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Tuesday, June 14, 2016

Relmada's LevoCap ER Is A Target For Specialty Pharma

As most investors that have followed my work know, I've been a big fan of Depomed, Inc. for the past several years. Depomed, along with fellow specialty pharmaceuticals players including Purdue, Horizon, Endo, and Mallinckrodt, has shown that it is possible to build a successful commercial business focusing on the pain market. I say that because developing new drugs in the pain and neurology space is notoriously one of the most challenging areas of pharmaceutical development. The challenge is likely due to the diverse nature of the affliction, the vastly different ways in which individuals respond to pain medications, compliance, and pesky placebo response.

My article today will focus on a new potential player in the pain and neurology market, Relmada Therapeutics (RLMD). I'm intrigued by Relmada because the company has a diverse pipeline of pain medications in various stages of clinical development. The lead candidate, d-methadone, has characteristics that make the drug look very intriguing for neuropathic or psychiatric pain and depression, an enormous market opportunity validated by the success of some blockbuster drugs, including Pfizer's Lyrica® and Eli Lilly's Cymbalta®. I've already written about d-methadone, so I encourage investors to view that article >> HERE.

For this article, I focus on LevoCap ER, an extended release, abuse deterrent formulation of levorphanol. Relmada will request a Type-B meeting with the U.S. FDA for late summer 2016, after which time management would like to partner the asset for the initiation of a Phase 3 trial in 2017. Depomed's acquisition of the Nucynta® franchise and cebranopadol proves the market for novel pain drugs remains hot, and with companies like Purdue, Endo, and Mallinckrodt struggling to find growth and protect their core business, Relmada Therapeutics might be an excellent acquisition target as its pipeline matures. 

Some Staggering Statistics About Pain

Despite the challenges inherent in developing new pain medications, including an FDA that has become increasingly more scrutinous and critical of opioid medications, pain remains one of the largest pharmaceutical markets worldwide. Chronic pain affects 100 million people in the U.S., more than the total affected by heart disease, cancer, and diabetes combined. Pain costs the U.S. over $600 billion a year in medical treatments and lost productivity, according to a recent report from the Institute of Medicine (1).

Non-malignant chronic pain results in nearly 100 million outpatient visits to medical facilities each year in the U.S. (2). IMS Health reported over 328 million prescriptions for pain medications in 2014. Sales of prescription pain products totaled $13 billion in 2014 according to IMS Health, a staggering 71% of which were opioids. Including Canada, the U.S., France, Germany, the UK, Spain, and Italy, sales of pain medications, both prescription and over-the-counter, totaled $27 billion in 2009 (3). Approximately 85% of the market is for chronic pain.

Many Different Types of Pain

Perhaps the reason why the pain market is so large is that pain itself is such a diverse disease. Pain can be subcategorized into several classes by duration, pathogenesis, site of origin, and cause. There are also different types of pain, including nociceptive pain, neuropathic pain, and psychogenic pain. Primary examples of nociceptive pain include osteoarthritis, headache, and lower back pain. Neuropathic pain examples include post-herpetic neuralgia, diabetic peripheral neuropathy, multiple sclerosis, spinal cord injury, phantom pain, and sciatica. Some intense pains, including pain caused by late-stage cancer or ligament and joint damage, may have both nociceptive and neuropathic components. Psychogenic pain may be caused by stress or depression.

Pain is also highly subjective and difficult to treat. One patient might describe their pain as dull, throbbing, or aching, likely signifying a nociceptive pain. Another patient might describe a burning, stabbing, or tingling pain representative of a neuropathic component. Pain intensity is also difficult to quantify, leading to challenges for physicians when attempting to diagnose pain level. Pain can also vary throughout the day, triggered by stress, environmental factors, or movement. These factors make the diagnosis and selection of pain drugs a difficult task for neurologists or pain medicine specialists. 

An Unsatisfied Market

A recent study conducted by David Michaelson & Co. commissioned by the American Pain Foundation and Endo Pharmaceuticals found that 51% of chronic pain sufferers taking opioids report "only a little" or "no control" over their pain. Only 6% report having "a great deal of control" (4).

