Acura’s (NASDAQ:ACUR) lead product candidate, Acurox, is an immediate-release formulation of oxycodone containing niacin as an aversive agent to prevent “swallowing excess quantities of tablets.” Acurox also employs non-pharmacological mechanisms to deter nasal ingestion and to limit the potential for conversion into a form suitable for intravenous administration.
A 505(b)(2) NDA for Acurox is expected to be filed by the end of 2008. Acura’s SEC filings indicate that the company “convened a face-to-face meeting” with the FDA in early 2006. Based on these meetings and other interactions with the FDA, the company intends to request language in the label describing “the physical characteristics of the product and likely results if attempts are made to dissolve tablets in solvents suitable for intravenous injection, and/or snort crushed tablets, and/or swallow excess quantities of tablets (sic).” In part, Acura intends to rely on data from an extraction study and a phase 1 study (incomplete as of the date of this report) that will evaluate “the characteristics of crushed Acurox Tablets when snorted by 12-18 subjects with a history of opioid abuse”.
Investment Thesis Overview
Pharmaceutically-induced corporal punishment is not a feasible method of abuse deterrence: Niacin-induced side effects may or may not deter some drug abusers from swallowing too much Acurox but what is certain, in our view, is that niacin will deter physicians from prescribing Acurox. Since Acurox will inevitably be priced at branded pharmaceutical levels, the niacin will also likely deter third-party payors from reimbursing Acurox.
Acura’s data describing the amount of niacin that can provide effective deterrence while at the same time assuring the absence of niacin effects at recommended dosages is uninterpretable and the company’s apparently proprietary niacin disliking scales are unvalidated (these include the fancily named “Side Effects and Symptom Questionnaire” or SESQ, the “Niacin Tolerability Rating Scale”, and the “OxyADF Tolerability Rating Scale”).
Although the magnitude was not disclosed, flushing effects occurred at a higher rate in patients treated with Acurox compared to those treated with placebo in the pivotal safety/efficacy study. These effects occurred at recommended doses. We think the mere possibility of treating a patient suffering from acute pain with an opioid that might induce more pain or discomfort is unthinkable for most physicians. The pivotal data seem to confirm, not merely suggest, the induction of niacin reactions at standard doses.
Based on Acura’s dosing studies, niacin-induced side effects, even at doses 20 times higher than the dose proposed in Acurox Tablets, were virtually eliminated by food. Acurox contains no mechanism to prevent drug abusers from having breakfast, lunch or dinner and this is a problem because oral ingestion of oxycodone is by far the single most frequently cited route of abuse, even with ER formulations of oxycodone.
Numerous well-controlled studies have shown that niacin-induced cutaneous reactions can be mitigated by doses of aspirin as low as 325mg (and ibuprofen doses of under 200mg).
Data disclosed to date on the single Acurox “pivotal” extraction study that purports to demonstrate the complexity and perhaps impossibility of converting the drug into a form suitable for IV injection or snorting is no better than Purdue’s extraction data for its proposed deterrent formulation of OxyContin. The FDA mocked Purdue’s extraction studies (note that Acura has one, not multiple studies). But Acura claims the FDA has provided written guidance to the company stating “that language regarding abuse deterrence, which is supported by rigorous, scientific data, may be placed into appropriate sections” of the label. Based on our research, our opinion is that there is not a shred of rigorous data related to Acurox’s abuse-deterrence features.
Acura is a lone wolf in developing abuse deterrent formulations of IR oxycodone for a reason. Among other things, IR oxycodone is generic and making money on a branded generic is generally difficult. In addition, RADARS System data show that the rate of abuse for ER oxycodone is three times that of IR versions. And DAWN data show that emergency room admissions associated with ER oxycodone are three times as high as IR formulations. While abuse of any oxycodone-containing drug is a public health issue, the scope of the problem relative to ER formulations, particularly with regard to tampering, is more limited. Moreover, the rewards of developing a solution to abuse of ER formulations, which are patent protected, are considerably greater.
