Super-drugging the superbugs

Innovation is taking off again in the pharmaceutical industry with a healthy 20 percent growth in patents published in 2016. This follows a period of intense realignments, consolidations, mergers and acquisitions driven by the loss of patent protection for many blockbusters owned by the major companies and the consequent increase in generic competition. The recent Medicines for Europe 13th Legal Affairs Conference highlighted the anticipated approval of a large number of new products over the next few years flowing from pipelines bolstered by new investment. The conference also highlighted cancer, inflammatory diseases and diabetes treatments as continuing major areas of focus, with autoimmune therapies rising up the list. Companies are now also beginning to target niche or orphan diseases with smaller patient sets or areas that had previously been ignored or not deemed to have a good cost/reward ratio.

A study of the patents published in 2016 shows that, in addition to the top three indications, there is a renewed focus on antibiotics. This should not be too surprising as we confront the impending threat of drug-resistant superbugsIn June 2016, Hoffmann-La Roche subsidiary Genentech had two PCT (Patent Cooperation Treaty) applications published (WO2016090040 and WO2016090038 respectively) that protect a new approach consisting of binding particular antibodies to existing antibiotics to overcome resistance and/or enhance the ability of the antibiotic to kill the bacteria and is a modification of the antibody-drug-conjugate (ADC) approach being used to target cancer in particular.

Companies have also been focusing on means to combat the resistance mechanisms themselves, to give new life to existing antibiotics. Several approaches have been investigated that appear to show promise in initial studies. Amongst these, β-lactamase inhibitors have been one of the top areas in the last year. Primarily these act in combination with existing antibiotics to combat drug resistance, although at least some of these new candidates are additionally being investigated as monotherapies.

Companies active in this area in 2016 include Wockhardt, Rempex Pharmaceuticals Inc. and Mutabilis SA. Wockhardt is developing a portfolio of β-lactamase inhibitors, useful for treating bacterial infections. Its patenting for 2016 reflects this interest with WO2016116788 claiming novel substituted nitrogen containing bicyclic compounds that may be administered in combination with an anti-bacterial agent, e.g., sulbactam, and WO2016128867 claiming azetidinone- containing compounds for sole or combination use.

Rempex is investigating vaborbactam (RPX-7009) a boron-containing β-lactamase inhibitor for the IV treatment of multi-drug resistant Gram-negative bacterial infections, and also Carbavance® (a combination of vaborbactam and meropenem currently in phase III trials) for treating serious multi-drug resistant infections in hospitalized patients. Its published patents include WO2016149393 and WO2016081297 claiming boronic acid derivatives that are β-lactamase inhibitors, whilst the more recent WO2016172208 discloses an intravenous infusion comprising a combination of a boronic acid derivative (e.g. vaborbactam) and meropenem, which is presumably protecting Carbavance.

Mutabilis also published a set of PCT applications (WO2016156344, ‘346, ‘348, and ‘597) in October 2016 claiming heterocyclic β-lactamase inhibitors, useful for treating bacterial infections.

We expect the pace of innovation in β-lactamase inhibitors to continue to grow as basic research results appear in published patent applications over the next two years. If we are to avoid a post-antibiotic world, these innovations need to progress rapidly to fully approved medicines.