Alpharma Presents Data Addressing Abuse Liability Features, Safety and Efficacy on ALO-01 (EMBEDA(TM)) (morphine sulfate extended-release with sequestered naltrexone hydrochloride) at the American Pain Society Annual Scientific Session
TAMPA, Fla., May 08, 2008 /PRNewswire-FirstCall/ -- Alpharma Inc. , a global specialty pharmaceutical company, today announced results from clinical trials that showed ALO-01 (EMBEDA(TM)) (morphine sulfate extended-release with sequestered naltrexone hydrochloride) capsules demonstrated clinically relevant features addressing abuse liability alongside a promising safety and efficacy profile. The Phase I and II studies, presented at the 27th Annual Scientific Session of the American Pain Society, examined the effects of ALO-01 when crushed -- a common method of abuse -- among recreational drug users and when taken whole, as intended, by chronic pain patients.
ALO-01 is an investigational pharmacologic abuse-deterrent, extended-release opioid that Alpharma is developing for the treatment of moderate to severe chronic pain. Utilizing Alpharma's proprietary technology, ALO-01 combines an extended-release opioid, morphine sulfate, with a sequestered core of naltrexone, an opioid antagonist, which is designed to be released if the capsule is tampered with by crushing, chewing or dissolving, thereby significantly reducing the euphoric effect of the opioid.
According to Phase I study findings, recreational drug users found crushed ALO-01 to be significantly less desirable than an equivalent dose of immediate release morphine sulfate solution and no more desirable than ALO-01 taken whole. Although study participants had five times higher levels of morphine in their blood after taking crushed ALO-01 (versus intact ALO-01), they reported significantly reduced drug liking, feeling high and good effects, including euphoria, compared to immediate release morphine sulfate solution.
Data presented from a separate Phase II study including patients with moderate to severe chronic pain due to osteoarthritis showed that the efficacy and tolerability of ALO-01 was comparable to marketed extended-release morphine sulfate capsules (KADIAN(R) Capsules). Additionally, when ALO-01 was taken as directed, the sequestered naltrexone had no impact on either pain relief or tolerability.
"The undertreatment of chronic pain and the abuse of prescription opioids are both serious health problems that require urgent attention," said Joseph Stauffer, DO, Chief Medical Officer of Alpharma Pharmaceuticals. "As the data suggest, ALO-01 has the potential to address issues of abuse liability while effectively treating patients with chronic pain."
On April 21, Alpharma announced that it withdrew its New Drug Application (NDA) for ALO-01 and plans to resubmit a revised application in approximately two months. While the initial NDA submission qualified for a priority review, certain technical issues around data presentation prevented a complete evaluation by the U.S. Food and Drug Administration (FDA) within the six month time period permissible for a priority review. Alpharma expects to address the submission issues and re-qualify for priority review in its resubmission, and continues to anticipate a first quarter 2009 launch following approval.
Pain is a serious, undertreated public health problem in the United States, with 19 percent of American adults reporting chronic pain and 34 percent reporting recurrent pain.(1A) Opioids provide effective pain management and are especially useful in treating appropriately selected patients with moderate to severe chronic pain who have not responded adequately to other pain management therapies.(2,3A) However, prescription opioid abuse has escalated along with increased legitimate use in pain management.(1B,4A,5) In fact, 70 percent of people who have abused opioids got them from friends and relatives (by stealing, buying, or being given them).(6) Because of potential prescription opioid abuse, patients and physicians may be reluctant to initiate opioid therapy for pain relief(4B) and, therefore, there is a need for products that deliver effective pain relief while minimizing the potential for misuse, abuse and diversion.(3B,7)
The first study, a Phase I randomized, double-blind, 4-way crossover trial, compared the effects of ALO-01 (2x 60 mg capsules), when taken whole as intended, against ALO-01 crushed and taken orally, immediate-release morphine sulfate solution (120 mg) and placebo capsules. Participants were healthy adults (N=32) who were not currently physically opioid-dependent but had used opioids to attain non-medical effects on at least 10 occasions during the past year and at least once in the 12 weeks before the study. Study participants sequentially received the four treatments, administered in a randomized, double-blinded fashion, with each treatment separated by a 14-21 day washout period.
Following each treatment, participants assessed drug liking, feeling high, good and bad effects using a visual analog scale (VAS) and completed questionnaires designed to rate abuse potential, stimulation/euphoria and subjective drug value. In addition, plasma levels of both morphine and naltrexone were measured pre-dose and at specified intervals up to 24 hours after each treatment.