A vast majority of IR oxycodone is prescribed post-surgically (compared to a limited amount of ER formulations in this setting). Doctor shopping is a primary means of oxycodone diversion. While drug abusers can fake chronic pain, they can’t fake surgical procedures. As for hardcore abusers, they typically obtain their drugs from dealers, theft, cross-border smuggling and the internet. Unless the entire market shifts to ADF IR oxycodone, a change in prescribing behavior will have zero effect on hardcore addicts. Acura seems to agree in that it says “anticipate[s] that most potential drug abusers or recreational drug users will seek alternative opioid analgesic products that are generally much easier to abuse than Acurox Tablets.”
Acura has filed patent applications covering equally unconvincing combinations of abuse-prone drugs that contain punishing agents. Among these are laxatives, stool softeners, emetics, tissue staining agents, “malodorous and repugnant agents” such as cod liver oil, and other “discomfort and/or pain inducing agents”. We view the commercial promise for these combinations with equal skepticism.
While Acurox may be deemed bioequivalent to its reference drug (Roxicodone) and possibly approved, we do not believe its abuse resistant features will result in product specific claims. If we are correct, then Acurox will simply be an uncompetitively-priced generic oxycodone with no special marketing or promotional efforts permitted by the FDA.
Finally, Acura’s enterprise value is almost 3 times that of Pain Therapeutics’ EV, which is inexplicable, in our view.
Acura Pharmaceuticals, Inc. (ACUR) is a specialty pharmaceutical company focused on developing abuse-deterrent drug formulations (ADFs) using its so-called Aversion technology. The company’s lead product candidate is Acurox, an immediate release version of oxycodone combined with niacin as an aversive agent in a ratio of 5mg oxycodone to 30mg niacin. Acurox is also designed to be resistant to preparation for IV and nasal use. On June 17, 2008, Acura reported that an Acurox pivotal safety and efficacy study was successful. This study will form the basis for an NDA filing under section 505(b)(2) by the end of 2008.
In our view, Acura’s ADF formulations are among the weakest and most fundamentally flawed of the ADF formulations currently in development and we think Acurox is nothing more than a solution looking for a problem. In our view the company’s Aversion technology, at least with regard to Acurox, verges on the comical in that its primary “mechanism of abuse-deterrent action” derives from pain (i.e., the nasty side effects of an overdose of immediate release niacin). Based on the data we have reviewed, Acura has failed to answer many of the most important questions facing Acurox, including whether the aversive effects of niacin will occur in patients who take Acurox exactly as directed and in those who accidentally take the medication inappropriately but are not drug abusers. Also unanswered are questions related to the safety issues associated with snorting or injecting a “gelatinous mass” of Acurox.
Acura has completed niacin dose-ranging studies to determine an aversively appropriate amount of niacin in both healthy individuals and experienced opioid abusers. The data, which are based on several never-before heard of niacin-aversion scales that are apparently unvalidated and proprietary to Acura, are uninterpretable. The niacin disliking scales used in these studies include the “Side Effects and Symptom Questionnaire” or SESQ, the “Niacin Tolerability Rating Scale”, and the “OxyADF Tolerability Rating Scale”.
Of course Acurox’s deterrent features include more than just niacin. The company also claims to have designed robust snort-deterrent and injection-deterrent features into Acurox. Like Purdue’s ADF Oxycontin, the FDA is likely to mock these features and the studies that support them. Besides, the primary route of oxycodone abuse, even ER formulations, is oral (although abusers typically transition from oral administration to more dangerous forms of IV and inhaled use over time). Unlike ER formulations, abusers don’t even have to waste time crushing Acurox to alter the delivery characteristics and they might even avoid the niacin effects entirely by pre-treating themselves with one 325mg dose of aspirin. Cutaneous flushing and the other bothersome side effects of niacin are thought to be mediated by prostaglandin release and aspirin is an inhibitor of prostaglandin.
If avoidance of niacin effects with aspirin doesn’t work, patients can pretreat themselves with a cheeseburger. Acura’s studies show that a high fat meal blocks the effects of niacin even at doses 20 times higher than the amount in one Acurox tablet, which would be translate into 100mg of oxycodone in Acurox’ 5mg/30mg ratio.
