Today , ICPT released the first intermediate results of their trial REGENERATE, OCALIVA in NASH with fibrosis.
RECALL
REGENERATE is a Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment
Study Type :Interventional (Clinical Trial)
Estimated Enrollment : 2370 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in Subjects With Nonalcoholic Steatohepatitis
Study Start Date : September 2015
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2022
The intermediate results were initially suposed to be calculatad on 1350 patients but this number was modified during the trial and now they are calculated on only 931 patients enrolled in 3 arms :
- 311 patients who received placebo
- 312 patients receiving a dose of OCALIVA of 10 mg / day
- 308 patients receiving a dose of OCALIVA of 25 mg / day
The expected results focused on two independent primary endpoints:
- The proportion of Obeticholic Acid treated patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH
- The proportion of Obeticholic Acid treated patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis.
RESULTS
The published results on the first endpoint are the following:
Proportion of Obeticholic Acid treated patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH
10mg dose : OCALIVA 16,6% vs PLACEBO 11,9% p=0,0446
25mg dose : OCALIVA 23,1% vs PLACEBO 11,9% p=0,0002
The published results on the second endpoint are the following:
Proportion of Obeticholic Acid treated patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis.
10mg dose : OCALIVA 11,2% vs PLACEBO 8,0% p=0,1814
25mg dose : OCALIVA 11,7% vs PLACEBO 8,0% p=0,1268
Adverse effects
- Pruritus 19% in placebo arm 28% in OCA 10mg arm and 51% in OCA 25mg arm !
- LDL levels increase +22,6 mg/dl at W 4 and +4 mg/dl at 18 months
The Pruritus is twice higher than in FLINT for a similar dose, it is close the pruritus rate noticed for 40mg dose in the SUMITOMO Japan trial. Data’s provided on LDL are few and the rate seems close to the one in Phase 2b
It is interesting to see how many patients defected during the trial we only know that 9% defected because of pruritus ine the 25 mg arm ( it mean about 30 patients)
If other cause of defections are known they are not provided yet!
ANALYSIS
First Endpoint - Fibrosis
The first endpoint is a mitigated success but open a field on NASH induced fibrosis treatment for Intercept.
It would be interesting to know the results on the criteria recommended by EMA for intermediate results.
If an intermediate endpoint strategy is used in such compounds, it is currently recommended to use a stronger endpoint denoted as a composite at the individual patient level such as “fibrosis regression of at least 2 stages without worsening of NASH”, in which stage 2 fibrosis patients would need to achieve complete resolution of fibrosis, and patients with stage 3 would need to regress into a stage associated with only minimally increased risk for disease progression
15 November 2018 EMA/CHMP/299976/2018
Second Endpoint - NASH reversion
Intercept failed to reach the second endpoint regarding the statistical significance (p=0,18 / 0,12)
It will be interesting to read the full publication of data to see if they didn't’ succeed in subgroup of patients, opening the gate for a discussion with health agencies.
As Nashbiotechs wrote for months, it was not easy for Intercept to reach an endpoint never reached in phase 2.
Adverse effects
The pruritus is higher than expected by far, it will be a real problem for a treatment supposed to be taken for Years
As Nashbiotechs wrote for month, This pruritus rate prevent Ocaliva to become a backbone treatment.
CONCLUSION
As we expected, INTERCEPT got an mixed success in their Phase 3 in NASH!
It is now confirmed that OCALIVA need to be prescribed in combo's to complete the action of the compound and to balance its adverse effects.
The best and most advanced complement could be Elafibranor if the compound confirm the results obtained in phase 2 on NASH reversion.
NASH MARKET FORECAST IS RECOMPUTED INCLUDING THE NEW DATA'S
G Divry
Notice that I am neither a physician nor a biologist or financial analyst, my point of view is only that of an enlightened amateur, so it must be taken for what it is, a questionable point of view