Albireo And Odevixibat In Orphan Pediatric Cholestatic Liver Diseases: Making Magnificent Progress

Jun. 19, 2019 3:14 PM ETAlbireo Pharma, Inc. (ALBO)CBAY, ICPT2 Comments2 Likes


  • Albireo differentiates from adult cholestatic liver diseases by clinically focusing on the pediatric patient population, orphan diseases, and limiting enterohepatic recirculation.
  • Odevixibat, an ileal bile acid transporter inhibitor, is a Phase 3 investigative drug candidate in clinical trials for Progressive Familial Intrahepatic Cholestasis, Alagille syndrome, and Biliary Atresia.
  • IBAT positively regulate the enterohepatic recirculation by mediating the reabsorption of the bile acids from the small intestine for recirculation back to the liver.
  • Odevixibat, an IBAT inhibitor, limits/inhibits IBAT function by promoting increased colonic excretion of bile acids to reduce circulatory bile acids and prevent de novo bile acids synthesis.
  • The preliminary data in the pediatric cholestasis clinical program that demonstrates odevixibat providing symptomatic pruritus relief is a very important finding. I elaborate in text.
  • This idea was discussed in more depth with members of my private investing community, Liver Therapy Forum (LTF). Get started today »


Albireo (NASDAQ:ALBO) is one or the only publicly-listed biopharma that has an orphan pediatric cholestatic liver diseases clinical program. Albireo through its unique drug pipeline employs a distinct mechanistic approach to dealing with the distressing adverse event of pruritus (i.e. intense itching) associated with rare pediatric cholestatic liver diseases. The lead investigative drug candidate, Odevixibat (formerly A4250), is in mid-late phase clinical trials for orphan pediatric cholestatic liver diseases, Progressive Familial Intrahepatic Cholestasis (PFIC), Alagille syndrome, and Biliary Atresia.

Albireo is a small market cap ($389M) commercial-stage biopharma that is still under the radar. The focus on pediatric rare cholestatic liver diseases and the clinical development of therapeutic inhibitors for ileal bile acid transporter (IBAT) offers significant clinical differentiation from biopharmas for adult cholestatic liver diseases. Mechanistically, Odevixibat pharmacologically targets IBAT function to restore normal bile acid levels that should improve these diseases. I will first outline the distinct pathophysiology for each of the aforementioned cholestatic liver diseases.

Orphan/Rare Pediatric Cholestatic Liver Diseases

Cholestasis is initiated by a reduction or stoppage of bile flow due to obstruction in the biliary tract that leads to bile acids accumulation and ensuing liver toxicity. Disorders of the liver, bile duct, or pancreas can cause cholestasis. Common symptoms include yellowing skin and eye whites and pruritus (intense skin itch).

Bile is a dark green to yellowish brown fluid, produced by the liver, the body's second largest organ. An estimated 400-800 ml of bile is produced daily in a healthy adult, then stored and concentrated in the gallbladder. The liver is responsible for processing what we ingest and removing toxins from the blood. As the epicenter of metabolic homeostasis, the liver performs many functions, including hormone biosynthesis, protein and bile synthesis, drug metabolism, gluconeogenesis, and lipid metabolism.

Bile acids, the major constituent (~80%) of bile with small amounts of phospholipids and cholesterol, are produced in the liver from cholesterol. Bile is released into the small intestine in response to food ingestion to aid the digestion and absorption of dietary fats. Following digestion, bile acids bind to IBAT also known as the apical sodium bile acid transporter, (ASBT), located at the terminal ileum (i.e. end of the small intestine), for transport back to the liver via a portal vein in a process known as enterohepatic recirculation (Fig. 1).

In a healthy individual, increased production of bile acids produces an increase in bile flow. Bile acids also exert hormonal actions throughout the body, via the farnesoid X receptor (FXR). Notably, ocaliva by Intercept (ICPT), the breakthrough therapy for PBC is an FXR agonist.

PFIC: Is a progressive chronic genetic cholestatic liver disease linked to mutation in the IBAT gene that leads to a defect in IBAT function. PFIC is characterized by severe pruritus (intense itching), persistent cholestasis and subsequent liver failure. PFIC encompasses a group of autosomal recessive rare genetic disorders involving the liver-biliary tract transporters which are caused by a defect in bile secretion from hepatocyte to canaliculi that clinically manifest as cholestasis in infancy or early childhood, affecting 1 per 50,000-100,000 children born globally. The 3 classes of PFIC are presented in Table 1.

Biliary Atresia: Biliary atresia is a rare disease of the bile ducts that affects only infants, becoming symptomatic 2-8 weeks after birth. In biliary atresia, the bile ducts become inflamed and blocked soon after birth. Consequently, bile accumulation in the liver destroys liver cells by causing scarring (i.e. cirrhosis).