Other interesting findings from the national survey (n=303) were:

- 71% of responders report having visited a physician or other medical professional in the past month.
- Vicodin® (acetaminophen and hydrocodone) is the most commonly used pain medication with 45% market share, followed by Percocet® (acetaminophen and oxycodone) with 18% share and OxyContin® (oxycodone) with 16% share.
- 31% supplement their prescription medications with over-the-counter medications, such as NSAIDs.
- The average chronic pain patient is taking 2.2 medications at a time to control their pain.
- 55% of chronic pain patients are taking 3 or more pain pills per day.
- 76% of chronic pain patients are also receiving some form of treatment for depression, with fluoxetine, bupropion, and sertraline as the most common concomitant medications.
- 41% of chronic pain patients are on anti-anxiety medication, with alprazolam and clonazepam being the most common.

Do We Need Another Pain Drug?

I note the above statistics because investors may wonder, "Do we really need another pain drug?" I think the answer to that question is a resounding, yes; and it relates to what I said in the opening paragraph. Pain is such a diverse disease and individuals with pain respond to drugs in vastly different ways, both in terms of efficacy and tolerability. For example, OxyContin® sales eclipsed $3.1 billion only a few years ago. The drug is highly effective in the management of moderate-to-severe post-operative pain (5) and cancer pain (6). However, opioids like oxycodone are relatively ineffective for the management of fibromyalgia pain (7).

Opioids are also not recommended for first-line use in patients with neuropathic pain. Work published in The Lancet in 2015 found that for indications including post-herpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and painful polyneuropathy (PPN), drugs such as amitriptyline, gabapentin, pregabalin, and duloxetine are far more effective than opioids or tramadol (8). Yet Lyrica® (pregabalin), a drug which Pfizer sold $4.8 billion worth of in 2015, is ineffective for the treatment of lower back pain (9).

Beyond the diverse nature of pain that requires drugs with various mechanisms of action, responses to pain medications vary on both an inter- and intra-patient level. For example, a paper published in the Journal of Pain in 2011, notes that individual patient response to opioids is controlled by factors, including gender, psychological attributes, age, and genetic profile (10). These factors can influence both the level of efficacy and tolerability. Quite simply, what drug works for one may not work for another, and just because the drug works today does not mean it will continue to work tomorrow.

Opioid tolerance and opioid-induced hyperalgesia are two other major issue for patients with chronic pain. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug's effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxical increase in atypical pain that appears to be unrelated to the original nociceptive stimulus (11).

It is for the many reasons noted above that the pain market is both so large and so under-served. The slide below from Depomed's March 2016 R&D day sums up the point above rather nicely.

Levorphanol for the Treatment of Severe Chronic Pain

- Background Info

Levorphanol (levo-3-hydroxy-N-methyl-morphinan) is a potent opioid analgesic first approved for use in the U.S. in 1953  for the treatment of moderate to severe pain where an opioid analgesic is appropriate (12). The drug has relatively high bioavailability and a longer half-life than most other opioids. It also exhibits uni-directional cross-tolerance with morphine (13), a convenient trait for patients that have built up morphine-tolerance over the years. 

Researchers believe that the uni-directional cross-tolerance with morphine is due to levorphanol's ability to interact more potently with other relevant opioid and non-opioid receptors. Specifically, levorphanol acts predominantly as an agonist of the μ-opioid receptor but is also as an agonist of the δ-opioid, κ-opioid, and nociceptin receptors. It also has activity as a NMDA receptor antagonist and as a serotonin-norepinephrine reuptake inhibitor (14). 

As such, levorphanol’s multimodal mechanism of action provides for a more robust efficacy profile and potentially could be used alone for patients who take multiple drugs. From a relative potency perspective, at steady state, a 2 mg oral dose of levorphanol is approximately equivalent to 10 mg oral oxycodone or 15 mg oral morphine (15). Hence, levorphanol is approximately 7.5 times as potent as morphine. The side effects and adverse reactions observed with levorphanol are similar to those of most μ-opioid analgesics. It is classified as a schedule II controlled substance.

Gudin J., et al., 2015 characterized the receptor binding affinity of levorphanol for the μ-opioid receptor at 0.42 nM, which is far greater than the affinity of morphine at 1.24 nM. Relmada's own in vitro pharmacology work from two separate studies found the binding affinity at the μ-opioid receptor to be 0.13 nM, and 17 nM and 4.7 nM at the δ-opioid and κ-opioid receptors, respectively. Levorphanol, unlike morphine, easily crosses the blood-brain barrier, with high affinity for the NMDA receptor. Relmada's pharmacology work shows strong inhibition of serotonin-norepinephrine reuptake (IC50: 5HT - 52 nM, NE - 2.1 uM).

- Clinical Data 

The prescribing information for generic levorphanol tartrate 2 mg states that approximately 1,400 patients were treated in controlled clinical trials during its early development (16).

