Need to know:

  • Nonalcoholic steatohepatitis (NASH), triggered by the build-up of fat in the liver, is a type of chronic liver disease that can lead to cirrhosis. NASH is forecasted to be a multibillion-dollar industry, with no available therapeutic options.
  • Last year, the FDA rejected Intercept’s first attempt to secure accelerated approval. It’s back with more biopsy and safety data to help the company’s second approval bid.
  • Yet NASH experts noted that initial uptake may be slow due to the possible need for biopsies either by the FDA or payers.
  • The drug’s side effect of itch and increase in LDL-cholesterol may also be an issue for prescribers, with added training and extra patient monitoring necessary.

Despite Intercept Pharmaceuticals’ obeticholic acid (OCA) having a stronger shot at its second attempt at approval in nonalcoholic steatohepatitis (NASH), experts are still cautious of its initial uptake prospects. Liver biopsy requirements either by the FDA or payers will delay use, and its safety profile will require prescriber training and monitoring.

OCA’s potential to secure FDA accelerated approval was resurrected on 29 July when Intercept announced it is in data gathering and analysis mode for its Phase III REGENERATE trial (NCT02548351). In June 2020, Intercept received an FDA Complete Response Letter for OCA in NASH due to its efficacy data not sufficiently outweighing risks to support accelerated approval.

Different types of restrictions possible

While REGENERATE is recruiting both stage 2 (F2) and stage 3 (F3) fibrosis patients, it is possible OCA’s initial approval will be in F3 patients only. However, it is also possible that this may not limit its use, as pathologists may be more lenient in distinguishing both patient groups.

REGENERATE enrolled F2 and F3 patients. And it is also possible that OCA would be approved in F3 patients first before expanding to F2 patients with even more data, noted REGENERATE investigator and Swiss NASH Foundation president Dr Jean-François Dufour. F3 patients have a higher unmet need and so OCA’s risk-benefit profile may lean more positively in F3 patients, explained Dr Frank Tacke, professor of medicine at Charité Universitätsmedizin in Berlin, Germany. There are five fibrosis stages, from F0 (no fibrosis) to F4 (cirrhosis or advanced scarring).

But requiring both an F3 status and a biopsy may not limit OCA’s potential market. Classifying patients between F2 and F3 can be challenging because some parts of the liver can be categorised in either stage, Tacke said. This means pathologists may be more inclined to mark patients as F3 to access OCA, he added. Using OCA in F2 patients is logical anyway because these patients are more susceptible to reversible fibrosis, Dufour noted. F3 patients have harder-to-treat lesions.

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By GlobalData

Pruritus (severe itching) and LDL-cholesterol increase will be two of the main side effects hepatologists need to monitor. LDL-cholesterol can be managed via generic statins, but some hepatologists may be averse to prescribing both, particularly in patients who are not taking statins already.

Nevertheless, OCA’s reanalysis in NASH based on 18-month REGENERATE data allows it a clean slate at demonstrating its safety and efficacy. It is the only NASH drug so far with a positive efficacy signal in the Phase III stage, on the back of other late-stage NASH trial failures. OCA’s clinical trial development being under close regulatory monitoring is logical as its approval would set a precedent as the first ever NASH drug in the market, experts noted. Intercept did not respond to a comment request.

Third pathologist will be the tiebreaker

According to the company presentation, three different pathologists will be reviewing baseline and month 18 biopsy samples from REGENERATE. If there is discordance between the first two pathologists, the third will break the tie, according to Intercept’s 2Q21 earnings call presentation on 29 July. Interim REGENERATE data was based on reading from one pathologist. The new approach can improve data quality and avoid pathology bias, noted Dufour.

But the third pathologist could still have subjective bias based on how the first two pathologists interpreted the sample, noted Professor Bart Staels of the University of Lille’s Faculty of Pharmacy. On the other hand, there are not many NASH pathologists, which could mean there is a high chance of consistency among them on how to study samples, he said. To ameliorate the issue surrounding the third pathologist’s bias, the three pathologists should review samples independently, added another REGENERATE investigator, Pinnacle Clinical Research medical director Dr Stephen Harrison.

Nevertheless, further biopsy analysis in REGENERATE underscores its importance in NASH. In fact, it is possible that the FDA would require a biopsy to confirm advanced fibrosis for OCA to be prescribed, noted Tacke. This requirement would stifle uptake, Dufour added.