The cause of biliary atresia could be idiopathic during pregnancy or by viral infection acquired after birth. Biliary atresia can only be treated by surgical intervention called hepatoportoenterostomy or Kasai procedure that re-establishes bile flow from the liver into the intestine. Biliary atresia affects about 1:12,000 infants in the United States.

Alagille syndrome: It was first described in France in 1975 by a pediatric hepatologist. The gene that caused Alagille syndrome was identified in 1997. In contrast to PFIC and biliary atresia, Alagille syndrome affects multi-organ systems including liver, eyes, heart, skeletal abnormalities, and characteristic facial features.

Patients with this genetic disorder have fewer number of small bile ducts inside the liver compared to a healthy individual. This leads to bile builds up in the liver causing liver damage. Symptoms and complications of Alagille syndrome are treated with medicines and in some cases surgery based on the specific symptoms that are apparent in each individual. It affects between 1 per 30,000 -45,000 individuals.

Mechanism of Action: Odevixibat

As you can see from the description above, these rare pediatric cholestatic liver diseases are different but have a unifying goal of inducing obstruction in bile flow that triggers cholestasis and associated pruritus.

In a healthy individual, enterohepatic circulation mediates ~95% of bile acids re-circulation back to the liver, with the remaining 5% secreted into the colon for excretion. An IBAT promotes enterohepatic recirculation by mediating the reabsorption of the bile acids for recirculation back to the liver from the small intestine.

Odevixibat is an IBAT inhibitor that limits/inhibits IBAT function. As depicted in Fig. 1, in the presence of an IBAT inhibitor, Odevixibat, IBAT reuptake of bile acids from small intestine for recirculation back to the liver is blocked. Therefore, Odevixibat negatively regulates enterohepatic recirculation to: (i) promote increased colonic excretion of faecal bile acids that leads to a reduction in circulatory bile acids and (ii) prevent de novo (NEW) bile acids synthesis.

De novo bile acids synthesis is achieved by Odevixibat inhibiting functional activation of the bile acid receptor, FXR that subsequently leads to reduced formation of fibroblast growth factor (FGF19) and its interaction with cognate receptor, hepatocyte FGF receptor 4 (FGFR4). These effects negatively impact CYP7A1 expression, the rate-limiting enzyme, CYP7A1 in bile acid synthesis resulting in decreased de novo bile acid synthesis in the liver (Fig. 1 right).

In summary, Odevixibat therapeutically prevents further accumulation of bile acids that induce toxicity, by increasing its colonic excretion while suppressing de novo bile acids synthesis. Albireo's mechanistic approach of blocking the bile acid transporter is very unique because it is like extinguishing the source of fire to dampen its effects.

Clinical Trials And Data

PFIC: A Phase 2 study in pediatric cholestasis-mediated liver toxicity and pruritus, determined changes in serum bile acid levels (primary efficacy endpoint), pruritus and sleep disturbance. Substantial reductions in bile acids levels from 43% to 98% were observed in PFIC patients after odevixibat treatment.

The authors (Sturm et. al. AASLD abstract, 2017) also found that odevixibat therapy improved pruritus as reflected by the visual analog scale (VAS-Itch; 0-10) with absolute mean (±SEM) decreases of 2.9±1.1 points for pruritus (VAS-itch) from baseline and 3.0±0.9 points for sleep disturbance (patient-oriented score of atopic dermatitis-sleep; 0-10). The authors also noted that a significant (P≤0.008) correlation between reduction in serum bile acid levels and improvements in pruritus scores and sleep disturbance.

Albireo on Phase 3 trial:

The Phase 3 program studying odevixibat in PFIC, the PEDFIC program consist of PEDFIC 1, a single randomized double blind placebo controlled multi-center clinical trial designed to enroll approximately 60 patients with PFIC Type 1 or Type 2 (see Table 1).

The topline results are expected by late Q4/2019 or early Q1/2020 with the potential approval and launch in H1/2021.

On PEDFIC 2, the long-term open-label extension study, Albireo notes:

we submitted a protocol amendment for an additional cohort that would include PFIC patients who have elevated serum bile acids and pruritus that aren't eligible for PEDFIC 1. That includes people with all types of PFIC along with patients over the age of 18, and younger than six months. We anticipate initiation of this additional cohort in H2/2019.

Biliary Atresia & Alagille syndrome: An open-label, multicenter, dose-finding Phase 2 clinical trial that assessed the safety and tolerability of odevixibat in Alagille syndrome and biliary atresia with efficacy endpoints of change in serum bile acid levels and pruritus.

Odevixibat demonstrated marked reductions of up to 92% in serum bile acids levels in the majority of Alagille patients, that also showed improvement in pruritus as measured by three different scales.

