12/31/19

Keeping ALKS 5461 Out of the Spotlight?

Alkermes has been stubbornly attempting to gain FDA approval for ALKS 5461 as an adjunctive treatment for major depression. After the FDA informed Alkermes it was refusing to review the NDA (New Drug Application) for ALKS 5461 on March 30, 2018, it rescinded its refuse-to-file letter, and said it would review an NDA for ALKS 5461. The target action date was set for January 31, 2019. The Chief Medical Officer at Alkermes noted there have been no new pharmacological treatment approaches for depression in 30 years and said, “FDA’s filing of the ALKS 5461 application is a positive step forward for patients suffering from major depressive disorder.”

Strategically, at the end of October 2018 Molecular Psychiatry published an article that indicated buprenorphine/samidorphan (ALKS 5461) was “a promising potential adjunctive treatment for patients with MDD.” In one clinical trial, FORWARD-5, adjunctive ALKS 5461 (BUP/SAM 2mg/2mg) consistently reduced depression symptoms compared to placebo across multiple timepoints in patients continuing their current antidepressant therapy (ADT). And it met the primary endpoints of reducing core and overall depression symptoms. In the previous FORWARD-4 clinical trial the primary endpoint of change was not statistically significant; it failed to meet its primary endpoint of change. But in post hoc analysis it did demonstrate greater reduction in MADRS-10 scores than placebo at all timepoints in both stages. “Reductions in symptom scores at multiple timepoints are consistent with the observed efficacy in FORWARD-5.”

This post hoc-analysis was bit like cheating, in that it reanalyzed the data from FORWARD-4 after the fact, and found one aspect of the trial with a significant result. Alkermes used the finding to “update” their methodology for FORWARD-5 to match the post-hoc analysis. It then attempted to argue that despite failing to meet its primary endpoints in the two previous phase III clinical trials, the FDA should approve ALKS 5461. See “The ‘Hotel California’ Effect” and “Nearsighted Drug Development” for more on the problems with this process.

Then on November 1, 2018 the results of the meeting of two combined FDA committees, the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was released. The Committee voted unfavorably for ALKS 5461. There were three core questions. Has there been substantial evidence presented to support the effectiveness of ALKS for adjunctive treatment of major depression? The vote was against the first question, 20 to 3. The second question was: Has Alkermes adequately characterized the safety profile of ALKS 5461 for adjunctive treatment of major depression? The vote was for the question, 13-10. The third question was also answered negatively, Do the data show a favorable benefit-risk profile of ALKS 5461 to support approval? The vote was against, 21 to 2.

Healio Psychiatry went on to note several concerns of the Committee. The FDA did not agree with Alkermes that the studies met the standard for substantial evidence for effectiveness. Three of the studies used a novel study design: a 2-stage, sequential parallel comparison meant to reduce the higher placebo response often seen in antidepressant studies. This was the first time a sequential parallel comparison design was submitted to the FDA to provide evidence of efficacy for a new drug. “This design has not yet been determined to be statistically acceptable to the FDA.”

Usually studies for antidepressant treatments examine an efficacy endpoint at a specific time point following several weeks of therapy, according to the FDA. These trials achieved primary endpoint because researchers averaged patients’ depression symptoms over multiple weeks, which is not standard for antidepressant trials. Although averaging scores from multiple weeks can reduce the symptom changes that often vary over time throughout treatment, scores at the final time point carry less weight.Although one of the phase 3 studies met its primary endpoint, the committees expressed worry because the trial investigators used an abridged 6-item version of the Montgomery Asberg Depression Rating Scale-10 for the primary endpoint of this principal study. The FDA’s Clinical Outcomes Assessment staff believe MADRS-6 cannot replace the MADRS-10 because it excludes concepts important in major depression, like reduced sleep, reduced appetite, concentration difficulties and suicidal thoughts, according to the review.

So MADRS-6 would not include data on the excluded depressive symptoms such as reduced sleep, and appetite, concentration problems, and significantly, suicidal ideation. Averaging scores would hide a pattern of progressively lower scores throughout the trial, suggesting the antidepressant effect of ALKS 5461 gets weaker over time and will eventually be no better than placebo—not the efficacy pattern to demonstrate when trying to have a NME approved by the FDA. Given the novelty of the methodology used in these clinical trials and the significance of the excluded depression symptoms, the FDA made it clear to Alkermes that any studies using the MADRS-6 would be “considered exploratory.”

The use of an opioid, buprenorphine, was also a concern of the committee. Given the growing opioid epidemic, there were concerns about use, misuse and abuse of buprenorphine. Predicting what might happen in patients being treated for depression is challenging due to the high-risk nature of the populations being treated. “It is not known whether similar misuse and abuse patterns will be seen.”

Finally on February 1, 2019, the FDA said it was not able to approve ALKS 5461 in its present form and requested additional clinical data (likely another clinical trial) to provide substantial evidence for its effectiveness. A review of the Alkermes website on October 12, 2019 failed to see ALKS 5461 listed in its Pipeline under Research and Development. But that doesn’t mean Alkermes has given up on it. There are two active clinical trials for ALKS 5461 listed on Clinical Trials.gov; one of which is recruiting. Its primary outcome measure is a change from baseline in the MADRS scores; the time frame is 11 weeks. The other trial is by invitation, and is a long-term study. The time frame is up to 68 weeks. Both are projected to be completed in 2021 and both have been updated after the FDA sent its complete response letter on February 1^st.

