Reporting top-line data from the first phase IIa segment of its ACHIEVE study of SB-9200 in patients with chronic hepatitis B virus (HBV), Spring Bank Pharmaceuticals Inc. suggested its lead candidate more than met its mark, showing strong safety and evidence of efficacy at week 12 compared to placebo, dosed as monotherapy at just 25 mg daily.

CEO Martin Driscoll launched a company conference call to describe the first clinical results for the oral selective immunomodulator in HBV patients by exhorting listeners to "manage your expectations" about the extent of data that Spring Bank could share from the ongoing trial, but he acknowledged the company was "very encouraged and excited" by the findings. Investors appeared of the same mind. Shares (NASDAQ:SBPH) of the Hopkinton, Mass.-based company, which completed its IPO in May 2016, rose to an historic high of $15.39 Wednesday before settling back to close at $13.65 for a gain of $1.65, or 13.8 percent.

The phase IIa segment of the sequential-cohort, double-blind ACHIEVE trial has an adaptive trial design that enables the company to enroll 80 chronically infected HBV patients between ages 18 and 70 and assign them to one of four dosing cohorts: 25 mg, 50 mg, 100 mg or 200 mg of SB-9200, or placebo, once daily for 12 weeks. Participants then receive Viread (tenofovir disoproxil fumarate, Gilead Sciences Inc.) 300 mg once daily for another 12 weeks of treatment.

The initial phase IIa cohort comprised 20 treatment-naïve chronic HBV patients without cirrhosis who were enrolled across sites in Canada, Hong Kong and Korea. Patients were randomized on a 4:1 basis to SB-9200 or placebo. Primary endpoints included safety, measured by adverse events (AEs), and antiviral activity, measured by change in HBV DNA at week 12 from baseline, with multiple exploratory secondary endpoints.

The initial cohort consisted of 11 hepatitis B e antigen (HBeAg)-positive and 9 HBeAg-negative patients, of whom 80 percent were genotype B/C, the most common Asian genotypes. No serious AEs were observed over the 12-week treatment period. Treatment-emergent AEs ranged from mild to moderate – mostly constipation, diarrhea, nausea and fatigue – and did not require intervention, according to company officials. No interferon-like side effects or grade 3 lab abnormalities were seen.

Alanine aminotransferase (ALT) flares, defined as an increase in ALT above 200 IU/ml, were observed in three patients, but two of these were viral flares identified in patients on placebo. The other ALT flare, identified in one patient on SB-9200 at week four, was associated with a reduction in HBV DNA of 2.26 log10 and a 1.01 log10 reduction in HBsAg, consistent with a beneficial immune flare, company officials explained. Investigators did not observe increase in bilirubin or evidence of hepatic decompensation.

EFFICACY AT LOWEST DOSE NOT FORECAST IN MODELING

Overall, SB-9200 demonstrated a statistically significant reduction in HBV DNA at week 12 (unpaired t-test 2.85, p=0.01) compared to placebo, with a mean reduction of 0.6 log10 (range 0 to 1.87 log10) in the SB-9200 treatment group. For the secondary endpoint of quantitative HBsAg reduction, five of 16 patients (31 percent) in the SB 9200 treatment group had greater than 0.5 log10 reduction at any time point (range 0.52 to 1.01 log10), compared to none in the placebo group.

Spring Bank officials pointed out that the HBeAg-negative patients in the SB-9200 treatment group saw the greatest mean reduction in HBV DNA, at 0.9 log10; three of the seven had a greater than 0.5 log10 reduction in HBsAg. Although both the HBeAg-negative and -positive groups showed sustained response at 12 weeks, at 48 weeks this effect was stronger in the HBeAg-negative group.

Patients in the initial cohort have since transitioned to Viread for the additional 12 weeks.

Despite early days for the trial, Spring Bank officials were understandably encouraged, given that substantially higher doses – up to 900 mg daily – were studied in phase I. The initial phase IIa findings suggest the company may find a therapeutic dose in a range of 50 mg to 100 mg, Nezam Afdhal, the company's chief medical officer, said on the conference call.

"Our modeling did not expect us to see any efficacy at this dose," he said. "When we look at the data, patients who have less viral burden – the e antigen-negative patients – are those that appear to be responding best at this dose. In the e antigen-positive patients, there is a response. However, it's hard to sustain that response, particularly on surface antigen, simply because the viral burden is so high."

Spring Bank officials hope to see a greater dose response in the second, 50-mg cohort of the phase IIa, which is already enrolling.

"This is a monotherapy," Afdhal pointed out. "We're not using anything else to try to help us reduce the virus. The only thing that's being activated is the immune system here, and this is a very high burden for an immune-modulating drug to deal with."

He added, "When you see a dose response at the lowest dose, you're pretty comfortable that you're going to find an [optimal] dose as you accelerate through the different cohorts."

With 26 patients screened to date, officials are hopeful this stage may be fully enrolled in four to six weeks and yield top-line data by the fourth quarter – perhaps even in time to report at a medical conference this year, along with full data from the initial cohort.

Spring Bank is aiming for the annual meeting of American Association for the Study of Liver Diseases, scheduled for October in Washington.

In the phase IIb segment of ACHIEVE, Spring Bank plans to examine the concomitant use of SB-9200 and Viread in approximately 200 HBV patients. Subject to findings from the phase IIa trial and receipt of additional funding, the company plans to initiate the phase IIb segment next year.

In addition, early findings have encouraged Spring Bank, which is developing the small-molecule nucleic acid hybrid compound both as monotherapy and combination therapy, to accelerate development of a fixed-dose combo candidate of SB-9200 and an HBV nucleoside/nucleotide (nuc).

"Our team has already done the early work to show that SB-9200 is compatible in formulation with the nuc," Driscoll said. "We're now going to do more work to develop the formulation so that we have the capability to take that into clinical investigation sooner than, perhaps, we'd earlier forecast."