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Notes of 10/31/01 BMS Teleconference re Atazanavir Expanded Access Program and Reports of Lactic Acidosis
In Attendance:
BMS: Robert Blair, Stephanie Brooks, Michael Giordano, MD
Community: Jules Levin, Tracy Swan, Yvette Delph, Linda Grinberg, Bill Bahlman, Lynda Dee, Jeff Gustavson, Bob Munk, Ron Baker, Dave Gilden
Michael Giordano explained that there have been ongoing discussions with the French Regulatory Agency (ATU) and the FDA regarding safety issues and reports of lactic acidosis that will delay the initiation of the Expanded Access Program until 1st Quarter 2002.
There was a review of safety data in the following three Atazanavir studies:
Study #007: ddI + d4T + Atazanavir
Study #008: d4T + 3TC + Atazanavir
Study #034: Combivir (AZT+ 3TC) + Atazanavir
There have been a total of 15 new case reports of lactic acidosis,
representing <1% of all patients enrolled in the first two
studies. There were no reports in Study #034, which has only completed
12 weeks of follow-up and so would not be expected to show lactic
acidosis. This incidence of lactic acidosis is similar to that
found in the literature, although there
are many different definitions of lactic acidosis A link to obesity,
gender and possibly pregnancy has been identified in both the
BMS studies and in the literature. All but one or two of the 15
were women and many patients were "substantially" obese.
They have not been able to tease out a direct correlation to the
use of Atazanavir, nor does it appear that the combined use of
d4T plus ddI increases the risk of lactic acidosis. However, the
literature and case reports from these studies do point to the
use of either ddI OR d4T. (BMS had previously reported last Spring
3 deaths in pregnant women, who were taking ddI + d4T concurrently;
no other deaths have occurred since.)
There is no standard Adverse Events (AE) grading system for
lactic acidosis. Instead, they are using Kees Brinkman's definition
of "lactic acidosis syndrome", which basically lists
a constellation of symptoms, ranging from nausea, fatigue, hepatic
enlargement, neuromuscular problems, respiratory distress, loss
of consciousness linked to an elevated lactate reading. BMS
included patients with one or more of these symptoms and a confirmed
elevated lactate level in their assessment of lactic acidosis.
Particular attention has been paid to one or more combination
of symptoms, defined as "symptomatic hyperlactactatemia",
e.g. fatigue + elevated lactate or nausea + elevated lactate,
etc. (They will provide the Brinkman definition to us.) There
is no specific lab marker. Lactate levels alone are not a sole
indicator and therefore they were not routinely monitoring lactate
levels. Giordano stated that they are trying to heighten the awareness
of lactic acidosis so that signs and symptoms may be identified
earlier. Giordano also mentioned some specific steps they had
taken to educate study staff on the symptoms linked to acidosis
syndrome, as well as techniques for verifying that blood tests
were accurately done and confirmed.
Drugs were interrupted if symptoms were severe. In the case of mild symptoms, the symptoms resolved spontaneously.
The symptoms of lactic acidosis mainly appeared after 40 weeks of therapy. There doesn't appear to be a higher frequency in treatment-experienced vs. treatment-naïve subjects, but clearly gender and obesity play a major role.
They are measuring obesity by Body Mass Index (BMI). They have not evaluated a correlation to visceral adiposity. There was no association with race. BMS has been providing a number of analyses to the FDA.
Regarding the association of lactic acidosis to neuromuscular
problems, Michael Giordano stated he was not as knowledgeable
about this as he probably should be, because many of the case
reports had not occurred in clinical trials he was conducting,
but he had reviewed the data on the 5 or 6 case reports from Spain
reported at the IAS conference, which evidently implicated
d4T. No neuromuscular problems were seen in the Atazanavir trials.
BMS agreed to communicate progress with the FDA on the EA programs on an ongoing basis and will also give us an update at ICAAC in December.
The filing of the NDA (new drug application) is now up in the air. The following four Phase III studies have been initiated: #034 completed enrollment in July2001, two Phase III pivotal trials started one month ago and a nucleoside-sparing naïve study has just begun.
BMS discussed the elevations in bilirubin seen with ATZ. When asked whether the FDA was concerned about the elevation of bilirubin with Atazanavir, he said they were not concerned. If bilirubin levels exceeded 5 times the upper limit of normal (>5x ULN), ATZ doses were reduced by 200 mg. Dose reductions were as follows: 10% of patients on the 600 mg. QD dose were reduced to 400 mg. and 4.5% of patients on the 400 mg. QD dose were reduced to 200 mg. Less than 1% have discontinued, representing 1 patient out of 400. The dose for both naïve and experienced patients in Phase III studies and in the EA program will be 400 mg.
BMS has not submitted the EA protocol to the FDA, but are awaiting "informal feedback". They intend to speak to the agency about satisfying the agency on the safety issues as well as the EA program in about 2 weeks. They have the protocol written and a Clinical Research Organization (CRO) selected.
Linda Grinberg, Bob Munk and Yvette Delph
Questions Submitted to BMS prior to the Teleconference
1. How many case reports of lactic acidosis and how many patients
are currently enrolled in studies?
2. How serious or what grade AE (adverse events) were reported?
3. How are you defining lactic acidosis?
4. Did any patients progress to symptomatic acidosis, or was it
just a lab abnormality?
5. What are the "warning signs" of acidosis, and can
patients be monitored to avoid it?
6. What is the relationship between lactic acidosis and neuromuscular
problems?
7. What other ARVs were patients taking in the trials? (Or is
lactic acidosis showing up in various studies using different
drug combinations?)
8. Are the patients treatment-naïve or treatment-experienced?
If tx-experienced, any there any patterns or trends related to
their drug history or time on treatment?
9. What was the average time to onset of lab abnormalities or
symptoms?
10. How many patients in the trials may be at high risk for developing
acidosis, based on their lab profiles?
11. How was it dealt with in the trials? Were all drugs stopped
and added back one at a time, including study drug?
12. Does a B-complex with or without carnitine at about 1-3 grams
per day and/or possibly using coenzyme Q10 attenuate the risk
of lactic acidosis or hyperlactatemia?
13. What position has the FDA taken?
14. How will this impact and will it delay the initiation of the
expanded access program due to begin October/November?
Posted October 31, 2001