lupus expert conference call
The expert panel included:
• Dr. David Isenberg, Professor of Rheumatology at University College London, past
President of the British Society of Rheumatology, member, founder, and recent chair of
the Systemic Lupus Erythematosus International Collaborating Clinics, founding editor of
the journal "Lupus", author of the text "Lupus" and one of the
creators of the BILAG tool for assessing lupus activity. He is also chair of the British
Society's For Rheumatology Biologic's Register committee and Chair of the Arthritis
Research Campaign's autoimmune rheumatic disease clinical trials sub-committee.
• Dr. Jan Hillson, Medical Director of Clinical Research, Immunology and Inflammation
at ZymoGenetics. Dr. Hillson served as Clinical Associate Professor of
Medicine/Rheumatology at University of Washington Medical Center, and as Division Head of
Rheumatology for Virginia Mason Medical Center, consulting rheumatologist for Group
Health of Puget Sound and Assistant Professor of Medicine for University of Washington
Medical Center Division of Rheumatology. She is an editorial reviewer for Lupus and is on
the Medical Advisory Board for the Lupus Foundation.
The following are excerpts from the call.
Q. How do you read BLISS-52 trial?
HILLSON. It's a milestone trial. It demonstrated that one can design a successful lupus
trial. It validated the BLyS pathway. It's good news for lupus patients.
ISENBERG. It demonstrated a lupus drug can meet endpoints. It's a psychological positive
to clinicians and companies who are developing lupus drugs.
Q. Any red flags from the data?
ISENBERG. Don't see much from the top line data available so far. In terms of adverse
effects, there are no untoward side effects. Efficacy -- clearly met end points.
HILLSON. Endorse that. Safety profile so far looks favorable. The drug can add safely to
standard of care.
Q. Benlysta worked in 58.3% of the patients, versus standard of care 45%. Is this a
meaningful clinical benefit?
ISENBERG. The results are highly statistically significant. Need to see more details.
Need to see which organs and systems are improved. It may turn out one biologic is better
to treat one system or another.
HILLSON. Lupus is a very heterogeneous disease. We will learn if patients who responded
are the ones likely to respond. Some analysts say the results indicate 14% of the
patients will benefit. That's too simplistic.
Q. The trial excluded patients who are serologically negative. What does that mean in
the real world?
ISENBERG. Normally, there are only 4% of lupus patients who are serologically negative.
In Benlysta's Phase 2 trial, there were 20% of the patients who were serologically
negative. That's a little puzzling.
HILLSON. This may demonstrate the difficulty in standardizing the diagnosis of lupus.
Q. BLISS-52 appears to have missed the BILAG end point.
ISENBERG. If they separate A flare and B flares, there might be a different conclusion.
HILLSON. In order to achieve the flare end point, there is a need for sufficient time
for flare to occur. Patients were on steroids for the first 40 weeks. There is not enough
time in a 52 week trial.
Q. Better chance to achieve flare end point in the 76 week trial?
HILLSON. Don't want to put it so strongly. The trial is powered to achieve treatment
effect. Not flare.
Q. Any thoughts on the geographic effects on the two trials?
ISENBERG. Lupus is more severe in certain ethnic groups. For example, African Americans,
Asians tend to have a more severe disease course than Caucasians. It will be interesting
to see.
Q. Does concurrent medication interfere with the results?
ISENBERG. Principal reason Rituxan failed. If sustained high dose steroids were not the
case, the Rituxan trial may have succeeded.
HILLSON. As in oncology drug development, initially one needs to layer on the
experimental drug to current standard of therapy. Later, one aims to minimize the
concurrent meds.
Q. Would you care to give an odds ratio that BLISS-76 trial will do better or worse than
BLISS-52 trial?
ISENBERG. Not really. If the drug works in 52 weeks, it should work in 76 weeks.
HILLSON. Curves between placebo and drug separated early. They separated again later in
the study, after steroids were tapered. That adds confidence the drug may work in 76
weeks.
Q. Can you lay out the competitive landscape?
ISENBERG. Current medication is not satisfactory. There is about 15% infection risk.
Biologics are more targeted. Rituxan had encouraging early results. Disappointed in the
large trial. If we have a better designed trial, it may work. Anti-IL6 antibody is
interesting. Atacicept study can also be positive.
HILLSON. Anti-CD20 drugs are promising. All three drugs in this category: Rituxan,
ocrelizumab and Arzara. Some immune suppression approaches could also work. The success
of Benlysta is encouraging for Atacicept. In addition to targeting BLyS pathway,
Atacicept also targets the APRIL pathway. It could be a better drug.
