Akero Thinks It Will Produce A Next-Wave Therapy For NASH With Former Amgen Compound
Executive Summary
Akero is entering the NASH race with a mechanism it thinks will be more powerful than current Phase III candidates and offer better efficacy than two other FGF-targeted candidates now in Phase II.
Newly unveiled Akero Therapeutics Inc. is jumping into the crowded non-alcoholic steatohepatitis (NASH) drug development race with a Phase II-ready FGF21 analog licensed from Amgen Inc. that it believes will offer best-in-class potential by addressing both metabolic and fibrotic aspects of the disease.
The Cambridge, Mass.-based firm announced both a $65m Series A financing and the licensing of AKR-001 on June 25. The long-acting novel fibroblast growth factor 21 (FGF21) analog administered by subcutaneous injection was studied in nearly 100 diabetes patients by Amgen before being made available for out-licensing, explained Akero co-founder and CEO Jonathan Young. The deal gives Akero global rights to AKR-001 in all indications, with undisclosed potential earn-outs back to Amgen.
“Our conclusion as we went through this process was that we’re essentially the beneficiary of an Amgen senior management strategic decision on therapeutic areas,” Young told Scrip. “They have nothing in the metabolic space. We are taking advantage of an opportunity to progress this really exciting compound forward, looking at other data that has come out around the target, viewing it as most ideally suited for NASH.”
Young, the former VP of policy and general counsel at Apple Tree Partners portfolio company Braeburn Pharmaceuticals Inc., said he and fellow co-founder Timothy Rolph teamed up at Apple Tree to look for promising clinical-stage assets that offer transformational therapeutic benefit in conditions of broad unmet medical need. Rolph previously headed up cardiovascular and metabolic disease research at Pfizer Inc. and now will serve as Akero’s chief scientific officer. Apple Tree co-led the $65m Series A, along with Atlas Venture, venBio Partners and Versant Ventures.
The founders were not specifically focused on NASH when they settled on the Amgen compound, Young added. He and Rolph like AKR-001 based on early data they saw from the Amgen studies showing potential for triglyceride reductions of about 50% compared to placebo, increased HDL cholesterol levels of about 50% and reductions in LDL cholesterol levels in the 20%-30% range.
Bristol, NGM Already In NASH With FGF Candidates
Young acknowledged the deep competition in the NASH space, but said he thinks AKR-001 presents the possibility of offering greater benefit in NASH than any of the candidates that have reached Phase III and many now in Phase II. Bristol-Myers Squibb Co. has an FGF21 candidate, ARX618 in Phase II for NASH, while NGM Biopharmaceuticals Inc. has FGF19-targeted NGM282 in Phase II. (Also see "Stealthy NGM And Bristol Emerge As Serious NASH Competitors" - Scrip, 25 Apr, 2017.) The latter also is in Phase IIb for primary biliary cholangitis and in Phase II for type 2 diabetes and primary sclerosing cholangitis.
“We view this particular compound as getting at the heart and the breadth of what is involved with treating NASH effectively,” Young said. “When you look at the [R&D] landscape, so far there is a lot of emphasis on liver-fat reduction,” he noted, but Akera believes AKR-001 acts directly to address the root drivers of disease.
That includes the excessive liver fat and liver toxicity that emerges in NASH patients, leading to hepatocyte stress. Across the NASH field, absolute liver fat reduction ranges from 4%-5% to about 10%-11%. “We’ve not yet evaluated liver fat; that will be part of our next clinical study, so coming out of that study we expect to have a more direct comparison,” Young said.
But AKR-001 also acts peripherally to mitigate adipose tissue drivers of disease in the liver, he said. “Roughly 50% or more of the fat in the liver is coming from the adipose tissue, so we’re addressing those underlying drivers, both in the liver and the adipose tissue,” the exec added.
The drug also has indicated the ability to directly and indirectly suppress fibrosis of the liver in downstream disease pathology, Young said. “So we think FGF21 as a target generally offers extraordinary promise in the broader NASH landscape,” he said, “and then among the FGF21-targeting candidates, we view AKR-001 as having best-in-class potential, particularly for very balanced reproduction of native FGF21.”
As an endogenous hormone, FGF21 has been shown in multiple studies to play a key role in regulating metabolism, the company notes. While FGF21 is recruited naturally in the body to fight cellular stress and restore metabolic balance, AKR-001 – as a modified Fc fusion protein – could offer substantially better stability and half-life compared to naturally occurring FGF21, along with enhanced receptor binding and activity, Akero asserts.
Phase II Will Focus On Liver Fat Reduction
Having just in-licensed the compound and still in the process of building up a clinical team, Young offered few details on the planned Phase II trial, other than the primary endpoint likely will be liver fat reduction from baseline as measured by MRI-PDFF. Amgen tested the drug as both a weekly and every-other-week injection, and Akero sees weekly dosing as likely optimal for the drug in NASH, Rolph said.
“We’re not putting any timing on it right now,” Young said about the Phase II plans. “We’re big believers from the vantage point of overall drug development [that] we want never to go backwards in drug development. You see examples where companies step backwards to modify their dosing, to increase their dose-ranging, so we want to make sure that we get this study done right and build the kind of momentum we need to go into a longer-term Phase IIb study.”
The $65m fundraising is intended to get Akero through that Phase II study and into planning a longer-term Phase IIb trial, he said. This process will include transferring the manufacturing process from Amgen. The financing also was structured to give Akero flexibility to acquire other assets that might offer synergistic effects to AKR-001 in NASH or other cardiometabolic indications the company may investigate, but there are no specific plans right now to add anything else to the pipeline, Young added.
Realizing that its program is well behind other NASH programs, Akero seems to be looking at AKS-001 as part of a second wave of NASH therapies that will improve upon the first drugs to obtain approval. Right now, they see the drug as a monotherapy – Rolph went as far as to predict that its efficacy might outstrip some early combination therapies that will be studied and possibly approved.
He also noted the recent excitement about Madrigal’s Phase II data showing that selective thyroid hormone receptor beta agonist MGL-3196 can yield NASH resolution at 36 weeks that surpasses any data seen in similar NASH studies to date. (Also see "Madrigal May Shake Up NASH Race With Phase II Resolution Data" - Scrip, 31 May, 2018.)
“I think if you talk to opinion leaders in the NASH field, there’s a strong view that to really have a big impact on the disease, we’re going to need more powerful mechanisms and combinations of mechanisms than the current Phase III candidates,” Rolph said. “Which molecules combine best together to give you a chance of transformational change in disease and resolution of disease, I don’t think we know, and we’re only going to find out by taking compounds into the clinic. But we are confident that when you look across the Phase II candidates, that [AKR-001] is going to be up there, if not better than most.”