It could be that Alkermes terminated these clinical trials after the FDA response letter, but why update the information on ClinicalTrials.gov? If Alkermes is still working on the studies, why does it not have ALKS 5461 listed in its Pipeline? It does not seem that ALKS 5461 is dead yet. One of the studies (clinical trial NCT03188185) apparently plans to use the same parallel assignment method used in FORWARD-4, which the FDA said it had not yet determined was statistically acceptable. The MADRS will be used for its primary and secondary outcome measures, but does not specify whether it will be MADRS-6 or MADRS-10. One of the listed outcome measures is the Columbia Suicide Severity Rating Scale, for suicidal ideation and behavior, but that isn’t necessarily suggestive Alkermes plans to use the MADRS-6.

It is possible that Alkermes is going ahead with a final attempt to gain FDA approval for ALKS 5461, but is trying to keep its efforts quiet and out of the media spotlight. We’ll have to wait and see.

07/24/18

Doubling Up On Depression

Photo by Kat Jayne from Pexels

Alkermes seems to be presenting contradictory opinions when it comes to promoting two of its drugs. When discussing Vivitrol, its extended release injectable version of naltrexone, Alkermes refers to it as “nonaddictive.” This is in contrast to other FDA-approved addiction medications such as methadone or buprenorphine, which are opioids. Alkermes has also persisted in its attempts to get ALKS 5461 approved by the FDA as an adjunctive medication to treat major depression. The active ingredient in ALKS 5461 is buprenorphine and Alkermes has emphasized that upon discontinuation of ALKS 5461 there was no evidence of withdrawal.

The conundrum is rhetorically-based and not scientific. Buprenorphine is classified as a Schedule III controlled substance, meaning it has “a moderate to low potential for physical and psychological dependence.” Yet when ALKS 5461 is being promoted, research findings conclude “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.” Michael Thase, the Alkermes poster presenter for ALKS 5461 at the 2018 American Psychiatric Association annual conference was quoted by Healio as saying, “there was essentially no hint whatsoever of opiate-like withdrawal or discontinuation symptoms.”

But when buprenorphine is a medication-assisted treatment (MAT) in competition with Vivitrol, it is described by Alkermes and its lobbyists as being addictive in contrast to naltrexone, the ingredient in Vivitrol, which is not addictive. STAT News published an article written by Daniel Wolf, the director of international harm reduction development at the Open Society Foundation. Wolf cited and linked investigations by the New York Times, National Public Radio and ProPublica noting how Alkermes promoted Vivitrol at the expense of other MAT drugs like buprenorphine. One example, found in the NPR article, was where the Indiana Senate passed a bill approving the use of “a federal Food and Drug Administration-approved long acting, nonaddictive medication for the treatment of opioid or alcohol dependence.” The only drug approved by the FDA that meets that description is Vivitrol.

An investigation by NPR and Side Effects Public Media has found that in statehouses across the country, and in Congress, Alkermes is pushing Vivitrol while contributing to misconceptions and stigma about other medications used to treat opioid addiction.

Wolfe noted for STAT News that the investigations he cited showed how Alkermes marketers and lobbyists derided the daily administration of methadone and buprenorphine. The pitch is apparently working, as the sales of Vivitrol rose 600% between 2011 and 2017. Legislators in 15 states have written Vivitrol (by brand name) into their laws. And multiple jurisdictions now require drug offenders to agree to use the medication if they want to avoid imprisonment. In effect, state established Drug Courts have become “Vivitrol courts.”

Alkermes highlighted Vivitrol’s properties as an opioid antagonist. This means it blocks (instead of activating) the effects of opioids like methadone, burpernorphine and heroin on opioid receptors in the brain. Naltrexone, the active ingredient in Vivitrol, will not get you high. Methadone and buprenorphine can be used alone or in conjunction with other drugs to produce a high. Their differences as MAT treatment are illustrated in the following graphic, which was found in the NPR article.

Turning to ALKS 5461, we see that Alkermes had a series of setbacks as it attempts to have the FDA approve ALKS 5461 as an adjunct treatment for major depression. As FierceBiotech noted, Alkermes failed to meet their primary endpoints in two of three phase 3 clinical trials for ALKS 5461. “But Alkermes used the success of the third trial to paint the overall dataset as supportive of the efficacy of ALKS 5461.” What Alkermes did is use its statistical analysis of the second failed clinical trial (FORWARD-4) to discover a significant result within a subpopulation of the study that wasn’t targeted by its primary endpoint. They then modified their methodology and analysis of the third clinical trial (FORWARD-5) to match the post-hoc analysis and it successfully showed a statistical significance.

