BridgeBio's Investigational Gene Therapy For CAH

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

You may have read the news that BridgeBio dosed the first patient in ADventure, the biopharma's Phase 1/2 clinical trial of BBP-631, an investigational adeno-associated virus (AAV) 5 gene therapy for the treatment of classic congenital adrenal hyperplasia (CAH). CAH is one of the most prevalent genetic diseases, with more than 75,000 cases estimated in the United States and European Union. BridgeBio’s investigational gene therapy BBP-631 would be the first therapy for CAH to restore the body’s hormone and steroid balance by enabling people with CAH to make their own cortisol and aldosterone. BridgeBio’s CEO Eric David, M.D., J.D. was one of my guests on Cell & Gene: The Podcast and during the episode, we discussed the company’s Canavan disease and the CAH-301 trial (read on to learn more). Here, Dr. David and I discuss the details of CAH and the highlights of the Phase 1/2 open-label study.

Explain CAH gene therapy in detail.

Congenital adrenal hyperplasia (CAH) comprises a group of life‑threatening, inherited endocrine disorders caused by critical enzyme deficiencies in the adrenal gland. The most common form of CAH, accounting for greater than 95% of cases, is caused by deficiency or absence of the 21‑hydroxylase enzyme (21‑OHD), due to mutations in the CYP21A2 gene. It is screened for at birth in the United States and many other countries.

People affected with CAH cannot produce the hormones cortisol and aldosterone, which are essential for survival (maintaining blood pressure, keeping blood sugar levels from getting too low, and responding to stress). The inability to produce these hormones results in three main challenges: (1) life-threatening adrenal crises; (2) the effects of high levels of androgenic hormones; and (3) the myriad destructive consequences of the current standard of care, lifelong corticosteroids.

Prior to the advent of newborn screening, many babies and children died from CAH because they could not make cortisol and/or aldosterone. Cortisone was discovered in the 1950s as a treatment for CAH and has allowed many affected by CAH to survive. However, even with the improvement in formulations and the development of longer-lasting analogs, people with CAH continue to experience adrenal crises. Parents of younger children worry because their babies and toddlers may not be able to communicate that they are sick and typical infections can trigger life-threatening crises. Parents of teenagers worry that their kids aren’t taking their daily medication or may not take higher doses when needed if they are sick and may succumb to adrenal crises. Even now, there are adults who experience life-threatening adrenal crises. We recently heard from a woman in her 60s who went into an adrenal crisis when she was hospitalized for a planned surgical procedure. A recent review from last year in the New England Journal of Medicine from prominent CAH experts who are investigators in our Phase 1 study noted there continues to be increased mortality in classic CAH.

But people affected with the classic form of CAH also struggle immensely with a second aspect of the disease – when the 21‑OHD isn’t functional, the adrenal gland still tries to make cortisol and aldosterone, but it can’t, and it winds up shuttling the precursors into the production of androgens—hormones associated with masculinization that have testosterone-like effects. This has untoward effects on growth and pubertal development in both boys and girls and continues to have particularly morbid effects in women, impacting fertility and causing hirsutism and other masculinizing effects. Men may also develop fertility problems, stemming from testicular masses that, although benign, can compress the testes and impact proper spermatogenesis.

Finally, there’s the CAH treatment itself: steroids. The current standard of care does two things: it provides critical life-sustaining hormone replacement, and it reduces the level of androgenic, testosterone-like hormones. The issue is that chronic steroid treatment, in particular at higher doses, carries with it significant side effects and morbidity. Chronic treatment leads to several effects including cardiovascular disease, metabolic disease, obesity, osteoporosis, diabetes, and weight gain. Doctors who treat CAH need to thread that needle – give enough medication to prevent adrenal crises and high androgens, but not so much that there’s a risk for side effects from the regimen.

Bottom line: The standard of care for CAH  has not changed significantly in over 70 years and patients across all age groups suffer from significant morbidity and from five-fold higher mortality than their age-matched controls. An ideal treatment that could help address this severe unmet need would be one that restores the body’s hormone and steroid balance by enabling people with CAH to make their own cortisol and aldosterone.

