PARIS – Assembly Biosciences Inc. presented much-anticipated interim results Thursday from the phase Ia and ongoing phase Ib study of ABI-H0731, an antiviral directed at chronic hepatitis B virus (HBV) infection, in a late-breaking poster at the International Liver Congress (ILC), the annual meeting of the European Association for the Study of the Liver (EASL).

The data met the mark. The oral core protein allosteric modifier (Cpam), designed to provide selective and potent activity against major HBV genotypes, was safe and well-tolerated, had a dose-proportional pharmacokinetic profile in patients similar to that in healthy volunteers and showed impressive antiviral activity with once-daily dosing.

Chronic HBV is a topic of much discussion at the ILC, given that HBV infections affect more people globally than hepatitis C virus (HCV) and HIV infections, combined – a point that Derek Small, co-founder, president and CEO of Indianapolis-based Assembly, was quick to make to analysts following the ILC presentation.

While standard-of-care therapies with nucleoside medicine, such as entecavir and tenofovir, are good at blocking one step in the viral replication of HBV, they have little or no effect on the key target, cccDNA, which fuels the HBV replication engine that sustains chronic infection, Small explained. Assembly's Cpams are active across multiple points in the HBV life cycle, including the establishment of cccDNA.

"This is the key," Small said. "We believe combining standard-of-care nucleosides with the Cpam, targeting multiple points of attack on this virus, can increase cure rates. We believe we have developed one of the strongest portfolios of potent, chemically distinct Cpams."

Data presented at the ILC appeared to support his optimism. To date, two cohorts (100 mg and 200 mg) of HBV patients have completed dosing in the phase Ib trial, on top of three (100 mg, 200 mg and 300 mg) cohorts in the phase Ia study in healthy volunteers. A third HBV patient cohort receiving 300 mg is ongoing. Two HBeAg-negative patients also were treated at 400 mg, according to the company.

The phase Ib study enrolled both HBeAg-positive and negative patients. In the ongoing 300-mg dose cohort, the mean overall decline from baseline is currently ≥2.8 log10 IU/mL, with ≥2.9 and 2.5 log10 IU/mL mean declines in HBeAg-positive and negative patients, respectively. Maximal viral load declines of 3.6 to 4 log10 IU/mL were observed in certain HBeAg-negative patients treated at all dose levels (100 mg to 400 mg).

Across all cohorts in the phase Ia and phase Ib studies, ABI-H0731 was generally safe and well-tolerated, with no severe adverse events or dose-limiting toxicities and no pattern of treatment-emergent clinical or laboratory abnormalities observed. Among the 62 patients and volunteers treated, treatment-emergent adverse events (AE) were observed to be minor, except for a grade 3 rash at the 400-mg dose that resolved rapidly without intervention other than treatment discontinuation.

Compared to data from Johnson & Johnson (JNJ) with JNJ-6379 and Roche Holding AG with its PADD-ON study of peg-interferon added to an ongoing nucleos(t)ide-based treatment – both publicly disclosed showing HBV DNA reductions of 2 to 3 logs – "these data make ASMB's drug the most potent in the class," Jefferies LLC analyst Michael Yee wrote in a flash note. As he pointed out, details revealed by Assembly beyond the confines of the poster indicated that multiple patients went to undetectable levels, and 3-log reduction was seen even in harder-to-treat HBeAg-positive patients.

Yee dismissed concerns about the grade 3 AE since the rash, he pointed out, occurred in a patient at day 10 following a seafood meal. The drug was discontinued "out of conservatism," and the rash disappeared. The same patient had a 4-log virus drop within eight days, Yee wrote, "and 60+ other patients had no issues."

The 300-mg arm of ABI-H0731 would have been even stronger but one of the four patients could only drop 2.5 logs, as he was undetectable, Yee added.

