(please read financial
conflict at the end)
We are in the midst of the largest recorded outbreak of Ebola hemorrhagic fever virus ever and there is little evidence that its spread is being contained. Here, I will make the case how TKM-Ebola,
the most advanced Ebola therapeutic in clinical development, could help in avoiding
ever more damage from the deadly virus.
How TKM-Ebola could
help
1. Give suspected cases an incentive to go to the
treatment centers.
2. Provide medical personnel with a stand-by
and therefore help in their recruitment.
The continued spread of Ebola can be partly attributed to a breakdown in confidence in the authorities and fear by medical personnel.
I have been viciously attacking the World Health
Organization (WHO) that by downplaying the significance of the outbreak it has been a key factor in
re-igniting viral spread. It is the WHO
who have tried to minimize the true numbers of infected, possibly in
cahoots with local authorities, and laughed off the suggestion that the virus could
get on a plane in arguing against any kind of travel restrictions. Of course, it recently did and I am still waiting to see top WHO officials send their families
on a vacation to Western Africa. But
probably the most outrageous insult was in suggesting that the spread of the virus
is explained by ‘funny’ cultural practices in these countries such as kissing
the dead during burials.
The WHO, probably in the comfort of their headquarters in Geneva, even attacked on-the-ground Medecins Sans Frontieres
as alarmist for calling the outbreak ‘unprecedented’ in late March.
This notion that the virus is very bad in spreading from
person-to-person and can only do so with the help of obscure practices is obviously wrong given that more than 100 medical personnel have
become infected. While I am still waiting for an explanation by the WHO of how this could happen, I refuse to believe that they kissed the dead in the
treatment centers or licked any other of their body fluids for that matter. Has the WHO (and others) maybe considered the
unthinkable, namely that the reason why this is the biggest ever spread of the
virus is because the virus has mutated and new routes of infections are
possible, such as by aerosol? The US
military will have its reason to believe that this could happen, otherwise why
would they be so concerned about it being weaponized and spending hundreds of million dollars on the development and stockpile of an Ebola therapeutic such as TKM-Ebola?
And if people that protect themselves with space-suits get
infected, how would you feel as a suspected case of Ebola?
I know I would do anything NOT to go to these treatment centers,
because what is obviously for the good of the overall population would
only exponentially increase my risk of contracting the infection in case I was one of those wrongly suspected to have Ebola.
In my opinion, providing individual isolation wards with the
best medical equipment possible, a dignified environment, and a drug as an option for the patient could
make the difference in whether suspected cases will turn themselves in or
not. The argument that ‘this is Africa’
and you cannot expect good medical care there should not count in this day and age
when equipment can easily be shipped between continents. It’s probably far cheaper to do it now than
further risking for the virus to go global (obviously, the WHO thinks this is impossible).
And for medical personnel, the benefit of making TKM-Ebola
available is obvious and most tangible: since the onset of flu-like symptoms in
this population is highly likely to be due to Ebola and because they have ready
access to the necessary equipment such as infusion apparatus, they could be
treated immediately with the agent.
Treating as soon as possible is thought to be critical for TKM-Ebola to
be efficacious.
What is TKM-Ebola?
TKM-Ebola is an intravenously infused RNAi Therapeutic that has been demonstrated to save the lives of monkeys infected with an otherwise fatal
dose of Ebola. It is being developed
under the ‘Animal Rule’ in efforts funded by the US government which is afraid
that this virus could be weaponized and used as a bioterror agent. The ‘Animal Rule’ is a development pathway
instituted by the US FDA for diseases such as Ebola for which it would either be
impractical or unethical to conduct efficacy studies in humans.
Because natural outbreaks are unpredictable and
experimentally infecting volunteers with the virus out of the question, these
monkey studies are as good as it gets regarding drug efficacy (so much for
the mantra that there are ‘no drugs for Ebola’).
An important second element of the Animal Rule is that human volunteer studies demonstrate acceptable safety at the doses corresponding to the efficacious dose in monkeys. For this reason, pivotal phase I safety studies have begun this year in
healthy volunteers (so much for the notion that licensed Ebola drugs are far
off- ‘phase I’ is misleading).
Clinical Hold
Unfortunately, in the midst of the outbreak, the FDA instituted
a Clinical Hold on the TKM-Ebola safety study because a case of
dangerously high cytokine elevations was observed at the highest dose planned in this dose-escalating/dose-finding study (0.5mg/kg). I agree that this is to be
considered a serious adverse event in a volunteer that is not infected with the
virus.
The reason for the cytokine stimulation is likely due to
TLR-mediated, lipid-amplified innate immune stimulation, a known risk of
liposomal RNAi delivery, especially at doses of 0.5mg/kg and higher. It is also the reason why all other active
development candidates by Tekmira and their licensee Alnylam are conducted in
the presence of transient immune suppression with steroids and the like which in many cases is acceptable given the severe diseases these treatments go after.
As indicated, the adverse event at 0.5mg/kg should by no
means spell the end of TKM-Ebola. Firstly, the company argues that the pharmacologic corresponding dose to those
curing the monkeys is lower than 0.5mg/kg.
Secondly, a side effect that is not tolerable in healthy volunteers
(usually ~20-year old male students) could be well tolerated in subjects with a
70-90% likelihood of dying from a disease in a matter of days. It is ethically more troubling to involve
healthy volunteers in such drug development just as aggressive experimental cancer drugs are
hardly ever tested in healthy volunteers. Lastly,
there may be ways to avoid the side effect altogether, such as by using
transient immune suppression. However, I
do not know whether transient immune suppression is possible for Ebola, but I
expect Tekmira will have the answer for this from their large-scale animal experience.
Next steps
For TKM-Ebola to have the best impact on the current epidemic,
the first step would be to start manufacturing it at scales sufficient to treat at least ~1000-5000 patients. This takes time and
given the uncertainty around the future course of the epidemic, the investment
needs to be made now instead of waiting until it is too late for a
treatment center-focused approached involving an intravenously infused agent.
The next step depends on the feasibility of steroid
pre-treatment during an Ebola infection.
In case that it is known that steroid pre-treatment was of
little concern (e.g. based on infected monkey studies), start treating rather
aggressively (e.g. start at doses of 0.25mg/kg). In case it was not, go about more slowly by
starting at sub-therapeutic doses as low as 0.025mg/kg and treat the initial
experience like a dose-escalation study in actually infected patients. Of course, everybody would need to provide
informed consent. In general, any
semblance that the use of TKM-Ebola was imposed by the Western world and the
local population used as guinea pigs is to be avoided which is probably a key
reason why Tekmira to my mind has been almost in hiding during this whole episode almost to the point that they (and the FDA) are glad about the Clinical
Hold.
Disclosure: Tekmira
constitutes a meaningful part of my investment portfolio and I have to credit
the WHO for greatly increasing its value.