In previous articles, “Nearsighted Drug Development” and “The ‘Hotel California’ Effect,” I said this seemed like cheating, even though it was allowed. Alkermes then wanted the FDA to count its failed FORWARD-4 trial as a successful one, based on its post hoc statistical analysis. So far the FDA hasn’t bought the Alkermes attempts to justify its claims. In late January of 2018 Alkermes submitted a New Drug Application to the FDA for ALKS 5461. The company claimed ALKS 5461 “demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.”

Then on April 2, 2018, the FDA informed Alkermes it was refusing to review the NDA application for ALKS 5461, saying there was “insufficient evidence of overall effectiveness for the proposed indication.” They wanted to see “additional well-controlled clinical trials” prior to the resubmission of ALKS 5461, disagreeing with the Alkermes attempt touse the success of the third trial to the overall dataset as supportive of ALKS 5461 efficacy. The FDA also wanted a bioavailability study to generate more bridging data between ALKS 5461 and buprenorphine. Alkermes disagreed with the FDA’s conclusions and planned to request a Type A meeting where they could clarify what additional information the FDA needs. FierceBiotech said:

The FDA’s refusal to buy into that line of thinking is a blow to people in Alkermes and beyond. Having talked up the strength of the dataset, Alkermes CEO Richard Pops and his colleagues emerge from the setback with dented reputations. More broadly, the FDA’s refusal to even review the data is a blow for any biotech hoping the arrival of Scott Gottlieb, M.D., as commissioner would usher in an era in which the FDA waves through drugs with patchy data packages.

Two weeks later, the FDA rescinded its refuse-to-file letter. FierceBiotech said: “The company did not provide the FDA with additional data or analyses and the agency expects to return a decision by Jan. 31, 2019.” Alkermes CEO Richard Pops said the FDA’s initial refusal was based on a “misunderstanding” of the NDA submission. He declined to say what the FDA initially thought was missing from the NDA. “I think it just took a while to get that lens focused the right way for FDA to accept the file.”

While ALKS 5461 is back on schedule, the FDA’s about-face is by no means a guarantee of success—the agency has deemed the data complete enough for review, but could still reject it.

At the May 2018 American Psychiatric Association Annual Meeting, Alkermes presented a poster on its research into the “Long-Term Efficacy, Safety and Tolerability of Adjunctive ALKS 5461 in Patients With Major Depressive Disorder.” The reported results of a completed long term study (NCT02141399) were that 49% of the 1454 enrolled patients completed the 1-year study, 11% discontinued due to an adverse event. The remission rate, defined as a score of 10 or less on the MADRS-10, was 52.5%. Time to remission was 59.0 days. Adverse events occurring with a frequency of less than 10% were nausea, headache, constipation, dizziness and somnolence (drowsiness). “There was no evidence of withdrawal upon discontinuation of treatment with ALKS 5461.”

Overall, ALKS 5461 showed durability of antidepressant effect up to 52 weeks of treatment in patients with MDD. ALKS 5461 was well tolerated with an AE profile consistent with that reported in the short-term trials.

These results were repeated in Healio: “ALKS 5461 well-tolerated in major depression” and in Psychiatry Advisor: “Novel Buprenorphine Combinayion Therapy Shows Efficacy for MDD in Long-Term Trial.” Psychiatry Advisor has links to the Alkermes clinical trials referenced, which are all completed, but none had reported their results by June 1, 2018. Michael Thase’s report in Healio seemed to be in conflict with the research program noted above by FierceBiotech, unless he was counting the recently completed long term study. He said: “The research program for this compound has included a number of double blind studies, of which two are unequivocally positive; these data are being reviewed by the FDA for a possible indication as an adjunct to antidepressants.”

FierceBiotech pointed out where two of three clinical trials phase 3 clinical trails failed to meet their primary endpoints. And the third had its methodology and analysis modified after post-hoc analysis of the second clinical trial showed statistical significance in a subpopulation. Can the results be “unequivocally positive” when the primary endpoint for one of the positive studies was changed after it had begun?

There are some questions I have with regard to the assertion there was “no evidence of withdrawal upon discontinuation” for the long term study. What specifically were the researchers looking for as “evidence of withdrawal”? And when was the assessment done—immediately upon conclusion of the 52-week study?

Mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal. Granted, the buprenorphine dose is relatively small at 2 mg, but the time period of use at 52 weeks was long. “Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses.” See “A Double-Edged Drug” for more on buprenorphine withdrawal.

However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

Another thing to remember is that Suboxone (buprenorphine and naloxone) and ALKS 5461 (buprenorphine and samidorphin) appear to be biochemical twins. Also remember where employees of Alkermes have characterized buprenorphine as “addictive.” And the addictive potential of buprenorphine has not been entirely neutralized by its combination with Alkermes’ patented opioid antagonist, samidorphin (ALKS 33).

In “The Coming Depression Apocalypse,” I said I’m concerned the use of ALKS 5461 for treatment resistant depression would generate a population of individuals dependent upon buprenorphine. The problems coming off of ALKS 5461 would eclipse what we now know happens with SSRI withdrawal. A New York Times article said originally, antidepressants were supposed to be used short term for episodic mood problems—six to nine months. Now, almost 7% of Americans have been using antidepressants for at least five years. Patients who try to taper off antidepressants often find withdrawal symptoms are so severe they cannot stop. “Nearly half who tried to quit could not do so because of these symptoms.”