Perhaps the easiest way to thwart the abuse-deterrent features of Acurox, however, is to get a prescription for non-abuse deterrent IR oxycodone. Most abusers of oxycodone get their prescriptions from their physicians and they obviously aren’t going to ask for Acurox tablets. Were such a physician suspicious of a patient’s motives for obtaining an oxycodone prescription he would have two alternatives (assuming Acurox were approved): He could either (1) refuse to prescribe oxycodone or (2) prescribe Acurox. If he prescribes Acurox he will also have to warn the patient of the potential side effects of the niacin contained in Acurox. At that point, the patient can either (1) take the Acurox prescription or (2) go to another doctor. It doesn’t require a Ph.D. in behavioral science to predict what would happen in this situation.
As for hardcore abusers, they most typically obtain their drugs from dealers, theft, cross-border smuggling and the internet. Unless the entire market shifts to ADF IR oxycodone throughout the world, a change in prescribing behavior will have zero effect on these users.
Acurox Licensed to King Pharmaceuticals
In October 2007, Acura and King Pharmaceuticals (KG) announced an agreement to develop and commercialize Acurox tablets in the United States, Canada and Mexico. King also licensed a second undisclosed product as part of the deal. Under the agreement, King made an upfront cash payment of $30 million, consistent with its historical largesse, and agreed to make additional cash payments of up to $28 million to Acura. Recall that King’s deal with Pain Therapeutics (NASDAQ:PTIE) on Remoxy, signed in November 2005, had an upfront payment of $150 million, which is approximately the enterprise value of PTIE today. As in the deal with PTIE, King also agreed to reimburse Acura for all R&D expenses beginning September 2007 with regard to the development of the products covered under the agreement. The agreement calls for King to pay Acura a royalty ranging from 5% to 25% of net Acurox sales based on volume and King will make a cash payment in the amount of $50 million to Acura if annual sales exceed $750 million, which will likely occur never, in our view. In late May 2008, the original agreement was expanded to include a third opioid product.
Background - Oxycodone
Oxycodone is a schedule II narcotic currently marketed either alone in controlled release form (OxyContin)), in single-entity immediate release formulations (Roxicodone and generics), or in combination with nonnarcotic analgesics such as aspirin (Percodan) or acetaminophen (Percocet). There are over 80 schedule II oxycodone products approved in the U.S. including generics. However, there are a limited number of single entity oxycodone products that do not also contain nonnarcotic pain relievers (acetaminophen or aspirin). According to the Orange Book, there are currently 14 such single entity formulations of oxycodone (including generics). Of the 7,185,000 prescriptions of these single-entity oxycodone products sold in 2000, approximately 5.8 million were for OxyContin (or 81% of the single entity product market).
The Lone Wolf in Abuse Deterrent Immediate Release Opioid Formulations
As noted by Acura in its SEC filings and on its website, numerous pharmaceutical companies are developing ADF formulations of extended-release [ER] oxycodone and other opioids while Acurox and Acura’s other products using its so-called Aversion technology are immediate release ADF formulations. Acura cites government studies that show that immediate release opioid-containing pain relievers have a “ratio of abuse” that is approximately ten-fold higher than controlled release opioids. While the definition of “ratio of abuse” cited by Acura is not specifically disclosed, it refers to the number of reported non-medical uses of IR opioids relative to medical uses. The specific figure cited by Acura may be accurate but characterizing the nonmedical use of any particular prescription opioid in terms of the absolute number of cases is misleading in that some prescription opioids are far more likely to be abused than others and far more dangerous when abused. For example, single-entity oxycodone products are more popular than formulations that contain aspirin or acetaminophen, higher doses are more popular than lower doses, ER versions are more popular with experienced drug abusers than IR versions and hydrocodone is significantly more popular among abusers than oxycodone.
Data compiled by the RADARS System (Researched Abuse, Diversion and Addiction-Related Surveillance - developed in 2002 in response to increasing concerns of prescription opioid abuse) demonstrates that the rate of abuse for ER versions of oxycodone is three times as high as the rate of abuse of IR versions. Moreover, DAWN data (Drug Abuse Warning Network) demonstrate that the rate of emergency room visits associated with ER formulations of oxycodone is approximately three times as high as IR formulations.
