From the Ashes of the Best Damn Medicine Ever (Part 2 of 3)
In Part 1, we asserted that most anxious and depressed people cannot achieve long-term relief with fast action and safety by using anxiolytics and antidepressants. That’s because these drugs target the wrong brain signals. Here we describe how pioneer scientists developed drugs that block the melanocortin signal in the brain. Those early-generation versions of our prototype medicine clearly outperformed antidepressants in depressed people. It’s a tragedy that they are not available today, but we’ll explain why that’s the case.
The First-Generation Depression Super Drug
There were actually three sibling super drugs for depression – kind of like triplets. As you might expect, they were all related to the medicine that we’re developing. Otherwise, why tell you about a thing that some other guys did decades ago that was awesome, but didn’t work out long-term, and has nothing to do with our work? To continue the family analogy, those early-generation medicines were like the grandmother and great aunts of our medicine. Let’s focus on grandma.
The discovery of the first super drug for depression comes from a naturally produced molecule found in the brain region called the hypothalamus (pronounced high-po-THAL-uh-muhs). As shown in the simulated image of the brain on the right, the hypothalamus is kind of behind the nose. In other words, over the decades that neuroscientists have lied awake at night thinking of a chemical basis for improving anxiolytics and antidepressants, the biological basis for a much better treatment has been kind of right under our noses all along.
The scientific name of the first super drug for depression is melanocyte-stimulating hormone release-inhibiting factor 1. Now you get why scientists use lots of acronyms. Fortunately, its abbreviated as, MIF1. MIF1 has a mechanism of action that slows the release of melanocortins from a specific set of nerve cells, called neurons. By the way, the word, melanocortin, is a more recent term for melanocyte-stimulating hormone. Melanocortin-releasing neurons stretch out of the hypothalamus to make contact and communicate with brain regions that control the emotional state. They are also activated by stress, a big contributor to anxiety and depression.
Previous work in animals since the 1970s has suggested that overactive melanocortin neurons contribute to hyper-emotional states. Separately, it was also shown beginning in the 1970s that MIF1 contributes to the brain’s natural way of curtailing melanocortin release. Who cares? Lots of people should care. That’s because soon after its discovery, MIF1 was developed into a medication and shown to reduce depression-related states in animals and people. The results: MIF1 worked, and it was better than antidepressants (including those currently on the market). In our opinion, the main reason that MIF1 is not currently on the market is that it is produced naturally in the brain, and naturally occurring molecules are difficult, if not impossible, to patent. Drug Makers’ Unofficial Rule # 387: No patent? No money (at least not $1B dollars per year). That is why you never have seen, and likely never will see, an ad for MIF1.
Just how much better was MIF1? It was 3X more effective than antidepressants at reducing the symptoms of depression. In one clinical study, it enabled depressed people to attain a score in the “normal” range on the Hamilton Depression Scale! To our knowledge no drug had done that before. By the way, it worked 8X faster – in just a few days (antidepressants take a few weeks).
What about side effects? Every antidepressant has harsh side effects, right? That’s why dozens of them are available – so users can decide, over a period of months, which side effects they can and cannot tolerate. For example, confused thinking might be tolerable for some. Sexual dysfunction might be okay for others. An increase in suicidal thinking anyone? If you don’t like particular side effects, switch to a new antidepressant. Just be sure to switch gradually, oh … so … very … gradually. Otherwise, you could crash and burn from a new set of side effects.
This phenomenon is called antidepressant withdrawal syndrome. Oops! Sorry! As neuroscientists, we are under solemn obligation, to our local pharmaceutical conglomerate and the physicians they buy … uh, we meant sponsor, to inform you that you cannot experience “withdrawal” from antidepressants because they are not addictive. Instead, under no coercion whatever, we are pleased to say that stopping the use of antidepressants abruptly (or slowly, or even very slowly) might cause you to experience antidepressant discontinuation syndrome. So, if you feel nausea, vomiting, headache, dizziness, “brain zaps” (yikes!), etc., ad nauseum (pun intended) (the list is so long that the symptoms are grouped together and labeled a syndrome … you are experiencing discontinuation, not withdrawal (wink, nudge).
The thing is, MIF1 and other first-generation melanocortin blockers were not antidepressants. Accordingly, MIF1 did not show many side effects. Bottom line: MIF1 outperformed antidepressants. Hang on a moment! In academic publications, we say “outperformed”. This is not an academic publication. So, we can tell you what we really think. MIF1 kicked much antidepressant ass!
Here’s another fascinating thing. As we mentioned above, when antidepressant treatment stops for about 10 days, withdrawal symptoms kick in. Oops! Sorry! We meant to say that discontinuation symptoms (air quotes) kick in after 10 days. If MIF1 was such hot stuff, when did its withdrawal symptoms kick in. (We don’t have an obligation here because MIF1 isn’t owned by anyone. So we can say “withdrawal”. The therapeutic effects of MIF1 were persistent, and there were few, if any, withdrawal symptoms. Moreover, when treatment was stopped after just 5 days, the therapeutics effects continued to the end of the study – a month later! Based on the features described above, MIF1 was the first best damn medicine for depression on the planet.
The Second-Generation Depression Super Drug
Alright, the conglomerates couldn’t patent (i.e., make a billion dollars a year) with MIF1 or other naturally occurring compounds. Couldn’t scientists whip up something like MIF1, which could be patented? Yes, it was called nemifitide. See what they did there? They called it ne-MIF-itide? Did it work? Yes! Nemifitide made it to phase II clinical trials, which is a massively huge step toward FDA approval, and it also outperformed antidepressants. By that, we mean that it kicked ass like MIF1. Did its therapeutic effects persist? Yes, even longer than those of MIF1. When depressed people were treated with nemifitide for just five days, most of the symptoms were gone in most of the people for an average of 3-4 months! In other words, nemifitide became the best damn medicine for depression that you’ve never hear of!
Why haven’t you heard of nemifitide? The main reason is that by the time the small company making it got past necessary business and regulatory hurdles, there were only four years left on their patent. When a popular drug goes over the so-called patent cliff, generic drug makers are allowed to flood the market with less expensive knock-offs. After that point, the conglomerate selling the more expensive branded drug watches its annual sales plummet. To see what might happen, if a new drug were to be sold with just four years of patent protection, check out the table below.
|Hypothetical Drug Sales|
|Year 1||$100 M|
|Year 2||$150 M|
|Year 3||$200 M|
|Year 4||$250 M|
|Year 5||$200 M|
|Year 6||$150 M|
In this scenario, we would be ecstatic if we had invented and sold this hypothetical drug. That’s because we’re not a conglomerate that has to pay for a huge workforce, marketing effort (It’s hard out there for a company that wants to make a $1 billion a year on a marginally effective antidepressant), and legal team (It’s also hard out there, for a company that has to fight against a bunch of lawsuits related to marginally effective antidepressants that cause bucket-loads of side effects).
It’s unfortunate, but MIF1 and nemifitide, the ancestors of our prototype medicines, were destined to never hit the market. Fortunately, we are committed to learning from the past. In Part 3, the final installment of this series, we’ll describe our development of third-generation melanocortin blockers. We will also touch on features of our prototype medicine that are as good or better than MIF1 and nemifitide (i.e., clearly better than antidepressants. Finally, part 3 will outline steps taken to protect the intellectual property underlying our medicine much more rigorously than nemifitide was protected.
John Shannonhouse, PhD Candidate
Caurnel Morgan, PhD