The first step to bringing a drug to market is inventing a new drug. The invention is based on an original idea that is spurred by previous science. The science should support treating what you expect to treat. We mixed up some new drug in the lab and did some testing, just to make sure our idea was valid. We burned the midnight oil and did this in a few weeks. We had our eye on submitting an Investigational New Drug application (IND) to FDA as quickly as possible. (Note: we did this project through our not-for-profit Neurodegenerative Disease Research Inc. Read about us at No More ALS).
The path to manufacturing is pretty standard. Experimental batches are made from the raw ingredients just like we did in our lab. Then a manufacturer is located, they are given the recipe and they make experimental batches. Then they make an engineering batch. Finally, there are 3 GMP batches (Good Manufacturing Practice) paving the way for commercialization of the product. Most of the manufacturing section of the licensing process is documentation for the protocols to be followed, the validation of procedures and protocols for each step and also the production of the drug.
At the end, we had over 250 documents and a Master Batch Record that is meticulously followed for each subsequent batch along with scrupulous records.
Oddly enough, this is done before the new molecule can be used in the pre-clinical data development steps. Developing the manufacturing process usually takes a year or more. We went with an experienced company, paid a premium to move swiftly, and arrived with our packaged, labeled drug in 15 months. We made the bold decision to develop the pre-clinical data concurrently. Bold, because we guessed on some things. You know we kept our fingers crossed!
The generation of pre-clinical data presumes you have an idea how the drug will be given—orally or injected, you must decide on little information. You have to have a ball park idea how much you will need to give, by weight, to get a certain effect and how to measure that effect in an animal that got treated. And hope the guess is right. All the procedures must be validated. The new drug has to be tested for how long it lasts in the treated animal, where it goes (which tissues, pK or pharmacokinetics), and to detect and measure all the metabolites that are formed once the drug is given. Part of the pre-clinical development is done in cultured cells. The safety, pK, and effects on reproduction, development, and carcinogenicity have to be tested in three species of lab animals rats, mice, and dogs. You must anticipate unintended consequences of the drug, there will be some. This takes months and can be done in conjunction with animal studies.
The idea of a potential treatment to pre-clinical development of the drug is often called the valley of death. If you are in a hurry, with an educated guess and concurrent studies, years can be shaved off the project, generally 8-10 years. Our development team asked some tough questions and we needed to get some answers from additional studies.
Our new drug is intended to treat neuroinflammation associated with ALS, also known as Lou Gehrig’s disease. It will likely treat disease in septic foals and chronic renal disease in older companion animals. What we needed didn’t exist, so we invented it. Initially, we were going to give the drug orally, but after considering some study results we changed to a sterile formulation that will be given by a sub-cutaneous injection. We hedged our bet; if necessary the IND can be resubmitted to FDA as an intravenous drug without changing the formulation.
We needed data to support our idea and chose ALS animal models to test our drug. Models aren’t perfect and we still need to invent some things later for another Get-Drugs-To-Humans step, an Orphan Drug Designation; but we needed a direction and mouse models were the most prudent compass. The experiments, from breeding the mice to the final report, took twenty-eight months to test molecules for hints of effectiveness. If time was available we would repeat these experiments.
The pre-IND submission is the opportunity to ask FDA if there are any steps that need remediation and give them a chance to comment on our proposed IND submission including the first human study. If all goes well with human safety, the field studies can commence. Field studies are long and very expensive. Today we submitted the pre-IND package to FDA. It includes the Phase 1 study protocol and we hope to go into our first patient by May 2023.
The idea for our drug was spawned from a conversation with Dr. Gideon Goldstein, August of 2019, a month after of learning of our neighbors recent ALS diagnosis. And that conversation adhered to the 10,000 hours rule (Malcom Gladwell’s Outliers: The Story of Success) that we put in equine neurodegenerative disease research. Two months after the meeting with Dr. Goldstein we were exploring all options for a lead molecule. We began modifying a molecule he had isolated in 1975, by July of 2020 we settled on a structure. Our goal was simply to bind a drug target for a longer period of time that the 23 seconds Goldstein’s drug remained engaged by changing the structure.
By November 2021 we had enough data to begin the path to an FDA license. We found a good company, paid well for speed and now we are filing our paperwork. We hope the next two months will bring us the IND. The tab so far, from the idea to making 1000 vials to run the trial, is $5,479,726, not counting my time. Drug development is expensive. Drug manufacturing is expensive. Please, don’t grump at FDA or pharmaceutical companies. It is what it is. To give our drug away to the 18,000 patients with ALS would cost $66,240,000/year to manufacture it, no mark up or paying back the costs of development. There isn't a path forward to give it away to patients. Inventing it and making it available will have to be enough.
We aren’t the first not-for-profit (NFP) to invent a new drug, nor the second. We may be the third. However, we will be the first NFP to take the invention to a patient trial, a Phase 1 human safety study. It took us 37 months from learning about ALS and the desperate need for ALS treatments. From the day of diagnosis an ALS patient has, on average, 3-5 years to live. We want to change that. We hope we have.
What do we expect? We believe the new drug will treat neuroinflammation and regulate dysregulated energy pathways in ALS neurons and microglia. Our drug is expected to impact neuromuscular transmission, immune cell differentiation and regulate dysregulated immune responses.
As an aside, it may improve immunological parameters in neoplastic, immune deficiency, and autoimmune diseases including chronic lymphocytic leukemia, rheumatoid arthritis, cancer immunodeficiency, acquired immuno-deficiency syndrome (AIDS), and chronic heart failure because Dr. Goldstein's molecule does. We believe that we may impact end-stage renal disease in dialysis patients improving the quality of their lives. Other aspects of the drugs utility include affecting diseases such as the inflammation caused by Covid19 infections or the infection itself and reducing the need for steroids after organ transplant. These are anticipated, unintended consequences of our new drug. Possibly others will license these new indications for our ALS treatment with FDA. We’re spent.