Why The Corbus Pharmaceuticals Holdings Inc (CRBP) Cystic Fibrosis Results Are Very Positive

Last week, Corbus Pharmaceuticals Holdings Inc (NASDAQ:CRBP) announced data from a Phase II study of its lead development asset Anabasum. The data appeared positive from a headline perspective, and the company spiked as part of an initial market response to the release.

Almost immediately afterward though, shares began to fall as financial bloggers challenged the positive interpretation. The arguments stems from the fact that despite proven safety, the main efficacy endpoint of FEV1 (the volume of air expelled by the lungs in 1 second) stayed stable in both active and placebo arms. Presumably, this means that Anabasum has no efficacy. This interpretation, however, flies in the face of a positive data review by the Cystic Fibrosis Foundation, a $5 million nonprofit sponsor of this trial.

So who are we to believe? Corbus and the Cystic Fibrosis Foundation, or the other side?

We believe the CFF is in the right here and the Phase II results are actually very positive, FEV1 notwithstanding. Here’s why.

Data Recap

The study was a Phase II designed to primarily asses the safety and tolerability of Anabasum in cystic fibrosis (CF) sufferers. It’s an anti-inflammatory drug and its mechanism of action is based on it binding to the CB2 receptor and resolving inflammation and in turn fibrosis, which is caused by chronic inflammation among other things.

The trial randomized 89 patients to either a placebo arm or an active arm initially. Four of these patients withdrew prior to dosing, so the total number reduced to 85. Of these 85, 26 entered a 1mg dose group, 24 entered a 5mg dose group, and 35 entered a placebo group. After four weeks, 11 in the placebo arm crossed over into the active arm, and the active arm increased dosing to 20mg.

This means that the highest dose cohort, the one that showed the most efficacy, was only treated for a total of two months’ time. Put that into context with the fact that FEV1 tends to decrease in CF patients at an average rate of 1% a year (0.17% on average over 2 months), and a stable FEV1 begins to make more contextual sense.

Importance of Safety in Anti-inflammatories

What is being overlooked here is the importance of safety in this indication. Safety data is not usually as compelling for investors as efficacy, but in this case safety is a big deal. Both for the CF indication itself as well as for the inflammation target, safety is no shoe-in. Going after inflammation usually means messing around systemically with the immune system, which often causes toxicities. This is what happened to Boehringer Ingelheim and Nivalis Therapeutics, Inc. (NASDAQ:NVLS) with their CF drugs targeting inflammation, and the trials were stopped subsequently.

The numbers for Anabasum, however, showed quite clearly that the drug is safe and tolerable. The numbers were as follows. A small number of discontinuations (3) were judged as related to the study drug, but these were mild in class (one was driven by a lack of motivation, one was a lack of cognitive clarity and one was a decrease in focus) and one of the three was in the placebo arm.

Of the treatment adverse events reported, two were considered related to study drug (dry mouth and cognitive impairment) and neither were particularly serious. The number of TEAEs slightly increased in Anabasum-treated subjects compared to placebo, but the increase was seen in mild TEAEs, not moderate or severe.

Basically, there is no concern about the safety implications of dosing, and this is what the trial was set up to show. Primary endpoint hit.

What About Efficacy?

Of course, in these sorts of studies, investors tend to discount safety and are really looking for any obvious indication of clinical benefit. Anabasum saw that, too, but it wasn’t as obvious as a sharp improvement in FEV1, which we cannot expect to see over the course of only 2 months. The Anabasum arm did however see a sharp drop in the annualized rate of pulmonary exacerbations – basically disease flare-ups – compared to placebo, as follows.

In the second stage of the study with the higher dosing cohort at week 5 and beyond, 16.7% of patients in the placebo arm reported acute pulmonary exacerbations. In the two dosing groups of the active arm, this number was 6.5% and 3.3% respectively. This translates to a 75% reduction in the 48-week rate of acute pulmonary exacerbations for Anabasum at the two highest doses, in a dose-dependent manner.

While this is only a small number of patients, the rate of dose-dependent reduction coupled with the fact that inflammation biomarkers were also reduced in a dose-dependent matter in sputum analysis, makes a causal link here seem likely rather than just a statistical fluke.

