Transcript Document

RAC protocol 0307-588
PI: Philip Mease, MD
Sponsor: Targeted Genetics
Ad hoc Reviewer: Robert H. Carter, M.D.
Summary statement
• This protocol addresses a major clinical need localized therapy for RA patients with partial
responses to systemic therapy.
• The study profits from the expression of a protein
that has been well studied in this population.
• The rAAV-delivered gene therapy has advantages
over repeated administration of proteins while
using a vector currently thought to be relatively
safe.
Potential Concerns:
1.Transgene-associated
2.Immunological
3.Disease-specific
Potential Concerns:
1.Transgene-associated
A. Systemic exposure
• Circulating vector
• Circulating cells
B. Integration
• Rare
• Difficult to document
Potential Concerns:
2. Immunological
A. Pre-existing antibodies to AAV
B. Induced antibodies to TNF-R-Fc
Potential Concerns:
3. Disease-specific
A. Participant selection criteria
B. Withholding therapy
Initial Critique and Responses
(taken in order of written comments)
Initial Critique and Responses
I. The trial is designed to recruit participants with RA
with one or two active joints despite therapy with
disease-modifying drugs. This leads to three
problems:
A. This criteria increases the chance of recruiting
subjects whose disease in some form of arthritis
other than RA
B. This criteria will make this trial not comparable to
other trials in RA, which require six active joints
C. This criteria will decrease the ability to detect
responses in other joints (“contralateral effect”).
Initial Critique and Responses
A. This criteria increases the chance of recruiting subjects whose
disease in some form of arthritis other than RA
It is highly unlikely, but possible, that patients with persistent
swelling in one or two joints could have another cause of arthritis,
such as crystalline arthritis or infection, superimposed on their
RA. The distinction will need to be based on good clinical
judgment. If the Investigator deems it necessary, joint aspiration
will be performed, and the synovial fluid will be sent for crystal
examination, Gram stain and culture to rule out those possibilities
prior to injection of tgAAC94.
[Response to Dr. Simari]
If a patient has significant polyarticular disease, then it is anticipated
that systemic anti-TNF therapy would be suggested and not
involved in this study.
Initial Critique and Responses
B. This criteria will make this trial not comparable to other trials
in RA, which require six active joints.
The primary purpose of this study is to evaluate the safety of intraarticular injections of tgAAC94. It is not necessary to change the
entry criteria to match those used in other clinical trials, because
there are no plans to compare the results to other trials.
Initial Critique and Responses
C. This criteria will decrease the ability to detect responses in
other joints (“contralateral effect”).
[Other TNF-inhibitor] trials were conducted in patients with active RA
involving multiple joints, hence the requirement for involvement of at
least six joints. In contrast, this trial is aimed at patients who have
reasonably well-controlled disease in most joints, but one or two
persistently inflamed and swollen joints which are at risk for
cumulative damage.
Initial Critique and Responses
II. Systemic effects
A. Studies did show DNA in other organs, suggesting systemic spread
of the virus.
B. The trials in rodents demonstrated an effect of inoculation into one
joint on disease in the contralateral joint.
The inoculation into a single joint could have reduced inflammation in the non-injected joint
either directly by systemic protein production (or release) or indirectly by secondary effects of
the reduction of the inflammation in the injected joint (decreased local production and release of
inflammatory mediators in the injected joint, or decrease systemic acute phase response).
C. An important question to be addressed is whether the effect of intraarticular inoculation is local or systemic. … Ultimately, if this
therapy appears successful, one question will be whether there is
any benefit to intra-articular therapy over IM.
Initial Critique and Responses
II A. Studies did show DNA in other organs, suggesting systemic
spread of the virus.
In the non-human primate model, after a single intra-articular injection,
biodistribution of vector DNA was detected in the spleen, left (non-injected)
femoral tibial joint tissues and right iliac lymph node by the limit of detection PCR
assay (1 in 104 cells to 1 in 103 cells). At the intra-articular injection site (bone,
cartilage, synovium, tendon and ligament) gene transfer was documented in a
quantitative DNA PCR assay and the amount of vector DNA was dose dependent,
with the highest amounts being … 6000 copies/cell. In contrast, while vector DNA
in the contralateral joint was quantitated in this assay, the amount of vector was not
dose dependent and the highest amount of vector DNA (1.2 copies/cell) was three
orders of magnitude lower than at the injection site. Human TNFR:Fc transgene
mRNA was present at the injection site using a qualitative RNA-specific PCR
assay. In samples from non-injection sites there was no consistent detectable
expression, particularly in the spleen and lymph node.
Initial Critique and Responses
II B. The trials in rodents demonstrated an effect of inoculation
into one joint on disease in the contralateral joint.
