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Iroko Pharmaceuticals Reports Phase 2 Study Results For Nano-formulated Naproxen, Diclofenac and Indomethacin

CHICAGO, November 7, 2011 A novel way of formulating a widely used class of pain medicines may allow reduced and more tolerable doses to be administered while preserving the pain-relieving effects of higher doses, according to multiple reports presented today at the annual meeting of the American College of Rheumatology (ACR).

The clinical data result from a broad Phase 2 development program conducted by Iroko Pharmaceuticals, which has applied a proprietary nanotechnology to reformulate certain products in the large class of pain medicines called NSAIDs (non-steroidal anti-inflammatory drugs). Nano-formulations reduce drug particle size and enhance drug dissolution in the body.

Iroko has initiated its Phase 3 clinical program with patients already enrolled in studies evaluating diclofenac in the relief of acute pain and osteoarthritis pain.

The Phase 2 studies presented at ACR enrolled 659 patients to evaluate pain treatment with nano-formulations of oral naproxen, diclofenac and indomethacin in active-component doses 20% lower than those of standard formulations.1 Over a recent 12-month period, about 97 million prescriptions were written for these three NSAIDs in the United States alone. 2 NSAIDs are used to relieve the pain associated with arthritis, back pain, bursitis, tendonitis and other painful and inflammatory disorders.

Iroko’s nano-formulation program aims to lower the dosing and the systemic exposure to NSAIDs and thus improve their tolerability while maintaining their effectiveness. The risk of adverse events, including ulcers, gastrointestinal bleeds and cardiovascular events, such as heart attacks, associated with currently marketed NSAIDs has been shown to increase with higher doses.3

The US Food and Drug Administration (FDA) and the European Medicines Agency

(EMA) have advised that NSAIDs should be administered at the lowest effective dose for the shortest duration consistent with treatment goals.4,5 Medical organizations including the Osteoarthritis Research Society International and the American Gastroenterological Association have published similar guidelines.6

“Pain remains a difficult challenge in medical practice because of the need to find the balance between providing relief and minimizing side effects,” said Dr. Allan Gibofsky, Professor of Medicine and Public Health at Weill Medical College of Cornell University.

“Nano-formulated NSAIDs may provide a new treatment option if the potential indicated in these Phase 2 studies is confirmed in Phase 3 trials.”

John Vavricka, chief executive officer of Iroko, commented, “The ACR presentations are the most comprehensive report to date of our work in applying nanotechnology to medicines that are mainstays of pain management. It is these data that have given us the confidence to progress our clinical program into Phase 3 in anticipation of a 2012 regulatory filing to obtain marketing approval of our first new product.

Nano-formulated naproxen

One of the Phase 2 studies reported at ACR evaluated naproxen in both lower-dose nano-formulations (200 mg and 400 mg) and in standard formulations (250 mg and 500 mg) in comparison with placebo.7 The primary efficacy endpoint was total pain relief as reported over 12 hours (TOTPAR-12) following third-molar extraction.

Although the nano-formulations were administered in lower doses, their treatment effect, like that of the standard formulations, was highly statistically significant versus placebo (p<0.001). Each dose of a nano-formulation was associated with numerically higher (better) TOTPAR-12 scores than the corresponding higher dose of a standard formulation, though the study was not powered to show statistically significant differences among active treatments.

Similarly, as pain relief was reported over intervals of 8 or 4 hours, improvement in TOTPAR-8 and TOTPAR-4 scores for each of the lower-dose, nano-formulations was highly statistically significant (p<0.001) versus placebo and numerically higher than for the corresponding higher-dose, standard formulation.

Also assessed were times to pain relief. All the active treatments had significantly faster mean times to meaningful pain relief than placebo, and each nano-formulation had a numerically faster time than the corresponding higher dose of a standard formulation. For example, the mean time to pain relief for nano-formulated naproxen 400 mg was just over an hour, versus more than 3 hours for placebo (p<0.002) and an hour and a half for standard naproxen 500 mg.

