Motif Bio – Saving humanity one antibiotic at a time

 
Source: https://www.linkedin.com/company/motif-bio/about/

Source: https://www.linkedin.com/company/motif-bio/about/

While it sometimes seems as if humanity is doing its best to destroy our planet, another non-human threat is creeping back up on us: bacterial infection. The advent of antibiotics heralded a golden age for humanity, gifting us the ability to treat and control the spread of infectious disease, saving millions of lives. But bacteria evolve rapidly and, through over-prescription, misuse in patients and negligent overuse in agriculture, strains of bacteria resistant to many of the most common antibiotics have already emerged. While this aspect of the problem can and must be addressed by implementing educational changes and stricter legislation, one seemingly obvious solution is the development of novel antibiotics. 

Source: www.motifbio.com

Source: www.motifbio.com

Motif Bio, a London-based company originally focused on population genetics, has realised the urgency of this problem. In 2012, it redirected its focus towards the development of a new antibiotic compound, effective against multi-drug resistant bacteria.  [In 2011, the US Centers for Disease Control and Prevention counted more than 80,000 infections of MRSA in the US alone, 11,285 of which were lethal.]

It is relatively hard to find novel classes of antibiotics which act in a different way to kill microbes, and yet have few side-effects for patients. And even if such an antibiotic were to be developed, the global policy wouldn’t allow the drug to be sold freely. Instead, due to the looming threat of microbial resistance, the drugs would only be used as reserve-options, sitting at the back of the shelf waiting to be picked up when all other antibiotics have failed, creating very little incentive for pharma companies to channel efforts into their development.

This paints a grim picture of a future which hurls us back into the past, where simple infections could not be dealt with by swallowing a little pill. Not only that, but it would make many aspects of modern medicine essentially impossible, causing communicable disease to surpass non-communicable disease in developed countries for the first time in decades. 

MRSA (methicillin-resistant Staphylococcus aureus) is a gram-positive bacterium, which is harmless when it colonises people’s skin, but nasty when it enters the body and causes infections. MRSA is a strain of Staphylococcus aureus that, over the decades, has become increasingly resistant to most current antibiotics, making it a threat to inpatients in hospitals, who are particularly vulnerable. Vancomycin is a highly potent reserve-antibiotic, a last resort option when an infection is life-threatening and other antibiotics have failed. With reports of MRSA strains resistant to Vancomycin, the call for a new antibiotic against MRSA has been urgent.

Iclaprim, the antibiotic that Motif Bio is trying to license worldwide, inhibits a bacterial enzyme (dihydrofolate reductase, or DHFR) involved in the synthesis of purines, some amino acids and thymidine and results in subsequent bacterial cell death. Since the majority of antibiotics produced and used to date attack the cell wall, resistance against Iclaprim is less likely to arise. Iclaprim was also developed with the mutations in mind that caused bacteria to evade the only other DHFR inhibitor used as an antibiotic. These two properties of Iclaprim suggest it might take longer than usual for bacteria to develop resistance against it. 

Graham G. Lumsden, CEO Motif Bio PLC  Source: https://www.ashtontweed.com/ceo-leadership-series-graham-g-lumsden-ceo-motif-bio-plc/

Graham G. Lumsden, CEO Motif Bio PLC
Source: https://www.ashtontweed.com/ceo-leadership-series-graham-g-lumsden-ceo-motif-bio-plc/

Iclaprim is through phase 3 trials for the treatment of complicated and acute bacterial skin and skin structure infections (ASSIST-1&2, REVIVE-1&2, respectively) and a phase 2 trial for the treatment of hospital-acquired bacterial pneumonia. These studies showed that Iclaprim was no less effective at treating these infections than Vancomycin, and is not associated with renal impairment. Acute kidney injury, especially in patients with diabetes and pre-existing poor kidney function, is a very common side effect of high doses of vancomycin, with up to 30-40% of patients affected by vancomycin-associated renal toxicity. This means that, with Iclaprim, patients would suffer less and hospital costs would be greatly reduced. 

How was it possible for a small start-up to get this far? One key factor goes by the name of Graham G. Lumsden. Having spent 26 years at the pharma giant Merck, it was the newly appointed CEO of the startup who decided to steer Motifbio in one direction only: antimicrobials. According to an interview with Ashton Tweed, being part of a start-up allowed him to make decisions swiftly, avoiding the complicated and stretched-out process of decision-making that afflicts big pharma companies. But why was the decision to focus on antimicrobials, and a single antimicrobial compound at that, so crucial for their success? You probably guessed that one: funding. 

Before his arrival at Motif Bio in 2013, the start-up had several compounds for different therapeutic areas in preclinical trials, and struggled to find investors. Lumsden funnelled all their efforts into Iclaprim, which had previously completed two phase-3 trials (ASSIST-1&2) but failed to get approval because it slightly missed the non-inferiority margins set by the FDA. Due to how far Iclaprim had come in the clinical trial process, it was much easier to find investors. 

However, under Motif Bio’s roof, the FDA granted the antibiotic Fast Track designation and priority review for the intravenous administration to treat acute bacterial skin and structure infections and hospital-acquired bacterial pneumonia. 

The story of Motif Bio is not only one of a promising novel antibiotic, but also of how a previously unsuccessful product can be turned into a winner, not with the infrastructure and capital of big pharmaceutical companies, but with the right mindset and business model.


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