Thinking Ahead: Building a Broad Arsenal Against Infectious Disease

Ankit Mahadevia, CEO, Spero Therapeutics

After a late start, I’m optimistic the community will adapt and get the SARS-Cov-2 pandemic under control. But what happens next? Months from now, does the urgency of the battle against infection fade away?

That is the sad truth about so many disease outbreaks of the past. Truly being prepared for the next one means keeping up a sustained, multi-faceted effort over many years. This includes everything from testing to data surveillance to the continuous development of treatments and vaccines. 

Evolution is relentless. Nature is already developing the next viral, bacterial, or fungal invader that will pose a threat. These threats often come in rapid back-to-back succession; recent studies have noted that secondary bacterial infections afflict many patients hospitalized with COVID-19 and caused over half of the deaths related to the H1N1 pandemic. Even in a typical year without a pandemic, the CDC estimates that at least 3 million Americans each year suffer from infections that are resistant to today’s available therapies.  

I’ve discussed the opportunities and challenges of developing therapies for infection with Luke on The Long Run podcast in August 2018. We continue to be dedicated here at Spero Therapeutics to staying in the fight over the long term. Our mission is to develop new medicines for serious infections that afflict millions of Americans each year.

Until COVID-19, most people in the US didn’t think much about our vulnerability against infectious diseases – whether they be viral, bacterial, or fungal in nature.

Here’s how we think about developing treatments, as one important component of a strong defense arsenal for public health.

The issue   

The pharmaceutical industry used to have considerable capacity for discovering, developing, and manufacturing anti-infective medicines. That capacity, particularly for the fight against bacterial and fungal invaders, has been dwindling for many years. The bugs, of course, are oblivious to such things. They continue, through the relentless march of evolution, to develop means of resistance and escape from our existing arsenal of antibiotics and antifungals. The tools we have are becoming obsolete (see our team’s primer on resistance here).    

Why are we in the position of being this unprepared across the board against infectious disease?  We thank collaborators such as Kevin Outterson, a professor of health law at Boston University, who with his colleagues has undertaken comprehensive review of the issue.  

For those looking for the short version, it goes something like this.

Scientific hurdles: Discovery of an anti-infective poses unique hurdles.  It needs to be toxic to pathogens without being toxic to humans. It needs to have a reasonable pharmacokinetic and pharmacodynamic profile, which translates roughly into a distribution, absorption and dosing profile that makes for a practical drug people can take. Many patients with serious infections (like COVID-19) are best treated outside of a hospital to prevent patients from spreading infection, which unfortunately happens too often. That means an intravenous treatment that works is good, but oral bioavailability really needs to be a top priority, because pills can easily be taken by patients at home. Add all these factors to the list of desired characteristics for anti-infectives, and it’s no surprise why novel, broadly effective oral medications in particular are not part of our arsenal against infection. It’s a tall order, scientifically.

Economic hurdles: The economics just don’t work for some anti-infectives even if they are needed for public health. These economic hurdles are exemplified by the IV antibiotic therapies introduced into the commercial marketplace by Tetraphase Pharmaceuticals, Melinta Therapeutics, and Achaogen. The former company was recently acquired for a bargain price, and the latter two companies went bankrupt after attempting commercial launches.  

What’s the core of the problem?