Moreover, ER oxycodone is the formulation of choice for hardcore oxycodone abusers for a reason. In large part, it is a function of the amount of drug available in each tablet. A 12-hour supply of extended release oxycodone can exists in one dose of an ER formulation compared to a 4-hour supply in an IR formulation of oxycodone. In light of this and OxyContin’s commercial success, it makes sense that there is so much competition in the quest for the first abuse-resistant ER formulation of oxycodone. It also makes sense to the extent that ER versions of oxycodone actually require tampering to convert them into IR versions whereas IR formulations simply require swallowing.
The bottom line is that the risks of abusing sustained release opioids are significantly higher than IR opioids – they have a higher addiction risk when abused and a higher risk of inadvertent overdose. DEA data clearly show that there are very few OxyContin-related deaths and very few oxycodone-related deaths associated with the presence of a "recent injection site" and even fewer that are associated with snorting the drug. The vast majority of OxyContin deaths have been associated with oral consumption of the drug either in an intact form or after having been crushed, milled or altered in another way. Acurox may mitigate the risk of oral abuse by incorporating niacin in its formulation but, as detailed below, the data demonstrating this potential is weak to non-existent and its aversive qualities appear to be thwarted completely by “pretreatment” with a high fat meal.
Background on Aversion Technology
Acura’s abuse deterrent technologies incorporate aversive agents and modifications to the delivery carrier to hamper tampering for illicit administration including inhaling and injecting. Issued patents include one covering an opioid combined with tamper resistant features and an emetic as an aversive agent. The company has also filed patent applications covering other unusual aversive agents including stool softeners, laxatives and tissue staining agents.
Acura intends to file an NDA for Acurox before the end of 2008 and states that, if approved, Acurox will be the first immediate-release opioid treatment for relief of moderate to severe pain designed to deter common methods of abuse. While this may be correct, designing deterrence into a formulation is insignificant absent a differentiated label and it may even be a regulatory liability to the extent that it “misleads prescribers or patients into thinking that the new formulation is less likely to be addictive or unlikely to be abused or result in addiction or overdose” (as a member of an FDA advisory committee has noted). There are numerous examples of statements related to abuse-resistance in product labels that have had essentially no meaning in the context of a commercial advantage including Lomotil, Lunesta, Marinol, Strattera, and Amerge. Types of statements in these labels include information about the intention of the formulation (“…a subtherapeutic amount of XX is present to discourage deliberate overdosage”); absence of addiction-related AEs (“…diphenoxylate has not produced addiction…”); extractability (“the insolubility of XX in aqueous media precludes intravenous self-administration”); withdrawal symptoms; abuse-related outcomes in high-risk patients; subjective responses in abuse liability studies; and episodes of diversion.
While Acurox may be deemed bioequivalent to its reference drug (Roxicodone) and possibly approved, we do not believe its abuse resistant features will result in product specific claims. If we are correct, then Acurox will simply be an uncompetitively-priced generic oxycodone with no special marketing or promotional efforts permitted by the FDA. We have even less confidence that it will be commercially viable. Our view is that prescribers of IR oxycodone formulations will be reluctant to risk the effects of the aversive agent (niacin) on patients who have undergone surgical procedures and for other conditions. Surgical procedures represent a majority of IR oxycodone prescriptions (in stark contrast to ER formulations of oxycodone).
