Ebola Emergency Tests Oligo Manufacturing Readiness

With officials scrambling to put in place measures to contain the further spread of Ebola, it is highly likely that RNAi Therapeutic TKM-EBOLA will be on their shopping list.  This, however, requires the ability to manufacture the oligonucleotide-based medicine in quantities sufficient to treat at least 10 thousand or so either infected or potentially infected persons.  In the absence of commercial Oligonucleotide Therapeutics success stories this could prove to be a challenge, although in this case, I believe it's doable.

Manufacturing, an advantage of TKM-EBOLA over PMOs and antibodies

When the US Department of Defense selected TKM-EBOLA as its preferred Ebola development project a few years ago, manufacturing, and not just efficacy and safety should have been part of the equation.  The reason is that e.g. currently about 0.3mg/kg*70kg/day*7 days= i.e. approx. 140mg of TKM-EBOLA RNA oligonucleotide is required per treatment course.  Since its simple chemistry (a couple of spiked-in standardd 2’-O-methyls in an otherwise unmodified RNA) makes it one of the cheapest RNA oligonucleotides conceivable, let’s ballpark its manufacturing cost at $300 per treatment course at some of the largest possible manufacturing scales possible today (kilograms).  Note that the cost of the lipids in TKM-EBOLA is negligible compared to the oligo component.

1.4kg oligo and $3 million for 10,000 treatment courses.

Taking into account that these are the pure manufacturing costs when protocols have been established, and other monies will have to be spent when starting from sequence design---let’s say conservatively $5 million. I believe given the gravity of the current situation, this is a number we can live with (1/200 of investment in the response).

If you do the same Gedankenspiel for Sarepta’s Ebola therapeutic morpholino antisense candidate, you have to multiply the $3M number first by a factor of 30 for the much larger amount of oligonucleotide required and then by another factor of 6 or so for the greatly increased costs of making morpholinos over standard RNAà $500M+.  A non-starter not just for the increased costs, but also because the manufacturing capacities for that amount of oligonucleotides are not readily available today, let alone for the morpholino chemistry where Sarepta has experienced significant delays in obtaining sufficient oligo supplies for a relatively small (~100 patients on drug at 30mg/kg/week for 48 weeks) phase III program in an orphan diseases indication (DMD).

When we move to Tekmira’s antibody competition, in particular ZMapp, the situation is not all that different from Sarepta’s with the slight advantage that ZMapp could somewhat tap into the established know-how of monoclonal antibody production.  But in the end, we’d be talking about years of process development and scale-up compared to a few months TKM-EBOLA.

Wake-up call for oligonucleotide manufacturing

Although TKM-EBOLA should be within current oligonucleotide manufacturing capacities, the Ebola situation should get oligonucleotide manufacturers wondering whether they are ready for the upcoming surge in Oligonucleotide Therapeutics approvals and sales.  Following years of disappointment about the lack of big manufacturing requests, CMOs have been loath to build the plants that can churn out hundreds of kilos or even tons of oligonucleotides.

Consequently, I attribute the decisions of first ISIS and Sanofi/Genzyme, then Alnylam (for GalNAc conjugates), and more recently also Sarepta, to shift oligonucleotide manufacturing in-house, to this lack of outside manufacturing capacity.  While having manufacturing in-house may sound attractive for a number of reasons, spreading manufacturing risk across multiple vendors is an accepted risk reduction strategy in this and other industries. 

I am therefore hopeful that the ongoing Ebola outbreak will end up increasing oligonucleotide therapeutics manufacturing capacities to rule out a situation that manufacturing constraints could limit commercialization of agents like ISIS-ApoCIIIRx or the HBV agents with potentially very large patient populations.