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On 21th September, 2017,  FDA  published a Safety alert on OCALIVA 

"[09-21-2017] The Food and Drug Administration (FDA) is warning that the liver disease medicine Ocaliva (obeticholic acid) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death. These patients are receiving excessive dosing, particularly a higher frequency of dosing than is recommended in the drug label for them. Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on Ocaliva are described in the current drug label. We are working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.

Ocaliva is used to treat a rare, chronic liver disease known as primary biliary cholangitis (PBC). PBC causes the bile ducts in the liver to become inflamed, damaged and destroyed. This causes bile, a fluid that helps in digestion, to build up in the liver. This build-up damages the liver over time, eventually causing it to lose its ability to function. Ocaliva has been shown to improve a certain blood test that measures liver problems.

Health care professionals should determine the patient’s baseline liver function prior to starting Ocaliva. Patients with moderate to severe liver impairment (Child-Pugh B and C) should be started on the approved dosing schedule of 5 mg once weekly, rather than the 5 mg daily dosing used for other PBC patients, and if needed, can be increased up to a maximum approved dose of 10 mg twice weekly. Health care professionals should monitor patients frequently for disease progression, and reduce the dosing frequency to once- or twice-weekly for patients who progress to moderate or severe liver impairment. In all patients treated with Ocaliva, monitor frequently for liver injury (e.g., worsened liver blood tests and adverse liver-related reactions that may be inconsistent with the patient’s extent of disease). If liver injury is suspected, discontinue Ocaliva. After the patient has stabilized, weigh the benefits against the risks when deciding whether to re-initiate treatment. Educate patients on the symptoms of potential liver injury.

Patients should contact your health care professional if you have questions or concerns about taking Ocaliva. Report new or worsening severe skin itching to your health care professional. Also contact them immediately if you develop any of the following symptoms that may be signs of liver injury:

  • New or worsening fatigue
  • Diarrhea
  • Weight loss
  • Abdominal pain
  • Decreased appetite
  • Nausea and vomiting
  • Change in behavior or confusion
  • Vague symptoms such as anxiety or unease
  • Abdominal swelling
  • Yellow eyes or skin
  • Bloody stools

In the 13 months after Ocaliva was approved in May 2016, FDA received reports of serious liver injury or death associated with Ocaliva.* The FDA's Adverse Event Reporting System (FAERS) includes only reports submitted to FDA, so there may be additional cases about which we are unaware.

Nineteen cases of death were identified, of which eight provided information about the patient’s cause of death. The cause of death was reported to be worsening of PBC disease in seven cases, with cardiovascular disease cited in the other case. Seven of these eight cases described patients with moderate to severe decreased liver function who received Ocaliva 5 mg daily, instead of a dose no greater than 10 mg twice weekly as recommended in the label prescribing information for patients with this extent of decreased liver function.

FDA also identified 11 cases of serious liver injury with Ocaliva use. Six of the patients who had moderate or severe decreases in liver function at baseline and developed serious liver injury were receiving Ocaliva 5 mg daily, instead of a dose no greater than 10 mg twice weekly as recommended by FDA in the drug label. Three of these six patients died, which were included in the 19 death cases mentioned previously. Ocaliva was discontinued in four of six cases, which resulted in one patient experiencing symptom resolution and an improvement in a liver blood test. The remaining three cases did not report the response after discontinuation. The other five cases of serious liver injury were reported in patients with no or mild decreases in liver function prior to initiating Ocaliva. Four of these five patients received Ocaliva 5 mg daily, and one did not report the dose. Ocaliva was discontinued in all five cases, which resulted in one patient experiencing symptom resolution and one patient experiencing improved liver blood tests and symptom resolution. The remaining three cases did not report the response after discontinuation.

We urge health care professionals and patients to report side effects involving Ocaliva and other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page."

This is a copy of the FDA warning  published here

The 19 deaths quoted were a report at the beginning of July 2017, 7 more patients were reported to have died between the beginning of July and the 20 of September bringing the number of deaths counted to 26 in 15 months of prescription.

The number of patients who have died must be put into perspective because PBC is a serious disease in which the most affected patients have a short life expectancy.