Scores for drug liking, feeling high, and good effects were similar for ALO-01 crushed compared to ALO-01 whole (68.1 to 67.6, 55.0 to 60.6 and 52.1 to 59.4, respectively). These scores were significantly higher for morphine sulfate solution (89.5, 90.4 and 89.7, respectively, p less than or equal to 0.002), and peaked sharply around 1.5 hours after exposure, consistent with the time of maximum plasma levels for immediate-release morphine. Scores for stimulation/euphoria, abuse potential and subjective drug value were also similar for ALO-01 crushed and whole, but were significantly higher for morphine sulfate solution. Plasma levels of morphine and time to maximum concentration for ALO-01 crushed (80.6 ng/mL, 1.1 hrs) were similar to morphine sulfate solution (92.5 ng/mL, 1.2 hrs), while significantly lower (19.3 ng/mL) and longer (8.1 hrs) for ALO-01 whole. For ALO-01 crushed, naltrexone levels reached a peak concentration (1.1 hrs) at a time similar to morphine; for ALO-01 whole, naltrexone was not detected or was present in only trace amounts. Adverse events were mostly mild to moderate. The most common adverse events during treatment were euphoria (28.1 percent and 56.3 percent), pruritus or itching (28.1 percent and 53.1 percent) and somnolence or drowsiness (43.8 percent and 34.4 percent) for ALO-01 whole and morphine sulfate solution, respectively.
The second study, a randomized, double-blind, crossover Phase II trial, compared the effects of ALO-01 taken whole (intact orally) with an extended-release morphine sulfate formulation not containing naltrexone in 113 patients with moderate to severe pain due to osteoarthritis of the hip or knee. Patients had required treatment of the affected joint with non-opioid analgesics or had received the equivalent of less than or equal to 40 mg/day of oral morphine sulfate. After an initial washout period from previous medications until a pain flare (scored greater than or equal to 5 on a scale of 1-10) occurred, patients were titrated on extended-release morphine sulfate open-label until their pain subsided (scored less than or equal to 3) for a minimum of four consecutive days with no unacceptable adverse events. Qualified patients were then randomized to receive either ALO-01 or extended- release morphine sulfate double-blinded during two 14-day treatment periods, each followed by a seven-day open label period on extended morphine sulfate, all at the dose established in the titration period.
Efficacy assessments conducted during the study included continuing in-clinic pain intensity ratings; daily patient diaries during the treatment periods using the Brief Pain Inventory (BPI); and pre- and post-treatment scores using the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index of pain, stiffness and function. Plasma levels were evaluated for morphine sulfate and naltrexone pre-dose and at specified intervals up to 12 hours post-dose on days seven and 14 of the treatment periods, and at the end of the study. Follow-up calls with patients a further seven days after the end of the study were conducted to assess the occurrence of any adverse events.
During treatment, ALO-01 was similar to extended-release morphine sulfate for mean pain intensity (2.3 to 2.4 at Day 14) and BPI (average 2.1 to 2.2). WOMAC scores were also comparable with composite indices of 24.5 for ALO-01 and 26.6 for extended-release morphine sulfate. Plasma concentrations of morphine were similar over time, and naltrexone levels at the end of each treatment period below a quantifiable limit for most patients (82.1 percent). In patients with detectable levels of naltrexone, there was no impact on pain scores. Adverse events were mostly mild to moderate, and included constipation (15.5 percent and 12.7 percent), nausea and somnolence (both 9.9 percent and 8.5 percent) for ALO-01 and extended-release morphine sulfate, respectively.
Statements made in this release include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements, including those relating to future financial expectations, involve certain risks and uncertainties that could cause actual results to differ materially from those in the forward-looking statements. Information on other important potential risks and uncertainties not discussed herein may be found in the Company's filings with the Securities and Exchange Commission including its Form 10-K for the year ended December 31, 2007.
Alpharma Inc. is a global specialty pharmaceutical company with leadership positions in products for humans and animals. Alpharma is presently active in more than 80 countries. Alpharma has a growing branded pharmaceutical franchise in the U.S. pain market with its KADIAN(R) (morphine sulfate extended-release) Capsules, and the FLECTOR(R) Patch (diclofenac epolamine topical patch). In addition, Alpharma is internationally recognized as a leading provider of pharmaceutical products for poultry and livestock.
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Contact: Jack Howarth Vice President, Investor Relations 908-566-4153 Jack.email@example.com References
1. Kuehn BM. Opioid prescriptions soar: increase in legitimate use as well as abuse. JAMA. 2007;297:249-251.
2. Katz NP, Adams EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain. 2007; 23:648- 660.
3. Woolf CJ, Hashmi M. Use and abuse of opioid analgesics: potential methods to prevent and deter non-medical consumption of prescription opioids. Curr Opin Invest Drugs. 2004;5:61-66.
4. Gagnon AM, Kahan M, Srivastava A. Opioid use and abuse: is there a problem? Clin J Pain. 2007;23:661-662.
5. Birnbaum HG, Whiate AG, Reynolds JL, et al. Estimated costs of prescription opioid analgesic abuse in the United States in 2001: a societal perspective. Clin J Pain. 2006;22:667-676.
6. Substance Abuse and Mental Health Services Administration. (2007). Results from the 2006 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-32, DHHS Publication No. SMA 07-4293). Rockville, MD.
7. Wright C, Kramer ED, Zalman MA, et al. Risk identification, risk assessment, and risk management of abusable drug formulations. Drug Alcohol Depend. 2006;83(Supp 1):S68-S76.
CONTACT: Jack Howarth, Vice President, Investor Relations of AlpharmaPharmaceuticals, +1-908-566-4153, Jack.firstname.lastname@example.org
Web site: http://www.alpharma.com/
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Posted: May 2008