Legitimate Pain Sufferers and Physicians May Be Averse to Aversive Agents
Generally speaking, the inclusion of an aversive agent in a pharmaceutical is intended to elicit an undesirable physical or emotional response to tampering. Aversive agents that act on the peripheral senses such as taste or smell are often readily avoidable or ignored by the illicit user. Other aversive agents, such as those that work via internal or central nervous system senses or receptors, such as drug antagonists, are more effective and more difficult for the illicit user to bypass. However, these agents can be problematic for legitimate users unless the aversive agent is formulated in such a way that it is not released in a significant quantity unless the dosage form is tampered with since for example, even a small amount of a bioavailable aversive agent can cause undesirable side effects. In the case of Acurox, Acura has incorporated a sub-therapeutic amount of niacin. Unfortunately, sub-therapeutic levels of niacin, although they may not alter lipid profiles, may very well cause cutaneous flushing and other niacin-related side effects even when taken at prescribed maximum doses. Our understanding is that Acura’s technology provides no mechanism to limit the bioavailability of the aversive agents in any of its products through sequestering, sustained release or other means. This is a particularly serious practical problem with Acurox in our view because IR formulations of oxycodone are prescribed primarily for acute pain. Whereas patients on ER formulations of oxycodone containing aversive agents might become desensitized to the aversive agent over time (such as the flushing effects associated with niacin), short-term users will not. A vast majority of IR oxycodone is used in a post-surgical setting (compared to virtually no ER oxycodone in this setting). For example, in 2003, 2.4 million prescriptions were written for single entity IR formulations of oxycodone in a post-surgical setting compared to approximately 300,000 prescriptions written for ER formulations of oxycodone in a post-surgical setting. It seems to us that few post-surgical patients would want to risk a negative reaction to the niacin contained in Acurox. Moreover, doctor-shopping, which is a primary method of oxycodone diversion, is quite difficult for non-chronic pain patients in that a surgical procedure is required.
According to Acura, the FDA has provided written guidance to the company stating “that language regarding abuse deterrence, which is supported by rigorous, scientific data, may be placed into appropriate sections” of the label. Acura says that it intends to request language in the label describing “the physical characteristics of the product and likely results if attempts are made to dissolve tablets in solvents suitable for intravenous injection, and/or snort crushed tablets, and/or swallow excess quantities of tablets (sic).” Acura has said that it intends to use the results from an in vivo snorting study for product labeling and says that they “have evaluated the potential for reducing nasal absorption using a standard in-vitro experimental process.” To our knowledge, not a single study conducted by Acurox has been published or will be published prior to the time an NDA is filed.
Among the data that Acura will use for labeling purposes is that from a single extraction study that it conducted “in concert with a leading pharmaceutical laboratory CRO.” This study was limited to extraction into a form “suitable for I.V. use”. The definition of suitable is not disclosed on Acura’s website but what’s suitable for injection for a bench-tester running simulations at a CRO is likely very different than what’s suitable for a hardcore drug abuser willing to inject or snort opiates. Moreover, there are currently no industry standards for the evaluation of tampering or extractability. Finally, I.V. injection of opioids represents at most 20% of non-medical use of oxycodone formulations and is primarily practiced by the hardest of hardcore drug abusers, whose methods of manipulation of highly sophisticated. Since oral abuse is the most common route of illicit abuse, approaches that deter intravenous injection will have no impact on the vast majority of prescription opioid abusers who chew or swallow oxycodone intact.
The FDA advisory committee concerns expressed about the extraction studies conducted by Purdue for its proposed ADF OxyContin product are enlightening. Among these concerns were the fact that no data existed to show a correlation between in vitro and in vivo data, the small size of the studies and the validity of the extraction methods. All of these concerns and likely more will surface during FDA’s evaluation of Acurox. Moreover, we see no material difference between Purdue’s approach to demonstrating the reduced abuse liability of OxyContin and Acura’s proposed approach. In fact, Acura’s extraction study is arguably worse than the multiple studies conducted by Purdue.
In addition to the extraction study, Acura’s website indicates that the company has completed a study (AP-ADF-102) to evaluate the relative dislike of oxycodone with niacin compared to oxycodone alone. This study was presented in a poster session at the 2008 annual meeting of the American Society for Clinical Pharmacology and Therapeutics [ASCPT].
In addition, the company commenced enrolment in a 30-patient phase 2 abuse liability study in March 2008 in patients with a history of opioid abuse. Results from this trial are expected in late 3Q:08 or early fourth quarter 2008. In addition, Acura intends to commence a third study in the second quarter of 2008 to evaluate the effects of snorting Acurox intranasally that it intends to use “for product labeling”.