But so what? What’s the big deal about pulmonary exacerbations? The trial protocol said little about these as an endpoint, so how do we know that Corbus Pharmaceuticals Holdings Inc (NASDAQ:CRBP) isn’t just massaging the data and pulling something new out of its hat with some clever misdirection?

Because FEV1 is closely correlated to the amount, frequency, and severity of pulmonary exacerbations. If FEV1 decline is the effect, exacerbations are the cause. A 2010 study published in the journal Pediatric Pulmonology for example concluded as much:

THERE IS A STRONG ASSOCIATION BETWEEN THE FREQUENCY OF PULMONARY EXACERBATIONS AND SUBSEQUENT DECLINE IN PULMONARY FUNCTION. IN ADULTS, HAVING 3+ EXACERBATIONS, AND AMONG CHILDREN, HAVING ANY EXACERBATIONS IS ASSOCIATED WITH A GREATER RATE OF DECLINE IN THE ENSUING 3 YEARS. IMPROVED PREVENTION, IDENTIFICATION, AND TREATMENT OF PULMONARY EXACERBATIONS ARE LIKELY TO HAVE LONG-TERM BENEFITS FOR PATIENTS WITH CF, ESPECIALLY CHILDREN.

Many other studies linking exacerbations with FEV1 have been conducted with similar findings. Pulmonary exacerbations happen because of inflammation, the very process that Anabsum targets, so the fact that they were reduced in a dose-dependent manner also makes intuitive sense. During and exacerbation, the immune system flares up, causing severe inflammation in the lungs and patients end up in hospital for 2 to 4 weeks on IV antibiotics at a cost of about $10K to an insurer. According to the Cystic Fibrosis Foundation itself, stopping pulmonary exacerbations is even more important than improving FEV1. FEV1 is just a number, but the exacerbations are the most acute and damaging part of CF.

Most importantly, Corbus Pharmaceuticals Holdings Inc (NASDAQ:CRBP) and the Cystic Fibrosis Foundation believe that a reduction in the annualized rate of these exacerbations is an approvable endpoint for the FDA. In other words, this Phase II trial accomplished exactly what it was supposed to accomplish. It established safety in what is usually a very dangerous inflammation target, and it was able to point Corbus and the CFF in the direction of a measurable endpoint for an upcoming pivotal trial.

Going a bit deeper into the pulmonary exacerbation numbers, annualized pulmonary exacerbations for the Vertex Pharmaceuticals Inc. (NASADAQ:VRTX) Texacaftor/Ivacaftor combination therapy saw a 35% reduction of .64 vs .99 placebo. Anabasum saw a greater pulmonary exacerbation drop of 75%, from 0.89 to 0.22 annualized in the highest-dose cohort. If this number can be replicated in future trials, the chances of approval for this indication are high. Both the CFF and its European counterpart the Cystic Fibrosis Society (ECFS) know this, and both are involved in funding these trials, which is why these two nonprofits view the trial results in a positive light.

Why No Open Label Extension for CF?

Many who follow Corbus closely are aware of the open label extensions granted the company by the FDA in the dermatomyositis and scleroderma indications. That these were granted in itself is evidence of positive efficacy. So why not in CF is well? Is this a bad sign? The answer is that CF already has 9 drugs available and patients can live 20 to 40 years with the disease. The FDA is less generous in granting early stage open label extensions in these cases. This is not the case with either scleroderma or dermatomyositis, which have no medications available and can be fatal much more quickly.

So before investors sell shares in response to what some financial bloggers have viewed as underwhelming and cherrypicked data, it is important to keep in mind two things. First, if these data can be replicated in a larger trial, Anabasum will likely be approved for CF. Second, the scleroderma and dermatomyositis trials, both with open label extensions, are ongoing.

Conclusion

There is a strong correlation between the frequency and amount of pulmonary exacerbations in CF patients and FEV1 decline. If Corbus Pharmaceuticals Holdings Inc (NASDAQ:CRBP) can show a 75% reduction in annualized exacerbations over 2 months, what will likely follow over a longer period of time is an improvement in FEV1. Regardless of how you may interpret the data, speaking just in terms of the actual hard numbers, if they can be replicated in a larger and longer trial, Anabasum will likely be approved for cystic fibrosis.

Note: This article is written by David Rich and originally published at Market Exclusive.