Stealthy NGM And Bristol Emerge As Serious NASH Competitors

No longer quiet NGM Bio unveils Phase II data at EASL showing rapid and significant reductions of hepatic fat, while Bristol announces a partnership to produce a non-invasive diagnostic for NASH and presents promising Phase II data for its FGF21 analogue.

The already packed drug development race in non-alcoholic steatohepatitis continues to draw interest from all sides, with privately held NGM Biopharmaceuticals Inc. and big pharma Bristol-Myers Squibb Co. unveiling promising Phase II data for their NASH candidates at the just-completed European Association for the Study of the Liver meeting. Bristol also announced a partnership with Nordic Bioscience AS to potentially produce a companion diagnostic for the disease.

(Just after the EASL meeting, Genfit SA, one of the first companies to advance a NASH drug candidate to Phase III, revealed that is has pushed the enrollment timeline for its pivotal study back four to six months. (Also see "Genfit's Enrollment Delay In NASH May Aid Intercept's First-To-Market Goal" - Scrip, 25 Apr, 2017.).)

Both companies' candidates – NGM282 and BMS-986-036 – address the metabolism-regulating human fibroblast growth factor (FGF) pathway. Bristol's compound (previously known as ARX618 and acquired with its purchase of Ambrx Inc.) is a pegylated analogue of FGF21 and was investigated previously in type 2 diabetes. NGM's drug is a non-tumorigenic, engineered variant of the FGF19 hormone that is also being studied in type 2 diabetes, as well as primary sclerosing cholangitis, with Phase II data in the latter indication expected during the second half of 2017.

Another similarity is that both companies used the non-invasive MRI-PDFF (proton-density fat fraction) method to evaluate their drug's efficacy in reducing patients' liver fat. NGM, which despite a significant R&D partnership signed with Merck & Co. Inc. in 2015 is more or less coming out of stealth mode, garnered significant attention with data showing that 79% of patients in its Phase II study met the primary endpoint of absolute decrease in liver fat content by a minimum of 5% as measured by MRI-PDFF, with 34% of patients achieving normal liver fat levels after 12 weeks of treatment.

Despite the parameters of its deal with Merck, which gave the big pharma options rights to nearly the entire NGM pipeline, NGM282 remains a wholly owned asset for NGM. In an interview prior to EASL, President Jeff Jonker said that because the Merck deal resulted from a competitive process, his company was able to negotiate appealing terms while keeping the NASH candidate off-limits. (Also see "NGM Aims For Three Drugs In Clinical Trials, Padded By Cash From Merck" - Pink Sheet, 26 Jan, 2016.)

The goal with NGM282 was to create a drug that might be able to offer similar benefits to the current standard of care in NASH, gastric bypass surgery, which more commonly is used to offset morbid obesity, he explained.

Post-surgery, these patients generally "have remarkable body-weight loss, but even faster than that … they see their liver return to a normal, healthy state very fast," Jonker noted. "One of the most significant hormones that changes after this surgery is FGF19 … and so people with NASH have low levels of FGF19 and people who've just had surgery have significantly elevated levels of FGF19."

NGM Bio President Jeff Jonker

Source: NGM Bio

The catch is data going back to the 1990s showing that with FGF19 increase comes a risk of hepatocellular carcinoma. NGM thought the FGF19 approach offered too much therapeutic potential to just abandon, however, so it sought to create a therapy that avoided tumorigenic properties. To date, NGM thinks it has succeeded with its recombinant form of FGF19, the exec said.

NGM's Phase II study tested daily subcutaneous injections of 3 mg and 6 mg doses of NGM282 compared to placebo for 12 weeks, and showed a 9.7% absolute reduction in liver fat content with the smaller dose and an 11.9% reduction with the larger dose, both statistically superior to placebo. The drug also met secondary endpoints for liver function and lipid metabolism, while the study additionally measured exploratory endpoints for biomarkers of fibrosis.

Patients had triglyceride reductions of 39% and 44%, respectively, for the 3 mg and 6 mg doses, at 12 weeks, along with LDL cholesterol increases of 52 mg/dL and 38 mg/dL, which is an indicator that the FGF-targeting mechanism is working. NGM now has a safety database of 275 patients dosed with NGM282, and the most common adverse events in the NASH study were gastrointestinal symptoms, nausea and injection-site reactions. A single serious adverse event of acute pancreatitis was seen in the 3 mg arm.

Jonker noted that while NGM282 increases LDL, an effect also seen with the FXR agonist class such as Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid), his company is studying how co-administration of a statin might help ameliorate that effect.

Broad Range Of Therapeutic Benefits

If it can replicate these data in pivotal studies, NGM believes it has a drug that will offer a range of benefits to NASH patients, including more robust benefits than seen in the Phase II FLINT study for Ocaliva, the first NASH candidate to reach Phase III. Jonker noted that Ocaliva provided benefit in roughly 30% of patients in Phase II, while NGM282 met its primary endpoint in 79% of patients.