In summary, the exact mechanism of the observed systemic effect
after local intraarticular delivery (in the experimentally induced rat
model) is not completely understood. We do not know if we will
observe a similar systemic effect after intra-articular delivery in the
proposed clinical trial. As mentioned above, recent clinical trials of
intra-articular administration of etanercept at doses of up to 8 mg per
injection were considered safe and did not result in any systemic
effect (Bliddal et al., 2002). However, we plan to measure the
circulating levels of TNFR:Fc protein.
Initial Critique and Responses
II C. Ultimately, if this therapy appears successful, one question
will be whether there is any benefit to intra-articular therapy
over IM.
Our current pre-clinical data supports equivalent efficacy with both
approaches in the rat SCW model, despite very different levels of
circulating, systemic TNFR:Fc (approximately 2 log difference in
serum TNFR:Fc). The benefit of intra-articular route of delivery is
the potentially reduced exposure to systemic TNFR:Fc protein
compared to either etanercept or intramuscular delivery of a rAAVTNFR:Fc vector.
Initial Critique and Responses
III. [The] protein that will be expressed, is immunogenic, despite
having a human TNF-R fragment and the Fc portion of human
IgG1. The hinge region, the junction between the two components,
is thought to be the target. Perhaps the inflammation at the site of
expression of the fusion construct will have an adjuvant-like effect.
There is a risk that treatment with the active agent could induce
antibodies that would reduce the efficacy of etanercept.
Initial Critique and Responses
III. [The] protein that will be expressed, is immunogenic…
If we can develop and validate a reliable assay to detect antibodies to
the human TNFR:Fc protein we will test the serum or joint fluid
collected during the trial.
Initial Critique and Responses
IV. For some chimeric proteins, efficacy has been linked to particular
allotypes of the FcR, which alter affinity.
Initial Critique and Responses
IV. For some chimeric proteins, efficacy has been linked to
particular allotypes of the FcR, which alter affinity.
This is a small study focused on safety. We will take this suggestion
into consideration for future trials.
Initial Critique and Responses
V. There is theoretical possibility that adenovirus could reach the joint
and rescue the AAV. There is no evidence that this is a problem
from previous studies with AAV. Should there be restrictions on
participation in this trial in subjects with RA and upper respiratory
symptoms?
Initial Critique and Responses
V. … theoretical possibility that adenovirus could reach the joint
and rescue the AAV.
Subjects who are acutely ill should be excluded from the protocol
under the last exclusion criterion, which includes “other concurrent
medical condition that, in the opinion of the Investigator, would
make the subject unsuitable for the study”. We do not believe that it
is necessary to exclude subjects with upper respiratory symptoms,
per se, because the tgAAC94 particles are non-replicating as they
lack the wild-type AAV viral genes (rep and cap) required for viral
replication and encapsidation of DNA. Thus, even in the presence of
a helper virus infection (adenovirus 5) the particles are not capable
of replication. Simultaneous joint infection with both wild-type AAV
(containing rep and cap) and adenovirus 5 is required to rescue the
vector.
Initial Critique and Responses
VI. The selection criteria suggest that participants should have active
disease despite therapy with a DMARD, and that the DMARD will
be continued for the study.
A. Consideration should be given to making this more specific,
perhaps including a trial of methotrexate at a full dose. This option
would include candidates with persistent disease while on stable
methotrexate. This is a relatively common scenario.
B. The protocol states that, “all changes in concomitant medication
during the study period will be recorded” - how will they be
considered?
C. There is also significant variability of immunosuppressive
properties of different DMARDs. Should these be considered?
Initial Critique and Responses
VI. DMARD selection criteria.
Although most patients will likely be receiving methotrexate, it is
not necessary to standardize baseline treatment, because this is
primarily a safety study. … However, baseline medications and
changes in medications will be recorded, so it will be possible to
perform exploratory retrospective analyses about at the conclusion of
the trial to see if the “strength” of the DMARD at baseline, or
addition of other medications has an impact on the outcome of the
study.
Potential Concerns:
1.Transgene-associated
2.Immunological
3.Disease-specific
Summary:
1. Transgene-associated
A.Systemic exposure
• Risk from protein itself is low
• There is circulating vector but little
evidence of problem in preclinical
studies.
• Theoretical risk from transfected
circulating cells (dendritic) but little
evidence of clinical problem at this
time.
Summary:
1. Transgene-associated
B. Integration of transgene
• Difficult to define
• No evidence of risk from preclinical
studies but these might not define
long-term risk
Summary:
2. Immunological
• There is a risk of immunizing to the
expressed protein, and antibodies
should be measured
• Agree that understanding
“contralateral effect” not the goal here.
• FcR allotypes might be linked to side
effects. Consider genotyping.
Summary:
3. Disease-specific
• Accept rationale for oligo-articular
activity, with added safety of not
denying those with polyarticular
disease systemic TNF-inhibitor
• Later study should compare intraarticular to intra-muscular.
• Accept diverse DMARD for phase I
but would limit to those with disease
on methotrexate in Phase II.