Adlea Clinical Data

Adlea — Novel Mechanism of Action

Adlea is a TRPV1 agonist based on capsaicin (derived from chili peppers). Administered locally to the site of pain, Adlea has been shown to provide site-specific pain relief by binding to TRPV1 receptors, which are found predominantly on C-fiber neurons.

Two main types of pain sensing nerves are C-fiber neurons and A-delta neurons. Long-lasting “noxious pain” is transmitted in the body by C-fiber neurons and is associated with longer-term, dull, aching, throbbing pain. In contrast, A-fiber neurons transmit immediate “adaptive pain,” such as that experienced milliseconds after slamming your fingers in a door or after touching a hot surface.

Because Adlea acts primarily on C-fiber neurons, in clinical trials it has been shown not to have an adverse effect on normal sensation such as temperature or touch.

Clinical Data

Adlea is intended to provide rapid, long-acting, site-specific, pain relief for the treatment of post-surgical, musculoskeletal and trauma-induced neuropathic pain.

Data from clinical trials in the following indications demonstrate the efficacy of this compound in treating moderate to severe pain.

Post-surgical pain:

• Total knee replacement
• Bunionectomy

Musculoskeletal pain:

• Osteoarthritis of the knee
• Tendonitis of the elbow

Trauma-induced neuropathic pain

• Interdigital neuroma

Adlea Demonstrates Statistically Significant Pain Reduction After Knee Replacement Surgeries

In February 2007, we reported full clinical results from a Phase 2 clinical trial in total knee replacement surgeries demonstrating that treatment with Adlea resulted in significant reduction in pain on first ambulation on day 1 post-surgery (p=0.0273) and reduction in “pain right now” as well as “worst pain in past 24 hours” on Brief Pain Inventory at two weeks post-surgery (p=0.0071). Additionally, Adlea was shown to be well tolerated. Further results of the study presented at the American Academy of Pain Medicine Meeting showed a trend toward lower concomitant morphine usage in the Adlea-treated group over the placebo group, one of the exploratory endpoints. This is an important finding, as an advantage of Adlea is its potential to reduce the need for opioid drugs, which are well known to have side effects such as sedation, respiratory depression, euphoria, and nausea and vomiting during acute use, and constipation and physical dependence during chronic use.

The difference in average daily pain scores between the Adlea-treated group (n=25) and the placebo group (n=25) on day one was statistically significant and showed a relative difference in pain on first ambulation of 24 percent. On a numerical rating scale of zero to 10, the average pain score for the treated group was 5.4 compared with the placebo group’s average of 7.1. It is noteworthy that this difference was detected despite all patients being on concomitant morphine. On day 14, the patients’ “worst pain in the previous 24-hour period” using the Brief Pain Inventory form showed a relative difference of 34 percent with the average pain scores being 3.9 and 5.9 for the treated group and placebo group, respectively.

Total knee replacement (also known as total knee arthroplasty) is performed in patients with end-stage osteoarthritis of the knee. These patients have disabling pain which imposes severe limitations on their mobility, and knee replacement is performed with the goal of restoring or improving patients’ quality of life. There were an estimated 565,000 total knee replacement procedures performed in the United States in 2005, and the number of replacements will continue to grow as the average age of the U.S. population increases and as these individuals conduct more active lives. The American Academy of Orthopedic Surgeons projects that approximately 3.5 million of these procedures will be done each year by 2030.

Phase 3 Trial

On December 16, 2008, we announced the results of our ACTIVE-2 randomized, double-blind, Phase 3 clinical trial which compared Adlea (15 mg in 60 mL of solution; 0.25mg/mL) to placebo in 217 patients undergoing total knee arthroplasty (TKA; ie, knee replacement surgery). Similar to the previous acute postoperative studies evaluating Adlea, the study drug was injected into the wound at the end of the surgery immediately prior to wound closure in this randomized, double-blind study. The primary efficacy endpoint was assessment of the post-operative pain in the four to 48 hour period using the area under the curve of NRS (0–10) pain scores and was determined to be statistically significant (p=0.03). ACTIVE-2 met a secondary endpoint by a statistically significant reduction in opioid requirements during this same time period (p=0.005). This analgesic effect of Adlea on pain continued as a consistent trend over the six week post-operative assessment period, and was also supported by a similar trend in rehabilitation and range of motion in the operated knee. There was a significant reduction in the severity and distress caused by the side effects of opioid medications throughout the entire six-week period of postoperative assessment in the Adlea group, and the adverse event and wound healing findings from ACTIVE-2 continued to support the safety profile of Adlea as compared to placebo.

Adlea Shows Reduction in Rescue Medication Need for Bunionectomy.

Phase 2 Trial

A phase 2 (n=185) trial evaluated three dose levels of Adlea (100micrograms, 500micrograms and 1000micrograms) versus placebo. Dose response was demonstrated as follows: the Adlea 1000microgram (concentration of 0.25 mg/mL) treated group demonstrated statistically significantly less pain as measured by the Numeric Rating Scale (NRS) in the first 32 hours following surgery and a significantly lower proportion of patients requiring rescue medication relative to placebo; the Adlea 500microgram (0.125 mg/mL) treated group demonstrated a favorable trend both in pain rating and in the use of rescue medication. All three dosage levels of Adlea were shown to be well tolerated and side effects were similar among patients receiving Adlea or placebo.