Payers: the final hurdle

Intercept may garner approval in both F2 and F3 patients as REGENERATE recruited both groups, Harrison said. Also, the agency may not require biopsies as this diagnostic measure is not typically used outside clinical trials, noted a third REGENERATE investigator, Dr Arun Sanyal of Virginia Commonwealth University. A variety of noninvasive fibrosis tests are available and may be enough, he added. If the FDA does not require biopsy diagnosis, payers might push for them depending on OCA price, he said.

OCA is marketed as Ocaliva in primary biliary cirrhosis (PBC), where it costs around $7,940 for a supply of 30 5mg tablets. In REGENERATE, once-daily 10mg and 25mg doses have been studied. OCA has peak sales estimates of $1.39bn in 2027, according to GlobalData’s consensus forecasts.

More than double the safety data for OCA

In the company call, Intercept noted its OCA safety data is more than double what it reported for its interim analysis. For context, in 2019, the data was based on 1,900 patients with a median of 15 months of drug exposure. The new data is from 2,500 patients with a median of 30 months of exposure. In addition, 650 of these patients have been on OCA for 48 months.

Yet, pre-existing side-effect concerns with OCA are still pertinent. Upon its potential approval, Intercept will likely increase awareness for NASH among general practitioners to boost the number of diagnosed patients, Harrison said. Yet, all these patients will likely be passed on to hepatologists for OCA prescriptions due to the drug’s side-effect risk, he noted. Further, OCA will likely have restricted use in terms of required training to be able to prescribe OCA and side-effect monitoring, Sanyal added. There will likely be tight follow-up parameters around ceasing treatments to mitigate risk, Harrison said.

Pruritus is a big concern considering the only option that clinicians have is to decrease the dose, which will likely be in the label, Harrison said. However, severe cases may not be too frequent, Dufour noted. Interim REGENERATE data showing high rate of pruritus could be due to bias, as investigators may be proactively asking participants of pruritus, he added. In 1,968 REGENERATE F1–F3 patients, the most common adverse event was pruritus: 19% in the placebo arm, 28% in the 10mg arm, and 51% in the 25mg group.

As for OCA’s LDL-cholesterol increase, this can be alleviated by generic statins, Dufour said. But it is possible clinicians may be averse in prescribing patients two drugs, especially those who do not take statins normally, he added. There is some data showing blood sugar levels may increase with statins and can trigger type 2 diabetes, Staels noted.

But Sanyal countered that most NASH patients should already be taking statins in the first place as these patients are at high risk of cardiovascular disease. OCA is linked to an increase of LDL-cholesterol with a peak increase of 22.6mg/dL at four weeks, which can reverse and return to baseline at month 18, according to an April 2019 media release.

Other issues that need monitoring in the long term are cholestasis and cancer but there is no convincing signal at this point, Dufour said. While OCA is already in PBC, the safety data in PBC is not applicable in NASH because PBC is a cholestatic disease, which is not the case with NASH, he added.

Clean slate for Intercept

Nevertheless, experts agreed Intercept’s new analysis gives OCA a clean slate in NASH. Intercept’s efficacy analysis will study samples from a total of 1,700 REGENERATE patients, including an additional 500 patients who were not a part of the interim analysis. These additional patients had yet to reach the 18-month data time point when the interim analysis was done. A presubmission meeting with the FDA is expected the first half of 2022.

Of the other NASH candidates, OCA is the only one so far to demonstrate an efficacy signal at the Phase III stage, which draws success optimism, experts noted. There is a growing list of unsuccessful NASH assets, with notable Phase III failures from Genfit and Gilead.

Interim REGENERATE data shows the fibrosis improvement coprimary endpoint was achieved by 18% of patients in the 10mg OCA group (p=0.045) and 23% in the 25mg arm (p=0.0002), versus 12% with placebo. However, both arms did not reach the NASH resolution coprimary endpoint.

Intercept will make data-driven decisions regarding its potential NASH resubmission, the company has stated. There are questions around whether REGENERATE’s 48-month data should also be opened up for efficacy analysis, Sanyal added. If a patient has positive data at 18 months, it is likely there will be sustained fibrosis improvement at 48 months, he said. But opening this 48-month data set could affect the trial’s integrity as the result could lead to participants opting out, he noted.