"Where we are differentiated [is] we are seeing in the span of just 12 weeks, an improvement in steatosis and likely an improvement in inflammation which we think eventually would correlate, when we get to a biopsy, with ballooning and fibrosis, that is probably twice as strong as the data that are out for other agents in about four-times the speed," Jonker said. "It's also working in close to double the number of patients. Essentially, at 12 weeks you're achieving what these other drugs do in a year, and you're doing it in a substantial majority of patients who receive the drug."

What NGM doesn't know much about yet is the durability of NGM282's treatment effect, he admitted. But the rapid and broad effects seen so far suggest a range of therapeutic possibilities, including monotherapy or combination therapy. The clinician community generally anticipates that, as in HIV and hepatitis C, treatment involving multiple mechanisms of action and/or pathways will yield the best results in NASH. (Also see "Combination Strategies A Common Thread In NASH R&D" - Scrip, 21 Nov, 2016.)

"We don't know much," Jonker said about durability. "The study design was 12 weeks of dosing with four weeks of follow-up. We don't have much data, we weren't expecting this kind of rapid and profound effect. And so we are trying to gather that data that we can, but it's definitely one of the things that we're going to have to ask in the next study with this drug, 'what exactly is going to be the utility of this in the treatment of NASH?'"

"Is this something that you use acutely to bring somebody's liver fat back down to a healthy range and then do some kind of maintenance dose after that, or maybe even not need anything after that," he continued. "Or possibly switch to another therapy at that point? Those are really important questions that we just don't know the answers to at this point."

Bristol Hopes To Find Optimal Dose For Weekly Injection

Bristol unveiled data during EASL showing that BMS-986036 offers promise for reducing hepatic fat and other NASH symptomatic measures with both a daily 10 mg dose and a weekly 20 mg dose. Going forward, one of the pharma's challenges is going to be determining an optimal dose for weekly dosing, since a daily subcutaneous injectable therapy likely won't be received positively by patients, physicians or payers, Mike Burgess, Bristol's head of cardiovascular, fibrosis and immunoscience, told Scrip.

The study assessed 68 patients with biopsy-confirmed NASH (fibrosis scores in the F1-F3 range) and hepatic fat fraction of 10% or greater as measured with MRI-PDFF. After 16 weeks of treatment, both doses reduced hepatic fat by a statistically significant measure compared to placebo, 6.8% for the daily dose and 5.2% for the weekly dose.

The 10 mg daily dose resulted in 57% of patients (13/23) reaching a risk reduction of 30% or greater, while the 20 mg weekly dose resulted in 52% (11/21) achieving at least 30% risk reduction, Bristol noted. Both regimens also demonstrated improvement for markers for fibrosis (serum Pro-C3 levels), liver stiffness (magnetic resonance elasticity), liver injury (levels of adiponectin, ALT and AST), as well as reductions in triglyceride and LDL cholesterol and increases in HDL cholesterol.

Burgess said these findings indicate that '036 may offer benefits in metabolic injury, inflammation and fibrosis. In an April 24 note, BMO Capital Markets analyst Ian Somaiya pointed out that the fat-reduction benefit seen with the daily 10 mg dose compares with Phase I data seen for Gilead Sciences Inc.'s ACC inhibitor GS-0976.

Somaiya added that Gilead is moving toward the front of the NASH competition with its ASK-1 inhibitor selonsertib now in Phase III as NASH monotherapy, while a combination of selonsertib, GS-0976 and FXR agonist GS-9674 is under Phase II investigation as combination therapy, giving Gilead the most-advanced proprietary combination regimen for the disease. (Also see "Intercept’s NASH Phase III Enrolling Slowly; Gilead Could Gain Ground" - Scrip, 13 Jan, 2017.)

Burgess said Bristol now will work to find an optimal dose for weekly administration of '036, since across the Phase II data there were indications of a dose response favoring 10 mg daily over 20 mg weekly. Previous studies with the drug in diabetes give Bristol more dosing data to consider, he added. "We're taking the totality of the data to look at what might be the best dose to come forward with in a next study," the exec said.

Bristol won't know if the next study of '036 in NASH will be a Phase IIb trial or Phase III until it talks with regulators, Burgess said. One of the pharma's hopes for the just completed study is that its data on non-invasive markers of disease will move forward the industry-wide goal to establish a less invasive method than liver biopsy for both selecting patients for treatment and assessing the benefits of therapy, he said.

The agreement with Nordic Bioscience announced April 17 will result in the two companies collaborating to develop translational biomarkers and diagnostics for the evaluation on NASH in preclinical models of fibrotic disease and in clinical settings. "Clearly, the intent is that we would come forward with a diagnostic approach to both stratify patients and monitor therapeutic response," Burgess said.

He added that the pharma's goal is for Nordic to take the process forward in terms of possibly getting a companion diagnostic approved. Burgess compared the partnership to offering potential for a relationship like the one Bristol has with Dako AS, which developed and markets a companion diagnostic for immuno-oncology drug Opdivo (nivolumab). [See Deal]

"It's pretty clear Bristol is a pharma company, we do not intend to be a diagnostic company, so our intent is to develop this as part of an R&D strategy," Burgess explained. "Nordic, on the other hand, is a diagnostic company and we will work them to make sure that any markers that we discover or use in this clinical trial that prove beneficial to patients they can commercialize and develop."