  • Reimbursement: Certain medicines, like agents marketed by these firms, require healthcare institutions to pay for them out of a fixed fee, regardless of what is needed for their care. This is known as the diagnosis-related group (DRG) payment for an inpatient admission. The DRG is a natural disincentive to use innovative medicines since their cost comes directly out of an institution’s bottom line. If a hospital limits its usage of a patented (more expensive) medicine, it gets to keep a larger portion of the fixed fee it collects from the health insurance provider. For some patients, this may be good enough (for others it is not). The concerning implication is that this places a brake on the uptake of hospital-based medicines and therefore on private incentives for their discovery and development. The problem for our public health is magnified as evolution renders the anti-infectives we do have obsolete.
  • Market size: Second, for certain unmet needs, like those addressed by the three companies mentioned above, there just aren’t enough patients. Some medicines needed for our public health fight are infections that aren’t prevalent yet (but would be catastrophic if they were). Who will buy these medicines, and how much would they be willing to pay for something that doesn’t pose a clear and present danger like COVID19? This issue is compounded by the short course required for a cure (a feature otherwise), and the DRG disincentive we’ve reviewed. The data tell the story – fewer treatment days correlate with dramatically lower initial sales (see our blog for more). On the positive side, the data also identify areas, such as oral medicines for complicated urinary tract infections (cUTI) and non-tuberculosis mycobacterial (NTM) disease – where prevalence of need can drive a pragmatic solution, which is the core of our strategy. 

A pragmatic solution for our public health we can undertake: Smarter, sustainable business models and collaboration for the public health

Building a sustainable infrastructure to fight future threats requires a multi-strategy approach. It requires investment for sure, but the multi-trillion dollar cost of COVID-19 to our economy suggests that for a far smaller sum, we can be better prepared for the next big one.

As Bill Gates wrote in a Feb. 28 editorial in the New England Journal of Medicine:

“In any crisis, leaders have two equally important responsibilities: solve the immediate problem and keep it from happening again. The COVID-19 pandemic is a case in point. We need to save lives now while also improving the way we respond to outbreaks in general. The first point is more pressing, but the second has crucial long-term consequences.” 

Here are a few places to start in thinking about a long-term approach to developing our arsenal against infection:

Build a base with sustainable products: Policy solutions contemplate a base community of drug developers willing to take on the charge once incentives align. Infectious disease requires specialized expertise. The key to ensuring this part of the solution lies with us in the industry. We need to invest in therapies that serve sustainable markets, which keep talented people motivated and engaged on a multi-year quest. This is the core of our strategy and that of other firms, focusing on oral solutions for cUTI and NTM disease. These are indications where there are enough treatment days of unmet need to support a market, delivered outside of the reimbursement-constrained institutional setting.

With a base built by sustainable products, sustainable companies can exist. Companies supported by sustainable products are stronger collaborators, better equipped to support our public health infrastructure. While we advance sustainable products, we also collaborate with groups such as the US military’s Biomedical Advanced Research Projects Agency (BARDA), the National Institute of Allergy and Infectious Disease (NIAID) and the Bill & Melinda Gates Research Institute. Even though we don’t yet have revenue-generating products, we dedicate some of our efforts to the advancement of medicines for diseases such as TB, and hospital-based drug resistant infections – areas that we could not prioritize for private sector investment. 

Collaborate with public and private institutions to serve public health needs: Complementing a smartly constructed portfolio, policy is required to align incentives to develop approaches to certain public health threats. Julie Gerberding of Merck, a former CDC director, does an excellent job of explaining the charge to policymakers to ensure a strong arsenal against infection for the future. For IV medicines and others with a “treatment days” problem, this is particularly required. The Orphan Drug Act and business models that evolved from this paved the way for orphan medicines to solve their treatment day issue, by facilitating adequate reimbursement. Fortunately, policymakers are thinking ahead here with a variety of potential solutions, such as the DISARM Act that aims to address the disincentives that DRG poses for anti-infectives.

COVID-19 has brought to life for all of us how it feels to be attacked by an unseen invader for which we don’t have any effective weapons. This feeling is not unique to COVID-19; millions each year suffer this way. The unmet need for new therapies is vast. We have to do better in our comprehensive approach to infection; by applying the lessons from COVID-19 with a pragmatic approach to portfolio selection and drug development.

With the right public and private investments to support treatments in the public interest, we will make a difference.

Thanks to Sharon Klahre and Cristina Larkin at Spero Therapeutics, Kevin Outterson from Boston University, and Aleks Engel from the Novo REPAIR Fund for their advice and input.

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