Explain the highlights of the Phase 1/2 open-label study.

Our clinical trial (CAH-301) in adults with classic CAH is built upon the substantial data we’ve accumulated preclinically and is focused on characterizing the unique potential of this approach to restore endogenous cortisol production in people living with CAH.

To date, our preclinical studies have shown that our investigational drug resolves key aspects of the phenotype of the CAH mouse model, such as weight gain and hormone levels.  What’s also incredibly encouraging is that our studies in non-human primates have shown that our investigational drug gets into the adrenal gland after IV administration and that the functional human 21-OH protein from our gene therapy is made in the adrenal gland of these primates in quantities that we believe could allow patients with classic CAH to produce enough cortisol and aldosterone to move them to the “non-classic CAH” phenotype, which is largely asymptomatic and generally does not require daily cortisol and aldosterone therapy.

The CAH-301 trial involves testing several different doses of our gene therapy delivered as a one-time, single IV infusion in adults with classic CAH. These doses were chosen for two reasons: (1) even the lowest dose is predicted to have a significant beneficial impact on hormonal physiology based on preclinical data; (2) the highest doses are within the safety range covered within all of our preclinical studies.

Broadly, the study design includes looking at a handful of participants over three dose ranges, with enrollment being sequential both within and between dose cohorts as is usual for a first-in-human gene therapy trial. The participants will be followed in the initial 301 study for one year, and then followed for an additional four years in a long-term follow-up study.  Again, long-term follow-up is the standard in gene therapy studies where a therapy is designed to maintain its effect over time.

Finally, at BridgeBio, we are committed to patient-focused drug development. This has led to a couple of specific and even unique aspects of our program. Many sponsors use high-dose glucocorticoid steroids to prevent commonly observed immune reactions after AAV dosing.  However, because of the sensitivity of people living with CAH to high-dose steroids, we are employing a steroid-free immunosuppressive regimen. In addition, we also learned from our discussions with the patient community that travel to clinical sites could be a burden; therefore, we’ve reduced the number of in-person visits to the trial sites and increased the ability to conduct remote visits.

What has been the response so far?

We have had wonderful engagement with the CAH community and their patient advocates from the time we started this program. They have helped guide us to what the unmet need truly is and what matters most to people living with CAH. Even in our first conversations with patients at a CARES Foundation meeting in 2018, patients and parents described the ability for the body to make and regulate its own cortisol and aldosterone, if achieved, as the “holy grail” of CAH gene therapy. We continue to engage with the patient community and open more treatment sites and continue to see strong interest from the patient community.

BridgeBio has 14 programs in the clinic or commercial setting. We discussed CAH-301 during an episode of Cell & Gene: The Podcast. Explain Canavan disease and the CAH-301 trial.

In addition to the CAH-301 trial in CAH, BridgeBio has also entered the clinic in another rare disease called Canavan disease, with the first patient dosed in our gene therapy trial last fall. Canavan disease is a devastating neurodegenerative disease affecting the myelin in the white matter of the brains of babies and toddlers. The inability to properly myelinate results in the inability to gain, or sometimes retain, core neurodevelopmental milestones. This includes such basic functions as sitting without support, speaking, and tracking with their eyes.

We have been incredibly fortunate to partner on this program with Dr. Guangping Gao at UMass Medical School in bringing a potential gene therapy treatment approach to Canavan disease into the clinic. Dr. Gao is a renowned gene therapy expert and was involved in the initial isolation and characterization of AAV9, which seems to have the unique ability to cross the blood brain barrier into the central nervous system (CNS). Since that time, Dr. Gao has maintained a strong interest in Canavan disease and has a close relationship with the Canavan patient community. He and his lab partners have shown the potential effects of AAV9 gene therapy, including BBP-812, in preclinical data for Canavan disease.  Preclinical proof-of-concept data have shown that the approach could restore survival and normal motor function.

In gene therapy, BridgeBio also has preclinical programs in classic galactosemia TMC1 hearing loss, tuberous sclerosis, cystinuria, and a genetic dilated cardiomyopathy.