As far as study AP-ADF-102, the data is uninterpretable in our view. This 25-patient study evaluated a combination of 40mg of oxycodone and three doses of niacin (240mg, 480mg, and 600mg) on subjective patient-reported and physiologic measures in patients with a history of opioid abuse compared to 40mg oxycodone and 0mg niacin. Subjective measures of drug liking were measured by the Treatment Enjoyment Assessment Questionnaire [TEAQ] and the DRQS (or subject-based Drug Rating Questionnaire). Also measured were responses on the short form Addiction Research Center Inventory [ARCI]. The ARCI is comprised of the Morphine Benzedrine Group Scale (a measure of euphoria), the Pentobarbital Chlorpromazine Alcohol Group Scale (primarily a measure of euphoria) and the LSD Specific Scale. Questions from the DRQS include: Do you feel a drug effect now? Do you like the drug effect you are feeling now? And, do you dislike the drug effect you are feeling now? The primary efficacy variable was the maximum response to the third question (or Disliking Score) on the DRQS.
According to the company’s SEC filings, “all three doses of niacin [240mg, 480mg and 600mg] in combination with oxycodone 40mg produced significant differences (p ≤ .05) on the Disliking Scores compared to oxycodone 40mg alone (in fasted patients).” In fact, this does not appear to be correct. The ASCPT poster indicates significant differences in Disliking Scores only at the 480mg and 600mg doses of niacin. The only other significant difference was at a 480mg dose of niacin on the PCAG.
In our view, patient responses to the TEAQ (“Which of the Five Treatments Would You Take Again?”) produced unconvincing results. Approximately 25% of patients selected a drug combination that contained niacin vs. 8% that selected oxycodone without niacin. 25% selected none of the drugs. 42% selected oxycodone + 600mg niacin after a standard high fat meal. Beyond this, there were no statistically significant differences on any other subjective drug-liking measures at the 240mg dose of niacin. How this data could possibly find its way into the product label is beyond comprehension. Perhaps a statement to the effect that “Patients liked straight oxycodone more than Acurox Tablets containing 480mg or 600mg niacin more - unless they ate first” will make it into the label.
Acura has completed three studies to evaluate the tolerability of niacin in various doses and the flushing response to varying doses of niacin including a phase 1 study and two phase 2 studies.
The lengthy title of this study was: “A Phase I Single-Center, Randomized, Double-Blind Study in Fasted and Non-Fasted Healthy Volunteers to Evaluate the Dose-Response for Flushing and Safety and Tolerability of Varying Doses of Niacin.” 50 patients enrolled and each received up to five doses of niacin (15, 30, 45, 60 and 75mg) and one placebo dose taken orally. Half took each dose of study drug following a standardized low-fat breakfast and half remained fasted prior to study drug administration.
According to Acura, each subject completed the “Side Effects and Symptom Questionnaire” (also referred to as the “SESQ” by Acura) prior to and three hours after dosing. Patients also completed the “Niacin Tolerability Rating Scale” which, according to Acura, is a five-option scale including: 0 – no effect; 1 – easy to tolerate; 2 – mildly unpleasant; 3 – unpleasant and difficult to tolerate; 4 – intolerable and would never take again).
While we may have missed something in our research, we have been unable to find any validated scale called either the SESQ or the Niacin Tolerability Rating Scale (and Acura discloses nothing about SESQ). Moreover, Acura doesn’t disclose what the SESQ is. Although Merck prospectively developed and validated a niacin-flushing tolerability scale for the purpose of developing Cordaptive, we are unaware of any similar efforts by Acura to develop or validate either of its scales.
As for the results of the study, Acura merely says that it “suggested” that the niacin ingredient in Acurox Tablets should be tolerated by most subjects with minimal, if any, side effects.” No actual data is available in the company’s SEC filings or website and the FDA unfortunately doesn’t allow suggestions in product labels.
The title of this study was: “A Phase II Single-Center, Randomized, Double-Blind, Multiple-Dose Study in Healthy Volunteers to Evaluate the Safety and Tolerability of Niacin in Combination with 5 mg of an Opioid vs. 5 mg of an Opioid Alone.” As with the first tolerability study, this study employed the Side Effects and Symptoms Questionnaire [SESQ]. However, the Niacin Tolerability Rating Scale was replaced by the “Acurox Tolerability Rating Scale”, formerly known as the OxyADF Tolerability Rating Scale (according to Acura’s SEC filings). Subjects were assigned to one of three treatment groups (22 subjects per treatment group). A run-in phase was conducted on an outpatient basis for five days (oxycodone alone). The treatment phase took place on an inpatient basis for five days and included dosing with Acurox (with or without niacin). Acura has reported the following “data” from this trial:
- The mean post-dose SESQ total score during the run-in phase was very low in all groups (highest possible score = 33; Group results = 0.84 - 1.6). What this means is entirely unclear to us.
