The Phase II Trial That Will Change Trevena Forever

  • The as yet unheard insider argument as to why TRV130 detractors have it all wrong about nausea and vomiting rates in the soon to report Phase-2b abdominoplasty trial is compelling.
  • This real world titration setting with patient controlled analgesia will redefine the drug, validate g-protein biased ligand technology and set Trevena’s stock on a steep upward trajectory.
  • The pseudo-scientific base their claims on a slippery slope of only 31-patients in the first, exploratory bunionectomy setting proving once again why they make the worst sector investors.
  • Over-stimulation of the self-protective intruder alert centers of the brain caused this anomaly in the first place. But that won’t happen again through the avoidance of excessive and unnecessary dosing.

I am long Trevena (TRVN)

I have an open mind allowing the criticisms of others to shape my opinions on the equities I hold. Perhaps, a bit too much. Trevena (TRVN) has been no exception. But what I’ve uncovered recently by way of an unsolicited email from Jonathan Violin of Trevena Investor Relations, ostensibly to compliment me on my last article, has provided me with an ah-ha moment of exquisite realization that has left me more optimistic than ever before.

As crazy as it might seem, all presumptions about Trevena’s acute pain therapeutic TRV130 have been predicated upon the adverse event profile of only 31 patients in the exploratory Phase-2a bunionectomy setting. Words to describe such erroneous extrapolations would be ludicrous and absurd, made even more so by extending those arguments to undermine confidence in Trevena’s entire g-protein biased ligand technology. The reason why we have a progressive clinical phase trial system in place is to avoid drawing such conclusions from inadequate sample sizes.

That said, the argument against TRV130 can be summed up like this. Yes, the analgesic benefit of the 3 mg dose is unquestionably better than that of morphine at 4 mg, and reduction of the risk of respiratory depression (the only meaningful side-effect) is impressive, but the increased risk of nausea and vomiting are a trade-off the FDA will not ultimately approve of. In my last article, I sent you to this web page where that argument was enunciated best. I furthermore added that because this now underway Phase-2b abdominoplasty trial was in an area of the body most susceptible to pain aggravated by vomiting, that the analgesic benefit of TRV130 could, therefore, be reduced. But that’s because I too easily bought into this fallacious argument in the first place.

What was revealed to me by Jonathan Violin, I’m about to reveal to you. And when you see what we’ve overlooked, you too will ignore the noise of the over-stated and chronically insecure. Furthermore, I’ll graphically illustrate why Jonathan is absolutely right. But before I do, I want to address why patients experience nausea and vomiting while under the influence of opioid pain relief.

A Well Functioning Brain Will Protect The Body From Harm

I’ve read many scholarly articles on this subject, but a simple one written by, David E Weissman states the following.

Commonly ascribed by patients as an “allergy”, opioid-induced nausea/vomiting is not an allergic reaction. In fact, rather than indicating a pathologic reaction, nausea indicates normal functioning of the brain! Opioid-induced nausea occurs through two mechanisms:

At the base of the 4th ventricle lies the chemoreceptor trigger zone (CTZ), a “sampling port”, to detect substances that don’t belong in the blood. Adjacent to the CTZ lies the medullary vomiting center [VC], which controls the complex muscular sequence of vomiting. When the CTZ detects a noxious chemical in the blood, a signal is sent to the VC and voila! vomiting ensues. Of note, this is the same reason why patients vomit after receiving chemotherapy. Although this mechanism works well for orally ingested chemicals, it was evolutionarily never designed for intravenous morphine!

A second cause of opioid nausea/vomiting is due to stimulation of the vestibular apparatus-patients note a spinning sensation with their nausea.

Beyond this, it should be noted that there is no predictable pattern which suggests that a patient’s physiology predisposes them to these symptoms or a particular procedure is more likely to induce them. Nausea and vomiting can cause for cessation of, or limits to, analgesia and remedies include anti-emetics and/or switching to alternative pain killers. Nausea and vomiting occur in nearly a third of all post-surgical settings where today’s gold standard of morphine is applied.

Why Is Respiratory Depression More Important?

Because it can kill you. When a person over-doses on an opioid pain reliever, this is how they perish – breathing slows to a stand still and the distribution of oxygen necessary for the correct functioning of all bodily organs is severely diminished. Although that rarely occurs in the aftermath of surgical procedures today, that’s primarily because physician’s deliberately under-dose their patients to begin with. Note this hospital memoranda on the administration of morphine by intravenous injection. It starts with only a 1 mg – 2-mg bolus. This leads to 60% of patients claiming that their pain is under-medicated in post-operative settings.

TRV130 Is A Powerful Analgesic Designed To Limit The Effects Of Respiratory Depression

In the first Phase-2a bunionectomy trial, the 3 mg dose TRV130 proved to be 2.4x more powerful than the 4 mg dose of morphine at reducing patient pain in the first 30 minutes following their return to consciousness. The nature of this pain reduction was consistent over 48 hours of clinical observation. Also noted was a reduction in the symptoms associated with respiratory depression (albeit not statistically significant).

