Michael Goodman, Contributing Writer
Last May, a Pennsylvania woman was found to be infected with a strain of E. Coli that is resistant to a last-resort antibiotic called colistin. What was concerning was that the bacteria became resistant not through mutation but through the acquisition of a plasmid-borne colistin-resistance gene called mcr-1.
The bottom line is that plasmid-based genes can easily spread to other bacteria, perhaps to so-called “Super Bugs” like carbapenemresistant enterobacteriaceae (CRE) that are already resistant to other antibiotics of last resort. That prospect caught the attention of the CDC and other public health officials.
Antibiotic resistance is on the rise, in part spurred by the pharma industry’s 30-year neglect of antibiotic research. Most antibiotic R&D has been focused on incremental changes to existing classes of drugs; while useful, that will do little in the long term to head off antibiotic resistance. The CDC estimates that more than two million people worldwide come down with serious resistant bacterial infections each year, and at least 23,000 will die as a result.
Big Pharma has by and large steered clear of antibiotics R&D — and until recently, M&As — not wanting to get involved in heavily genericized markets where physicians are cautioned against overprescribing. But government inducements and the relaxing of clinical requirements are easing the industry’s return to antibiotics.
THE PRESCRIPTION FOR MEETING THE CHALLENGE OF MULTIDRUG RESISTANCE
Government and industry are working on several solutions to solve the growing problem of resistance, including regulatory support, policy initiatives, and a renewed focus on pharmaceutical R&D.
Under the GAIN Act (Generating Antibiotic Incentives Now), which became law in July 2012, the FDA extended patent protection for qualified infectious disease products (QIDPs) by five years. It also sped clinical development by granting fast-track-priority review status to QIDPs and also by relaxing the study size requirements for QIDP trials. The EMA (European Medicines Agency), while not as far along, has put out regulatory guidance in final form that mirrors those at the FDA.
The accelerating public health crisis has pushed CMS to propose rules calling for hospitals to implement antibiotic stewardship programs to cut back on unnecessary antibiotic use. The USDA promotes similar practices among farm workers, encouraging cleaner environments for farm animals and less use of antibiotics in feed.
Hygiene is also important, particularly the use of sterile equipment and regular hand washing. But stewardship and hygiene will only prolong the efficacy of current antibiotics before resistance sets in. What’s needed are novel ways of attacking bugs.
Industry and investors have responded to the GAIN act by jumping with both feet into antibiotic R&D, developing new classes of antibiotics and markedly improved versions of existing classes.
A growing number of pioneers are focusing their efforts on the biological mechanisms of pathogen resistance rather than on approaches that directly target the bug. Some early-stage approaches being investigated include:
But the antiresistance approaches that are most advanced and that will soon enter the clinic are in the hands of commercial companies.
TWO COMPANIES PUSHING THE NEW ANTIBIOTIC R&D PARADIGM
SPERO THERAPEUTICS was founded in April 2013 by Dr. Ankit Mahadevia, its current CEO and an advisor at Atlas Ventures, in collaboration with SR One and the Partners Innovation Fund and supported by the Atlas Venture seed program.
Mahadevia stresses that Spero takes a multimodal approach to its portfolio, including novel antibiotics and programs focused on resistance mechanisms. Spero was founded on the research of Laurence Rahme, Ph.D., into virulence factors produced by a variety of gram-negative bacteria. Virulence factors typically help bacteria to invade the host and to evade host defenses. Spero’s virulence blocker program was licensed out to Roche in April 2014.
But virulence blocking was quickly overtaken in priority at Spero by the potentiator program licensed in June 2015 from Northern Antibiotics Ltd. According to Mahadevia, although virulence technology has some nice benefits (e.g., you’re not killing the bacteria, and you’re impacting the cell in a way that doesn’t lead to the emergence of bacterial resistance), there are still some scientific and clinical challenges.
The scientific challenges are surmountable, he says. But the clinical challenges are more formidable and relate to the existing development pathways for narrow-spectrum antibiotics that target a single pathogen. “Federal regulations make it difficult to create a trial design that doesn’t take forever to recruit,” he says. Virulence blockers typically target a single pathogen; it can take time to recruit a trial because fewer patients have that documented pathogen. Also, sponsors may have to run a protocol that calls for a large study. Mahadevia says the FDA is aware of the problem and is working hard to resolve it.
