Developing Next Gen Multiple Sclerosis Therapies: Part 2

The following is part two of an MStranslate exclusive series which highlights the struggles and obstacles in developing the next generation of therapies and drugs for human disease. It is written by Dr. Travis Stiles, a neuroscientist who has worked to develop regenerative therapies capable of reversing neuronal damage caused by disease and trauma, such as multiple sclerosis and spinal cord injury.  Part one of this series can be read here.

You can help support his efforts by clicking here. Every contribution helps move this work closer to these revolutionary discoveries becoming therapeutic realities.

So how exactly does a drug come to the market?

The Process

Below is a flow chart for the drug development process. While this is an oversimplification, these 7 steps represent a good approximation of the drug approval process. This is by no means meant to encompass all the nuance and variations that can lead to a new drug on the market, but this summary represents a strong foundational understanding that I think will facilitate an informed discussion going forward.

Discovery

This is the fun stuff. This is what the scientists and professors in the Ivory Tower live for. This is when smart people trying to figure out cool new stuff happen to find something that might lead to a new way to treat disease. This can be a result of a lot of things. Maybe it’s the discovery of a new role for a specific gene, a previously unappreciated interaction between two proteins, a clarification for how something in our environment impacts our cells or tissues, etc. These discoveries can literally begin hundreds of different ways, but they fundamentally have the potential to change the way we understand and address specific aspects of human biology and/or disease. However, once this new cool bit of info is observed, the scientific process takes over and an explanation for the observation must be formulated and tested. Now, this can also happen in a lot of ways, but for the sake of this argument, lets simplify to what this article is focused on – new drug targets.

First off, what is a drug target? Truth is, it’s pretty much exactly what it sounds like. A drug target is the molecule, cell, protein, etc. that is important for a disease process. Manipulating these targets can change or modify a disease process. As such, drugs designed to interact with these targets can modify disease. When it comes to the observation of new drug targets, the next step is to test the target, which can be conceptually simple, but is almost always more difficult in practice. Testing a novel drug target usually consists of genetic silencing and/or molecular targeting. I won’t go too much into detail on this except to say if you think a target does something, a really good way to test that function is to either get rid of it genetically, or mess with it using some form of interacting agent (basically the crudest predecessor of an eventual drug). If these studies confirm your suspicions, then you’re off to the races!

Preclinical Development

This can get complicated, so once again bear with me. There is always some overlap from the discovery phase to the preclinical development phase, and that largely exists in the use of models of disease (disease models are how we mimic a disease in animals or cells so we can test how drugs may have a benefit). To put it simply, preclinical development consists of two parts; proof that the target can be exploited for therapeutic ends, and the subsequent development of a treatment (or drug) to do so. The latter portion of this is really tedious and expensive (not to mention boring in relation to finding out you might be able to cure something). As such, its really important that before jumping down the rabbit hole of development, you need to make sure that you can manipulate a target and make good things happen. Doing so is commonly called POC, or proof of concept, and is the necessary milestone needed to justify moving on to the development stage.

Preclinical development is where things get important. The truth is, there are so many variables that become critical here that it becomes almost impossible to dive into every aspect. This is the aspect of drug development that is often (in my humble opinion) under emphasized, especially in conditions effecting the brain and spinal cord. This is a critical portion of the process, and in future posts I will delve into the pitfalls and what researchers like me can do to improve the drugs being tested. For now, let me just highlight some of the general concepts addressed in this phase.

The discovery process is what gives us our initial proof of concept that validates our therapeutic target as a worthwhile focus for our new drug. However, making the BEST version of that drug is a major focus of preclinical development. As such, probably one of the most important activities in this phase is lead optimization/selection (where we pick the drug that we think will work best). Basically, this is the step where we take our molecule that interacts with our target and refine it to work more safely and efficiently. For small molecules, this involves a pretty standard medicinal chemistry approach. This basically means a bunch of really smart chemists test a bunch of tweaks to a molecule and see if they can make it better. When it comes to biologics, it’s harder. Biologics are different from small molecules because they are created from genetic material, usually in the form of proteins or antibodies. In my case, I make recombinant derivatives of proteins to use as a drug. In other words, I play with the gene sequence for a known protein and modify it so it does what I want. You can change proteins by creating mutations, joining to other proteins, deleting portions, etc. Because every protein is different, this process is often less linear and takes more time and resources. As we talked about before, this level of expertise can get diluted in a large pharma company, but it’s an area of strength for groups like mine. One area where big pharma excels in terms of biologic drugs is the use of antibodies.