I’m going to include two documents from the November 18, 2014Form S-1/A for your consideration. The first, can be found on page 89 and the second on page 88. I’ll be annotating this latter figure and referencing both as we progress for clarity.

Adverse Events

Pain Intensity 48 Hours

Insider Hypothesis: If Nausea & Vomiting Rates Were Attributable To The 3 Mg Dose Of TRV130 It Was Likely Because Patients Were Over Treated With The Drug – Especially On The 2nd Day

A quick look at Figure 6 above will demonstrate why this hypothesis is likely to be validated in this 2nd Phase-2b study in abdominoplasty patients. Look at the placebo pain score on day 2 and note that the very same 3 mg dose of TRV130 was given every 3 hours even while patients slept. So, while pain barely crested the barrier between mild and moderate, patients were being blasted with a pain killer that dropped patient pain scores by 85.7%, from 7 points to 1 point in the first 30 minutes. I’ve annotated this chart which employs a fluctuating timeline to denote precisely when doses of TRV130 were administered.

TRV130 3-Hour Dosing

Now take a look at the same annotations made for morphine.

Morphine 4-Hour Dosing

We can clearly see that patients were given excessive amounts of TRV130 on the second day of treatment. Those chemoreceptor trigger zones and medullary vomiting centers of the brain referred to by Dr. Weissman must have been ringing off the hook.

This Second Phase-2b Trial Utilizes A Patient Controlled Analgesia Format With A Loading Dose Of Only 1.5 mg of TRV130

The loading dose (also known as the knock-out dose) for Morphine remains unchanged at 4 mg but TRV130 will be administered at only 1.5 mg when the patient first awakens in discomfort – more than enough to allow for comparatively greater effect. All participants will then be allowed to self-administer either drug for additional pain relief throughout the 24-hour trial period at 1 mg every 6-minutes as needed. If a physician determines that this amount is inadequate to the task at hand, either dose can be increased by 50% after the 1st hour of administration.

If we look again at the graphic above, we can clearly see that the 1 mg dose of TRV130 was at least as effective as morphine in the bunionectomy trial. More importantly, we can see that only 34% of patients became nauseous and only 10.5% vomited while on that dose. Consequently, it’s highly unlikely that the rates of nausea and vomiting will be any higher than morphine in this clinical setting.

My Personal Experience

You’ll note that I’ve added some sleeping times to my annotations of Trevena’s illustrations. I’ve done this because this is the reality of post-surgical recovery environments. Patients self-apply the amount of pain relief they need and then allow the body to heal itself by sleeping.

10-years ago, I fell off the roof of a house I was rebuilding and broke my left arm so severely that the bone completely disintegrated. On the way to two different hospitals, I received morphine treatments which helped a great deal in managing my pain that was both physical and mental – there’s anguish in realizing your life is suddenly changing.

When I woke up the next day in my hospital bed, I was no doubt given a loading dose of morphine, and then, I was instructed by my nurse to give myself as much additional pain relief as I wanted by pressing the clicker in my right hand. Fortunately, I was not made aware of the 6-minute lockout period. I can remember clicking a lot and then passing out for about 2-3 hours before awakening again. Throughout the day, I then stayed awake watching TV and the poor, unfortunate soul in the bed beside me who also fell off a roof onto his driveway breaking all four of his extremities (yes it looks exactly like it does in the old cartoons – heavily wrapped legs and arms all hoisted into the air).

The point is, that when my pain was relieved, I was inclined to nap. Therefore, I believe that patients receiving TRV130 will use far less of the drug this time around than they did before. To illustrate how much less, I’ve prepared my own predictive plot of pain and side-effects for your consideration. The number inside a 1 mg box of either drug indicates how many times that treatment will be self-administered in 1-hour’s time.

Projected Rates of Efficacy and Side Effects in Phase 2b Abdominoplasty Trial

 

To Conclude

Because we’re still in the exploratory stage of drug development, Trevena has the luxury of employing this non-standard titration format in this particular Phase-2b setting. By doing so, we’ll learn a lot about the drug. Ironically, almost all I.V. use of morphine in post-surgical applications employs patient controlled analgesia. In pivotal clinical settings, however, this isn’t possible as it doesn’t provide the clarity needed to evaluate treatments on a comparative basis.

I’m comfortable with my predictions of nausea and vomiting rates in this Phase-2b trial set to report in a few months time.  If I’ve erred in any parameter aspect, it likely is in the assumption that patients receiving morphine won’t experience better pain relief thereby reporting lower pain scores.  We’ll see.

What the results here will clarify, however, is whether or not the side-effect profile is dose related. Should that be the case, the issue then will shift to how to mitigate the problem in a registration format.  It is possible that CEO Maxine Gowen could argue for a protocol that employs a reduced, fixed-dose application of TRV130 administered on a more frequent basis – think 1.5 mg every 2-hours.

Always be well…