Memorandum

Gilead 4Q17 – Management suggests selonsertib could be first-to-market NASH treatment by 2020; New phase 2 combination study for three NASH candidates to start 2Q18 – February 20, 2018

Executive Highlights

  • Gilead announced in its 4Q17 update that the phase 3 STELLAR 4 trial of ASK-1 inhibitor selonsertib for NASH has completed enrollment; STELLAR 3 is on track to complete enrollment in 1H18. CEO Dr. John Milligan commented that data is expected in early 2019, and explained that positive results could support a regulatory filing that would allow Gilead to potentially bring the first NASH therapy to market in 2020. Notably, STELLAR 4 is the only phase 3 NASH trial enrolling patients with F4 fibrosis (cirrhosis), an area of particularly high unmet need (though NASH overall, including earlier disease stages, still has no approved treatment options available). Dr. Milligan mentioned that rapid enrollment of patients has pushed Gilead into the lead in development for patients with the most severe forms of NASH.
  • In 2Q18, Gilead will initiate a large phase 2 study evaluating combinations of its three NASH candidates: selonsertib/GS-9674 (FXR agonist), selonsertib/GS-0976 (ACC inhibitor), and GS-9476/GS-0976. This study will be larger than the current phase 2, eight-cohort combination trial (n=123), which is expected to report data at EASL in April. Notably, there was a section of Gilead’s forward-looking statement addressing risk and uncertainty around whether safety/efficacy data will support further development of candidates including GS-0976, raising some questions over whether Gilead will advance GS-0976 into phase 3 on its own, or whether the agent will solely be investigated within a combination regimen. Regardless, the company’s commitment to NASH continues to shine, and Gilead holds advantage in the combination therapy arena, given its three candidates targeting distinct aspects of pathophysiology.
  • The phase 2 trial of FXR agonist GS-9674 wrapped up in January 2018, according to ClinicalTrials.gov. During Q&A, management suggested that the company will submit phase 2 data for presentation at an upcoming scientific conference, hopefully in 1H18.

Gilead provided its 4Q17 update in a recent call led by CEO Dr. John Milligan (see the press release and slides, and listen to the webcast). Management emphasized the company’s commitment to NASH throughout the call. Indeed, Gilead is developing one of five phase 3 NASH candidates in the pipeline (ASK-1 inhibitor selonsertib), and also has two promising molecules in phase 2 for NASH (ACC inhibitor GS-0976 and FXR agonist GS-9674).

CSO Dr. Norbert Bischofberger shared that the phase 3 STELLAR 4 trial of selonsertib is now fully enrolled, while STELLAR 3 will complete enrollment in the next few months (2Q18). These trials started in January and February 2017, respectively, and it’s certainly a positive that recruitment is progressing, particularly in light of the recruitment woes that have delayed enrollment for NASH candidates across the board (a function of low NASH diagnosis rates given the requisite liver biopsy, combined with fierce competition over the small pool of diagnosed NASH patients from the growing number of companies in the NASH competitive landscape). STELLAR 4 (n=800) has enrolled patients with F4 cirrhosis due to NASH (i.e. F4 fibrosis), while STELLAR 3 (n=800) is enrolling patients with NASH and bridging (F3) fibrosis. Both studies have primary completion dates of January 2020, but Dr. Milligan clarified that some data is anticipated in early 2019. If positive, these results would form the basis of regulatory filings, and Dr. Milligan forecast that Gilead could launch the first therapy for NASH in 2020.

To be sure, the prospect of an approved NASH treatment on the market in the next two years is beyond exciting, though many things would have to go right for this to happen. This chronic disease persists at high prevalence and remains an area of tremendous unmet need, with no FDA-approved drugs to-date despite a robust competitive landscape.

We would have loved more detail on the exact timeline for selonsertib readouts and submission, and our guess is that perhaps FDA has indicated to Gilead that interim data could support an NDA (New Drug Application), but this is complete conjecture on our part. Alternatively, it’s possible the ClinicalTrials.gov pages are simply not up-to-date and the STELLAR program will complete sooner than is listed.  

STELLAR 4 seems to be the only phase 3 NASH trial enrolling patients with F4 fibrosis; Gilead management has previously commented on the lack of competition for this patient population. The fact that this trial completed enrollment before STELLAR 3 speaks to the extremely high level of unmet need among people with advanced NASH. Dr. Milligan mentioned during prepared remarks that rapid enrollment of patients has pushed Gilead into the lead in development for patients with the most severe forms of NASH.

Combination Therapy for NASH

  • In 2Q18, Gilead plans to initiate a large phase 2 study evaluating combinations of selonsertib/GS-9674 (FXR agonist), selonsertib/GS-0976 (ACC inhibitor), and GS-9476/GS-0976. The study does not yet appear on ClinicalTrials.gov. Gilead has long been keen on combination approaches to NASH, and we view this as a very wise strategy given that single agents are unlikely to address all three pathological features of NASH (inflammation, steatosis, and cirrhosis). Enrollment is complete for a smaller (n=123), eight-cohort phase 2 trial investigating combinations of selonsertib, GS-0976, and GS-9674, and management announced that data will be presented at the April meeting of the European Association for the Study of the Liver (EASL) – a quick turnaround, since the primary completion date is April 2018, with full completion expected in May 2018 (according to ClinicalTrials.gov). That Gilead is already moving forward with plans for a larger combination study bodes well for positive results from the smaller, earlier trial – of course, we’ll have to wait for all the findings to be shared at EASL.
  • Gilead holds a meaningful advantage in combination therapy, with three promising candidates in development that target separate aspects of NASH pathophysiology. Selonsertib targets fibrogenesis and matrix remodeling, while GS-0976 and GS-9674 target hepatocyte dysfunction; preclinical data in rodent models suggests additive efficacy with selonsertib + GS-0976.