Nano-formulated diclofenac

A second presentation at ACR included study data regarding TOTPAR scores for nano-formulated diclofenac in doses of 18 mg and 35 mg. 7 Currently marketed oral formulations of diclofenac are typically prescribed in 25 mg and 50 mg doses. This study also included currently marketed celecoxib as an active treatment, at its highest starting dose of 400 mg.

The improvement in pain relief with each of the lower-dose, nano-formulations of diclofenac, as with celecoxib, was highly statistically significant versus placebo as measured by the primary endpoint of TOTPAR-12 and by TOTPAR-8 and TOTPAR-4 (p<0.001). Scores were numerically higher for the nano-formulations of diclofenac than for celecoxib.

Nano-formulated indomethacin

A third study presented at ACR compared nano-formulated indomethacin in doses of 20 mg or 40 mg against placebo.7 Currently marketed formulations of indomethacin are typically prescribed in 25 mg or 50 mg doses.

The primary endpoint was TOTPAR-8. Both TOTPAR-8 and TOTPAR-4 scores for each of the nano-formulations of indomethacin were significantly improved versus placebo (p=0.001), as were the scores for celecoxib 400 mg.

Nano-formulations

Iroko formulates NSAIDs using the proprietary SoluMatrix™ nano-technology platform of its partner, iCeutica. These product candidates are intended for administration at lower doses without compromising onset of action and effectiveness, in keeping with the public-health advisories of the FDA and the EMA.

About Iroko Pharmaceuticals, LLC

Iroko is a pharmaceutical company focused on specialty therapeutic areas. The company acquires, develops and maximizes the potential of currently marketed products on a global basis through focused selling and marketing efforts and product-life-cycle management activities including development of new formulations to improve patient treatment.

Contact

Lisa Gray
Managing Partner
Phoenix IP Ventures
lisa@phoenixipv.com
267-765-3233

Notes

1. The Phase 2 trials used an acute, dental-pain model that is validated in assessing NSAIDs. All of the trials were multisite, randomized, double-blind, single-dose, parallel-group, placebo-controlled studies; two of the trials also included a second active-treatment comparator group. All the study subjects, 18-50 years old, had at least two third molars extracted and experienced moderate to severe pain within six hours after surgery.

2. Source: IMS. Period: July 2010 – June 2011.

3. Dose–response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Lewis SC, Langman MJS, Laporte J-R, et al. British Journal of Clinical Pharmacology. 2002;54:320-326. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. Rodrıguez LAC, Tacconelli S, Patrignani P. Journal of the American College of Cardiology. 2008;52:1628-1636.

4. Public Health Advisory – FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). July 7, 2005.

5. Opinion of the Committee for Medicinal Products for Human Use Pursuant to Article 5(3) of Regulation (EC) No 726/2004, for Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). October 18, 2006.

6. Other medical organizations that have advised the lowest-dose, shortest-duration approach to various indications for NSAIDS include the European League Against Rheumatism and the Canadian Association of Gastroenterology.

7. The following tables show data presented at ACR with respect to total pain relief. The poster titles at ACR are: A Phase 2 Study Evaluating the Acute Pain Relief of a Nano-formulated Naproxen; Acute Pain Relief by a Proprietary, Nano-formulated Lower-dose Oral Indomethacin; and Application of Nanotechnology to Improve NSAIDs.

TOTPAR (Higher TOTPAR scores indicate better relief.)

^aP<0.001 compared with placebo. SD=standard deviation.

Several NSAIDS Intended To Improve Safety and Tolerability Are Advancing in the Iroko Pharmaceuticals Pipeline

SAN DIEGO – (September 15, 2011) A novel formulation of diclofenac provides pain relief at lower-than-standard doses during a Phase II clinical study as reported today at the 2011 World Congress on Osteoarthritis.¹ The Congress is organized by the Osteoarthritis Research Society International.

