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.
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.
