Ampio Pharmaceuticals, Inc.
AMPE today is issuing this response to the most commonly asked
questions in regards to the STEP study and clarify its plan for moving forward
with Ampion™ for osteoarthritis of the knee.
Ampio Pharmaceuticals Logo.
Letter to Ampio Shareholders from Michael Macaluso, Chairman & CEO and David
Bar-Or, MD, Chief Scientific Officer
The STEP study of Ampion™ had a technical problem that is being evaluated for
deviation from protocol in temperature excursions in over 70% of the drug
supply for this study. This excursion in temperature down to freezing is
likely to have affected the level of active ingredients in the injected dose
of Ampion^TM. One of the active ingredients of Ampion™, aspartyl- alanyl
diketopiperazine (DA-DKP) is extremely stable at low and high temperatures,
however if the glass vial containing the drug is frozen or is at freezing
temperatures, some of the DA-DKP will come out of solution and together with
other compounds present in Ampion™ will adhere/crystallize on the inner glass
surface of the vial. Thawing the vial to room temperature, without vigorous
agitation for a prolonged period of time, will not bring these active
ingredients back into solution. As this level of agitation is unlikely to have
occurred at the clinical site, it is anticipated that if vials reached those
low temperatures, a lower than expected level of DA-DKP than required by the
Study Protocol would have been administered in the trial.
A discussion with the FDA informing them of the protocol deviation was very
positive and the FDA will be evaluating the available data from the trial when
presented to them to decide what can be salvaged and how to proceed.
In parallel with the ending of the STEP study, the company began a
placebo-controlled, double-blinded multiple injections trial of Ampion^TM for
treatment of OA of the knee that is expanding to 14 clinical sites. This trial
was launched in order to expand the Indications for Use (IFU) to multiple
injections rather than a single injection. Approximately 300 patients with
moderate to severe OA will be enrolled and treated as soon as possible. The
study end point will be at 20 weeks from the first injection. The primary end
point is WOMAC A (pain) and secondary end point will be WOMAC C (function).
The open label portion of this trial enrolled 7 patients who demonstrated
remarkable results, both in pain reduction and improvement in function of the
knee at 4 and 6 weeks after initial treatment. We anticipate analyzing data of
the open label portion of the study, including MRI's and synovial fluid, at 12
weeks, which will occur in about a month. Forty (40) additional patients will
follow the same protocol as the open label portion of the multiple injections
study and enrollment is nearly complete.
The company currently is planning to file the BLA with the SPRING study
results in combination with either the STEP study or the multiple injections
study or a combination of all three. Based on the results of the open label
portion of the multiple injections study and in vitro work we believe that the
3 injections will offer significant relief to patients with KL3 and KL4 grade
OA. There is no current drug therapy for KL4 and there is no current therapy
drug with healing effects beyond the pain relief aspect in OA of the knee. In
all studies using other drugs and multiple injections, saline was used as a
"placebo". Multiple saline injections did not result in significant
improvements of results compared to a single injection of saline. Therefore it
is not anticipated that multiple saline ("placebo") injections will result in
significant added benefit and will not diminish the difference from Ampion™
injections. With regard to filing our Ampion^TM BLA, we are still planning to
accomplish this by the end of 1Q 2015, despite any delays as a result of the
STEP study technical problem.
Other common questions and answers:
1. Why wasn't the fact that some of the Ampion^TM was frozen discovered
before it was given to patients in the trial?
Ampio had not anticipated any problem in this regard because it had contracted
with a specialty Packaging and Distribution Company to handle all aspects of
clinical trial drug supply to clinical sites. As with all double-blinded
placebo-controlled clinical trials, the independent CRO executes the clinical
trial and, as the sponsor, Ampio maintained an appropriate "hands off"
relationship to the clinical sites during the whole trial until time of data
lock. Ampio was made fully aware of the temperature excursions at the time of
data lock, long after the completion of the patient's treatments. Only one
clinical trial site reported any frozen product and that shipment was replaced
immediately upon notice.
2. Why has Ampio been made aware of the freezing issue but not the actual
test data?
The analysis of the Data has still not been made available to Ampio, although,
as can be imagined we are anxious to view it. The Temperature excursions
problem was noted at the time of data lock by the CRO, therefore triggering an
investigation into how widespread the problem may have been. It is standard
practice to understand the full extent of the deviations before completing an
analysis of data that is likely to be flawed, leading to the need for more
time for the independent statisticians to analyze the data.