Coupling buprenorphine withdrawal in ALKS 5461 to the known issues with antidepressant withdrawal compounds the problems these medications were supposed to treat. And within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS 5461 and/or antidepressants.

12/30/16

The “Hotel California” Effect

Alkermes is a believer in the classic idiom, the third time’s the charm. The pharma company recently announced success on its third-late stage clinical for ALKS 5461, which it hopes will become a new antidepressant blockbuster. In January of 2016 two previous phase III trials failed to achieve their primary endpoints and the company’s stock price took a nosedive. After the positive results of the FORWARD-5 study, shares were up over 30%. Alkermes plans to meet with the FDA in order to argue that despite failing in its two previous phase III clinical trials, the FDA should approve ALKS 5461 and “bring this new medication to patients with MDD [major depressive disorder].” FDA regulations require a total of two successful phase III trials with statistical significance over placebo. What’s going on here?

The FORWARD-4 clinical trial tested two dose levels of ALKS 5461, 2mg and .5 mg and it failed to meet its initial primary endpoint, “change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score.” Post-hoc statistical analysis done on the FORWARD-4 data indicated the group receiving the higher 2mg dose of ALKS 5461 had a statistically significant difference on the MADRS. Alkermes then decided to “update” their methodology and analysis for FORWARD-5. In other words, Alkermes used statistical analysis of the failed FORWARD-4 trial to uncover a significant result within a subpopulation of the study that was not targeted in their initial study design. They then modified their methodology and analysis of the FORWARD-5 trial to match the post-hoc analysis.

In a previous article on the FORWARD-3 and FORWARD-4 failed clinical trials, “Nearsighted Drug Development,” I expressed the opinion that this seemed a bit like cheating. Nevertheless, it seems that changing the methodology from what was initially proposed for an ongoing trial is permitted. But would it be appropriate for the FDA to reconsider the post-hoc analysis of the FORWARD-4 trial as a “successful” clinical trial? It seems a bit like trying to argue that the FDA should give Alkermes credit for positive results in FORWARD-4 even though those positive results only became apparent after the fact—when they began to fiddle around with the data to see if they could find something positive.

Another disturbing claim by Alkermes is with how they describe ALKS 5461. It is “designed to rebalance brain function that is dysregulated in the state of depression.” As I pointed out in “Nearsighted Drug Development,” the chemical imbalance theory of depression is now said to be an urban myth even by pro drug psychiatrists like Ronald Pies.

If approved, ALKS 5461 is proposed as an add-on, adjunctive medication in the treatment of major depression for patients “with an inadequate response to standard antidepressant therapies.” However, there is a hint that if approved ALKS 5461 could be put forward by the company as a standalone treatment for depression. Elliot Ehrich, the CMO of Alkermes, said the studies in the FORWARD program contributed data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and if taken as an adjunct medication.

It also appears that if the FDA does not agree to approve ALKS 5461 as a treatment for MDD based upon the above discussed rationale, Alkermes will drop it. Richard Pops, the chairman of Alkermes, said they are not planning to conduct any additional studies on ALKS 5461. Is this just a cut your losses decision to forego the additional cost of another clinical trial for the company? Or is it a veiled threat to the FDA that Alkermes will shelve any future work on a product that was once approved by the agency for a fast track drug development status? In other words will the FDA permit post hoc analysis of a phase III clinical trial turn a failed trial into a successful one?

What is at stake here is that the active ingredient in ALKS 5461 is a known opioid, with an acknowledged addictive potential—buprenorphine. Buprenorphine is a Schedule III controlled substance. Combining it with an opioid antagonist (samidorphan) does not lessen its addictive potential. In higher doses buprenorphine is used as a maintenance drug therapy for opioid dependence (Suboxone; Subutex; Zubsolv). Regularly, opioid dependent individuals have told me that getting off of buprenorphine was harder than heroin or methadone.

Higher doses and longer term use of buprenorphine influence the length of time for withdrawal or discontinuation. And guess what, depression is one of the commonly experienced withdrawal symptoms. The Addiction Blog posted some helpful information on “How long does buprenorphine withdrawal last?” Note that the website is not taking an anti-buprenorphine position. It begins by saying “Buprenorphine can be a useful drug prescribed to treat opiate addiction.”

Within the first 24 to 72 hours, physical withdrawal symptoms peak in severity and intensity with common symptoms such as: diarrhea, sweating, nausea, dilated pupils, watery eyes and restlessness. As the first week progresses, aches, stomach cramps, and joint pain will probably continue. General feelings of discomfort and problems sleeping can occur. “Mood swings are also common, with bouts of anxiety or depression.” After two weeks, the pain and discomfort of acute physical withdrawal should be less severe, but depression and an extreme loss of motivation can set in.

After [the] three to four week mark, most of the physical withdrawal symptoms will be gone, however … intense drug cravings may be present for those addicted to buprenorphine. Depression is also common. This time is very important, as you will be very vulnerable to relapse. . . . However, psychological withdrawal symptoms can last for months after cessation.

