Stages of Drug Development

Discovery
To find new disease-modifying drugs, researchers look deep into the biological processes that cause ALS to develop and progress. This helps them identify specific components of these pathways that, if disrupted or modified, could help stop or minimize neuron damage and destruction. These are known as drug targets and can be things like a DNA sequence or a gene, an RNA molecule, or a protein. Researchers may also look for ways to reduce or improve common symptoms of ALS, such as muscle cramps or breathing issues, to identify new symptomatic therapies.
After a target has been identified, researchers search for the best way to modify or interact with it. This could involve a small molecule, gene therapy, or antisense technology, depending on the target. Usually, a variety of possibilities are identified, so researchers must do additional experiments to see which ones have the right combination of characteristics that could make them effective as a treatment. For example, to treat ALS, it is critical that any potential new drug passes through the protective blood–brain barrier to get to cells in the brain and spinal cord.
Pre-clinical Testing
Before giving a potential new drug to people, researchers must conduct extensive testing using cell and animal models to find out whether it could potentially cause serious harm or toxicity. Additionally, researchers look at what the potential drug does to the body and what the body does to the potential drug, which is referred to as pharmacodynamics and pharmacokinetics, or PK/PD. Preclinical testing also provides more information about the potential drug’s stability, the best way for it to be taken (administration method), and its bioavailability (how much is able to access the circulation and reach the target cells/area).
Once these preclinical tests have been completed, all the results, along with the plans for clinical testing, are compiled into an Investigational New Drug (IND) Application that is submitted to the Food and Drug Administration (FDA). The FDA reviews the IND and then decides whether the drug is safe enough to be given to humans.
Clinical Trials
After an IND has been approved, clinical trials can begin. Clinical trials help researchers figure out the best dose of the potential new therapy, identify any side effects, and determine whether the treatment can benefit people living with ALS.
There are several phases of trials that build on one another:
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Phase 1 – These trials are often testing potential new treatments for the first time in humans. Because of that, the drug is only given to a small group, often 20 or fewer people, who are usually healthy volunteers. The participants are closely monitored for any adverse reactions or side effects. If any appear that are considered too dangerous, testing is stopped, and the drug will not advance any further.
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Phase 2 – During this phase, researchers are usually trying to determine the best dose, route of administration (by mouth, by injection, etc.), and timing of doses. Information about the drug’s ability to benefit the health or function of people living with ALS may also be gathered; however, more testing with larger groups of people is needed to know for sure. Usually for ALS, less than 100 people are involved in a phase 2 trial.
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Phase 3 – This stage of testing involves enough participants to determine whether a potential new drug is effective as an ALS treatment. Phase 3 trials for ALS usually involve hundreds of participants because symptoms and disease progression can be so different from person to person.
If the clinical trial results support the potential new drug’s safety and efficacy, the pharmaceutical/biotech company then submits a New Drug Application (NDA) or a Biologics License Application (BLA) to the FDA, depending on the type of treatment being developed. These comprehensive applications contain all the data and information gathered during each phase of clinical testing and earlier preclinical research, as well as the proposed labeling and manufacturing plans for the new drug.
FDA Review
A team of experts at the FDA conducts a formal review of the NDA or BLA to determine if the drug should be approved and made available to people living with ALS in the U.S. Most of the time, this review is completed within 10 months, although sometimes the FDA can conduct a faster Priority Review that generally takes about 6 months.
During this review, the FDA is determining whether the drug is both safe and effective based on all the available evidence. For ALS, “effective” could mean slowing the decline of ALSFRS-R scores or increasing survival time. It could also mean reducing levels of a “surrogate marker,” such as neurofilament light chain (NfL), if the drug is following the Accelerated Approval Pathway. The FDA also makes sure the proposed drug label is appropriate and will inspect the facilities where the drug will be manufactured.
Sometimes, the FDA may organize a meeting of one of its Advisory Committees, also called an AdComm, to get independent, expert advice and allow the public to make comments. These Advisory Committees include a patient representative who provides input based on their lived experiences with the disease. At the end of the meeting, committee members vote on whether to recommend the drug for approval based on the reported patient outcomes, potential for side effects, and the drug’s risk–benefit analysis. This vote is non-binding, so the FDA does not have to follow the committee’s recommendation. If the agency does decide to approve the drug, manufacturing, marketing, and distribution can begin.
Real-World Data
Research continues even after a drug is approved by the FDA. For example, the pharmaceutical/biotech company continually monitors the drug’s safety, capturing any unexpected or serious side effects. The company also may gather additional data, both through formal clinical studies and the collection of real-world data, which may reveal therapeutic potential for other diseases or when used in combination with other approved drugs, for example.
Drug development can take at least 10 years and cost between $1–3 billion, on average. To help accelerate this process and ensure access to new treatments, we strategically collaborate with government agencies, other non-profit organizations, pharmaceutical/biotech companies, and academia to rapidly move forward research, patient care, and public policy initiatives. Additionally, roughly two-thirds of our research funding is committed to supporting drug development efforts, from discovery through early-stage clinical trials.
Our Support of ALS Drug Development
We support the preclinical assessment of emerging ALS therapies through our Lawrence and Isabel Barnett Drug Development Program, helping to drive the crucial transition from laboratory research project to industry drug development effort. This stage is often referred to as the “valley of death” since promising biomedical ideas often wither and die due to a lack of funding for this transition.
By supporting projects at this stage, our Barnett Drug Development Program helps fill this funding gap and has contributed to the expansion of companies and therapeutics entering ALS clinical trials. Approximately 60% of projects supported through this program have established partnerships to help advance their research, received larger grants from funders like the National Institutes of Health and the Department of Defense ALS Research Program, and/or attracted commercial support from pharmaceutical/biotech companies or venture capitalists.
We also support phase 1 and 2a clinical trials of new or repurposed approaches for treating ALS through our Hoffman ALS Clinical Trial Awards Program. Results from these studies help “de-risk” the next stage of drug development by attracting the follow-on funding necessary to conduct larger trials.
In addition, we recognize bolstering ALS clinical trial infrastructure is crucial to accelerating the development of new effective treatments. In 2020, we provided foundational funding for the HEALEY ALS Platform Trial, which tests and evaluates multiple investigational treatments simultaneously. We also support the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS), which has more than 20 years of experience developing and conducting multicenter ALS clinical trials. Finally, we launched our Trial Capacity Awards in 2022 to increase access to ALS clinical trials, especially for those in underserved populations, and help improve the efficiency and pace at which these studies are conducted.