The diclofenac study is part of a multi-drug development program at Iroko Pharmaceuticals to use proprietary nanotechnology in re-formulating a large class of pain medicines called NSAIDs (non-steroidal anti-inflammatory drugs). Nano-formulations reduce drug particle size to enhance drug dissolution in the body.

The Iroko program aims to use the proprietary SoluMatrix™ technology to lower the dosing of NSAIDs, reduce systemic exposure by 20%, and thus improve their safety and tolerability while maintaining their effectiveness. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both have advised that NSAIDs should be administered at the lowest effective dose for the shortest duration of time.^2,3

“Nano-formulations of NSAIDs may provide a new option for physicians as they balance efficacy and safety in treating pain,” said Dr. Allan Gibofsky, Professor of Medicine and Public Health at Weill Medical College of Cornell University. “Iroko’s results with nano-formulated diclofenac indicate this potential and merit larger-scale studies.”

Diclofenac in standard formulations is an NSAID that has long been used in various pain-relief indications including osteoarthritis. Standard, currently marketed formulations of diclofenac are typically prescribed in 25 mg and 50 mg doses.

In the Phase II study reported at the Congress, diclofenac in nano-formulated doses of 18 mg and 35 mg was compared to placebo. The primary efficacy endpoint was total pain relief as reported at intervals over 12 hours (TOTPAR-12) by patients with acute dental pain following third-molar extraction.⁴ The improvement in pain relief associated with each of the two lower dose nano-formulations of diclofenac was highly statistically significant (p<0.001).

Also included in the study was the pain remedy celecoxib, at a dose of 400 mg. Although the study was not sized to show statistically significant differences between active drug treatments, both of the lower-dose nano-formulations of diclofenac showed numerically better scores than celecoxib by TOTPAR-12 assessment.

TOTPAR scores were also evaluated at eight hours and four hours. By those measurements as well, the nano-formulations of diclofenac showed statistically significant superiority to placebo and numerical superiority to celecoxib.

Another assessment used during the study was the time to onset of pain relief. This time was significantly shorter for all the active treatments than for placebo (p<0.001) and numerically shorter for both of the lower dose nano-formulations of diclofenac than for celecoxib.

Further data from Phase II clinical studies of nano-formulated NSAIDs under development by Iroko will be presented at another major medical conference this year.

Iroko has initiated several Phase III trials of nano-formulated NSAIDs manufactured using the proprietary SoluMatrix™ nano-technology platform of Iroko’s partner, iCeutica. All these product candidates are designed for administration at lower doses without compromising onset of action and effectiveness, in keeping with the public-health advisories of the FDA and the EMA.

About Iroko Pharmaceuticals

Iroko, based in Philadelphia, is a pharmaceutical company focused on specialty therapeutic areas. The company acquires, develops and maximizes the potential of currently marketed products on a global basis through focused selling and marketing efforts and product lifecycle management activities including development of new formulations to improve patient treatment.

Contact

Lisa Gray, Managing Partner
Phoenix IP Ventures
lisa@phoenixipv.com
267-765-3233

Notes

1. A Phase 2 Study Evaluating the Efficacy and Safety of a Novel, Proprietary, Nano-formulated Oral Diclofenac

2. Public Health Advisory – FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). July 7, 2005.

3. Opinion of the Committee for Medicinal Products for Human Use Pursuant to Article 5(3) of Regulation (EC) No 726/2004, for Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). October 18, 2006.

4. In total, 202 subjects 18-50 years of age participated in this multisite, randomized, double-blind, single-dose, parallel-group study. All the study subjects had at least two third molars extracted and experienced moderate to severe pain within six hours after surgery. The subjects assessed baseline pain intensity at time zero before receiving either nano-formulated diclofenac 18 mg or 35 mg, celecoxib 400 mg, or placebo.

