Biotech Versus the Superbugs

Drug-resistant bacteria remain a significant problem so every biotech company contributing to the fight deserves recognition. UK-based immunotherapy company Centauri Therapeutics recently unveiled its first clinical candidate in its ABX-01 program, a compound designed to target serious gram-negative bacterial infections in the lung. Armed with a dual-action mechanism and backed by CARB-X and Innovate UK, this candidate is designed to protect when antibiotics are falling short.

We spoke with Centauri CSO Helen Bright to learn how this breakthrough might just be the first of many milestones.

Why is the development of new antibiotics so imperative?
 

Antibiotics underpin modern medicine, without them everything from cancer treatment to caesarean sections would not be possible. However, it is getting more and more difficult to treat infections. Traditional antibiotics are failing to effectively treat infections caused by Gram-negative bacteria. This is partly due to increased numbers of high-risk patients with underlying co-morbidities and/or immune suppression, and also due to the rise in anti-microbial resistance.

The current pipeline for new antibiotics is insufficient to meet this growing global need and there is a lack of innovation in the field. Many non-clinical antibiotics are still based on traditional antibiotic targets, so new approaches with novel mechanisms of action are therefore highly desirable.

How does a dual mechanism of action enhance the efficacy of ABX-01 against multidrug-resistant bacteria?
 

The novel peptide in our molecule provides broad-spectrum anti-bacterial activity against MDR and XDR gram-negative bacteria. This intrinsic antibiotic effect occurs when the peptide binds to the bacterial surface in sufficient concentration, and for sufficient time, to disrupt and destroy the bacterial membranes. 

On the other end of our molecule is a glycan effector moiety that engages natural anti-glycan antibodies and mediates immune-driven bacterial clearance. This requires binding at lower drug concentrations for a shorter time, providing rapid immune clearance at sub-bactericidal concentrations. This opens up the possibility of treating patients who have hard to treat infections that are less susceptible to traditional antibiotic modalities, as well as MDR and XDR strains.

Gram-negative bacterial infections are notoriously difficult to treat. What differentiates ABX-01 from existing antimicrobial therapies, and how do you see it fitting into the current treatment landscape?
 

Our ABX01 molecule has several differentiating properties that could make it a good fit for current treatment paradigms. The broad-spectrum activity, and effectiveness against MDR and XDR strains mean it could be a good option for first-line treatment for serious acute gram-negative bacterial infections, providing antibiotic cover whilst the microbiology lab is identifying the bacterial strain and antibiotic sensitivities.

Unlike Colistin and Polymyxin B (currently the only licenced antimicrobial peptides), our candidate has good lung exposure and tolerability (in pre-clinical infection models) so could replace their use as standard of care for hard-to-treat lung infections. Its immune-therapeutic mechanism of action could also synergize well with other classes of antibiotic, especially in biofilm infections where antibody-mediate immune clearance has been shown to be effective. 

The underlying immune mechanism employed by ABX01 is well known, universal, and has shown to be highly potent, even in severely immune compromised patients. Thus, the ability of our molecule to leverage the immune response and focus it to the site of infection may also be beneficial in the treatment of at-risk and vulnerable patients, who have significantly impaired immune activity. 

What have been the most promising preclinical results so far, and what challenges have you faced in the development process?
 

Our most promising results have come from translational infection models. In a nine-day mouse pneumonia model, our candidate delivered impressive survival rates over and above those of the clinical SOC after only a three-day treatment regimen. In a human ex vivo whole blood model, our candidate demonstrates rapid immune drive killing of bacteria in a time frame of minutes, way before the antimicrobial peptide is active.

The biggest challenges have also been in developing new translatable infection models to demonstrate and characterize the immune-mediated activity of our molecule. Traditional anti-bacterial models using broth and agar plates, and neutropenic mice, are not sufficient, so we have applied learnings from other therapeutic areas, such as oncology, where immune therapies are well established.

What key endpoints will you be focusing on to evaluate safety and efficacy?
 

In a phase I healthy volunteer trial, we will of course be closely monitoring a range of safety endpoints, including those related to nephrotoxicity (a common liability with peptide therapeutics) and immune related endpoints, which are standard for a modality with an immune stimulating mechanism of action.

We are still defining a patient population which we could include in a phase Ib, in which we can assess safety in a relevant patient population. This may also provide an opportunity for an early efficacy read out on bacterial lung burden in sputum, for example.

What are the biggest regulatory challenges in bringing ABX-01 to market, and how is Centauri preparing to navigate them?
 

The main regulatory challenge we have experienced during development relates to the fact that although the molecule is synthetically made, it does contain a peptide and has features more often seen in a biologic. Regulatory agencies have therefore taken recommendations from both NCE and biologics guidance documents for non-clinical development. We have navigated this by seeking early engagement with both the FDA and UK MHRA to ensure we had plenty of time to implement recommendations into our non-clinical development package.

How does ABX-01’s mechanism mitigate the risk of resistance development over time?
 

When tested using traditional agar and broth methods, the peptide portion of our molecule generates resistant strains with a similar frequency and profile as traditional anti-microbial peptides. However, what is difficult to model in the lab is the impact the immune effector end of the molecule will have on the rate of resistance generation. The immune clearance mechanism results in a rapid reduction in bacterial counts, which should have a positive impact on the frequency that resistance occurs (i.e. by reducing the risk of resistance development).

CARB-X and other funding bodies have played a key role in supporting Centauri’s development. How crucial have these collaborations been, and do you anticipate additional partnerships as you advance to clinical trials?
 

Centauri is a great case study in how effective funding partnerships can drive successful product development. In the early years, Centauri received some pivotal Innovate UK grants that provided seed funding for the Alphamer platform, resulting in some broadly applicable IP and an anti-bacterial program with interesting lead molecules.

CARB-X then came on board and provided incredible support to Centauri through the lead optimization and development of our clinical candidate. In fact, CARB-X was a key funder keeping the company going whilst we secured and then closed our series A. As we move forward now into the clinic, we would be open to exploring additional partnerships. Please get in touch if you’re interested!