On Tuesday, April 20, Human Genome Sciences (HGSI) released longer term data from its Bliss 76 Phase III study in Lupus, leading to a stock drop. First some back ground.
HGSI is developing Belimumab, an antibody to immature B cells, for the treatment of SLE by targeting the B Lymphocyte Stimulator (BLyS). Treatment with the antibody prevents B cells from maturing into auto-antibody secreting plasma cells. The Phase II data had been insipid, but data analysis by the company showed that patients who were sero-positive (i.e. HEp-2 ANA ≥ 1:80 and/or anti-dsDNA ≥ 30 IU/mL) were better responders than sero-negative patients. The Phase III studies were designed with that in mind. This is an important point that the reader should understand since not all SLE patients are sero-positive as defined in this trial - about 50% of patient in my practice are, and others report rates between 50 and 80% (which shows the heterogenous nature of the disease).
Two Phase III trials were conducted, one a 52 week trial (BLISS 52) in Asia, South America, and Eastern Europe, and the other a 76 week trial (BLISS 76) in North America and Western Europe. Doses looked at were 10 mg/kg and 1 mg/kg on a background of standard of care. At 52 weeks, both studies reported positive data with the 10 mg/kg dose. The response rates are below:
STUDY 10 MG/KG PLACEBO DIFF
BLISS 52 57.6 43.6 14
BLISS 76 43.2 33.8 9.4
Based on the above, it is clear that there is enough evidence to approve the drug. This was truly great news for us who have had no new treatment for our lupus patients in the past 50 years.
Now to the news from April 20. The 76 week data from BLISS 76 was released, and the company said 38.5% of patients responded to the 10 mg/kg dose (down from 43.2% at 52 weeks, a drop of 4.7%) compared to 32.4% of patients treated with a placebo (down from 33.8% at 52 weeks, a drop of 1.4%). The difference between the 10 mg/kg dose and placebo was not statistically significant. More curiously, the previously less appealing dose of 1 mg/kg was in many measures better than the 10 mg/kg dose. So, what is going on? And what are its implications?
It is unclear why the response rates dropped with time. Was it due to antibodies to the antibodies? After all, lupus patients are very adept at making antibodies. Or was it due to tachyphylaxis? Or some other reason?
The implications of this phenomenon are significant. Lets do the maths. Of my 20 patients who can be treated with Belimumab, lets say I put them all on it at (speculatively) $20,000 a year. That nets the company $400,000. After a year, I have to stop treating them, and can only use Belimumab on new patients (lets say about 4). Now the company is netting only $80,000, down from $400,000. But there is another, more important point. This relates to the question of why the effect wears off - does the effect, in fact, go into reverse? In other words, will there be a rebound? Will the disease, once the Belimumab is stopped, become worse than it was originally? Some may argue that no such rebound was seen in the clinical studies, but one must keep in mind that patients are not followed beyond a week or so after their last visit, so a rebound would not be captured by the study. So while the PI (principal investigator at the site) would know about it (assuming s/he knew the randomization), the companies would not.
Compare that to the anti-TNF story - one of the great advantages of anti-TNFs such as Enbrel (Pfizer and Amgen) and Humira (Abbott) used in the treatment of RA is that their efficay does not wane with time. No wonder they have 8 - 10 year safety and efficacy data. Similar long term safety and efficacy data would be very useful for Benlysta.