Phase 2 Candidates

  • Gilead’s ACC inhibitor GS-0976 and FXR agonist GS-9674 remain in phase 2 for NASH. Management again highlighted phase 2 results for GS-0976, announced in October 2017, which showed that the higher, 20 mg daily oral dose was well-tolerated and gave significant reductions in hepatic steatosis (as measured by MRI) and noninvasive markers of fibrosis (TIMP-1) after 12 weeks. Notably, this was the first RCT of an ACC inhibitor in NASH, enrolling patients with F1-F3 fibrosis. That said, some measures of liver stiffness and fibrogenesis were not significantly improved, and there was some cause for concern over initial triglyceride elevation. We noted a section of Gilead’s forward-looking statement addressing risk and uncertainty around whether safety/efficacy data will support further development of candidates including GS-0976, raising some questions over whether Gilead will advance GS-0976 into phase 3 on its own, or whether the agent will solely be investigated within a combination regimen.
  • The phase 2 trial of GS-9674 completed in January 2018, and we’re eager to see these results in the coming months. During Q&A, management suggested that the company will submit phase 2 data for presentation at an upcoming scientific conference, hopefully in 1H18.

Gilead NASH Pipeline Summary

Candidate

Product Details

Status

Timeline/Notes

Selonsertib

ASK-1 inhibitor

Phase 3

STELLAR 3 expected to complete October 2023; STELLAR 4 fully enrolled and expected to complete October 2023

GS-0976

ACC inhibitor

Phase 2

Phase 2 results presented October 2017 (trial completed July 2017); Positive proof-of-concept data presented at EASL 2017

GS-9674

FXR agonist

Phase 2

Phase 2 trial completed January 2018; Results expected 1H18

Combination regimens

Eight cohorts, each receiving a different combination of selonsertib, GS-0976, and GS-9674

Phase 2

Phase 2 trial of combinations expected to complete May 2018; Data expected at EASL in April 2018

Combination regimens

selonsertib/GS-9674; selonsertib/GS-0976; GS-9476/GS-0976

Phase 2

Expected initiation in 2Q18

Competitive Landscape

  • To our knowledge, four other phase 3 trials of NASH drugs are underway (below), and the most relevant candidate is cenicriviroc (CVC), also under study in HIV. Tobira and Allergan are both involved in the still-recruiting phase 3 AURORA trial (n=2,000) of CVC, which has an expected primary completion date of July 2019 (full completion expected July 2024). Zydus Cadila’s saroglitazar has more or less fallen off the map (recruitment status is listed as unknown). Genfit and Intercept should complete phase 3 trials of their candidates in December 2021 and October 2022, respectively. Gilead’s STELLAR program will, according to Dr. Milligan, likely support a filing ahead of these candidates. Overall in this landscape, we view Gilead’s commercial prospects as particularly favorable, pending positive STELLAR results. That said, we also want to emphasize that NASH presents an entirely untapped market with zero FDA-approved treatments right now, so there’s plenty (!!) of room for multiple products to be commercially-successful, and we hope this competitive landscape remains robust with additional momentum for the late-stage compounds.

Phase 3 NASH Pipeline Summary

Sponsor

Drug Name

Class

Status

Other Remarks

Zydus Cadila

Saroglitazar

Dual PPAR alpha/gamma agonist

Phase 3

Phase 3 trial in India, recruitment status “unknown”; Completion was expected September 2015;

Genfit

Elafibranor (GFT505)

Dual PPAR alpha/gamma agonist

Phase 3

Phase 2a results reported March 2015; Phase 3 trial recruiting with completion expected December 2021

Intercept Pharmaceuticals

Obeticholic acid

FXR agonist

Phase 3

Phase 3 trial recruiting; Completion expected October 2022 (delayed from 2021)

Novartis/Allergan/Tobira

Cenicriviroc

CCR2/CCR5 inhibitor

Phase 3

Phase 3 AURORA study launched April 2017, completion expected July 2019; Phase 2b combination study planned according to announcement of Novartis/Allergan clinical collaboration

Select Questions and Answers

Q: You highlighted both STELLAR studies for selonsertib and the ACC inhibitor GS-0976, but you didn’t talk a lot about the FXR agonist. Your slides say you completed phase 2 in NASH and have an interim analysis in primary biliary cholangitis – any comment on profile there?

A: So, the reason for a lack of emphasis is simply that the FXR agonist is somewhat behind the ACC inhibitor. We’re looking at the data and we intend to submit this to an upcoming liver conference. Just to remind you, with our FXR agonist, the hypothesis was that we don’t want a high systemic exposure, so it has a focused mechanism of action that releases FGF19 from the intestine, which then goes into circulation, which is opposed to an FXR agonist that goes directly to the liver.

Q: In STELLAR 4, what do you expect the placebo arm to track at on the percentage of patients who will have a one-stage improvement in fibrosis [primary endpoint]? I’m also curious what level of visibility you have on the STELLAR 3 and 4 trials, on the pooled event rate on a blinded basis.

A: The only thing I can point to is the phase 2 study that we’ve done. I’m very confident we will repeat those numbers – of course they won’t be exactly the same. As you remember, the total event number was somewhat small but we saw a difference between placebo and the high-dose active arm at 20%. As you know, the endpoint is fibrosis and something that improves fibrosis or prevents its progression would be a tremendous asset and contribution to the healthcare system. We, of course, are looking in an ongoing way at safety, and I can tell you the compound is very safe. We are not seeing anything that will concern us, in terms of laboratory abnormalities, adverse events, or discontinuation rates. I want to make sure everybody understands we’re blinded to the study, but there’s no concern from that dataset.

 

-- by Ann Carracher, Payal Marathe, and Kelly Close