Now “relapse” here refers to resuming active opioid use or abuse. But in reviewing the withdrawal symptoms described above, the relapse experienced could just as easily be interpreted as a depression relapse by individuals attempting to taper off of long term ALKS 5461 use.

So someone could add ALKS 5461 to their antidepressant of choice, take it for an extended period of time and see a clear remission of their depressive symptoms. If they were to then attempt a taper off of ALKS 5461, they would likely experience the above described buprenorphine withdrawal symptoms, interpret them as a return of depressive symptoms, and resume using ALKS 5461. If ALKS 5461 is used as a stand-alone treatment for depression, a misinterpretation of withdrawal symptoms as a relapse of depression is also likely occur. Similar to long-term antidepressant users, there could be a “Hotel California” effect—you can taper down any time you want, but you can never leave.

With continued use of buprenorphine, there comes a point where the brain produces an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS [post acute withdrawal syndrome] manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

I don’t know whether the above concerns will be considered in an FDA review of the Alkermes request to approve ALKS 5461. I hope they are. But if Alkermes is successful in bringing its drug to market, “where new therapeutic options are highly sought after as millions of patients in the U.S. do not respond to standard courses of antidepressant therapy,” be prepared for what seems to be an unavoidable cycle of depression treatment perpetuating depression and further treatment. While the rhetoric appears overblown to some, I do believe there is a “Coming Depression Apocalypse” if ALKS 5461 is approved by the FDA.

02/16/16

Nearsighted Drug Development

I was encouraged to hear that ALKS 5461 failed in two late-stage clinical trial studies. This isn’t because I have something against Alkermes, the pharmaceutical company developing the drug. I don’t own stock in a competing company trying to bring their new fast-acting antidepressant drug to market ahead of Alkermes. I do think antidepressants are overprescribed and have potentially harmful side effects for some people, but that’s not why I was happy to hear that ALKS 5461 is in trouble. I just don’t think that putting an antidepressant drug on the market that uses a potentially addictive opioid as its active ingredient is a good idea.

Reporting for Reuters, Amrutha Penumudi said that when news of the failed clinical trails for ALKS 5461 were made public by Alkermes, the company saw its shares fall in value by 42.8%, a $3.88 billion loss for the company. ALKS 5461 is the company’s main product, so the bad news about the clinical trials was a major financial blow. William Tanner, an analyst for Guggenheim Partners was widely quoted by Reuters and others as saying that “We believe trial failures present a major setback in the evolution of the company.” Even if ALKS 5461 succeeds in a third as-yet not completed clinical trial, more studies may be required, according to Ken Cacciatore.

ALKS 5461 is a new molecular entity (NME) that has been fast tracked by the FDA for approval as a treatment of Major Depressive Disorder (MDD) with patients who didn’t respond to standard antidepressant therapies. It is a combination of buprenorphine, a Schedule IV Controlled Substance and samidorphan, a naloxone-like substance. Suboxone, which is a combination of buprenorphine and naloxone, is commonly used as an opioid substitution medication for heroin and prescription opioid addicts. The major difference between ALKS 5461 and Suboxone as far as buprenorphine is concerned is that ALKS 5461 is currently being tested in 2 mg and .5 mg doses, where standard protocols for Suboxone as an opioid substitution drug could reach 16 mg or higher. You will find more information on ALKS 5461 and my concerns about its use to treat depression in: “The Coming Depression Apocalypse,” an article I published here a few months ago.

But it doesn’t seem Alkermes is going to give up the fight. In their press release, Richard Pops, the CEO of Alkermes said:

We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families. . . . Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS 5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.

In one of the failed trials, Alkermes did post-hoc analyses (reanalysis of the data after the fact) that indicated the 2 mg dose was more effective than a placebo. Given the results of the two failed studies, Alkermes said they plan to increase the number of patients in the ongoing trial and “update” the planned statistical analysis for FORWARD-5, the third efficacy study in the FORWARD program. The updated analysis sounds like it means they plan to use the same analysis process applied to the 2mg dose group for FORWARD-4 after the fact. This is bit like cheating if the researchers went p-hacking or data-dredging in their post-hoc analysis. See “How to Lie About Research” for more information on p-hacking.

Another factor regarding Alkermes and ALKS 5461 that concerns me is how the company describes the drug. In their above-linked press release, Alkermes said that ALKS 5461 acted “as a balanced neuromodulator in the brain;” and was “designed to rebalance brain function that is dysregulated in the state of depression.” This sounds eerily similar to the chemical imbalance theory of depression that even psychiatrists such as Ronald Pies have said was always a kind of urban legend. In an article in Psychiatric Times, he said: “To my knowledge, no professional psychiatric organization has ever publicly promoted a ‘chemical imbalance theory’ of mental illness in general.” Look at Robert Whitaker’s response to that article by Pies and the reams of additional evidence to show how Pies’ claim was clearly wrong.

But there is now another concern with the use of opioids to treat depression. A study by Scherrer et al., published in the Annals of Family Medicine, found that people who used prescription opioids for longer than a month may have an increased risk of developing depression. Scherrer was quoted by Agata Blaszczak-Boxe for Live Science as saying the researchers rigorously controlled for pain, “and we feel strongly that these results are independent of the known contribution of pain to depression.” The longer individuals were taking opioids, the greater was their risk of depression.

