuprofen) and a commercial formulation (Nurofen® Gel 5% w/w ibuprofen). The vehicle for the TPM®/Ibuprofen Gel was similar to the Voveran TPM®/Diclofenac Gel, previously optimized for delivery of diclofenac. The TPM®/Ibuprofen Gel delivered a statistically significant increase (about 2.5-fold; p<0.05) in average percutaneous absorption of ibuprofen compared to Nurofen®.