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proteins themselves in large bioreactors. And it would allow scientists to deliver proteins that act inside cells or span their membranes, which are a challenge to introduce from the outside. An mRNA drug would also be easier to control than traditional gene therapy”11. The elegance of the idea was undeniable, but the
practicalities of implementation were immense. One major issue faced by Moderna was that mRNA is subject to degradation when introduced into the human body, along with a myriad of other significant hurdles. In order for the process to work, the mRNA has to avoid degradation, enter the patient’s cells and be translated into a specific protein as determined by the ‘computer’ code of the mRNA base sequence. In order to overcome these difficulties Moderna had ‘built’ an mRNA molecular platform that consisted of the following: i) Delivery: mRNA is formulated in a lipid nanoparticle which acts as the delivery vehicle. ii) Avoid immune system: One of the mRNA bases (typically uridine) is chemically modified. This pre- vents activation of immune receptors that detect ‘foreign’ RNA and destroy it. iii) Enhance protein production: The order and fre- quency of modified RNA bases affect how mRNA folds and controls the efficiency of the ribosome to produce larger quantities of the specific protein. iv) Targeting correct cell: Other regions of the mRNA are modified to target specific cell types. The Moderna platform consists of a variety of
sophisticated chemistries; including nanoparticle chemistry and mRNA design algorithms, and of course the output of molecular mRNA therapies. Servick has written much more expansively about the platform11, and additional descriptive detail can be found in the abundant patent filings of the company. Finally,
in April 2017 Moderna
announced positive interim data from a Phase I clinical trial. A double-blind, placebo-controlled, dose-escalation study in 31 patients demonstrated induced high levels of immunogenicity for its mRNA vaccine (mRNA-1440) against avian H10N8 influenza These results were the first data that, in effect, validated the Moderna mRNA plat- form12.
Platform and reality: We have discussed above that pharmaceutical companies struggled with TTP implementation and integration into their DDD process. The lack of understanding of Technology Development, the THC, Technology Assimilation and TIC S-Curves was a pronounced contributory factor to “…a lack of any significant increase in DDD productivity by pharmaceutical companies”
Drug Discovery World Fall 2018
over the past two decades. Thus it was both startling and refreshing to read that in 2017, Dr Melissa Moore (CSO of mRNA Platform Development at Moderna) mused about the Gartner THC. “Where on this curve, she wondered was their [Moderna] technology?”11. The concern was that if the “trough of disillusionment” was ahead, then it “threatened to be deep”. The conclusions that Moore and senior manage-
ment came to about the THC in regard to a PD3 company like Moderna were both surprising and enlightening. The company had become increas- ingly aware of the secrecy label and the potential damage being done to Moderna. Management pushed back and argued that detailed disclosure did indeed exist in the form of patents filed and issued, and that controlled release of information had clearly not hindered their ability to raise monies and amass a considerable war chest of financial resources (see Table 1). Moore suggested that “wealth and secrecy may … be protective”11. In addition she said “you don’t have to ride up and down Gartner’s hype curve [THC] if you can work through the biggest setbacks before the public ever sees them”. She concluded that, “we’ve had fail- ures. We’ve gone down blind alleys. But because we’ve been quiet about it, nobody’s seen that”. She continued, “that’s why I think we’re going to end up on the slope of enlightenment without passing the trough of disillusionment”11. Do these thought-provoking comments suggest that this may become the model of how to implement a PD3 approach when employing a concerted, nuanced but
clear understanding of Technology
Development, THC, Technology Assimilation and TIC S-Curves?
Valuation and platform-DDD Noubar Afeyan was recently interviewed (June 7, 2018) on WBUR (a public radio station in Boston) about his views on DDD as well as Moderna Therapeutics13. Dr Afeyan was as usual, thought- ful, insightful and provocative. In particular, he clearly articulated the changing paradigm of DDD associated with a PD3 approach. He stated: “I’d say the one big shift that [we’ve seen] is that people are making this less of a bet on a single drug and more of a bet on a platform which can produce many drugs. All of our companies [Flagship Pioneering] have decided that the way to innovate and create new products in this field is not by bet- ting on a drug, but to bet on a platform that can generate many. And in that regard, those compa- nies require a lot more capital, but also provide a lot more opportunity for reward than the single bet
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