On biliary atresia, Albireo highlights that:

It is the only company to generate positive data suggesting an effect on bile acids and pruritus in biliary atresia patients using a pharmacologic approach (such as odevixibat). Odevixibat demonstrated significant serum bile acid reductions of 57.6% and 50.8% in two patients with high baseline bile acids (> 130 μmol/L) and showed improvement in pruritus across two different pruritus scales.

No effect was observed in a third patient with a low baseline sBA. These data, combined with the total dataset of n =24, form the basis for a pivotal development program in a second indication, biliary atresia.

The pivotal Phase 3 trial for odevixibat in biliary atresia will be initiated in H2/2019. Worth pointing out that at present, surgical intervention remains the only therapeutic option for these patients.


Anyone who has followed my previous articles on cholestatic liver diseases may be familiar with my working hypothesis on pruritus that-

My working hypothesis has been that any anti-cholestatic drug candidate that effectively decreases serum bile acid levels should induce anti-pruritogenic relief. Conversely, those drug candidates that do not suppress serum bile acid levels will not suppress pruritus.

The basis for this thesis was the clinical finding from Albireo on odevixibat in the Phase 2 study in PFIC patients. A recent pilot study in a small number of adult PBC patients provided preliminary evidence consistent with odevixibat improving pruritus. Furthermore, published reports that pruritus is initiated by retention of bile salts deposited in the skin.

Notably, cholestyramine is a bile salt binding agent used therapeutically to lower serum bile salt levels to effectively relieve pruritus in patients with cholestatic liver disease. In agreement, adult PBC patients treated with oral IBAT inhibitor, GSK2330672 by GlaxoSmithKline (GSK) documented significantly reduced circulatory bile acids levels that improved pruritus.

To the best of my knowledge, there is/are no evidence that Ocaliva by ICPT suppresses circulatory bile acids which may somewhat explain its lack of effect on improving pruritogenic responses. On the other hand, seladelpar, a selective PPAR-δ agonist in development by CymaBay (CBAY) has been associated with some improvement (to be confirmed in Phase 3 study) in pruritogenic responses, but its effect on serum bile acids levels are currently unknown. GS-9674 is an FXR agonist in development by Gilead and it suppressed serum bile acids levels to improve pruritus in the cholestatic liver disease, primary sclerosing cholangitis.

I surmise that effective anti-pruritogenic drug candidates may have a "flushing cleanse effect" on bile acids deposited in the skin due to their effectiveness at suppressing systemic serum bile acids. I reiterate that the skin is the largest body organ, and a minuscle flush of 10% of bile acids from skin is bound to definitely provide some noticeable anti-pruritogenic relief.

Actionable Event, Financials, and Risks

Odevixibat has orphan designations in both the U.S. and the EU for biliary atresia and PFIC. I invested in Albireo last year mainly due to the pediatric liver therapeutics clinical program. Pruritus remains the most distressing adverse event associated with cholestatic liver disease in pediatric and adult population. The focus on orphan diseases, pediatric and IBAT function are distinct clinical qualities from adult patients focused biopharmas.

Albireo recently initiated a NASH program on elobixibat, an IBAT inhibitor. I recently reviewed the NASH program and not as enthused on that as I am on the rare diseases program. Elobixibat is licensed exclusively to EA Pharma for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (excluding China). Albireo retains commercial rights to elobixibat in the United States, Europe, China. In Q2/2018, Albireo was granted a patent for using elobixibat to treat NASH in both the U.S. and Europe.

At the end of Q1/2019, Albireo had $150.3M in cash and cash equivalents. Cash burn in Q1/2019 versus Q4/2018 was $13.6M. Based on the cash burn, I believe the funding is sufficient until major catalytic event of Phase 3 PFIC top-line data readout.

The last word from CEO Ron Cooper on biliary atresia:

The unmet need in biliary atresia is significant, data suggest is for number one cause of the transplants in the pediatric population. 80% of those patients require a liver transplant within their first couple of decades of life. So we hope to be able to make a difference with these patients.

I think we're going to be excited to provide some initial data in PFIC and then additional data and other indications to build a very strong brand and a strong pediatric liver franchise with odevixibat.


Presently, the two clinic drugs, ursodeoxycholic acid (UDCA) and ocaliva approved by FDA are used for the adult patients with cholestasis. Making the pediatric patients with orphan and non-orphan cholestatic liver diseases an underserved patient population.

Abireo's forte on therapeutics for pediatric orphan liver diseases should capture a sizeable share of the addressable market due to clinical efficacy and exclusivity. Drugs for orphan diseases are highly priced especially if they are the only effective therapeutic option apart from surgical intervention.

The full-length article was discussed in more depth with members of my private investing community, Liver Therapy Forum

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