NIH Meetings 10-22-15

NIH: NIH Meetings 10-22-15 1 11/4/15

NIH Meetings 10-22-15

Female Speaker:
So we're going to have Denis Malvy give his presentation, and then I’ll leave it up to you if
you’d like to sit there or if you’d like to sit at the table because we’ll have a panel discussion
after it's done.

Male Speaker:
Sit here and then I'll come up after that.

Male Speaker:
Thank you.

Male Speaker:
You're good. Your mic.

Denis Malvy:
Thank you. Well, good afternoon, and thank you for giving me the opportunity to present the
last part of the experience of my team, which is involved in the Guinean field context of the
epidemic and who developed the devaluation of the Favipiravir among patients with Ebola virus
disease.

Female Speaker:
There you go.

Denis Malvy:
Okay. All right. So everyone do know by following this -- the very interesting presentation of
my colleague, Favipiravir is an oral route administered drug, a small molecule [spelled
phonetically] conditionally approved in Japan for resistant and pandemic influenza and which is
currently in phase 3 for evaluation during complicated influenza in the United States. The drug
was and still reported with an excellent safety profile and with no major effects reported. The
only contra-indication [sic] we have applied in the field is pregnancy. When we planned the
conception of the protocol for evaluation of the drug, we had already results from in vitro and
most model studies indicating that the drug was less effective against Ebola than influenza.
That's why we were aware that the doses used in the trial should be much higher than the ones
used for influenza.
Hence, in the setting of the clinical trial implemented in Guinea, we used a dosage of more than
1.5 higher than the one used in influenza. Of note, the clinical trial implemented for the
evaluation of the efficacy and the viral activity in human, is a part of a large program financed by
the European Commission and the European Union in which Favipiravir was also evaluated
among animal primates. Of note, the program was composed of a strong social and human
science work package.

The JIKI [spelled phonetically] trial is a non-comparative proof of concept phase 2 trial,
implemented at the peak of the epidemic in forest parts of Guinea when the population was really

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disoriented and terrified. And my team at the time dedicated to the implementation of the trial
had to face in quite hostile conditions for the acceptability of research activities within the
population. Thus, going ahead directly to the implementation of a comparative randomized trial
was not possible. Hence, JIKI is a non-comparative proof of concept phase to trial with
inclusion criteria imposing the validity to the informed consent and the ability of the use of the
oral route. The treatment was made of a dose computed to get a similar exposure than in mice
experiment using a population PK modeling. Finally the dosage, which was used for this first
evaluation was including a loading dose and a maintenance dose administered during a total
duration of 10d. The dosage for children was estimated and applicated [sic] according to body
weight. It has to be emphasized that the dosage used was the one constitutive of French national
guidelines for therapeutic care of evacuated patients with EVD.

The trial has been implemented in forest highlands of Guinea, during the peak of the epidemic in
in three Ebola treatment centers, the one in Kissidougou which was run by Medecins Sans
Frontieres, in Nzérékoré run by the NGO ALIMA, and the third located in Macenta run by the
Croix Rouge Francaise. Following the control of the epidemic in the forest highland Guinea, we
went back to the coastal place in Basse-Guinee close to the capital -- Conakry -- and moved to
implement the trial in a ETC located closely to the airport of Conakry. The latter was dedicated
for healthcare workers infected doing their job.
The primary outcome was mortality at day 14, and the secondary outcomes evolution were the
evolution of the Ebola plasma RNA and infectious loads; the grade 3 and 4 adverse events, the
profile of resistance mutations during follow-up, and concentrations of Favipiravir. The analysis
was completed by a comparison with the pretrial mortality, which was encountered in the same
centers with the same teams, same procedures and same laboratory's tools and scales during the
two and a half months preceding the implementation in the trial in the main important
investigative CTUs

The start of the JIKI trial was at the peak of the epidemic and at a time where there was no real
change in the case fatality rate over the country. So there is the JIKI trial progress. And just to
emphasize that all participants were included by the end of May. At this time, 126 participants
were both eligible, included and to be analyzed for the final analysis. The analysis was
conducted according to age and according to the baseline viiral load Ct value which were pointed
to be the most prominent parameters for fatality outcome. From interim analysis, you see here
the figure of the evolution of the PCR Ct value at baseline and during the follow-up.

