By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx)
Bob DeLuccia is a man on the move with a single mission: Addressing the worldwide epidemic of antimicrobial drug resistance, today commonly referred to as AMR. As Co-founder and Managing Partner of Acurx Pharmaceuticals, he is solely focused on developing novel, first-in-class selective antibiotics for difficult-to-treat bacterial infections caused by bacteria that both the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) term priority pathogens due to their resistance to currently available antibiotics.
What makes the Acurx story particularly interesting is the fact that this is a virtual company with only two full-time employees (DeLuccia and his partner David Luci). The pair have nearly 75 years combined experience in pharma operations, raising capital, serving on a variety of boards (big pharma and large biotechs, startups and publicly-traded entities), successful M&A efforts, and broad preclinical and clinical development projects across a number of therapeutic areas, most recently including antibiotics. Through assembly of a product development and support team of expert consultants and scientific advisors in the requisite functional areas, DeLuccia and colleagues have created a very streamlined organization, a fraction of the size of a traditionally common, small company R&D organization.
Since their founding in July 2017, Acurx quickly established a pipeline of antibacterial product candidates. Its pipeline includes an oral formulation of ACX-362E, a compound that has received Qualified Infectious Disease Product (QIDP) status and Fast Track designation by the FDA and has recently completed enrollment in a Phase 1 clinical trial. ACX-362E is a novel DNA polymerase IIIC (pol IIIC) inhibitor which has demonstrated nonclinical efficacy against C. difficile infection, a serious and potentially life-threatening intestinal illness, in a standard, predictive animal model. The second series of anti-Gram-positive drug candidates derive from ACX-375C and share the same unique mechanism of action as ACX-362E.
Strikingly, this was accomplished with $4.4M+ raised by Bob and his Co-Founder David Luci, through three successive equity financings since its inception. Acurx is currently looking to raise more capital in 2019. It is expected that by mid-2019, top line data for ACX-362E will be in hand for a potential IPO or crossover round in late 2019 or 2020.
Antibiotic resistance is a global concern once looming on the horizon but now a full-blown crisis. In the US, former FDA commissioner Scott Gottlieb called for “all-hands-on-deck” to tackle antibiotic resistance. According to the CDC, it is estimated that direct and indirect costs of antimicrobial resistance in the US economy is $55B annually. At least 2 million people in the US develop serious infections caused by resistant pathogens, like MRSA, with at least 23,000 people dying.
Drug-resistant “superbugs” kill about 33,000 people in Europe, a burden that is matched by flu, TB and HIV combined. According to a UK government-commissioned report, they account for 700,000 deaths globally occur each year. If resistance continues on its present trajectory, 10 million yearly deaths globally are predicted by 2050, surpassing cancer, and could cost up to $100 trillion.
Unfortunately, new antibacterial drug development has not kept pace with the need. Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research for the FDA, testified in a hearing before the House E&C Committee, Subcommittee on Health in September 2014: “The decline in antibacterial drug research and development in the private sector, at a time when serious antibiotic resistant infections are on the rise, is a tremendous public health problem, resulting in a very serious unmet medical need.”
Whereas there were 38 drug candidates in antibacterial development in December 2016, according to FDA reports in late 2018, there were only 11 antibiotics in clinical trials that even had the potential to address the pathogens as most critical threats by WHO. The lack of antibacterial drug discovery is a function of both scientific challenges of antibacterial drug development and low profitability that currently exists in the antibiotic marketplace in comparison to other therapeutic areas.
To stimulate and incentivize new antibacterial drug development to treat resistant and “high-priority” pathogens, a number of global initiatives have been undertaken outside the traditional pharma sphere, i.e., by governments (for example, SBIR and NIAID grants) and international non-profit organizations (for example, CARB-X, a $550M fund; and Novo REPAIR Impact Fund with $165M). Also, under active development by various relevant constituencies are “push” incentives to lower the cost of antibiotic drug development, and “pull” incentives such as higher reimbursement, fully delinked market entry rewards (set on pre-defined agreed pricing), and exclusivity periods.
Acurx sees these emerging incentive programs as important opportunities.
DeLuccia, a savvy and experienced drug developer, had kept his eye on new antimicrobial mechanisms to tackle drug resistant bacteria. He became aware of research targeting pol IIIC, which dates back five decades in the labs of Drs. Neal Brown and George Wright, most recently at U Mass Medical Center. Dr. Brown initially observed that the antibacterial mechanism of a novel series of anti-Gram-positive synthetic small molecules involved an enzyme, pol IIIC.
