Friday, October 3, 2014

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 millionI 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. 


Steve_382 said...

Today's WSJ says we need to make the drugs now, all of them, and then figure out which ones will be the best as we work through it. The cost to make is minor compared to doing nothing.

tettrazini said...

A dark horse company that may emerge as a significant player in the Ebola vaccine space is NOVAX (NVAX). Their technology allows them to develop and produce vaccines quickly and in quantity. They are progressing well in clinical trials with a number of other important vaccines. NVAX is a BARDA supported company.

Anonymous said...

Dirk take this a step further.. What's the price per dose?? Germans expect cost to care for a ebola patient in Germany 350k per person. If tkmr charge 10k per that's only 100m.. 10k is generous.

Anonymous said...

I think that it is safe to assume that quite a lot of medications that are able to possibly cure such a deadly disease as EBOV might have some side effects. Re. TKM-Ebola, especially since EBOV affects cells outside the liver and, thus, is somewhat outside the most optimal RNAi delivery site.

I am, however quite perplexed by the comments made by the head of the CDC on 10/5, especially in the light of what one of the african survivors told about his reaction to the 3rd dose(!) of Zmapp in an interview in the begining of Sept: "flies. A bed finally opened up, and a doctor treated me with Zmapp. He administered it to me three times. I believe my status as a doctor working internationally worked in my favour in getting me this drug. Still, it was risky – the third dose of Zmapp almost killed me, since I had a strong allergic reaction to it and went into anaphylactic shock." Note that he gave tremendous credit to ZMapp for saving his and a fellow colleagues life.

Notwithstanding, in a later interview the same survivor did not mention the adverse reaction (or it was left out by the reporters):

As ZMapp to my knowledge has been administered to only 7 humans, an extreme allergic reaction in one of them surely is even more concerning than the transenient immune-response seen with the first dose of TKM-Ebola. Do not have the Science to say if the anaphylaxia (ZMapp) or the immune resopnse (TKM-Ebola) is more dangerous per se, however, as the response to TKM-Ebola is much better understood it has a leg up re safety over ZMapp.

In the light of the facts (i.e. strong allergic reaction to ZMapp) it seems almost sinister to single out TKM-Ebola like the CDC Director did, considering that ZMapp probably has some potentially severe and more importanly un-understood safety issues! The quote may of course have been taken out of context or he may even have been missquoted to some extent (Note that in the first version of the article on reuters re the the CDC director's statements Tekmira was not mentioned by name, and the name was added later).

It also seems clear that the CDC do not really want to provide any experimental treatments for this patient, probably because they feel he cheated his way into the country and do not want to encourage this. If any treatment was going to be made available it is clear that it should and would have been offered straight away and not several days later.

Dirk Haussecker said...

You make great points with little to add except that to repeat that the best setting for TKM-EBOLA is very early on in the infection, where an immune stimulation, even anaphylaxis in the worst case, will not add to the risk of tipping the patient's life over the edge. Especially useful for medical personnel even remotely suspected to have been dangerously exposed to the virus.

TKM-EBOLA in its present, intravenous form, is part of the solution, not the cure-all.

Anonymous said...

Here is an exerpt from press in regards to the Dallas patient with Ebola. Sounds like CDC and doctors are less enthusiatic in using TKM agent than the Zmapp agent. Any explanations???? guesses????

"The man in Dallas, who is fighting for his life, is the only patient to develop Ebola in the United States," Dr. Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention (CDC), said on CNN's "State of the Union."
In a media briefing with reporters on Sunday, Frieden said he was scheduled to brief President Barack Obama on Monday.
Frieden said doses of the experimental medicine ZMapp were "all gone" and that the drug, produced by San Diego-based Mapp Biopharmaceutical, is "not going to be available anytime soon."
Asked about a second experimental drug, made by Canada's Tekmira Pharmaceuticals Corp, he said it "can be quite difficult for patients to take."
Frieden said the doctor and the patient's family would decide whether to use the drug, but if "they wanted to, they would have access to it."
"As far as we understand, experimental medicine is not being used," Frieden said. "It's really up to his treating physicians, himself, his family what treatment to take."
Duncan remained in critical condition, Wendell Watson, spokesman for Texas Health Presbyterian Hospital in Dallas, said on Sunday.

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