The development of biologics is one area of drug development where being super focused on a small area, as is the case with me and my work, comes in handy. For me, my depth of knowledge regarding our specific target, and the small handful of potential proteins that we may be able to use, makes it easy for us to leverage a specific, as opposed to broad, skill/knowledge set. However, identifying an optimized lead molecule is far from the end of the preclinical development process.

So, you developed a a fancy new molecule as your new drug (commonly referred to at this stage as your “lead compound”), now what? Well, let’s recap what we already know about our fancy new drug.

1) We already have evidence that a crude version of this drug can be therapeutically beneficial (proof of concept). 2) We know that drug hits a target. 3) We know that this NEW molecule is supposedly the “better” version of that crude molecule in some way.

Before you can do anything with this new molecule, you need to make sure it works at least as well as your old version. Ideally, you want to test it in the same way you demonstrated your earlier “proof of concept”, or more simply, just prove it does what the old version did at LEAST as well. But let’s just assume it does what we hoped and skip to the good stuff. Now we have a fancy new molecule that we know can be therapeutic. So, we can start treating people, right? Or at LEAST start doing more animal studies?

Unfortunately, its not that easy. You see, just because you have a drug that does something, doesn’t mean that it does ENOUGH to help with a disease, nor does it mean you know how to BEST use it. This is especially true for drugs meant to treat the brain. Because the blood brain barrier is a whole other level of complexity, we need to be really thorough in our development. This is also where optimal drug development can often get complicated, and sometimes lead to an abandoning of a potential drug.

There are a couple of very simple things you must know if you want to get the most out of a drug.

1) How much drug you need to get to your target tissue/cell to have a therapeutic benefit. This doesn’t just mean how much drug do you need to give someone. In disease like Alzheimer’s or cancer, you need to know how much drug in a specific area, in this case the brain or tumor, is needed to have an effect. Once you know that, THEN you can work on how much drug you need to give to achieve those levels.

2) How much of the drug can cause problems (toxicity). Knowing the amount of drug that provides benefit compared to how much drug can cause problems is sometimes referred to as a “therapeutic window”. Anything outside of this window will either not work or cause helth risks.

3) How to deliver the drug to make sure it has the desired effect. This is critical. Not all routes of administration (intravenous, oral, injection, patch, etc.) are the same in terms of how well the drug can then reach specific tissues. Characterizing the way the drug behaves in different administration protocols is often a very informative exercise.

Finding these answers is tedious, meticulous work that is critical for a drug’s success. However, the incentive structure for academic research makes work like this extremely difficult to support or conduct. As such, these are activities largely taken on by pharma. In the case of small molecules or other types of drugs that are commonly developed by certain companies, this is perfectly fine, and pharma is excellent at these processes. However, for the niche stuff (like biologics for brain disease) it gets messy. As I’ve hinted at before, that is where specific focus can be invaluable.

The final step in this process also happens to be the most expensive; manufacturing. Because the goal is to make this a drug you use on people, it must be manufactured in a highly regulated fashion. This process is known as CMC (chemistry, manufacturing and controls), and this is where all the details about how the drug is made, stored, purified, and quality controlled is done. Once you have human-quality product you can move on to….

Investigational New Drug (IND) Application

Specific details can be found here.

Once your preclinical work is done, including CMC, you can file for investigational new drug (IND) status with the FDA. I won’t go into much detail here because the link above can give you all the details you could ever want, but this is where all your clinical trial plans, safety considerations, justifications, etc. come into play. Basically, this is where you convince the FDA that you have a drug that can help, and not hurt, patients. As part of this, you must convince them that you know how to prove that it works. That is your clinical trial design. If the FDA likes what you have to say, they will grant you IND status, which allows you to commence clinical trial.

