Rx for Drug Development: New Modalities and Manufacturing Innovation

One clear way to stem this decline is to unlock previously undruggable targets through the development of entirely new therapeutic modalities. As we all know, this evolution of the industry is well underway. In 2000, the top ten selling medicines were all small molecule drugs but, in 2018, only three of the top ten were small molecules with the rest being biologics and, notably, one of the top selling drugs in 2021 was an mRNA vaccine. We have also seen the emergence of RNAi and cell and gene therapies during this time.

These therapies are following a journey up the central dogma of biology, with each successive modality more precisely targeting the cause of disease. This journey began with small molecules and then moved to its effectors, biologics; now, we are moving beyond biologics to mRNA and RNAi, with the final destination of DNA-based drugs. This transition has been enabled by a better understanding of the genetic basis of diseases facilitated by dramatic (i.e., more than exponential) declines in the cost of DNA sequencing and synthesis. Genetic data is becoming an increasingly important feature of FDA-approved drugs — human genetics was used as evidence for two thirds of those approved in 2021.

The success and the future of new modalities, however, relies on the bioprocesses used for preclinical, clinical, and commercial manufacturing. Traditionally, manufacturing had been viewed as a cost center rather than a key capability, but it is critical to the translation of a novel modality. Those discoveries are made at laboratory scale with very small amounts of drug but, to make an impact for patients, need to be scaled up, for example, to billions of doses of an mRNA vaccine.

As we move up the central dogma of biology, the complexity of the drugs increases, proportional to their molecular weight, and so too does the manufacturing process, resulting in the manufacturing process defining the product. Examples of the manufacturing process impacting the pharmacology of the drug abound — from epotein-associated pure red cell aplasia caused by interaction with the preservative polysorbate 80 to double-stranded RNA causing innate immune activation in mRNA medicines. Manufacturing complexity has always led to initial challenges in all three classical metrics — cost, quality, and time. The industry is assailed for high COGS, and product quality issues have led to regulatory delays and, in some unfortunate cases, to clinical events.

It turns out, however, manufacturing technology improvements reliably come to the rescue. These improvements parallel the same exponential improvements that we have seen in the semiconductor industry. The cost of penicillin dropped from $11,000 per kilogram right before WWII to $18 per kilogram by the mid 1970s — an order of magnitude reduction in cost per decade, as more efficient and scalable technologies were introduced for its production. Similar exponential improvement have been seen in monoclonal antibody production, from 0.1 g/L titer in the early 1990s to more than 50 g/L today, approximating an order of magnitude improvement per decade. mRNA process technology has seen an even more dramatic improvement. A decade ago, mRNA was considered unstable, immune-stimulatory, and difficult to produce and deliver. Technological innovations have addressed all of those challenges and dramatically scaled production from less than 100,000 doses in 2019 to more than 800 million doses in 2020 at Moderna. This exponential improvement in technology is a generalizable feature of every new platform technology, and it provides the impetus we need to continue to invest in new modalities.

While more needs to be done, the pharma industry is beginning to break the trajectory of Eroom’s Law. The introduction of new therapeutic modalities has reduced the cost of failure. These medicines more precisely target the genetic basis of disease, reducing the size and associated cost of clinical trials. We are at the initial stages of a bright and exciting future for the pharmaceutical industry that we can expect to look quite different in the next ten or twenty years