Citing a 2014 study by Howe and Sullivan in General Hospital Psychiatry, Scherrer et al. said that research on the efficacy of opioids in treating depression was limited by small sample sizes, short follow-up time and lack of control groups. So they do not support opioids as effective long-term treatments for depression. “This evidence, combined with the finding from the present study, supports the conclusion that opioids may cause short-term improvement in mood, but long-term use is associated with risk of new-onset depression.”

Buprenorphine was not one of the opioids studied, but the findings of the Scherrer et al. study does give me increased concern with the fast-track status the FDA has given ALKS 5461. Recent findings do suggest the risk of new onset of depression increases with a longer duration of opioid use. A replication attempt of Scherrer’s study with buprenorphine seems needed before approving ALKS 5461. The short-term projected improvements could lead to long-term problems with depression. “Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression.”

Hopefully the FDA will have the foresight to weigh all the potential adverse effects with ALKS 5461 before approving it. There is a very real potential for physical dependency to develop with ALKS 5461 given that its active ingredient is a Schedule IV controlled substance. Heroin addicts have told me buprenorphine was more difficult for them to come off of than heroin or methadone. And to top it all off, there seems to be evidence that using opioids longer than 30 days carries a risk of new-onset depression. This is not a very promising profile for a future treatment for depression.

Additionally, the initial statistical analysis done on the first two clinical trials failed to demonstrate that it was more effective than a placebo. Only after a post hoc analysis was there evidence of any statistically significant results. And then it was only with the higher, 2mg, dose. Will that lead to even higher doses of buprenorphine to increase its effectiveness? Read more on the concerns with outcome switching in clinical trials here.

Revising the statistical analysis (outcome switching) of the remaining clinical trial may produce statistically significant results, and if it does, it seems Alkermes intends to argue with the FDA to approve ALKS 5461. On the one hand, I can see where Alkermes would attempt to salvage their “lead product.” But I’m hoping their nearsighted focus on profits and the company’s market value will not blind the FDA to the long-term consequences of using opioids like buprenorphine to treat depression.

12/8/15

Another Head for the Hydra

Belbuca sounds like it is the name for new Italian recipe from a famous chef. Bel Buca sounds like the name of an Italian pop star. But Belbuca is actually the name of a new FDA approved pain medication for chronic pain management from Endo International and BioDelivery Sciences. And “Bel Buca” actually has a twitter account, with the picture of an attractive blue-eyed dark-haired woman posing as Bel. She doesn’t seem to tweet much, but she follows Dr. Oz and several health and medical accounts, probably to see what they say about the medication she was named after.

The FDA just accepted the New Drug Application for Belbuca in February 2015 and approved it on October 23, 2015. The fast turn around was because the opioid analgesic used for pain relief and the drug delivery mechanism were both approved by the FDA and used for other medications. The opioid is buprenorphine and the drug delivery technology is BioErodible MucoAdhesive (BEMA). BEMA technology is used with buprenorphine in Bunavail, a buprenorphine-BEMA drug from—no surprise—BioDelivery Sciences (BDSI). Belbuca contains .05 and .1 the amount of buprenorphine in Suboxone and other buprenorphine products like Bunavail used to treat opioid addiction.

Chronic pain relief is a much wider (and more lucrative) market for BioDelivery Sciences, so the sales from Belbuca should easily outpace Bunavail in a short time. BDSI only recorded $1.5 million in sales through the first six months of 2015, according to Jason deBruyn of the Triangle Business Journal. Endo will commercialize, market and sell Belbuca. BDSI is a relatively small company without the sales force to effectively market a drug like Belbuca, which has a large target market. Herein lies the potential problem, from my point of view.

Methadone, the first opioid maintenance medication, began to be used for chronic pain relief in the mid-1990s. By 2009, methadone accounted for almost 1 of every 3 prescription pain medication deaths. Six times as many people died from methadone overdoses in 2009 as did in 1999. The problem seems to have been the result of the length of time it takes methadone to be converted into inactive metabolites within opioid-naïve individuals. See “The Consequences of Ignoring the Past” for more on the problems with methadone as a pain reliever.

While there are some supposed biochemical advantages of buprenorphine over methadone, there is still a real potential for abuse, overdose and death with buprenorphine. It is a partial opioid agonist, meaning it binds to the mu opioid receptor and activates them, but not to the same degree as full agonists like heroin and methadone. It is by activating the mu opioid receptor that opioids exert their analgesic, euphoric and addictive effects. At a certain point, the effects of burprenorphine is said to reach a ceiling and not increase further. Nevertheless, buprenorphine has the potential for abuse and misuse. See “Is Buprenorphine Just Another Head for the Hydra of Opiate Addiction?” Also see the FDA medication guide for Belbuca.

At lower doses and in individuals who are not dependent on opioids, full agonists (like heroin or methadone) and partial agonists (like buprenorphine) produce effects that are indistinguishable. As doses are increased, both full and partial agonists produce increasing effects.

