Leerink talks up Gilead’s R&D shift from virology to NASH, cancer remains tricky proposition

Its success has been in Hep C treatments, but Leerink says its future will likely rest on its NASH and cancer pipeline

Analysts at Leerink have performed one of their deep dives with Gilead’s R&D chief as the Big Biotech, which remains under fire from some sectors for its lack of M&A, outlines its pipeline priorities away from its traditional focus.

These priorities do not, Leerink notes, really include HIV as the firm says there is “little room for improvement in HIV treatment,” but rather sees the main potential in its NASH programs, with room for growth from its cancer pipeline.

Speaking to Gilead’s chief scientific officer, Dr Norbert Bischofberger, Ph.D., he characterized Gilead as “having a small company feel with the ability to make quick decisions, and making those decisions from a deep scientific knowledge base that prioritizes medical need first.”

He says that the company is focused on remaining the market leader in anti-virals namely in HIV (and posted some positive data for a new HIV cocktail today that showed it was not worse than GSK's Tivicay) and Hep C, although revenue from its blockbuster HCV range is and will continue to fall.

Because of this, Gilead is increasingly turning its attention to oncology and inflammation with the goal of becoming the leader in one, if not both of these fields, according to Leerink.

NASH is one of the biggest opportunities, and though it’s had its setbacks in testing for some meds, it has seen positives for others.

Last month, it posted the first clinical data on GS-0976, which Gilead acquired from Nimbus Therapeutics in a $1.2 billion deal signed last year, and though a small study, it did reveal that GS-0976 was able to block the formation of new fat in the liver (de novo lipogenesis, or DNL) by 29% over the 12-week study period.

As shown at this year’s International Liver Conference, however, NASH is still in its infancy in terms of understanding how new drugs could and should treat the condition, and what endpoints biopharmas should be setting to help it gain the best footing in a new but potentially major blockbuster market.

Gilead, which among a host of other companies including Bristol-Myers, Shire, Novartis, Allergan, Genfit and others, are looking to reduce liver fat and scarring in the livers of patients, who are typically overweight or medically obese, and often have Type 2 diabetes.

In some patients, liver fat can lead to liver damage, scarring, and potentially cirrhosis and eventually liver failure (and sometimes even liver cancer); it’s predicted by some to become the number one medical reason for liver transplants in the coming years, replacing hep C and alcoholism, and could affect as many as 400 million people around the world.

Analysts at Bernstein, while noting the opportunities here, have also recently noted the challenges: “We see commercialization [of NASH drugs] as highly challenging. Diagnosis is currently tied to liver biopsy; there are no 'easy' measures of treatment effectiveness (like HbA1c, total cholesterol or blood pressure). Broad acceptance of less invasive disease markers is still years’ away.

It added that “treatment benefit for most patients is questionable,” and that the “disease will remain asymptomatic in the vast majority of patients.” It sees the “success case” for the market as being around $7 billion in global sales by 2025.

Many biopharma have also been going after reductions in liver fat for their trials, but Dr Bischofberger believes fibrosis is the most important biomarker to correlate with outcomes in NASH.

“Thus, Gilead is confident in the development of selonsertib (ASK-1 inhibitor) because it has demonstrated convincing evidence of anti-fibrotic effects,” Leerink says.  

Currently, they have initiated two phase 3 studies enrolling cirrhotic and F3 fibrotic patients and the cirrhotic trial is enrolling “very quickly”, according to Dr Bischofberger.

The primary endpoint of the cirrhotic trial is regression of fibrosis, with the other endpoints including no worsening of hepatocyte ballooning, steatosis and inflammation, which were included at the request of the FDA.

Dr Bischofberger noted that other advanced studies being run by competitors are not using fibrosis as a primary endpoint, and added that Gilead is the only company enrolling F4 (the latest stage) cirrhosis patients.

“This study is enrolling quickly, demonstrating the high unmet medical need in this setting, and because of this severity patients are more willing to undergo a liver biopsy,” Leerink notes.

Oncology has proved something of a frustration for the Big Biotech: Its blood cancer med Zydelig (idelalisib) won an FDA nod in 2014 for three kinds of blood cancer, but serious side effects including death halted six trials using the drug in combination with a variety of others as a first-line therapy.

Late last year, Gilead also posted subpar data from two phase 3 trials of JAK inhibitor momelotinib in patients with the bone marrow disorder myelofibrosis. The data raised serious doubts about momelotinib’s ability to hold its own against Incyte’s Jakafi (ruxolitinib), let alone unseat the blockbuster incumbent.

Gilead also isn’t currently involved in the latest and next-gen cancer classes of CAR-T and CRISPR, but is focused on the Syk, BTK and BTE inhibitors currently filling its pipeline. 

The company has said in the past that it is looking for “novel approaches” to immuno-oncology as it plays catch-up to Bristol-Myers Squibb, Merck and Roche. At the start of this year, Gilead also signaled its intentions by hiring former Novartis cancer vet Alessandro Riva to help it with this mission, which may also include deals.

Dr Bischofberger told Leerink that Gilead is “nearing the back-end of a long evaluation of what direction to take in this category [oncology].”

As a result of this, Gilead is looking to focus on three main areas, namely: targeted therapies; immuno-oncology, and cellular therapies.

Dr Bischofberger said that Gilead will not however be pursuing cytotoxic/chemotherapies as one of these, given that pretty much all the big players have or are now moving away from this therapy area.

But the company remains committed to targeted therapies that block kinase signaling, with their phase 2 Syk inhibitor entospletinib and a phase 2 BTK inhibitor tirabrutinib the big hopes.

Dr Bischofberger revealed that tirabrutinib, licensed from ONO, still “needed to be optimized for dosing in a variety of malignancies”, which has slowed its development, and stopped the team from doing a head-to-head test against Janssen/Pharmacyclics’ Imbruvica (ibrutinib).

Instead, tirabrutinib was put directly into combination therapies in CLL, with the aim of developing such combinations as potential first-line regimens.

Currently, Gilead is looking at the endpoint of minimal residual disease as a shorter path for development of this combination, but Leerink notes that “it is unclear if this is a viable regulatory endpoint that will be accepted by the FDA.”  

Leerink says that it maintains its market perform rating and $74 price target; the company was worth $64.50 at close last week before the holiday weekend, with a market cap of $84.2 billion.