ISENBERG. I want to emphasize one point. HGSI did very well in executing the study. The
trial was adequately prepared. Physicians and nurses must be carefully trained. HGSI did
that. Lupus is a complicated disease. It's not easy to standardize the evaluation.
Q (from audience). Can you comment on the geographic effects again? Lupus is a
heterogeneous disease. Considering the degree of background therapy, is it fair for HGSI
to make a blanket statement that geography does not have a major effect on the trials?
ISENBERG. With internet use, internationally the practice is not as disparate.
Q (from audience). What makes you think a new trial of Rituxan will do better?
ISENBERG. Previous trial enrolled mostly patients with lung and skin symptoms. If you
give 40 mg of steroids, you don't need Rituxan to make a difference. The physician
training in the trial could also be improved.
Q (from audience). Is it possible Rituxan is more efficacious than Benlysta?
ISENBERG. It is very likely each drug will find a different patient subgroup. Rituxan
may work in patients who are resistant to multiple therapies and in patients with
hematological symptoms. Benlysta may work in patients susceptible to T and B cell
responses.
Q (from audience). Is 45% placebo effect typical?
ISENBERG. It's rather high. In RA trials, we see similar a phenomenon. I don't have a
good explanation.
HILLSON. I thought the placebo effect is rather high also. It tracks efficacy by time.
Lupus waxes and wanes. But again, I am a little surprised by the placebo effect.
Q (from audience). How effective is micofenelate?
ISENBERG. There is an approximate equivalence between micofenelate and cyclophosphamid.
About 50% response rates. It does appear the drug can be effective for other than for
renal.
HILLSON. The issue is toxicity. The emergence of latent viruses, including neurological
viruses. Biologics will not be a simple substitution to micofenenlate/cyclophosphamid.
Rather, they will be a step up.
Q (from audience). Any comment on Lupuzor?
ISENBERG. It's a peptide. So far results are quite interesting. It lowers antibodies to
DNA. It's quite behind Benlysta in development.
Q (from audience). If Benlysta gets approved, what percentage of the patients will
benefit?
ISENBERG. Difficult to answer. Consider the inadequacy of the current therapies.
Probably Benlysta will be used first in the set of patients for whom immune suppression
has failed. Also for patients who have failed steroids. Also consider the flare data. In
one year, 10% of the patients will have A flare. 50% will have B flare.
Q (from audience). Do you envision the drug to be used in a continuous basis or used
intermittently?
ISENBERG. In my experience in treating lupus patients, beneficial effects on kidneys can
last a year. On joints, symptoms can come back in a few weeks. So, it depends. It may be
used intermittently.
Q (from audience). If one looks at SLEDAI scale, which symptoms are more important?
ISENBERG. One would think death or more visible signs such as rash. But most often, what
bothers the patient is fatigue.
Q (from audience). If pain and fatigue are not impacted, do you see patients being
motivated to receive monthly infusions?
ISENBERG. Need to see data. For most patients with whom the physician has good rapport,
they will be motivated.
HILLSON. Many lupus medications make the patient feel worse. Nonetheless, patients can
be motivated to remain on those drugs. Understanding the consequences of failing therapy
makes them motivated.
Q (from audience). Do you have the relative number of lupus patients versus rheumatoid
arthritis patients who receive systemic therapies?
HILLSON. In the US, 1/200 people have RA, 1/2000 people have lupus. So, the disease
prevalence is 1 to 10. There are 330,000 lupus patients in the US, 350,000 lupus patients
in Europe. 2/3 of these patients are receiving some immune suppression meds. 60% suffer
flare in a given year. Look at it another way. 150,000 to 200,000 patients will be
candidates for biologics each year.
Q. Comments on Atacicept?
HILLSON. The drug is in a Phase 3 trial, under an SPA with the FDA. Full enrollment is
expected at the beginning of next year. Results a year later. Both Benlysta and Atacicept
work on the BLyS pathway. Atacicept may be more potent. Atacicept also inhibits a second
target on the B cell: APRIL. Hope to see additional data. It is subcutaneously
administrated.
Q. Are there differences in clinical trial design?
HILLSON. Benlysta trials are designed to treat active disease. Atacicept trial is
designed to prevent flare. Patients coming into the trials are very similar.
Q. The Atacicept trial randomizes only patients who have responded to initial high dose
steroid therapy. I assume this gives enough time to demonstrate flare?
HILLSON. The trial is powered to see flare. There is a 60% annual frequency of flare.
Out of 500 patients, we could expect to see 300 flare. This is an adequate size to
demonstrate a drug effect. An interim analysis to test the power has been included.