The adverse reactions highlighted in the Belbuca medication guide include nausea, constipation, headache, vomiting, dizziness and somnolence (drowsiness). Using them along with central nervous system (CNS) depressants may cause “profound sedation, respiratory depression and death.” Benzodiazepines may increase buprenorphine-induced respiratory depression.

The medication guide distinguishes between “CNS depressants” and “benzodiazepines” when they actually fall within the same category as CNS depressants. Benzodiazepines such as diazepam (Valium) and alprazolam (Xanax) and non-benzo sleep medications such as zolpidem (Ambien), eszopicione (Lunesta) and zalepon (Sonata) are all CNS depressants. And by the way, respiratory depression is what happens when someone overdoses on opioids, opiates or a combination of these drugs and the other CNS depressants like benzodiazepines. The accidental overdose potential of buprenorphine does not have a ceiling effect if it is used in conjunction with other CNS depressants like Ambien or Xanax.

When the target market for buprenorphine is dramatically increased from that of individuals seeking medication assisted treatment (MAT) for opioid/opiate addiction to that of individuals with chronic pain issues, there will be an increase in individuals with “buprenorphine-induced respiratory depression,” overdose and death. I expect that what happened when methadone was released to the wider market of chronic pain to be replicated with buprenorphine. Additionally, the discontinuation (withdrawal) syndrome from burprenorphine is anecdotally more severe than heroin and methadone. Regularly over the years I’ve worked with opioid/opiate addicts who have told me they had a much harder time coming off of buprenorphine than heroin or methadone.

The FDA is also looking to approve buprenorphine to treat depression. At this time, the buprenorphine drug formula is only designated as “ALKS-5461” by Alkermes. See “The Coming Depression Apocalypse” for more on this issue. Be aware of the potential adverse reactions and negative consequences from using buprenorphine for chronic pain relief or depression. As bad as the pain or depression can be, don’t jump from the frying pan into the fire with buprenorphine. If you think I’m overstating the risk, go to an open Narcotics Anonymous meeting and strike up a conversation with someone who has misused burprenorphine or who has simply tried to taper off of it after an extended time of using it for MAT.

We now have two approved medical uses for buprenorphine and it’s likely we’ll soon have a third. “Is Buprenorphine Just Another Head for the Hydra of Opiate Addiction?” is looking prophetic. Buprenorphine had just grown a second head and is the process of adding a third head for the Hydra of opiate addiction.

06/17/15

The Coming Depression Apocalypse

According to the Motley Fool, the pharmaceutical company Alkermes has a potential blockbuster drug for treating major depression in its pipeline. Currently in Phase 3 clinical trials, ALKS-5461 is one step away from Alkermes filing for approval by the FDA. Mental Health Daily reported that ALKS-5461 was given fast track approval by the FDA and is expected to be available in 2016. Its projected use is as a supplementary treatment to current antidepressant drugs. But once approved, the “supplementary” element will likely stop because it’s new and fast acting. The problem is, the drug in ALKS-5461 that is supposed to treat depression is an opioid with addictive potential.

Before going further on this issue, we need to take a short trip into pharmacology and neurotransmitter function in order to understand what’s going on. There are proteins embedded within the membrane of a cell called receptors. These receptors receive chemical signals from outside the cell, and in turn produce a biochemical reaction inside the cell. The chemicals that bind and activate a specific receptor are called agonists. While an agonist causes a reaction, an antagonist blocks that reaction from occurring within the cell. It turns the cell off from the influence of the agonist.

Receptors are activated by either endogenous agonists (hormones or neurotransmitters), or exogenous agonists (drugs). Endogenous agonists are produced by the body. The endogenous opioid agonists include dynorphins, and the more widely known endorphins. If you want more information on biochemistry and neurotransmitter activity, try these Wikipedia pages for starters: opioid receptor, mu-opioid receptor, and agonist.

Opioids are known to have energizing and mood enhancing effects with some users. This effect seems to be associated with dynorphin, which is elevated in depression. Dynorphin is a full agonist for the kappa opioid receptor (KOR). Studies like that done by Knoll and Carlezon, “Dynorphin, Stress and Depression,” suggest that KOR antagonists may have a potential therapeutic potential in treating anxiety and depression. While this biochemical hypothesis makes sense to psychiatrist Daniel Carlat, in The Carlat Psychiatry Report, he was more reserved on the treatment potential of ALKS-5461 than Mental Health Daily and the Motley Fool.

The efficacy of ALKS-5461 for depression remains to be seen. Some trials of ALKS-33 alone have already been performed, particularly in the areas of alcohol dependence and binge-eating disorder. These have been negative.

Now let’s look at my concern with ALKS-5461. First, it is a combination of buprenorphine, and samidorphan, or ALKS-33. Buprenorphine is used in addiction treatment as a detoxification drug and in opioid maintenance therapy, where its brand names are Suboxone (buprenorphine with naloxone) and Subutex (buprenorphine without naloxone). Suboxone and Subutex are classified as Schedule III controlled substances, meaning they have a moderate to low potential for physical and psychological withdrawal. Other Schedule III drugs include ketamine and anabolic steroids.