1) Glazebrook, 1952: Glazebrook reported on 200 chronic pain patients (primarily malignancies or chronic bone or joint disease patients) treated with levorphanol doses up to 4 mg. Results showed successful analgesia in 159 (79.5%) of the cases. The average duration of the analgesia was 8 hrs for a 1.3 mg dose (42 patients), 10 hrs for a 2 mg dose, 11 hrs for a 2.6 mg dose, and 14 hrs for a 4 mg dose. Respiratory depression (respiratory rate falling by more than two excursions a minute) was observed in 5% of cases of patients given an initial dose of 2.6 mg or less. 

2) Morrison et al., 1971: Morrison et al. studied 16 different analgesic drugs (see below), including levorphanol, at various dose levels, some in combination with antagonistic or neuroleptic agents, in groups of 20 to 80 patients.

Only levorphanol 2 mg achieve an incidence of “success” of > 75% reduction in pain and proved significantly superior to pethidine 100 mg, the standard reference drug. Oxycodone 10 mg, pentazocine 20 mg, and the morphine 10 mg and cyclizine 50 mg combination were the most successful of the remaining drugs. 

3) Banister, 1974: Banister studied six potent analgesic drugs in a total of 436 patients. Although levorphanol did not fair as well as the Morrison et al., 1971 study, results still showed satisfactory pain relief in 68 of the 86 (79.1%) of test subjects.

4) Rowbotham et al., 2003: Researchers at the Pain Clinical Research Center, Department of Neurology, University of California, San Francisco randomly assigned 81 adult patients with neuropathic pain that was refractory to treatment to either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of levorphanol for eight weeks under double-blind conditions. Results showed high-strength levorphanol capsules reduced pain by 36% compared to a 21% reduction in pain in the low-strength group (P=0.02). In addition, 66% of patients in the high-strength group achieved moderate or better pain relief. 

5) McNulty, 2007: McNulty conducted a retrospective analysis looking at the efficacy of levorphanol in patients who did not respond to other opioids, including methadone, at the Palliative Care Institute of Southeast LA, Covington, Louisiana. During a 5-year period in a single palliative medicine practice, 20 of 244 patients with chronic nonmalignant pain in a palliative care clinic and 11 of 1,508 terminally ill patients enrolled in hospice care whose severe chronic pain was not relieved by treatment with other opioids were treated with oral levorphanol. Of those 31 patients, 16 (52%) reported excellent relief of pain and 7 (22%) reported fair relief for a total response rate of 74%. McNulty suggested that, "Levorphanol has a role in the treatment of pain syndromes that are refractory to other opioids."

- Current Use

Despite being around since the 1950's, current use of levorphanol is not common. An Op-Ed by Dr. Jeffrey Fudin on explains that supply interruptions and manufacturing difficulties hampered the uptake of the drug over the past decade, and sole manufacturer, Roxane Pharmaceuticals, stopped production in July 2015. Shortly after that, California-based Sentynl Therapeutics, Inc. started making a new formulation of levorphanol tartrate 2 mg; only the company raised the price from roughly $2 per tablet to $46 per tablet (note: recommended dose is three tablets per day). 

Levorphanol does have some very loyal prescribers, so Sentynl's strategy was quite similar to what Turing Pharmaceuticals did with daraprim - i.e. secure full manufacturing to an old generic drug and jack-up the price to astronomical levels. Only there are therapeutic alternatives to levorphanol (e.g. OxyContin, Opana, Nucynta), and chronic pain is not an orphan disease, so current use is virtually non-existent (17).  

Relmada's LevoCap ER

Relmada Therapeutics is developing LevoCap ER (REL-1015), an extended release, abuse deterrent, proprietary formulation of levorphanol. LevoCap ER utilizes Relmada's SECUREL technology platform designed to create abuse and tamper-resistant extended-release formulations of proven drug candidates. Specifically with levorphanol, management believes the multimodal mechanism of action, combining opioid receptor agonism with serotonin-norepinephrine reuptake inhibition / NMDA receptor antagonism, confers potential utility of LevoCap ER as a useful analgesic to treat chronic and neuropathic pain in patients resistant to other strong opioids like oxymorphone, oxycodone, fentanyl, and morphine.

Extended release technology is a "must have" for the management of chronic pain in today's market. There are no extended release formulations of levorphanol, and the current dosing is three times daily (TID). At the American Association of Pharmaceutical Scientists (AAPS) conference in 2011, Relmada (formerly TheraQuest Biosciences, Inc.) presented a poster on the "Pharmacokinetic Evaluation of Novel Abuse Deterrent, Extended Release Dosage Forms of Levorphanol" (18). An abstract on the data was published in the Journal of Pain (19).

