Rigel’s R788 is one of the most promising oral agents in development for RA, although it is not alone in the race, as both Pfizer (PFE) and Incyte (INCY) have oral drugs for RA. Each of the three companies presented promising data at last month’s ACR (American College of Rheumatology) meeting, showing a meaningful benefit in comparative placebo-controlled trials. With respect to stages of development, Pfizer is furthest along, with the largest number of patients tested and longest treatment periods, followed by Rigel and Incyte, who presented data from smaller trials. Although comparing results from different clinical trials is problematic for obvious reasons, the different trials shared some similarities, as all three compounds were evaluated in combination with the same drug (MTX) in comparison with a placebo arm that received MTX alone among similar patient populations. The clinical efficacy of the three investigational drugs seemed comparable, but it does not mean that all three will get approved, as results from larger trials may be differ materially from those of smaller trials. While Pfizer’s and Incyte’s compounds hit closely-related but not identical targets, Rigel’s R788 inhibits a totally different target (Syk), which might serve as a good differentiator.

Because the three drugs do not inhibit the exact same target, each compound may have different safety and efficacy profiles, and there may be patients who will derive more benefit from one drug and no benefit from the other. Consequently, the company that will be able to identify the right patient populations for its drug should have a great edge over competition. Even if all three drugs become approved in RA, the market is big enough for everybody, as demonstrated in the case of anti-TNF drugs.

Despite the exciting activity Rigel’s R788 demonstrated, the company presented some safety and efficacy data the market did not like.

On the efficacy side, investors were concerned with the response rate in patients who received the drug in Mexico, which was higher than the response rate in the American patients. The company explained that the response rate in the placebo arm in Mexico was also higher than that of placebo patients in the US, making the relative response in the two groups similar. The reason for the difference between the groups can be explained by cultural differences that impact the way patients and doctors assess the disease, but it can also be partially explained by the relatively limited number of patients in the trial (less than 200). Regardless of the basis for the phenomenon, it is important to note that such geography-based differences were also observed with other approved RA drugs, including Orencia (approved in 2005) and Rituxan (approved in 2006).

But it seems that the panic selling in the stock can be primarily attributed to a slight blood pressure increase in the patients who received the drug. Because R788 is intended to be taken for very long time periods, the concern about its safety profile is obvious, especially given the current FDA’s stance on safety issues. Nevertheless, when things are put in perspective, it seems that the market reaction to this issue was somewhat exaggerated.

There is little doubt that R788 leads to an elevation in blood pressure, but the real issues here are the magnitude of this effect and its clinical relevance in a “real-world” setting. The average blood pressure in the trial increased from a level of 120-130 mmHg  to 125-135 mmHg. In most cases, this increase did not necessitate any action, and in the few cases (5% of patients) in which physicians decided to lower the patient’s blood pressure, they were able to do so with conventional blood pressure medicines. Moreover, even when a patient that had already been taking a blood pressure drug had an increase in blood pressure, it was completely manageable by increasing the dose of the anti-hypertension drug. This may be particularly important since RA patients have a higher tendency of developing elevated blood pressure and  are often treated with blood pressure medicines in parallel to RA treatment. In addition, there was no constant increase in blood pressure, but instead, blood pressure levels increased shortly after treatment initiation with R788 and stabilized for the rest of the trial period.