For example, cirrhotic patients with Child Pugh B or C scores have very short life expectancies.

for Child Pugh B score

81% survival at 1 year and 57% at 2 years.

for Child Pugh C score

45% survival at 1 year and 35% at 2 years.

No wonder that deaths are noticed.

However the FDA alert brings forward several disturbing factors.

1- Many patients would be overdosed and this would have led to the death of 7 of them.

On this point it is worth recalling that the FDA while giving marketing authorization for OCALIVA with the indication of PBC drew attention to the need to dose the Child-Pugh B score and C only 5 mg / week at the start of treatment and not at 5 mg / day as requested initially by Intercept. It appears that some practitioners have ignored this FDA recommendation.

2- Patients with no cirrhosis or cirrhosis with a Child-Pugh score A and who were dosed as prescribed in the dosage (no overdose) had very severe liver function disorders (5 cases are cited ).

3- The cessation of treatment in one of the affected patients allowed him to recover his liver functions which is a fairly obvious proof of the link between treatment and liver dysfunction.

4- The FDA requires practitioners to evaluate the liver function of their patients prior to any treatment, to closely monitor any signs of hepatic dysfunction during treatment and to discontinue treatment immediately in case of doubt.

Basically the drug is to be handled with great precautions.

It should also be noted that all these incidents occurred in patients suffering from PBC and that the marketing authorization of OCALIVA for PBC was obtained under atypical conditions.


The question is whether this alert could also concern NASH for which INTERCEPT is currently conducting a Phase 3 clinical study.

The typology of NASH patients and PBC patients is significantly different, although both relate to liver dysfunction.

PBC, primary biliary cholangitis (formerly known as primary biliary cirrhosis) is a chronic (probably autoimmune) inflammatory disease of the intrahepatic bile ducts.

These small pathways gradually degrade and can no longer ensure their function of bile acid drainage (cholestasis).

Now, OCALIVA is a synthetic bile acid that acts in conjunction with natural bile acids, so it is present in the liver and if bile drainage is imperfect OCALIVA can then concentrate at levels where it becomes lethal for the liver.

This is not the case for the majority of NASH patients who are predominantly hepatic dysfunction related to disease-induced fibrosis.

However advanced fibrosis or hepatocyte damage may also be a cause of poor biliary drainage and may lead to an analogous configuration of bile acid overconcentration.

Thus, as some financial analysts do, it is impossible to conclude that the problems with OCALIVA and PBC patients do not affect NASH patients.


An FDA alert is not a small problem, deaths will be thoroughly investigated and, if they are clearly related to taking the drug, the FDA might require that a black frame be applied to the boxes of OCALIVA to highlight the associated risk of death.

The implications on the ongoing clinical study in NASH are evident:

Patients already under treatment in the Phase 3 study REGENERATE will inevitably ask questions to their doctors, and the rate of abandonment may explode.

Doctors participating in the study will now monitor their patients as milk on fire, and at the first worrying sign, will stop treatment.

This should lead to a much higher pessimistic withdrawal rate from patients in the REGENERATE study, and INTERCEPT, which had already found it difficult to recruit patients, modified its study protocol last spring to change the number of patients patients taken into account for the intermediate results from 1400 to 750, which reduced each arm of the study to 250 patients.

Generally, study designers anticipate a maximum drop-out rate of 20% to 25%, which leaves arms statistically significant (180 to 200 patients) but already borderline for a phase 3, according to some observers.

If the dropout rate explodes to 30% or 40%, INTERCEPT will have to recruit new patients to make its study statistically significant, this will make it lose its timing advantage over its direct competitor, GENFIT.

All the more, the doctors who recruit the patients in the centers risk being no longer very motivated or even worried and will probably now orient their patients towards a much less risky clinical study like RESOLV'IT of GENFIT which would accelerate at the same time its recruitment .

This alert of the FDA is bad news for patients, very bad news for INTERCEPT but should logically promote GENFIT which remains in the lead of the potential treatments in a market of several tens of billions of dollars with in addition, a remarkable treatment safety, for the time being, never questioned.

G Divry

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