- During the treatment phase, 64% of subjects in Groups 2 and 3 (oxycodone HCl + niacin) reported side effects and symptoms and 50% of subjects in Group 1 (oxycodone alone) reported side effects and symptoms.
- Irrespective of treatment group, approximately three quarters of subjects reported either “no effect” or “easy to tolerate” on the Acurox Tolerability Rating Scale.
- The majority of subjects (55%) reported adverse events during the treatment phase that were considered mild in severity.
Acura has not reported the following data:
- p-values for any comparisons;
- The definition of SESQ;
- The definition of the Acurox Tolerability Rating Scale;
- SESQ scores for either treatment arm of the study;
- Acurox Tolerability Rating Scale scores for any arm of the study;
- What side effects or symptoms were reported;
- What adverse events were reported;
- What adverse events were reported in the run-in phase.
In other words, we essentially know nothing from this study about the impact of niacin on the tolerability of oxycodone.
This study was titled: "A Phase II Single-Center, Randomized, Double-Blind Study in Fasted and Non-Fasted Healthy Volunteers to Evaluate the Dose‑Response for Flushing and Safety and Tolerability of Escalating Doses of Niacin." The treatment phase was conducted on an inpatient basis and included study drug dosing and safety and tolerability assessments. Each subject received eight doses of niacin (30, 60, 90, 120, 240, 360, 480, and 600 mg) and three doses of placebo administered orally in tablet form on eleven separate days. Half of the subjects (n=25) took each dose of study drug following a high‑fat breakfast and half (n=25) remained fasted for at least 2 hours after study drug administration.
In this study, tolerability was measured using a “Tolerability Rating Scale” or “TRS”. This scale appears to be the same 5-choice scale as the Niacin Tolerability Rating Scale used in study AP-ADF-101 with the only difference being choice 3, which represented an answer of “mildly unpleasant” in AP-ADF-101 and “mildly unpleasant but tolerable” in AP-ADF-107. Acura has reported the following “data” from this trial:
- In fasted subjects, 96% of subjects reported either “no effect” or “easy to tolerate” at doses of 30 to 60 mg.
- At 90 mg, 86% of fasted subjects reported either “no effect” or “easy to tolerate” and 14% reported “mildly unpleasant, but tolerable”.
- At niacin doses of 120 to 360 mg, 22% and 73% of fasted subjects, respectively, reported mildly unpleasant, unpleasant, or intolerable effects.
- At doses of 480 and 600 mg, 86% of fasted subjects reported mildly unpleasant, unpleasant, or intolerable effects.
- At least 40% of subjects dosed at 480 and 600 mg reported “unpleasant and difficult to tolerate” or “intolerable and would never take again” (we have no idea why they use the term “at least”).
- 54% to 88% of fasted subjects reported flushing at doses of 240 to 600 mg, respectively, while 64% of fed subjects reported flushing only at a dose of 600 mg.
- 100% of fed subjects (100%) receiving 30 to 240 mg niacin reported “no effect” or “easy to tolerate”.
- At doses of 360 to 600 mg 68% of fed subjects reported “no effect” or “easy to tolerate”.
Acura has not reported p-values for any comparisons. Regardless, the key take-away from this study, in our view, is that niacin’s reduction of abuse liability is thwarted completely by eating. It also appears that approximately 46% of patients dosed with either 480mg and 600mg niacin reported the effect as, at worst, mildly unpleasant. At Acurox’s ratio of 5mg oxycodone to 30mg niacin, a patient would have to take 16 Acurox tablets to hit this threshold. At that dose, the patient would also be receiving 80mg of immediate release oxycodone and would either be dead or so high that even a niacin biscuit would be of no concern.
