The future of ASN-100, the lead and only clinical candidate at Arsanis Inc., is in doubt after the Waltham, Mass.-based company halted the phase II test of the hemolysin alpha inhibitor for the prevention of Staphylococcus aureus (S. aureus) pneumonia in hospitalized, mechanically ventilated patients. A planned interim analysis of unblinded data by an independent data review committee (DRC) concluded the study was unlikely to meet its primary efficacy endpoint of preventing the virulent infection for up to 21 days in heavily colonized patients following a single intravenous administration, dosed at 20 mg.

Secondary endpoints for the double-blind, placebo-controlled superiority trial included safety; 28-day all-cause mortality; Cmax, Tmax and AUC; and measures of health care utilization. The trial was designed to detect a 50 percent reduction in the occurrence of S. aureus pneumonia in the ASN-100 arm, compared to placebo.

Although winding down the trial, Arsanis will conduct follow-up visits on patients who received ASN-100, per study protocol.

René Russo, president and CEO, said the company will provide an update on the program following a full review of the data. In the meantime, Arsanis is turning to its preclinical ASN-500 program, targeting the prevention of respiratory syncytial virus (RSV) infection in existing and untreated patient populations.

"We are disappointed to discontinue this ASN-100 phase II trial," Russo told BioWorld. "We continue to believe in the potential of our monoclonal antibody programs to prevent and treat serious infections and remain committed to progressing our other programs, including the development of ASN-500."

Lack of detail about the interim findings and lack of visibility on the next steps made for rough going Thursday. Arsanis shares (NASDAQ:ASNS) fell 78 percent to $3.95 – the low mark since the company priced its IPO at $10 last year – before closing at $4 for a loss of $14.19.

From the start, Arsanis took a different approach to infectious disease by applying monoclonal antibody (MAb) immunotherapies. ASN-100 is a human MAb cocktail comprising the human MAbs ASN-1 and ASN-2, which together bind to and neutralize the six pneumonia-causing cytotoxins produced by S. aureus. ASN-1 neutralizes the cytotoxin alpha-hemolysin and four leukocidins, which destroy human immune cells: gamma-hemolysin AB, or HlgAB, gamma-hemolysin CB (HlgCB), Panton-Valentine leukocidin (PVL) and leukocidin ED (LukED). ASN-2 neutralizes the fifth leukocidin, LukGH, also responsible for the destruction of human immune cells.

In 2016, the FDA granted fast track designation in the S. aureus indication.

The ASN-100 MAb cocktail was optimized by Adimab LLC, of Lebanon, N.H. Tillman Gerngross, co-founder and CEO of the antibody services company, also was an Arsanis co-founder and continues to chair the board.

In 2013, Arsanis, which operates its R&D outfit in Vienna, raised a $20 million series B to fund the phase I/IIa development of ASN-100. That round topped a $10 million series A in 2011, a year after the company was formed. (See BioWorld Today, March 7, 2011, and Sept. 6, 2013.)

Arsanis raised a tranched $20 million round in 2014 and added $15 million in 2016, according to SEC filings, before closing a $45.5 million crossover round in April 2017 led by the Bill & Melinda Gates Foundation, positioning the company for its IPO.

"We're at a pivotal time where we need something in addition to traditional antibiotic approaches," Russo told BioWorld at the time. (See BioWorld Today, April 17, 2017.)

The IPO in November 2017 raised $46 million. At the end of the first quarter, Arsanis reported $64 million in cash and equivalents.

'Preventative approach with monoclonal antibodies holds promise'

Despite the ASN-100 setback, Arsanis could have other formidable challengers in its approach to prevent and treat serious infections while reducing the threat of antibiotic resistance. In April, the company presented data on its ASN-500 series at the European Congress of Clinical Microbiology and Infectious Diseases in Madrid, Spain. Preclinical findings showed the company's human MAbs against RSV neutralized the virus in vitro, providing 50- to 100-fold potency improvements compared to Synagis (palivizumab, Astrazeneca plc/Abbvie Inc.), according to Cortellis Competitive Intelligence, as well as comparable virus neutralization compared to MEDI-8897, considered a next-generation successor to palivizumab. In vitro studies of ASN-500 also showed no escape mutants for theta MAb.

Arsanis expects to move ASN-500 into the clinic next year, Russo said. The RSV program was discovered by Adimab and attracted a grant of up to $9.3 million from the Bill & Melinda Gates Foundation to advance the selected antibody to IND filing.

Competing asset MEDI-8897 was deemed sufficiently attractive as a next-gen RSV play that Sanofi SA last year handed over €120 million (US$127 million) up front and committed to development and commercial milestones of up to €495 million more for a 50 percent share in the asset's economics. The fast track-designated antiviral is in phase II development. (See BioWorld Today, March 6, 2017.)

Despite a hefty price cut on Arsanis stock, to $7 from $33, Piper Jaffray analyst Edward Tenthoff voiced continued interest in the company's MAb approach.

"While too early to know the reason for [the ASN-100] failure, we believe every infection is different and a preventative approach with monoclonal antibodies holds promise for other infections," he wrote in a company update. "Antibodies have multifold mechanisms to neutralize and destroy microbes and long half-lives for durable effect."

Tenthoff saw continued promise in the company's preclinical MAb pipeline, which also includes ASN-200, targeting multidrug-resistant Escherichia coli (E. coli); ASN-300, for carbapenem-resistant Klebsiella pneumoniae (K. pneumoniae); and ASN-400, aiming at Streptococcus pneumoniae. Together with ASN-500, Tenthoff valued the preclinical assets at $125 million.

In April, Arsanis out-licensed MAbs targeting E. coli that were discovered as part of its ASN-200 program. The agreement granted BB100 LLC, a subsidiary of Bravos Biosciences LLC, an exclusive global preclinical development license with an option to a clinical development and commercialization license. Financial terms were not disclosed.

Earlier this month, Arsanis inked a similar agreement with BB200 covering selected MAbs targeting K. pneumoniae from the ASN-300 program, including lead preclinical development candidate, ASN-5.

The Phase II study of ASN-100 had enrolled 153 patients at the time of DRC review, Tenthoff pointed out, noting that "the exact reason for the study failure is not yet understood," with dosing, pharmacokinetics, efficacy and trial design under suspicion until proven otherwise. "Until we receive further information on the ASN-100 futility analysis, we are downgrading our rating on ASNA to Neutral," he added.