Although ContraFect’s Phase II CF-301 (exebacase) clinical trial for Staph aureus bloodstream infections including endocarditis may achieve the co-primary efficacy endpoint, or the key study goal, of bacterial clearance at day 14 versus placebo, there are concerns about the risk of relapse.

The bacterial clearance endpoint is feasible based on preclinical, or pre-human, and Phase I data, but long-term changes are difficult to predict due to bacteria residing in the tissues, increasing the risk of relapse and later complications. However, a potential drug benefit would be that exebacase will overcome antibiotic resistance, as seen with many antibiotics being used to treat methicillin-resistant Staph aureus strains (MRSA).

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MRSA’s resistance profile means infections can be harder to treat than other bacterial infections. Safety remains a question, some experts said, whilst others had higher Phase II hopes based on the lack of adverse events (AEs) to date.

Analysts said there are high Phase II hopes, as they noted that exebacase may overcome the need for surgery for endocarditis (inflammation of the heart’s inner lining). Yet, although experts agreed that surgical removal of heart valves is a complication of endocarditis, they would like to see Phase III data before knowing if exebacase treatment has the potential to replace heart valve surgery.

Analysts also noted that after completion of the Phase II trial, ContraFect will only carry out one Phase III trial before filing for an FDA approval. Two Phase III trials prior to an FDA regulatory submission is considered the norm. Experts did not comment on the number of Phase III trials, but did say that endpoints such as mortality and stroke should be measured.

If approved, analysts predict exebacase to launch in 2022 with US peak sales of $500m. ContraFect’s market cap is $158m.

The 115-patient, randomised, double-blind Phase II trial (NCT03163446) has results expected in the fourth quarter of 2018. Either exebacase or placebo is used along with standard of care (SOC) antibacterial therapy selected by the investigator. The study is testing infections caused by MRSA and susceptible Staph aureus (MSSA) strains. ContraFect did not respond to a request for comment.

Positive preclinical, Phase I has forecasting caveats

As Phase I did not indicate efficacy data, the positive preclinical work gives reassurance the Phase II may be positive in meeting its 14-day bacterial clearance coprimary endpoint, said three experts. In the data, an undisclosed exebacase dose combination with generic antibiotics vancomycin or daptomycin increased survival in staphylococcal-induced bacteraemia compared to antibiotic treatment alone (p < 0.0001). In time-kill studies with 62 strains, exebacase reduced S. aureus by 3-log10 within 30 minutes compared to 6-12 hours required by antibiotics (Schuch R. et al. J Infect Dis. 2014 May 1; 209(9):1469–1478).

The preclinical work looks promising for the Phase II based on the survival increase and exebacase’s superior effects to antibiotics, said Dr Paul Tulkens, emeritus professor, Université Catholique de Louvain, Belgium and Dr Amesh Adalja, senior scholar, John Hopkins University for Health Security, Baltimore, Maryland.

The 20-subject Phase I (NCT02439359) data in healthy volunteers did not indicate efficacy data, but demonstrated pharmacokinetics (PK) was linear across all intravenous doses (0.04mg/kg, 0.12mg/kg, 0.25mg/kg and 0.4mg/kg) with 0.25m/kg being the optimum dose according to an abstract from the 2016 European Congress of Microbiology and Infectious Diseases (ESCMID) meeting (abstract no. EVLB62).

PK is the branch of pharmacology that deals with the movement of drugs within the body. As this is the same dose and route of administration used in the Phase II study, results bode well for the Phase II, said Tulkens, Adalja and Dr Brad Spellberg, professor of Clinical Medicine, Keck School of Medicine of USC, Los Angeles. Other Phase II coprimary endpoints include maximum plasma concentration (Cmax) and drug time to clearance, both at 48 hours.

Despite the optimism for the bacterial clearance endpoint, the 14-day time frame means bacteria may lie dormant in the tissue, allowing for a chance of relapse, said Tulkens, Spellberg and Dr Lloyd Miller, associate professor of dermatology, John Hopkins Hospital, Baltimore, Maryland. Once relapse occurs, there is a risk of causing spinal cord damage and even death, said Spellberg. Therefore, a primary outcome should have been mortality measured for about 6-8 weeks, said Spellberg, Miller and Adalja.

The drug’s new mechanism will likely overcome the presence of antibacterial resistance, which is a common problem in MRSA treatmentsaid Adalja and Grace Lee, PhD, assistant professor of pharmacotherapy, The University of Texas Health San Antonio. Exebacase, a bacteriophage lysin, degrades the bacterial cell wall, causing immediate lysis and bacteria death, said Adalja.

Antibacterial resistance therapies include beta-lactamase inhibitors such as AstraZeneca’s Zavicefta (ceftazidime-avibactam) and vancomycin, said experts.

ContraFect announced recently it is presenting in vitro and preclinical data of exebacase at the ESCMID/American Society of Microbiology (ASM) in Lisbon in September, which will demonstrate the drug’s ability to resensitise MRSA to penicillin derivatives and first- generation cephalosporins.

In terms of exebacase’s safety profile, the Phase I found the drug to be generally well-tolerated with no AEs reported. Still, it is unknown whether the Phase II trial will show the same, said Spellberg and Tulkens, noting the minimal previous data. However, the lack of AEs is promising for the ongoing trial, said Tulkens, Adalja and Lee. The preclinical work did not have any safety data included.

Surgical removal and prosthesis heart valves are complications of endocarditis, said Adalja and Lee. But Phase III trial results will be required to identify whether exebacase has the potential to overcome heart valve surgery, said Tulkens. In the current Phase II trial, 14 days is a relatively short treatment period and so the bacteria may still remain in the heart valves, said Miller.

Phase III design options

A Phase III trial should be investigating patients with endocarditis or pneumonia, said Adalja, Tulkens and Lee. It should also measure bacterial clearance from the soft tissue, said Adalja and Tulkens. The number of in-patient hospitalisations should be a primary measure, said Adalja, as should comorbidities such as pneumonia, stroke and mortality, said Tulkens.

The patient size should be increased from 115 patients to about 1,000, said Adalja, Tulkens and Miller. The Phase III trial should also look to increase exebacase administration from the single administration in the Phase II to multiple time points to identify any possible superiority effects between the SOC and the study drug, said Miller.

If this study of exebacase as an adjunct to SOC is successful, future trials may investigate the drug as a monotherapy for MRSA, said Adalja and Lee.

by Arafa Salam, PhD, in London

Arafa Salam, PhD, is a reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.