Detailed results appear in the following tables. In the first table, higher TOTPAR scores indicate better pain relief. In the second table, lower numbers indicate shorter time to pain relief, as measured in hours.

Data from Study of Indomethacin Presented to American Headache Society

Several Novel NSAIDs Being Developed by Iroko Pharmaceuticals

WASHINGTON, June 3, 2011 — A novel, lower-dose formulation of indomethacin, a widely used pain reliever, is absorbed faster by the body than a standard formulation and maintains comparable maximum concentrations in the blood despite being administered at a lower dose, according to a study to be reported here tomorrow at the annual meeting of the American Headache Society (AHS)¹.

The presentation of the study marked the first disclosure at a clinical congress of data from a broader research program that is reformulating a large class of marketed analgesics by means of nanotechnology. Nano-formulations reduce drug-particle size to enhance drug dissolution in the body.

In this Phase I pharmacokinetic study, nano-formulated indomethacin in doses of 20 mg or 40 mg demonstrated a faster time to maximum concentration (Tmax) than a 50-mg dose of standard indomethacin.² Among patients who fasted ahead of drug administration, the maximum concentration (Cmax) was comparable for 40-mg nano-formulated indomethacin and 50-mg standard indomethacin, and lower for all other doses and feeding states in the study.

As anticipated, under both fasting and fed states, total drug exposure (AUC) was reduced by about 25% when the study subjects received 40-mg nano-formulated indomethacin instead of 50-mg standard indomethacin. Half-life (T1/2) was comparable across all doses, formulations, and feeding states, though slightly higher for 50-mg standard indomethacin under fasting conditions.

Indomethacin, which has been used in various indications for decades, is a member of one of the largest classes of pain medicines, called non-steroidal anti-inflammatory drugs (NSAIDs). To lower the potential for adverse events associated with NSAIDs, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have advised that NSAIDs should be used at their lowest effective dose for the shortest duration of time.^3,4

“These early data indicate the promise of re-formulating NSAIDs through nanotechnology,” said Stephen Silberstein, M.D., Professor of Neurology and Director of the Jefferson Headache Center at Thomas Jefferson University. “It is important now to progress studies evaluating the clinical benefit of these compounds.”

Dr. Silberstein continued, “NSAIDs are a mainstay in the treatment of pain, and new formulations to speed pain relief would be a welcome advance in analgesia. Lowering doses may also improve the tolerability and safety of this commonly used class of drugs.”

The study was sponsored by Iroko Pharmaceuticals, LLC, a Philadelphia-based company focusing on scientific innovation in analgesia. Iroko is initiating several Phase III trials of nano-formulated NSAIDs manufactured using the proprietary SoluMatrix™ nano-technology of Iroko’s partner, iCeutica, Inc.

All the nano-formulated NSAIDs under development by Iroko are designed for administration at lower doses without compromising onset of action and effectiveness, in keeping with the public-health advisories of the FDA and the EMA.

About Iroko Pharmaceuticals, LLC

Iroko is a pharmaceutical company focused on specialty therapeutic areas. The company acquires, develops and maximizes the potential of currently marketed products on a global basis through focused selling and marketing efforts and product-life-cycle management activities including development of new formulations to improve patient treatment.

Contact

Lisa Gray, Managing Partner
Phoenix IP Ventures
lisa@phoenixipv.com
267-765-3233

Notes for Editors

1. The Pharmacokinetic Parameters of a Novel, Proprietary Nano-formulated Oral Indomethacin – Poster # 129.

2. Forty healthy volunteers aged 18 or older participated in this single-dose, randomized, five-period, five-treatment, crossover study. Pharmacokinetics were assessed in fed and fasting states.

3. Public Health Advisory – FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). July 7, 2005.

4. Opinion of the Committee for Medicinal Products for Human Use Pursuant to Article 5(3) of Regulation (EC) No 726/2004, for Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). October 18, 2006.