Clinical Trial

Entire books have been written on the clinical trial process, and for good reason. It would be impossible to cover all the nuance of this process, so I will stick to some pertinent highlights.

The US clinical trial process, overseen by the FDA, is intended to establish the human safety and efficacy of a drug. This typically occurs in 3 phases. Phase I clinical trials are fundamentally intended to prove safety. As such, this stage is often conducted in healthy volunteers (when practical) carefully monitored for signs of physiological signs of toxicity. This is also where patients are closely monitored for adverse events (AE’s), which are a staple of the purpose of trials, as documenting and characterizing these events is an important component of the drug labels that the FDA requires of drugs. There are many factors that can be probed in this phase depending on the unique considerations of the drug investigated, but overall this is considered a safety trial.

Phase II trials are the first to focus on demonstrating disease efficacy. Because there is often a difference in the risk to healthy versus ill patients, phase II trials are usually done in a minimal cohort intended to prove a viable measure of efficacy in a manageable patient pool, small number of trial sites, and at a cost much lower than phase III trial. Like phase I, safety and indications of toxicity are important here, and because of the small number of patients used, the extent of significant findings has a little bit of wiggle room. Largely, this is the phase where “sponsors” (company testing the drug) test in humans the endpoints they think will prove the drug works. These endpoints are biomarkers, symptom ratings, and other measures of disease severity that can be monitored and quantified to demonstrate differences between treatment and control groups. Because this is the first time the drug is likely put into a sick patient, there are often a handful of endpoints tested to see where the desired efficacy is best demonstrated. These experimental endpoints are evaluated and approved by the FDA as valid measurements of efficacy. Successful demonstration of efficacy here can be somewhat flexible in terms of the endpoints that are used to justify a larger trial. Unlike phase III trials, data can be viewed somewhat subjectively and endpoints that may have been viewed as less important can become, in retrospect, the critical observations. Regardless, this phase is where the refinement of clinical studies is done in preparation for phase III.

Phase III trials are the final test. Using the safety, dosing, and efficacy outcome measures proven in phases I and II, the final phase III protocol is submitted and initiated in a large cohort, multi-center study. These are expensive, complex and tightly controlled studies. Unlike phase II, phase III studies must hit pre-determined and approved endpoints that the sponsor designates as the most important. In phase III, failure to meet these endpoints results in trial failure, even if there is obvious evidence of efficacy in other measurements. That doesn’t mean the drug fails totally, often phase III data can result in the launch of a completely new phase III study that uses the lessons learned from previous failures. Regardless, successful demonstration of efficacy based on pre-determined metrics approved by the FDA is what is necessary for advancement to……

New Drug Application

This is essentially what it sounds like. While this is a very complicated process, for all intents and purposes this is where a sponsor puts together all the data needed to ask the FDA to approve the drug for clinical use. The FDA then considers this application and waits for…

Approval

This is fairly straight forward, but the main purposes of this final approval process is; 1) confirm whether the drug is safe and effective in its proposed use(s), 2) whether the benefits of the drug outweigh the risks, 3) whether the drug’s proposed labeling (package insert) is appropriate, and what it should contain, 4) whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity. Once all this is hammered out, the drug can move on to….

Marketing

This is where no one does it better than big pharma. They have the distribution channels, specialized storage facilities, sales force, regulatory expertise, provider and payer network knowledge, etc. There are basically two main components to this process. Getting payers (insurance, medicare, etc.) to cover the new drug, and getting providers (doctors, hospital systems) to use it. This is much more complicated than it seems, and big pharma is uniquely situated to do this well.

Now that we have had the boring conversation and understand the basics, we can get into the more interesting conversation of why the rate of new treatments and cures has slowed. In the following articles we will delve into the moving parts of how this process works, the role of pharma and academia, and why public funding and small companies like mine are a critical part of the new drug development reality.

See you again soon!

Progress to Part 3 of Dr Stiles’ series by clicking here.