The study evaluated the pharmacokinetics of four novel abuse-deterrent ER dosage forms of levorphanol versus immediate release (IR) levorphanol. Fifteen healthy subjects participated in this single-center, randomized, analytically masked, fasted five-way crossover study. The elimination kinetics of oral levorphanol showed minimal variability, and all four levorphanol ER dosage forms provided robust release characteristics suitable for once-a-day dosing. The table below shows the Tmax, Cmax, and AUC data.

Also at AAPS in 2011, company scientists presented a poster on the abuse deterrence of 20 different novel formulations of levorphanol ER (20). An abstract was published in the European Journal of Pain Supplements (21). Dosage forms were subjected to tampering, including crushing, grinding, dissolving, melting, needle aspiration, filtration, and solvent extraction to determine their tamper resistance relative to marketed products. The stability of levorphanol ER capsule dosage forms manufactured under high-temperature conditions was assessed for 12 months. Results show four final abuse-deterrent levorphanol ER dosage forms with robust in vitro dissolution, tamper-resistance and release kinetics consistent with a once-a-day dosing regimen.

In September 2015, Relmada announced the U.S. Patent and Trademark Office (USPTO) issued U.S. Patent No. 9,125,833 entitled, "Multimodal abuse resistant and extended-release opioid formulations" (22). The issued patent covers LevoCap ER, as well as providing additional coverage for multiple opioid molecules that are prone to abuse.

Next Steps With LevoCap ER

Relmada is developing LevoCap ER under the expedited 505(b)(2) regulatory pathway. Management is taking a proven drug candidates with levorphanol and applying a novel delivery with abuse / tamper-resistant technology. It is a lower hurdle for approval and one that reduces both the cost and risk of development.

The next step for management is to conduct a Type B meeting with the U.S. FDA later in 2016. Management has targeted late summer for this meeting. After this event, the company should have an excellent idea of the requirements for the planned Phase 3 study in 2017. Relmada will likely look to engage partnership discussions with larger organizations following the completion of the Type B meeting. I view this as a near-term milestone that is readily achievable without significant expense.


Levorphanol has greater potency than morphine and a multimodal mechanism of action that potentially offers utility to patients resistant to other strong opioids like oxymorphone, oxycodone, and fentanyl. The dual nociceptive (ascending) and neuropathic (descending) mechanism of action is reminiscent of Depomed's marketing message with tapentadol (Nucynta® and Nucynta® ER). With Nucynta® ER, Depomed is targeting both acute and chronic pain of a nociceptive and neuropathic nature (see slide below from Depomed's March 2016 Analyst Day). Analysts believe the Nucynta® franchise has peak sales potential in the $500 million to $1 billion range. Depomed paid $1.05 billion to acquire the commercial rights to the franchise from J&J in January 2015 (23).

Depomed's Phase 3 cebranopadol, acquired from Grunenthal in November 2015, is another example of a dual-mechanism opioid / NOP receptor potent and broad spectrum analgesic that validates the strategy for Relmada's LevoCap ER. Depomed paid Grunenthal $25 million in cash for the rights to cebranopadol (24), but also settled outstanding patent litigation as part of the transaction, so the exact value of the deal is convoluted. Nevertheless, it is clear that late-stage dual or multimodal mechanism of action pain drugs are worth a significant amount of money.

Levorphanol has been called underutilized and the forgotten opioid (25). Perhaps this is because of previous supply constraints or because the only existing immediate release formulation is incredibly expensive at nearly $150 per day. Much of the peer-review I found on levorphanol concluded that the drug has less potential for adverse drug-drug and drug-food interactions seen with many opioids, and a limited risk of known concerns with comorbidities, such as cardiac QT prolongation. 

Relmada's extended release and abuse / tamper-resistant formulation will compete directly with products like OxyContin® ER, Opana® ER, Exalgo®, Zohydro® ER, Embeda®, Nucynta® ER, and even late-stage assets like ALO-02 and cebranopadol. It's a crowded market, but as noted above, the major players including Depomed, Purdue, Horizon, Endo, Mallinckrodt, and Pfizer are perpetually on the hunt for these types of late-stage assets. Relmada's novel LevoCap ER should be at the top of their list following the Type B meeting in the next few months.


This article was written by Jason Napodano, CFA of BioNap, Inc. 
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