In collaboration with Dr. Brown, Dr. Wright’s lab produced several molecular classes of agents that selectively inhibited “low G+C” Gram-positive bacteria, ultimately resulting in the clinical candidate ACX-362E. Dr. Wright had advanced ACX-362E into IND-enabling studies utilizing SBIR grants, and had scaled-up API, but perceived the need for additional assistance to advance his drug development effort. Continuing to do this on his own was arduous and exceedingly slow. DeLuccia and his team, sensing an attractive clinical and commercial opportunity, offered to collaborate with Dr. Wright to advance development using Acurx’s resources and experienced network of scientific advisors.
To build on Dr. Wright’s discovery and expand Acurx’s product portfolio, “We selected WuXi AppTec after considering several vendors and chose WuXi based on their exceptional capabilities, particularly in antibacterial agents,” noted DeLuccia, “I am impressed with their professionalism, attention to detail, commitment to timelines and generally outstanding service we’ve received, especially considering our small company size.” DeLuccia added, “We view WuXi AppTec as a critical partner working as one team. Our WuXi project team is rapidly advancing to our lead product candidate from the ACX-375C series. I’m delighted to see this kind of progress from program start to in vivo models in just nine months.”
In December of 2018, a first-in-man clinical trial of a pol IIIC inhibitor was initiated with ACX-362E; in February 2019, Acurx successfully completed the single ascending dose portion of the Phase 1 trial in healthy volunteers with promising preliminary data. DeLuccia comments, “Although data are still blinded, we observe fecal concentrations of the drug that far exceed the inhibitory concentration for C. difficile and we also see low systemic absorption, as predicted and desired. The multiple ascending dose portion of the trial has now been completed and data are expected in June.”
An innovative aspect of the trial is analysis of fecal samples obtained from healthy volunteers given ACX-362E or a standard dose of vancomycin to determine the extent of normal microbiome disruption, which will be useful to assess dose optimization of ACX-362E. These results will provide the most comprehensive evaluation of microbiome changes and dose optimization studies ever undertaken during Phase 1 studies and has the potential to create a new paradigm for drug development for C. difficile infection. The impact on drug development could be profound and has the potential to lower the risk of failed Phase 3 clinical trials observed historically.
Acurx is planning a Phase 2 program targeted to initiate in Q4 this year which will be a randomized, controlled study of ACX-362E in the treatment of patients with C. difficile infection. This trial, as well as the Phase 3 program of two large comparative non-inferiority trials, will use oral vancomycin as the standard-of-care positive control treatment.
Acurx’s new series of ACX-375C-derived pol IIIC inhibitors, being developed in a scientific collaboration with WuXi AppTec, are notable in that they exploit a novel bacterial target, are fully synthetic small molecules, and exclusively target sensitive and resistant Gram-positive pathogens involved in approximately six million infections per year in the U. S. alone, including Staphylococcus, Enterococcus and Streptococcus.
The ACX-375C derivative, is being developed as a systemic therapy for Gram-positive bacterial pathogens, including those that are resistant to conventional antibiotics. Since DNA polymerase IIIC inhibitors have a novel biochemical mechanism, they are expected to be active against a wide spectrum of resistant Gram-positive bacteria.
How do these compounds differ from established antimicrobials? Vancomycin and beta-lactams, for example, work at the level of cell wall synthesis, fidaxomicin at RNA synthesis, and fluoroquinolones at the level of DNA topoisomerase. Thus, ACX-362E is unique in its mechanism of action and represents a new class of antibacterial treatment, particularly against resistant strains. This class of novel therapeutics will help to transform the drug-resistant antibacterial landscape so that pathogens on the WHO priority list will be treatable.
How has Acurx been able to move so quickly in building out their pipeline? WuXi’s Research Service Division (RSD) has played a key role with support from an integrated team in medicinal chemistry, molecular modeling, biology, DMPK and pharmacology that we anticipate will lead to new molecules Acrux can bring forward into in vivo infection models and IND-enabling toxicology studies in the coming months. DeLuccia commented “We’ve benefited from WuXi’s experienced modeling group using a three-pronged approach: virtual screening, SAR-based design, and scaffold hopping. We’ve been able to prune from thousands of possible structures to tens of promising compounds. The rapid synthesis and turnaround at WuXi have made this program go very quickly. I compliment the team on its speed and proficiency.”
DeLuccia concluded “With the continuing emergence of resistance to currently available antibiotic treatment a growing problem, we have a compelling need for ACX-375C and ACX-362E, as prototypes to mechanistically novel approaches to a number of product candidates for Gram-positive infections. With no new class of antibiotics discovered since the 1980s, there has never been a more urgent time to pursue this unmet need to create therapeutics that could be transformative in how patients are treated.”
He sums it up by saying “With nearly a 50-year rear view mirror in the pharmaceutical industry with antibiotics, I have a clear vision and a passion to succeed in advancing development of a new class of antimicrobials and in so doing be part of the solution to combat this global AMR crisis.”