'It's a new frontier'

Assembly plans to advance ABI-H0731 around midyear into phase IIa combination studies. The first will enroll HBeAg-positive patients on standard-of-care nucleos(t)ide therapy with fully suppressed viral loads. Patients will maintain their existing therapy and be randomized to either placebo or ABI-H0731 for six months, in a design seeking to demonstrate that ABI-H0731 can inhibit the generation of cccDNA molecules by showing a decline in surrogate markers of cccDNA.

A second phase IIa will enroll treatment-naïve HBeAg-positive patients to compare for six months the antiviral effectiveness of standard-of-care nucleoside therapy alone vs. standard of care in combination with ABI-H0731.

Assembly expects results from both studies during the first half of 2019.

"It's a new frontier," Small said on the company's conference call. "We're sort of starting from the premise of simplicity before we get to complexities. So if we can basically fix a nuc by simply adding a molecule that eliminates cccDNA, that may or may not be enough, but clearly we will ask that question to see if we can get that answer. If it's not enough, then clearly we will continue to build a regimen with other molecules or other strategies in terms of therapeutic strategies."

"We await additional data in from JNJ's and Roche's late breaker presentation this Saturday, and acknowledge that they could show added efficacy (although very unlikely given data seen so far)," Yee wrote. "Given what is already known, we still believe ASMB is best-in-class as Roche's drug has to be dosed BID and JNJ has already disclosed several grade 3 AEs and coupled with its very long half-life could potentially present issues in extended duration studies."

The ILC late-breakers are scheduled for presentation at the end of the day Saturday.

But even if J&J or Roche pull rabbits out of their hats, Assembly's data garnered "significant interest" at the ILC, Yee said, including mentions in two HBV symposia through the first two days of the EASL meeting.

"We think ASMB will increasingly be getting on the map of big pharma," he wrote, citing JNJ and Roche, "and big biotech (e.g., GILD), who are seeing this early data play out across the field."

The upshot, Yee said, is that Assembly "remains an attractive M&A candidate for big companies in the antiviral space."

The HBV findings failed to move the company's shares (NASDAQ:ASMB), however, which closed Thursday at $48.90 for a loss of $1.39, or 2.8 percent.

Allergan NASH asset fails to impress

Assembly already has a big partnership with Dublin-based Allergan plc for its gastrointestinal (GI) microbiome programs and additional GI programs, secured last year for $50 million up front and a potential payout of $2.78 billion in development and commercial milestone fees across six indications. (See BioWorld Today, Jan. 11, 2017.)

Ironically, Allergan was met with a cool reception at the ILC Thursday in reporting full data from the second year of the CENTAUR study of cenicriviroc (CVC), an oral CCR2/5 antagonist in development to treat liver fibrosis in adults with nonalcoholic steatohepatitis (NASH). The findings, presented during the ILC's general session by Vlad Ratziu, professor at the Hôpital Pitié Salpêtrière and Université Pierre et Marie Curie in Paris, essentially confirmed earlier data that cenicriviroc in NASH doesn't reduce fibrosis meaningfully for most patients, although it may be more effective for those with advanced fibrosis.

A higher attrition rate than expected and imbalance in missing liver biopsy also may have contributed to the previously reported lack of effect vs. placebo, Ratziu suggested, though the difference was small.

"Overall, uncertainty from the audience on inflammation biomarkers and lack of response in year [two] vs. year [one] dominated the discussion," RBC Capital Markets analyst Brian Abrahams wrote in an EASL update, accurately reflecting the mood in the plenary hall. "Overall, we believe these data confirm our view that CVC presents a reduced competitive threat to other late-stage NASH drugs, like ICPT's OCA or GILD's selonsertib," Abrahams concluded.

Allergan picked up cenicriviroc and a second candidate, evogliptin, in its 2016 acquisition of NASH specialist Tobira Therapeutics Inc. for $600 million cash and up to $1.1 billion in milestone-based contingent value rights. (See BioWorld Today, Sept. 21, 2016.)

On Thursday, Allergan's shares (NYSE:AGN) closed at $166.31, up $1.25.