Targeting Congenital Adrenal Hyperplasia at its source.
Adrenas Therapeutics is developing an investigational gene therapy designed to treat patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
WHAT IS CONGENITAL ADRENAL HYPERPLASIA?
Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affect the adrenal glands, which sit above each kidney and produce many of the body’s crucial hormones. The most common cause of CAH is a mutation in the gene encoding for 21-hydroxylase, an enzyme essential for making the hormones cortisol and aldosterone which are critical for various physiologic functions. Cortisol is necessary for the body to respond to injury, stress or illness, and aldosterone is required to maintain proper blood pressure and sodium levels.
CAH has a severe form known as classic CAH and a milder form known as non-classic CAH. A test for this inherited condition is included on every state’s newborn screening panel. Most individuals with classic CAH cannot produce cortisol, which can lead to an acute, life-threatening condition called adrenal crisis. Patients with salt-wasting CAH (75% of classic CAH) cannot produce sufficient aldosterone, which is important for sodium retention.
Unable to produce cortisol and aldosterone, people with CAH cannot mount the healthy physiological response to stressors, such as illnesses, that allows their heart, lungs, kidneys and other organs to compensate for the stress, which can be life-threatening. These adrenal crises can be particularly dangerous for young children.
Moreover, deficiency of 21-hydroxylase results in an excess of hormones like testosterone and progesterone, also known as androgens. These excess androgens affect many aspects of growth and sexual development in both males and females throughout puberty. Continued dysregulation of androgens often leads to infertility in men and women and a variety of other issues.
Patients with CAH Face a Great Deal of Unmet Need
Treatment of symptoms and risks of CAH are different in children versus in adults, and the main tool currently available for CAH management is the replacement of cortisol produced from synthetic sources.
Lifelong steroid treatment can have significant side effects, including metabolic and bone disease, obesity, psychiatric effects, and effects on the cardiovascular and immune systems. Additionally, these treatments often fail to control excess androgen levels, leaving many symptoms of the disease un-managed. Lastly, steroid supplementation does not recreate the normal daily rhythm of hormone production, which can lead to fatigue and sleep irregularities.
To learn more about CAH, please visit our partners at CARES and AI United.
Normal Hypothalamic Pituitary Adrenal Axis
HPA Axis in CAH Due to 21-Hydroxylase Deficiency
ABOUT GENE THERAPY
Gene therapy is a potential method for the treatment of genetic diseases. Gene therapies are designed to allow physicians to insert a healthy gene to take the place of a non- or poorly-functioning mutated gene in the body. If the healthy gene successfully replaces the mutated gene in the appropriate tissue and begins to function, the signs and symptoms of the disease may improve. In CAH patients, a durable gene therapy could reduce the need for other forms of treatment. For any investigational gene therapy for CAH to be approved by the U.S. Food and Drug Administration (FDA) or any applicable foreign regulatory authority, it must be shown in preclinical studies and clinical trials to be safe and effective.
The specific adeno-associated virus (AAV) that Adrenas intends to use to deliver the healthy 21-OH gene to the adrenal gland has been studied in a number of animal models, including mice and primates, and in human clinical trials. Currently there are several active clinical trials for gene therapies using this specific AAV. Gene therapies using similar AAVs, such as AAV9, have been approved recently by the FDA. One known as Zolgensma uses AAV9 and has recently been FDA-approved for the treatment spinal muscular atrophy. It is important to note, however, that similarity in the AAV vector is only one factor among many that can impact the safety and effectiveness of a gene therapy. Earlier success in other diseases does not mean that an investigational gene therapy for CAH will be safe or effective. The clinical significance of utilizing the AAV vector in our investigational gene therapy development remains unknown. The American Society of Gene and Cell Therapy has more information about gene therapy.
How AAV Gene Therapy Works
DNA
(GENE)
GENE ENCAPSULATED IN AAV
GENE THERAPY
AAV RELEASES GENE INTO CELL
TARGET CELL
GENE EXPRESSES PROTEINS
PROTEIN
OUR APPROACH
The treatment of classic CAH has not changed significantly since the first approval of steroid drugs in the early 1950s. While there has been some incremental innovation such as longer acting steroid drugs, no currently available therapies enable CAH patients to make their own cortisol and aldosterone—the right amount at the right time, in sync with the body’s diurnal rhythms and in response to the body’s changing demands.
Adrenas Therapeutics is developing BBP-631, an investigational AAV gene therapy, to treat the CAH due to 21-hydroxylase deficiency at its source. BBP-631 is designed to deliver a functional copy of the 21-hydroxylase gene to the adrenal gland.
Furthermore, if we are successful in expressing the 21-hydroxylase enzyme in the adrenal gland where hormones are naturally made, we hope to restore the body’s ability to self-regulate hormone production, which is not possible with current treatment options. In sum, we believe a gene therapy has the potential to restore the delicate balance of hormone production that is dysregulated in this disease.
HPA Axis in CAH Due to 21OHD
BBP-631 is designed to restore 21-hydroxylase
We have tested our CAH gene therapy in a mouse model with a mutation in the 21 hydroxylase gene. When untreated, the affected mice have poor weight gain and have severely elevated progesterone levels. Mice treated with gene therapy showed increased body weight and reduced progesterone levels, similar to normal mice.
Furthermore, we have performed testing in additional animal models, such as non-human primates, and have observed no significant safety findings in over 20 treated animals. Importantly, these animals show stable gene expression at least six months after treatment, indicating the potential for a durable treatment effect. We have recently presented the data from this experiment at the 2019 European Society of Gene and Cell Therapy conference. Poster available for more information.
Our investigational gene therapy for CAH has been shown to improve weight gain and reduce disease biomarkers in a CAH disease mouse model
Our investigational gene therapy for CAH has been observed to persist in non-human primate adrenal glands, up to at least 24 weeks
We are preparing the data necessary to submit to FDA an investigational new drug application (IND), which if FDA does not object, would allow us to begin a clinical trial. We hope to submit this IND to the FDA sometime in 2020. If the FDA allows us to start a clinical trial after evaluating the IND, we intend to deliver the CAH gene therapy by an IV injection.
ABOUT US
Adrenas Therapeutics, a subsidiary of BridgeBio Pharma, is a biotechnology company focused on developing a treatment for congenital adrenal hyperplasia (CAH) caused by a mutation in 21-hydroxylase. Adrenas is led by a team of veteran biotechnology executives. Together with patients and physicians, the company aims to bring a safe and effective treatment for CAH to patients as quickly and safely as possible.
LEADERSHIP
CLINICAL ADVISORY BOARD
RA
Richard Auchus, MD, PhD
The James A. Shayman and Andrea S. Kevrick Professor of Translational Medicine, Professor of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology & Diabetes (MEND) at the University of Michigan
ES
Ellen Seely, MD
Professor, Harvard Medical School and Director Clinical Research, Endocrinology, Diabetes and Hypertension Division at the Brigham and Women’s Hospital
PARENT COMPANY
Adrenas Therapeutics is a member of the BridgeBio family.
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development.
CONTACT
1001 William Moore Drive, Suite 100
Raleigh, NC 27607
For any patient-related inquiries, please email PatientAdvocacy@AdrenasTx.com.
