TARGET PRODUCT PROFILE (TPP)
Statement of medical need
A number of authorities globally including the UN, the WHO, the EU, the USA and the UK have spoken about the rapidly-emerging crisis of bacteria becoming resistant to our best antibiotics. It has been described as threatening ‘the end of modern medicine’
Multi-Drug Resistant (MDR) Gram-negative bacteria are a particular concern as we have few treatment options left for this class of bacteria. About 50% of all hospital infections are due to Gram-negative bacteria.
Antibiotic Research UK has decided to focus its research efforts on four key Gram-negative bacteria, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii. All four species are common healthcare-associated pathogens, with E. coli also a common community pathogen. These four species are representative of the global concerns around antimicrobial resistance because resistance to multiple drug classes is encountered in each species, including to carbapenems, our most powerful antibiotic class. Carbapenem resistance is increasingly associated with production of carbapenemase enzymes, which resist licensed beta-lactamase inhibitors (e.g. clavulanate and tazobactam); some are even unaffected by novel inhibitors such as avibactam. These bacteria are also resistant to virtually all antibiotics, including fluoroquinolones and aminoglycosides, with the exception of colistin, an old (somewhat toxic) polymyxin class antibiotic, though colistin resistance has now emerged in many countries. There are no new classes of antibiotic on the horizon that will solve this problem entirely; some novel compounds are not active against all of the four species, others cannot overcome all of the resistance mechanisms.
Effect of antibiotic resistance on patients
Pathogens carrying these antibiotic resistant genes cause many types of infections in the urinary tract, lungs, blood, and other organs. Patients with serious infections have high mortality. If resistance arises to colistin, which it will, then there will be no treatments left. If this happens, which seems likely, then we will be unable to treat or prevent these infections. Childbirth will become hazardous for both mother and child. Adults in large numbers will present with untreatable community-acquired infections. Organ transplants and bone marrow transplants will be impossible. Major surgery for cancers, and immunosuppression for cancer therapy will also be virtually impossible. Mechanical devices such as metal hips and pacemakers will become associated with a much higher mortality because of infection by these MDR Gram-negatives. Without effective antibiotics, large swathes of modern medicine will not be feasible.
There is an urgent need to to invent new antibiotics, though it may already be too late for this to happen in time and at the scale required. Therefore it is essential that we protect current antibiotics – particularly ‘last line of defence’ drugs – from resistance. ANTRUK has chosen to take a number of different approaches to break resistance. One approach is to take antibiotics in combination as has been used for nearly 50 years in cancer and TB treatment. ANTRUK is working with the University of Cambridge using Artificial Intelligence approaches to predict which double and triple combinations might be affective in overcoming resistance. Another approach pioneered by Professor Anthony Coates, St Georges, University of London is to seek to find and develop ‘Antibiotic Resistance Breakers’ (ARBs) that break the resistance that is sure to emerge. ARBs are drugs which one their own do not have antibiotic activity but when used in combination with an antibiotic can break resistance.
Antibiotic Research UK has screened the entire pharmacopoeia library for ARB activity against pan-resistant Gram-negative bacteria and has found activity in some drug / antibiotic combinations. If ARBs can be identified then these could be rapidly developed to fill the gap in the 2020s before new classes of antibiotic are discovered for clinical use in the 2030s.
Rationale for our approach
What is causing emergence of antibiotic resistance?
No new class of antibiotic for use against Gram-negative bacteria has been discovered for over 30 years. Yet resistance can begin to appear soon after introduction of a new antibiotic. The result is that European data indicate growing resistance to our major Gram-negative antibiotic classes such as carbapenems, cephalosporins, fluoroquinolones and aminoglycosides, and a 30% mortality rate for patients with septicaemia due to MDR E. coli. Data from the USA show a similar pattern. Asia, India and China have even higher rates of resistance to these classes, with levels reported in the range 50–80%. This has caused increased use of carbapenems which were earlier reserved for extreme cases in the very sick, immuno-compromised or as a last resort. This increased use is selecting for carbapenem-resistant Enterobacteriaceae (CREs; especially K. pneumoniae and E. coli) and other carbapenem-resistant organisms (including P. aeruginosa and A. baumannii), many of which produce carbapenemases. The most widely reported carbapenemases are KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi Metallo-beta-lactamase), VIM (Verona Integron-Mediated Metallo-beta-lactamase) OXA-type and IMP enzymes.They are encoded by genes transferable between bacteria, which greatly facilitates spread. CREs have been labeled “one of the three greatest threats to human health” by the World Health Organization and others.
Current known resistance mechanisms for our major classes of antibiotic
Our goal is to develop broad-spectrum Antibiotic Resistance Breakers (ARBs) that overcome many of these mechanisms of resistance
Antibiotic Research UK is focused initially on developing combination antibiotic therapies as well as ARB candidate drugs that are able to overcome the diverse mechanisms of resistance that have appeared to our major antibiotic classes. By selecting combinations and ARBs from current approved non-antibiotic drugs, clinical development can be much more rapid and lower risk than use of totally new molecules.
The validity of the antibiotic resistance breaker concept has been long proven with beta-lactamase inhibitor combinations, such as co-amoxiclav (amoxycillin plus clavulanic acid) and piperacillin-tazobactam; as testament to this successful strategy, several others are being developed currently. However, beta-lactamase inhibition alone may not solve the MDR Gram-negative problem. Broad-spectrum ARBs are required that can protect antibiotics classes other than beta-lactams. One ARB may be able to resuscitate several different classes of antibiotic, but not all of them. So more than one ARB will likely be required. We intend to bring three into clinical use during the 2020s.
Target Product Profiles for 3 Antibiotic Resistance Breakers
General criteria for selection of an Antibiotic Resistance Breaker (ARB):
ARBs are molecules to be co-administered with an antibiotic, to break resistance. Molecules will be selected from currently approved and available (non-antibiotic) drugs, nutraceuticals or pure active ingredients of foodstuffs acknowledged as satisfying internationally-agreed GRAS (Generally Regarded as Safe) standards, to allow rapid, safe and low-risk development.
ARBs will be selected based on the following criteria:
- Primary indication: combination therapy for treatment of life-threatening infection by Gram-negative bacteria requiring hospitalisation.
- Secondary indication: potential to be developed for oral therapy.
Route of administration:
- Primary: intravenous, for use in hospitals.
- Secondary: oral, for hospital and GP use.
- Fixed dose combination.
- Primary: single formulation for intravenous dosing. Available as a pre-formulated solution or as dry powder to be rehydrated.
- Secondary: single tablet for oral administration, total dose under 1 gram.
- Intravenous form storage minimum stability 6 months. Oral dose form storage minimum 2 years.
- Heat stable.
- Primary: intravenous, QD.
- Secondary: oral, 1-3 times daily.
Antibiotic resistance is reduced or eliminated allowing renewed use of antibiotic at approved therapeutic dose level and dosing schedule.
- No safety issues added incremental to those of the original antibiotic.
- Suitable for use in all age groups, infant, child, adult.
- No abuse potential.