Spero acquired the potentiator program “with a lot of work behind it already.” The potentiator candidate SPR741 can be combined with a variety of established antibiotics such as azithromycin and rifampicin. It works by disrupting the cell membrane of gramnegative bacteria (e.g., E. Coli), increasing its permeability, allowing antibiotics to enter the cell. (The composition of the cell membrane in gramnegative bacteria, in contrast to gram-positive bacteria, has been shown to be particularly resistant to antibiotics.) SPR741 has been shown to be safe in rats and nonhuman primates, and a human dose has been selected. Mahadevia expects it to enter the clinic in the fourth quarter of this year.
Spero is also progressing its DHFR inhibitor, licensed in early 2016 from Promilad Biopharma; the DHFR enzyme disrupts bacterial cell growth and division. And in May 2016, it licensed in gyrase inhibitors from Vertex Pharmaceuticals. Spero plans to pair them with SPR741. Mahadevia says the combination is 32x to 64x more potent than a carbapenem in treating multidrug-resistant infections.
QURETECH BIO AB is a Swedish biotech founded in 2010 to commercialize research from groups based at Umeå University and Washington University. CEO Fritiof Pontén joined in 2014 from AstraZeneca. QureTech was formed with IP and licenses to virulence blockers against mycobacteria tuberculosis and chlamydia. QureTech was funded by the Umeå Biotech Incubator with grants provided by the Erling-Persson Foundation.
Pontén notes that the availability of rapid and accurate diagnostics for determining the severity and progression of chlamydia infections makes it useful in the selection of a clinical regimen. He furthermore believes that this makes chlamydia suitable for a narrow-spectrum therapy, and that the FDA will agree. “This is why we chose chlamydia as a first indication,” he says.
The chlamydia agent blocks the life cycle of the intracellular parasite. Soon after the dysfunctional bacterium is released to infect new cells, it’s cleared by the immune system. The drug has an excellent PK (pharmacokinetic) profile and is easily absorbed. “Such compounds are rarely secreted unchanged. In the end, they’ll be metabolized and won’t reach the microbiome farther down in the gut,” says Pontén. In short, these compounds are selective, sparing normal bacterial flora; they target a pathogenic process rather than bacterial survival, reducing the risk of developing drug resistance.
Tuberculosis is a more serious disease. QureTech saw that by up-regulating the enzyme KatG it could not only boost the efficacy of isoniazid, a mainstay drug against TB, but also reverse resistance to it. Also, long duration treatment with antibiotics, typically six to nine months, gives the bacteria time to evolve resistance. But QureTech sees signs that it can shorten treatment to approximately one month, representing a potential breakthrough in TB therapy and saving approximately $5 billion in global drug costs.
Finally, there is no indication that the FDA would place regulatory restrictions on a drug to treat as threatening a disease as TB. In addition to life-threatening side effects, the direct and indirect costs (treatment, lost productivity, etc.) for a TB case ranges from $282,000 for a patient resistant to at least two drugs of last resort to $646,000 for a patient extensively resistant to key first-line and second-line TB drugs.
Pontén says he needs about $10 million for each program — to bring them through remaining preclinical work and early clinical trials.
OF EXITS AND PRICE FLEXIBILITY
The antibiotic M&A market has been relatively quiet over the past decade, sustained largely by Merck’s acquisition of Cubist for $8.4 billion in 2014, by Cubist’s acquisition of several smaller antibiotic specialists, and by the M&A activity of Allergan and its constituent companies, Forest Laboratories and Actavis.
But Mahadevia says that in the post-GAIN Act world, “you’ll see companies both large and small viewing this as an opportunity rather than a challenge.”
Spero’s lead potentiator program presents several options for monetizing the asset. Insofar as it holds the key to restoring the efficacy of many old-line antibiotics whose utility has been limited by bacterial resistance, it could build a commercial organization and sell the combinations itself. Or it could license the potentiator component on a nonexclusive basis to numerous parties. Mahadevia expressed a willingness to explore both options.
QureTech, at an earlier stage, hopes to get the funding, either through VC investment or through a partner, to advance its chlamydia program to proof-of-concept in man and its TB program to Phase 1. Pontén says he has noticed an uptick in EU venture interest in antibiotic plays. Rather than commercialize his pipeline, he plans to partner his two assets relatively early in development.
Whereas Spero can rely on a syndicate of investors and on funding from BARDA (Biomedical Advanced Research and Development Authority), a division of the U.S. Department of Health and Human Services, and from the Department of Defense, QureTech is at the mercy of a comparatively anemic venture climate in Europe.
Both companies believe that they will not be bound by the low prices of old-line antibiotics. Rather, the novel and superior attributes of their assets, particularly in the context of a worsening public health crisis, will raise the value of their pipeline in the eyes of payers and Big Pharma.