For the first time ever, the FDA has approved a treatment specifically for people with classic congenital adrenal hyperplasia (CAH), a genetic condition that affects the adrenal glands.
Crenessity, a twice-daily pill or liquid, is now available for ages 4 and up. It offers an innovative way to lower androgens and potentially reduce daily steroid doses. That’s big news for people with CAH, who haven’t had a new option in 70 years.
Doctors have long relied on high-dose glucocorticoids to manage CAH. These cortisol-like medications work, but long-term, high-dose use can lead to other health problems. In response, scientists have spent years searching for a safer alternative.
That’s where crinecerfont, the active ingredient in Crenessity, comes in.
Before the first prescription could be filled, crinecerfont had to clear multiple stages of research, lab testing, and clinical trials. This process ensures new treatments are safe and effective.
What makes this drug a breakthrough? And how did it move from the lab to the market? Let’s take a look.
Step 1: Understanding the Disease
Before creating a new drug, scientists need to crack the code of the disease they’re trying to treat. For crinecerfont and CAH, that meant figuring out why hormones become unbalanced in the first place.
CAH happens when the adrenal glands lack a key enzyme to make cortisol, a hormone that helps the body handle stress, illness, and injury.
Normally, when cortisol levels drop too low, the brain sends a signal to top off the tank. The body releases ACTH, a hormone that triggers the adrenal glands to make the right amount of cortisol based on your body’s needs. This happens like clockwork for most people.
But in CAH, the adrenal glands can’t produce enough cortisol, no matter how hard the brain pushes. This causes ACTH to build up and overflow. This constant signaling leads to an overproduction of androgens, another hormone produced in the adrenal glands. Both males and females need these testosterone-like hormones, but too much can trigger early puberty, infertility, or other growth and development issues.
The usual fix? Glucocorticoids to replace missing cortisol and keep androgens in check. But people with CAH need higher-than-normal doses to do both. Excess steroids can save your life but can also lead to weight gain, bone loss, sleep problems, and other side effects.
To break this cycle, scientists searched for a way to lower ACTH levels directly.
Step 2: Finding a Target
Researchers zeroed in on corticotropin-releasing factor type 1 (CRF1), a receptor in the brain that triggers the release of ACTH when cortisol levels drop. In CAH, this feedback loop goes awry.
Scientists had a thought: Block CRF1 to turn down ACTH levels and restore balance. And if that worked, maybe it could lessen the need for high-dose steroids.
Once they pinpointed CRF1 as a target, the next step was to develop a drug that could do just that. Enter crinecerfont.
Step 3: Testing in the Lab and in Animals
Crinecerfont is a CRF1 antagonist, meaning it’s designed to block CRF1. It’s the first drug of its kind used to treat CAH. But before researchers could test it in humans, it had to go through a series of lab and animal studies.
Although detailed results on crinecerfont’s early testing are limited, this stage is critical. Out of every 5,000 to 10,000 potential new drugs, only one or so make it through the approval process. Most don’t make it past preclinical testing because they’re too toxic or don’t work.
To weed out failures early, scientists start by testing promising drugs on cells in a dish. Or they give it to animals at “super doses” – sometimes 200 to 500 times the expected dose. This helps reveal risks, such as organ damage or fertility issues.
Crinecerfont had to clear these hurdles before moving on to human trials.
Step 4: Testing Crinecerfont in People
The FDA requires every new drug to go through multiple phases of clinical trials to assess safety, effectiveness, and how it compares to existing treatments. Each stage answers different scientific questions:
Phase I: Is it safe?
During this phase, researchers typically give a drug to a small group (20-80 people) to study how the body processes it and identify side effects. This stage is important for finding safety concerns. (Specific data from crincerfont’s early trials haven’t been widely published.)
Phase II: Is it safe, and does it work?
In phase II trials, researchers tested crinecerfont on a small group of teens and adults with classic CAH due to 21-hydroxylase deficiency (the most common form). The goal was to see if the drug could lower androgen levels.
Over 14 days, a group of eight teens (ages 14-17) saw meaningful drops in key hormone markers:
- 57% lower ACTH (the hormone that signals the adrenal glands to make androgens)
- 69% lower 17-hydroxyprogesterone (17-OHP)
- 58% lower androstenedione (a type of androgen)
- 50% drop in testosterone levels in more than half of female teenagers
A trial in 18 adults found similar results.
Phase III:Is it safe, and does it work in a larger group?
Encouraged by phase II results, scientists launched two large phase III studies – one in adults and one in children. Some of them received crinecerfont, while others received a different treatment (a placebo, or dummy medicine that has no effect) to compare results.
What happened in adults?
The adult trial included 182 people and found that crinecerfont helped reduce their steroid doses while keeping their hormones balanced.
Key details from the study:
- The crinecerfont group lowered their glucocorticoid dose by 27%, compared to 10% in the placebo group.
- Androgen levels remained stable, even with lower steroid doses.
What about kids?
The CAHtalyst Pediatric Phase III trial included 103 people (average age of 12). It aimed to answer two key questions:
- Could crinecerfont lower androgens in four weeks?
- Could children reduce their steroids over 20 weeks while keeping their hormones stable?
Researchers found:
- By week four, kids on crinecerfont had lower androgen levels, while kids in the placebo group had higher levels.
- By the end of the study, kids on crinecerfont took 18% less steroid medication, while kids in the placebo group had to increase their dose by around 6%.
How Safe Was Crinecerfont in Clinical Trials?
The data showed no major safety concerns. Side effects were mostly mild and temporary, with the most common being:
- Fatigue
- Headache
- Colds or a stuffy nose
- Muscle or belly pain
- Joint pain
Very few people dropped out of the studies, showing that crinecerfont was well-tolerated.
Crenessity does come with a warning: If you don’t take enough glucocorticoids, it could cause adrenal insufficiency, a dangerous and potentially life-threatening condition where the body doesn’t have enough cortisol. But this wasn’t seen in the trials when people took the drug as directed.
How Drugs Get the Green Light: The FDA Approval Process
After successful clinical trials, Neurocrine Biosciences (the company that makes Crenessity) submitted all their research for approval. Since treatment options for CAH are limited, the FDA granted the drug priority review, allowing regulators to evaluate it faster than usual.
Crenessity also got fast track, breakthrough therapy, and orphan drug designations – special statuses designed to speed up development for helpful drugs that address serious or rare conditions.
The FDA ultimately gave Crenessity the thumbs-up for several reasons:
- There was strong proof it helps lower excess androgens.
- It’s likely safer than long-term, high-dose steroids.
- It could make life better for kids and adults with CAH.
But approval isn’t the finish line. The FDA keeps an eye on all new drugs to make sure they stay safe.
Neurocrine Biosciences will also track how Crenessity works in the real world and watch for new concerns or side effects as more people start using it. This ongoing oversight is called post-market surveillance and is sometimes referred to as phase IV trials.
New Hope for CAH Treatment
Crinecerfont isn’t a cure, but it’s a big step forward in CAH care. Doctors can now prescribe it as an add-on therapy to support glucocorticoid treatment. It may help lower your steroid dose. This might mean fewer side effects, better hormone control, and a higher quality of life.
Researchers will keep studying crinecerfont. If you or a loved one has CAH, talk to an endocrinologist to see if it might be a good option for you.