Phase 3 Trial

On November 10, 2008, we announced the results of our ACTIVE-1 Phase 3 clinical trial which compared Adlea (1 mg in 4 mL of solution; 0.25 mg/mL) to placebo in 301 patients undergoing bunion removal surgery (bunionectomy). The study drug was injected into the surgical wound at the end of the surgery immediately prior to wound closure in this randomized, double-blind study. The postsurgical period of four to 32 hours was arbitrarily chosen for pain assessment as the primary efficacy endpoint and the area under the curve of pain scores from four to 32 hours were assessed using an 11-point numeric rating scale (NRS, 0–10). This primary efficacy endpoint did not significantly differentiate Adlea from the placebo group (p=0.07), although a secondary endpoint of opioid consumption during this period was significantly reduced in the Adlea group (p=0.012). A secondary endpoint of pain assessment as measured by the area under the curve of NRS pain scores for the four to 48 hour time period was significant (p=0.004) in favor of Adlea, and ACTIVE-1 met another secondary endpoint by a significant reduction in opioid requirements (p=0.007). This postoperative reduction in pain from treatment with Adlea was accompanied by a safety profile that did not distinguish Adlea from the placebo group. There was no difference in wound healing between the Adlea and placebo treatment groups, nor were there any effects on sensory testing around the wound, validating the sensory selectivity of the analgesic blockade produced by Adlea.

Phase 2 Studies in Osteoarthritis of the Knee Show Substantial Reduction in Pain

A Phase 2 study was conducted in 12 patients with end-stage OA of the knee who were scheduled to receive a total knee replacement. The study showed a continued reduction of pain scores throughout the six week observation period in patients receiving a single injection of Adlea. Using an ANOVA (analysis of variance between groups), the mean post treatment numerical rating scores (NRS) were 4.10 in the 1000 microgram treatment group and 7.27 in the placebo group. Adlea was well tolerated with the exception of transient pain on injection that was managed with ice packs and acetaminophen.

6 WEEK DURATION OF ACTION FOR END-STAGE KNEE OSTEOARTHRITIS

In a separate Phase 2 trial, 55 patients with moderate osteoarthritis of the knee were enrolled in an open-label study evaluating the safety and efficacy of four dose regimens of Adlea. Thirty-six patients were divided into three groups which received an intra-articular injection of lidocaine either 5, 10 or 20 minutes prior to their intra-articular injection of 1000 micrograms of Adlea. Group #4 also received 1000 micrograms of Adlea but in a stepped fashion of 100 micrograms the first week, 300 micrograms the second week and 600 micrograms the third week, each of which was delivered after lidocaine pre-treatment. Patients were followed for eight weeks and were asked if there was an improvement from baseline in their “pain when walking on a flat surface.” A statistically significant reduction in pain measured by the results of this WOMAC question was observed at weeks 1 through 8 with a p value of less than 0.001 in patients on the stepped dose. WOMAC is a validated instrument used to assess pain and function associated with knee and hip osteoarthritis. Large reductions in pain as measured by total WOMAC scores as well as by WOMAC subscales, including joint stiffness, pain and difficulty, were also reported and lasted from baseline through week 8 in all groups. As you can see on the graph below, patients also rated their pain on an NRS scale, and significant reductions in pain—well over 50 percent in most cases—were observed in all groups. Adlea was safe and well-tolerated in this study.

PHASE 2 STUDY IN MODERATE OA

Tendonitis of the Elbow Phase 2 Study Demonstrates Reduction in Pain

In this Phase 2 trial, patients with acute tendonitis of the elbow received a single, local injection of 100 micrograms of Adlea or placebo at the site of pain, preceded by an injection of a local anesthetic. At four weeks, 64 percent (14/22) of patients treated with Adlea experienced decreased pain during resisted wrist movement, compared to 30 percent (7/23) of patients treated with placebo (p = 0.026).

Treatment with Adlea reduced tendonitis pain and also increased function as demonstrated by an approximately 60 percent improvement from baseline in grip strength at four weeks, compared to an approximate 14 percent improvement in the placebo group (p = 0.009).

Importantly, treatment with Adlea produced a significant improvement on patients’ global impression of change in pain at all post treatment time points compared to placebo. At week four, 64 percent (14/22) of the Adlea patients categorized themselves as “very much improved” or “improved” since elbow injection versus 22 percent (5/23) of patients in the placebo group.

Adlea was well tolerated with the exception of pain on injection, which was managed with icepacks and acetaminophen. Other side effects were similar for Adlea and placebo.

RESISTED WRIST DORSIFLEXION PAIN

* Responders were defined as those who rated pain on resisted wrist dorsiflexion as either “no pain” (grade 0) or “full movement possible but slight pain” (grade 1).

IMPROVED FUNCTION/REDUCED PAIN

Phase 2 Study Demonstrates Reduction in Pain Associated with Interdigital Neuroma Four Weeks After Single Administration of Adlea

Data from a Phase 2 trial in patients with interdigital neuroma, a painful foot condition, demonstrated that Adlea produced a statistically significant reduction in foot pain compared with placebo four weeks after the single administration of study drug.

In the randomized, double-blind, placebo-controlled clinical trial conducted at two study centers in the United States, 58 patients were enrolled who had failed conservative treatments, including orthotics and steroid injections. Eleven of the 58 patients had a regrowth of a neuroma previously removed by surgical means. Patients received Adlea or placebo by a single injection into the neuroma preceded by a local anesthetic injection. Four weeks after the single, local injection, mean pain scores (Numerical Rating Scale scores) had decreased from baseline in the Adlea group by 59 percent versus 36 percent in the placebo group (p=0.0188). Patients in the Adlea group had a significantly lower sum of average foot pain intensity compared to placebo throughout the four week observation period. Adverse events experienced by patients receiving Adlea were similar to those experienced by patients receiving placebo.