3. Is it possible that significant usable data can still be ascertained from
the STEP study?
Yes it is possible.
4. When do you expect to receive that data.
As soon as possible, likely within several weeks.
5. What will the company do if the FDA is unable to accept sufficient data
from the STEP study to satisfy the requirements of the Biologics License
Application (BLA)?
We will not likely repeat the STEP study, even though it took only 39 days to
enroll those 500+ patients. The Multiple Injections (MI) Study for OA of the
knee is already underway and the expansion to 14 clinical sites is
progressing. Our goal is to complete enrollment and treatment of approximately
300 patients with moderate to severe OA (Kellgren Lawrence Grades 3 & 4) in
this MI study within the next several months. The injections are administered
on the first day, two weeks later and four weeks later and the study end point
will be at 20 weeks from the first injection. As with the STEP Study, the
primary end point of this MI Study is WOMAC A (pain) and secondary end points
will be WOMAC C (function). The open label portion of this trial enrolled 7
patients who demonstrated remarkable results, both in pain reduction and
improvement in function of the knee at 4 and 6 weeks after initial treatment.
We anticipate analyzing data of the open label portion of the study, including
MRI's and synovial fluid, at 12 weeks, which will occur in about a month. 40
additional patients will follow the same protocol as the open label portion of
the multiple injections study and is near completion of enrollment.
The company's goal remains to file the BLA in Q1 2015 and it will be supported
by the SPRING study results in combination with either the STEP study or MI
study or a combination of all three.
Based on the results of the open label portion of the MI Study and our in
vitro research we believe that 3 injections will offer significant relief to
patients with KL3 and KL4 grade OA. There is no current drug therapy for KL4
and there is no current therapy drug with healing effects beyond the pain
relief aspect in OA of the knee. In all FDA reviewed clinical studies using
other drugs and multiple injections, saline was used as a "placebo". Multiple
saline injections did not result in significant improvements of results
compared to a single injection of saline. Therefore it is not anticipated that
multiple saline ("placebo") injections will result significant added benefit
and will not diminish the difference from Ampion™ injections.
6. Why is Ampio confident that results from the MI study can be used along
with SPRING study results as the pivotal trial supporting the BLA?
Our regulatory consultants are former high level FDA reviewers and they are
of the opinion that the FDA will accept the multiple injections study as
second study for BLA filing and approval because the MI study has the same end
points and timing as the single injection trial As well as the same indication
for use and the same drug.
7: When do you anticipate clinical results from the MI study?
Sometime in early Q1 2015. Based on our experience, we are working diligently
to keep our time table and file the BLA before the end of that quarter. If
circumstances change, and it is clear to the company that we cannot meet this
time-table, we will inform our shareholders.
8. Have Ampio's plans to complete the drug manufacturing facility and begin
production of Ampion^TM in support of the BLA changed?
Plans for production of Ampion™ in our manufacturing facility have not
changed. We have added a vice president of manufacturing, a plant manager and
QA and QC staff, all with extensive pharmaceutical experience.
9. Does Ampio have enough money to maintain operations through this year and
all of next year while completing the planned clinical trials and filing for
regulatory approval for the two lead drugs?
Yes, as long as we do not directly commercialize either of our two lead drugs,
Ampion^TM or Optina^TM, which is not our intention.
Since our August 21^st release reporting technical problems with the STEP
study and delayed release of the analysis of Study data, we have received many
calls from interested parties for a more comprehensive explanation of the
issues and asked to address a number of incorrect rumors that have surfaced.
Ampio management has done its best to answer every call but has realized that
the fairest way to proceed is to present all shareholders with the questions
and our answers in this written format. While the events of the past few days
have certainly been frustrating for shareholders and Ampio management, there
is no change in management's excitement about the success of Ampio. As always,
Ampio has alternate plans to overcome unexpected events and meet our corporate
goals. We will always act responsibly to protect our company and its
shareholders. With all the positive activities taking place at Ampio, that
require the full attention of our executive management, it is time to focus
our attention to the tasks at hand, move forward and continue our work. The
company's goal remains to file the BLA in Q1 2015 and it will be supported by
the SPRING study results in combination with either the STEP study or MI study
or a combination of all three.
Michael Macaluso, Chairman & CEO Dr. David Bar-Or,
Chief Scientific Officer
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