According to Acura, if a person attempts to extract oxycodone from Acurox using solvents, including water or alcohol, the tablet converts into a viscous gel mixture thereby trapping oxycodone. To support this, Acura has conducted an in-vitro extraction study that the company alleges demonstrates that drawing the viscous gel through a syringe is extraordinarily difficult. The study compared the relative difficulty of extraction for Oxycontin, generic oxycodone, and Percocet. It was conducted by a CRO that was allotted up to 80 hours total time (or 4,800 minutes) to complete the evaluations and allowed to use any methodology desired to attempt to extract oxycodone HCl from the tablets in a form suitable for I.V. injection. According to Acura’s website, the study demonstrated that each of the comparator drugs could be manipulated in three steps to yield between 71% and 92% of the oxycodone contained therein. As for Acurox, Acura reports than 0% of the oxycodone could be extracted from Acurox after 23 steps and 355 minutes. There are several particularly peculiar issues with this data. First, Acura does not disclose why at least some of the remaining 4,445 minutes were not used in the Acurox extraction efforts (although it may be irrelevant given the fact that they had already spent about six hours before they gave up). Second, Acura does not disclose what the definition of “suitable for injection” is. Third, the suggestion that 0% of the oxycodone in Acurox tablets is accessible through advanced manipulation techniques is dubious. Fourth, Acura has not disclosed any of the extraction methods utilized.
And finally, extraction is not necessary for abusers willing to swallow Acurox. This is largely the case with most opioids. Unlike the clandestine chemists who engage in large-scale extraction and production of methamphetamine, the preferences of the Rx opioid abuser is to purchase a product that has not been tampered with and retains the pharmaceutical company’s branded “seal of quality”.
Acura says that Acurox tablets have three mechanisms intended to discourage nasal snorting, which is the least common route of administration of oxycodone abuse. According to Acura, if the tablets are crushed and snorted, the user experiences pain, described as a “mild burning and irritation of the nasal passages”. This burning sensation is the result of the presence of a surfactant (possibly sodium lauryl sulfate). We seriously doubt that mild burning or irritation of the nasal passages would be offensive to an opioid abuser who snorts oxycodone, particularly since oxycodone is a potent pain reliever and the effects of the surfactant are transient. Second, Acura says that when the tablets are crushed and snorted the moisture in the nasal passages forms a viscous gel, thus trapping the oxycodone and reducing the amount available for absorption. Acura further says that the viscous gel results in a “sticky mass producing an unpleasant sensation in the nasal passages of the prospective abuser.” These are interesting observations but they appear to be wholly unsupported. Acura has never run a snorting study in humans.
Deterrence of Swallowing Excess Quantities
Acurox tablets includes a sub-therapeutic amount of niacin (30mg) that is intended to produce an “unpleasant combination of symptoms, including warmth or flushing, itching, sweating and/or chills, headache and a general feeling of discomfort.” Acura believes that when administered at recommended maximum doses, the drug will provide “legitimate pain patients” with effective pain relief while avoiding the potential dysphoric effects of niacin. Given that niacin-induced flushing is dose dependent, Acurox tablets are not intended for patients requiring opioid dose escalation. Acura believes that most abusers or recreational drug users “will seek alternative opioid analgesic products that are generally much easier to abuse than Acurox Tablets and do not have the potential to cause these undesirable niacin effects.” In other words, even under the best of circumstances, the net effect on IR oxycodone abuse will be zero. That, however, is not the only problem.
Acura’s own data shows that niacin-induced flushing is eliminated following the consumption of a high fat meal. In addition, administration of 600mg of niacin (which is ten times the dose of niacin in the Acurox pivotal trial) with 40mg of oxycodone had virtually no effect on drug-liking measures after a high fat meal. And second, and more importantly, niacin-induced skin reactions, which are believed to be mediated by prostaglandin release, can be almost eliminated when taken with a prostaglandin inhibitor (for example, 325mg of aspirin). Even if these effects aren’t mitigated by aspirin, the real question is whether an oxycodone abuser cares about flushing.
Disclosure: We have no holdings (long or short) in any of the companies we write about.