Corbus Understates Positive Results from Cystic Fibrosis Study with Anabasum
William C. Stone, DVM, PhD
A friend told me about Corbus Pharmaceuticals and what they were trying to accomplish a couple of years ago. Since I have known four people that have died from complications arising from cystic fibrosis, I was interested in Corbus' story and began to follow the company.
Recently Corbus reported results from its Phase II study of Anabasum in cystic fibrosis patients. The main focus was on safety, which Anabasum easily met. This in itself actually is a very positive accomplishment, since CF patients are often more sensitive to drugs and, of course, Anabasum could not continue to move forward if there had been serious adverse events. The Forced Expiratory Volume in 1 sec (FEV1), a measure of lung function, wasn't expected to change in this short duration trial, and it didn't. More on this to come. The company reported the interesting observation that there was a stepwise reduction in the number of patients that experienced a pulmonary exacerbation (severe lung infection) requiring intravenous antibiotics as the dosage of Anabasum was increased (3 out of 24 in the Placebo group; 3 out of 31 in the Anabasum 20 mg SID group; and 1 out of 30 in the Anabasum 20 mg BID group).
An article written by Adam Feuerstein of The Street reported this as "cherry picking" by the company, and goes on to state that these results were probably due to Corbus getting lucky or because more of the Anabasum patients were on Orkambi or Kalydeco. He is somewhat right on that count; the Vertex drugs were used in 25%, 23%, and 37% of patients on the Placebo, Anabasum 20 mg SID, and Anabasum 20 mg BID patients, respectively, from wk 5-12 of the study.
However, an extremely important point was hardly mentioned by Corbus, and one could consider this "cherry picking" - except that it was an exceptionally positive result that was barely discussed. Dr. White, the CMO for Corbus, stated that they had only very recently received the results and would be doing subgroup analyses over time. I don't believe they had analyzed this subgroup at the time of the presentation. Also, the outcome that I want to discuss was not a prespecified event of interest, which is what the presentation focused on.
Page 31 of the presentation, which is available on Corbus' website, contains the number of patients that experienced a "First acute pulmonary exacerbation, defined as treatment with a new antibiotic." The main reason that a doctor will bring in a new antibiotic is that the current approach is not working effectively and the patient needs help. During wk 5-12 of the study when treatment patients were receiving a higher level of Anabasum, 9 of 18 Placebo patients needed a new antibiotic, while 4 of 25 Anabasum 20 mg SID patients needed a new antibiotic, and only 2 of 24 Anabasum 20 mg BID needed a new antibiotic. I ran a statistical analysis on these results, and found them to be highly statistically significant, with a P value of 0.022 for the Placebo - Anabasum 20 mg SID comparison, and P = 0.004 for the Placebo - Anabasum 20 mg BID comparison. The P value is 0.002 for the comparison of Placebo - both Anabasum treatments combined.
What does a P value of 0.002 mean? Simple. Cystic fibrosis patients are extremely less likely to get respiratory infections requiring a new antibiotic when they are on Anabasum. The odds of this being due to random chance as compared to the treatment are 4 out of 1,000 for the Anabasum 20 mg BID group, and 2 out of 1,000 for the two Anabasum groups combined. That's incredible! Patients also may be less likely to have an infection become severe enough to require the need for IV antibiotics, as the results indicated. Damage to lung tissue occurs with severe lung infections. Thus, if Anabasum reduces the number of severe lung infections that a patient experiences over time, there is less lung damage and there would be less of a reduction in FEV1 scores over time. Severe lung infections are what CF physicians and patients are most concerned about because they can require extensive hospital stays, reduce lung function (and thus FEV1 scores), and be fatal.
Why did so few Anabasum patients need a new antibiotic compared to control patients? The reason may not be exactly known, but Dr. White went on to share that there were significant reductions in inflammatory cells and mediators in the sputum of patients on Anabasum. If inflammation is reduced, the patient may be less likely to develop a worsening lung infection requiring a change in antibiotics. Also, antibiotics may be able to penetrate lung tissue more effectively when patients are on Anabasum, which would make any antibiotic the patient is currently on more effective.
Is it helpful to run statistics on data? Well, consider this. In June of 2015 Celator Pharmaceuticals reported the number of placebo and treatment patients that had entered remission in their Phase III leukemia trial. They did not include any statistics. Remission rates are correlated with overall survival. I ran an analysis on remission rates similar to what I did above and found that the probability of a treatment effect was about P = 0.04. I bought a lot of Celator stock over the next eight months, some for as little as $1.20 a share. That looked pretty good when Celator announced a positive treatment effect on survival in March of 2016, and then when Jazz Pharmaceuticals agreed to purchase Celator for $30.20 per share in May of 2016. Coincidentally, Mr. Feuerstein was not a fan of Celator either.
The Anabasum results are very exciting, especially for cystic fibrosis patients. Friends with CF - healthier days are ahead.
Note: Dr. Stone, a private investor, received his veterinary degree from the University of Wisconsin and his PhD from Cornell University.
Disclosure: I am/we are long CRBP.
Additional disclosure: I intend on holding my position in Corbus for at least a few more years - or at least until approval for systemic sclerosis, CF, and dermatomyositis.