The red dots and spots are from patients who died, and the grey dots are from patients who
survived. As you can see, most patients with baseline CT value below 20 died, and even if,
before they died, some of them could had an increase in the CT value. Most patients with
baseline CT value above 20 survived, and most of them experimented an increase in their CT
value during their follow-up. On the table on the right, you can see the percentage of people who
reach undetectability within four days, and the median gain in CT value during the four days
following the administration of the drug administration. Among participants with baseline CT
value below 20, you can see that 51 percent of them reach indetectability at Day 4 and the
median gain of CT was up to of +12 at day 4, which accounts nearly for a decrease in viral load
of a level 4, and an estimated decrease in viral load of 0.33 log per day of follow-up.

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On the left side you see the figureof the correlation between the baseline Ct viral load value and
the baseline creatininemia. Definitely the patients who had very low baseline CT had increase
creatinemia level, and most of them died.
On the table on the right, you see the value of creatinemia at baseline according to baseline CT
value. For patients with baseline CT value below 20, 81 percent of them had high serum
creatinine value, indicating the corrolate of acute kidney failure, and 100 percent of them died.
Among patients with baseline CT value above 20, only 42 percent had normal volumes for
creatininemia and providing the application of the standard of care with IV fluid resuscitation, 7
percent of them only died.

The powerful and prognostic [spelled phonetically] value of creatininemia was reinforced by its
strong correlation with the other biochemistry analytes, ie, the CPK and the AST. And this
composite indicator was indicating the global tissular damage linked to the Ebola virus disease in
patients with poor profile of outcome. You have a picture referring to a blood sample after
centrifugation among a patient with a bad outcome. And we can acknowledge that this picture
with very troubled plasma referring to a tremendous breakdown may be recognized as a
harbinger of a bad outcome in mirror with the results from the biochemistry analytes.

On this table are presented the modality of response to treatment by baseline CT value, and
findings from both JIKI and the pretrial picture. On the left side, you have the columns of the
mortality rates in the JIKI trial in patients receiving Favipiravir and in the right side, in patients
hospitalized in the same centers as pre-trial. Overall the mortality was 57 percent in the three
months pretrial and of 48 percent during the JIKI trial. Among participants with baseline CT
value below 20, we had no difference between the two pictures; ie, 85 percent in the three
months pretrial and 93 percent in JIKI.

Among patients with baseline CT value above 20, the mortality rate was 30 percent in the three
months pretrial picture and 15 percent in the JIKI. Herein, a pilot proof of concept trial deserved
no formal conclusion about the efficacy of the activity of drug monotherapy.
But our results are arguing for the positive signal for activity and he tolerability and safety of the
monotherapy under the condition of JIKI. Further PK analyzes are ongoing to optimize dosing.
Beyond the evaluation of the concentration measurements, we are seeking to the link with the
viral load decrease and the survival results over 200 patients (the 126 formally included in the
trial and 80 more included in the conditional accelerated approval process- phase 4 cohort) is to
be produced and reviewing today

By the presentation of the interim analysis, the WHO concluded that no firm conclusion
regarding the efficacy were to be provided. And we are confident that may be things could be
moved within the next times for seeking the perspective following the conclusions we published
today. The monotherapy with Favipiravir is definitely not effective in patients with low CT
value. But the regimen provided a signal of capacity for decreasing mortality in other patients,
deserving further evaluation in other phase 3 trials. Providing and given the high safety and
tolerability profile, high doses could be tested as definitely no side effects have been identified.

Now, last but not the least. As we do know, up to five patients today have received drug within

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compassionate use, mainly among evaluated and imported EVD patients, but with different
dosages, different durations of administration and also in combination with other experimental
drugs. So no firm conclusion can be provided today from this use. Mainly other important issues
to seek and may be to discussed, like the application of the drug among the patient with ocular
involvement, which may preclude the use of the drug in second-line treatment. Here we're doing
21 days. It's very interesting and impressive. And also, the first report of the use of the drug in
the context of post-exposure prophylaxis, which may deserve also interesting perspective.
All my acknowledgements to my team, of course, and to the numerous partners and collaborators
of the JIKI-1 trial. I want to thank, specially, the colleagues from the NGO MSF, ALIMA, Croix
Rouge Française and also of the laboratory directly involved in the field and who are also
conducting a fascinating and fantastic work closely to us with a very strong clinicians and
virologist toward connection, B-FAST and in lab of my colleague and friend Stefan Gunter in
Hamburg. Thank you very much.

[applause]

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