Benlysta trial – analyzed

How does Benlysta it work?

Per the company’s web site:

BENLYSTA inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein which is required for the survival and development of B-lymphocyte cells into mature plasma B cells.

Plasma B cells produce antibodies, the body’s first line of defense against infection. In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies – antibodies that attack and destroy the body’s own healthy tissues. The results of prospective observational studies show a significant correlation of elevated levels of BLyS with SLE disease activity.

Benlysta clinical trials

There are two phase 3 trials. Results from the first were announced earlier on July 20, 2009. That trial lasted 52 weeks and is referred to as BLISS-52. The second is a 76 week trial (BLISS-76) that is still ongoing. Recently announced results are those determined at the 52 week mark.

The primary efficacy endpoint of BLISS-52 and BLISS-76 is the patient response rate at Week 52 based on the SLE Responder Index, which is defined by:

(1) a reduction from baseline of at least 4 points on the SELENA SLEDAI disease activity scale (which indicates a clinically important reduction in SLE disease activity);

(2) no worsening of disease as measured by the Physician’s Global Assessment (worsening defined as an increase of 0.30 points or more from baseline);

(3) no new BILAG A organ domain score (which indicates a severe flare of lupus disease activity) and no more than one new BILAG B organ domain score (which indicates a moderate flare of disease activity).

Analysis for the primary endpoint is based on intention-to-treat (ITT) and adjusted for baseline stratification factors, including SELENA SLEDAI score, proteinuria and race.

Comments on the primary end point

What defines a positive outcome?

Three things:

1. A 4 point or greater reduction in the SELENA SLEDAI.

OK, so what’s a SELENA SLEDAI?

The SELENA SLEDAI is a cumulative, weighted index of lupus disease activity. The total score falls between 0 and 105, with higher scores representing increased disease activity. The SLEDAI has been shown to be a valid and reliable disease activity measure in multiple patient groups, and has also has been shown to be sensitive to changes in disease activity in children.

Rather than my trying to describe it, you might want to take a look at it. (You may need to click on the test name to open a pdf file.)

A 4 point reduction on a 105 point scale does not seem like a great improvement – but it depends largely on the baseline score – which I could not locate in the company’s press release.  I did find that an earlier trial had been conducted using a very similar protocol. In that earlier trial the baseline score was 9.6. Assuming a similar baseline for this most recent trial, a 4 point reduction might represent slightly better than a 40% improvement.

In addition, we don’t know how great the improvement was among those who improved. Many drugs work very well for some and not at all for others. So, for example, 50% might have “at least 4 points improvement” and among those some might have had 100% percent improvement.

2. The “Physician’s Global Assessment” does not increase (get worse) by more than 0.30 points.

Assuming that is the same assessment found at the top of the SELENA SLEDAI (0=no symptoms, 1=mild, 2=moderate, and 3=severe symptoms) it looks like a patient’s symptoms must not have worsened by more than 10%.

3. During the course of treatment they must not have experienced any severe flares, or more than 1 moderate flare.

Results

In each of the two Phase 3 trials, patients were randomized to one of three treatment groups: there was a 10mg/kg group, a 1 mg/kg group and a placebo group. Patients received an intravenous dose on days 0, 14 and 28, then every 28 days thereafter for the duration of the study. All patients receive standard of care therapy in addition to the study medication.

Primary end point results from BLISS-76 (at 52 weeks)

The 10 mg Benlysta dose resulted in statistically significant improvement in patient response rate as measured by the SLE Responder Index at Week 52 when compared with placebo.Adverse events (serious side effects) were similar between Benlysta and placebo.

43.2% of those receiving the 10 mg dose were improved at week 52.

40.6% of those receiving the 1 mg dose were improved at week 52.

33.8% of those receiving a placebo were improved at week 52.

Number Needed To Treat (NNT)

The number needed to treat (NNT) is simply the number of patients who must be treated in order to achieve one ‘good’ outcome. It is simply 1 divided by (active – placebo)

In this case: 1/(.432 – .338) = 10.7

Since the NNT is always rounded up to the nearest whole number, the NNT in this case would be 11.

In common sense terms, if 11 are treated, 5 will improve, but 4 would have improved even without treatment. That is one of the problems when using a relatively modest improvement as your primary end point – you get a large placebo response.

NNT is one of the most useful ways of looking at clinical trial results, since it gives you a good sense of how likely you are to benefit from the drug and, as a simple number, allows for easy and direct comparisons between treatment options.

NNT is of particular value when a drug is associated with significant side effects – which appears not to be the case with Benlysta. Since it might help a patient, or physician, more readily assess risk vs. reward – the chance of serious side effects vs. the likelihood of improvement.

Secondary end point results from BLISS-76 (at 52 weeks)

The percent of patients with a a reduction in SELENA SLEDAI score of at least 4 points by Week 52:

10 mg dose: 46.9%

1 mg dose: 42.8%

placebo: 35.6%

These numbers are higher than those above, suggesting in the case of the 10 mg dose (for example) that 3.5% of those with a sufficiently improved SELENA SLEDAI were disqualified as a success because of either the physician’s assessment or they had a major flare or more than one moderate flare.

Improvement in Physicians’ Global Assessment:

10 mg dose: 0.49

1 mg dose: 0.55

placebo: 0.46

Percentage of patients who were able to reduce their steroid dose by 25% or more by the last 12 weeks of the 52 weeks (from among the 46% who were taking at least the 7.5 mg of prednisone or equivalent per day):

No significant difference between either treatment group and the placebo group.

Improvement in health-related quality of life score after 24 weeks of treatment:

No significant difference between either treatment group and the placebo group.

Improvement in health-related quality of life score after 52 weeks of treatment:

10 mg dose: 3.41

1 mg dose: 4.37

placebo: 2.85

(I believe this is a 100 point scale.)

Here are the results from an earlier trial that appears to have been quite similar in its design:

Investigative B-Cell Inhibitor Shows Benefit in Systemic Lupus Erythematosus

“This study showed that treatment with belimumab (Benlysta) resulted in sustained improvement in SLE symptoms in patients with serologically active disease,” said principal investigator Ellen Ginzler, MD, professor of medicine and chief of rheumatology at State University of New York (SUNY) Downstate, in New York City, in a presentation. “We also confirmed that combining multiple disease-activity measures is a successful way to assess disease activity.”

“Clinicians need to know that the effects were significant but modest,” he said. “It was not a dramatic effect. In spite of this limitation, the study is useful because it opens the possibility for more treatments for lupus, and a drug like this could perhaps be combined with other treatments for even greater results.”


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