Buprenorphine is a partial mu opioid agonist, meaning it displaces morphine, methadone, and other full opioid agonists from activating the mu opioid receptor (MOR). But it does not provide the same degree of receptor activation as the full agonists (It doesn’t get you as high), resulting in a net decrease of agonist effect and the onset of withdrawal if it used soon after a full agonist like heroin. Patients planning to begin Suboxone maintenance therapy are told to abstain from opioids for twenty-four hours before their first dose of Suboxone.

At lower doses and with individuals who are not dependent on opioids, both full agonists like heroin and partial agonists like buprenorphine will produce identical euphoric effects. Partial agonists like buprenorphine also have a ceiling effect, meaning that past a certain point, typically 12 to 16 mg, no difference in analgesia, euphoria and respiratory depression will be felt.

Buprenorphine does produce physical dependence. Reportedly, this is to a lesser degree than full opioid agonists; and it is supposed to be easier to discontinue at the end of medication treatment. While this is the received wisdom on websites like NAABT, The National Alliance of Advocates for Buprenorphine Treatment, that has not been the case for what I’ve observed clinically with individuals who have tried buprenorphine. Generally I’ve heard that buprenorphine is harder to kick than heroin. So ALKS-5461 will be treating depression with a drug that may be harder to kick than heroin.

Buprenorphine is also a full antagonist of the kappa opioid receptor (KOR), which underlies its use in ALKS-5461 as an antidepressant. If the production of dynorphine by KOR receptors increases with depression, theoretically then buprenorphine would block these receptors and limit the release of dynorphine—elevating the individual’s mood. Peter Tenore, in “Psychotherapeutic Benefits of Opioid Agonist Therapy,” said that opioids like buprenorphine could be “effective, durable and rapid therapeutic agents for anxiety and depression.” The problem is with the partial agonist effect that buprenorphine has on mu opioid receptors (MOR) you can still use buprenorphine to get high.

That was the rationale for combining naloxone with buprenorphine in Suboxone. Naloxone is an opioid antagonist that counters the effects of opioids at the mu receptor, but doesn’t trigger a euphoric effect. Marketed under the brand name of Narcan, naloxone is used to counter the effects of opioids in overdose situations. The death of Phillip Seymour Hoffman led to calls for greater availability of naloxone (see “The Opioid-Heroin Cycle”) for individuals to use in overdose situations.

While naloxone is still the standard medication for emergency reversal of opioid overdose, its clinical use in long-term opioid addiction treatment is being superseded by naltrexone. Naltrexone (C20H23NO4) is structurally similar to naloxone (C19H21NO4), and samidorphan (C21H26N2O4). But it has a slightly increased affinity for κ-opioid receptors (KOR) and has a longer duration of action than naloxone. Naltrexone is used as a preventative medication for opioid use disorder in Vivitrol, whose marketing rights are owned by Askemet.

Samidorphan (ALKS-33) is also a full opioid antagonist, acting on the MOR receptor with mixed agonist-antagonist activity at the KOR receptor. Combining samidorphan with buprenorphine is supposed to block the agonist effect of buprenorphine on the MOR receptor, while not inhibiting the buprenorphine antagonist effect on the KOR receptor. A study by Shram et al. comparing samidorphan to naltrexone was published online ahead of the June 2015 issue of the Journal of Clinical Psychopharmacology. Samidorphin was found to have greater binding affinity than naltrexone to mu receptors and a longer half-life. This was suggestive of prolonged opioid receptor antagonism at lower doses of samidorphin. The study, though, was funded by Askemet.

Suboxone (buprenorphine and naloxone) and ALKS-5461 (buprenorphine and samidorphin) appear to be biochemical twins. And it does not seem to me that the addictive potential of buprenorphine has been entirely neutralized by its combination with samidorphin as claimed. The history of abuse and diversion with Suboxone supports this concern. If my fear is true, then in the name of treating depression, ALKS-5461 will create a huge population of individuals who become dependent upon buprenorphine.

Coming off of buprenorphine is not fun. Here is a personal testimony of someone tapering off of buprenorphine. Oh, and mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal.

Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses. Additionally, those who use buprenorphine other than prescribed (snort, inject, chew) may experience more severe symptoms than someone taking buprenorphine as prescribed. In these cases, physical buprenorphine withdrawal symptoms can last weeks after stopping.However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use.

The Substance Abuse and Mental Health Services Administration (SAMHSA) estimated that in 2013, 1.8 million people had an opioid use disorder; 517,000 of which had one related to heroin use. SAMHSA also estimated that each year, 9.1% of the adult population experience symptoms consistent with major depression. One 2012 study suggested that 10% to 30% of individuals with major depression suffer from treatment resistant depression. Using a U.S. population estimate of 320.94 million, with a median 20% for individuals with treatment resistant depression, that leaves a target population of over 5.84 million Americans with treatment resistant depression. God help us.

I don’t think it is too strong rhetorically to speak of a pending depression apocalypse. I hope I’m wrong. But widespread use of ALKS-5461 could instigate a huge population of individuals dependent upon buprenorphine. And the problems coming off of ALKS-5461 would eclipse what we now know happens with SSRI withdrawal. Within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS-5461. Sound familiar?

Faith Seeking Understanding

Charles Sigler, D.Phil.

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