On June 4, Indevus Pharmaceuticals reported that the FDA is likely to request additional safety data before approving NEBIDO®, its depot testosterone product for the treatment of male hypogonadism. The news sent the stock on a tumble – losing $2.46 to $1.26/share (a 70% decline) in the subsequent trading period (it has since recovered a bit, Friday’s close was $1.38).
Indevus indicates that the safety concern is injection site reactions. The company said that in its US clinical trial, they observed only one reaction out of 500 patients treated (and the patient with the reaction has continued with the therapy). The reaction, common to oil-based depot injections, is manifested by coughing and/or shortness of breath which can become more serious dizziness, flushing or fainting.
We always try to learn from the FDA responses. Some analysts have taken the disappointed investor route (how could FDA do such a thing!), others who are worried about the side effects of androgens applaud the FDA (but for the wrong reasons, as noted above). I’d like to look at this situation from a potential FDA reviewer’s point of view (just my opinion, and Indevus is not a client- though we have alot of experience with testosterone products, so I have no inside information).
Background: Indevus licensed the product from Bayer Schering Pharma AG in 2005. The product was approved in Europe in 2003 where the labeling discloses the site reactions, as noted above). In the U.S., the FDA requires that a testosterone product meet the following criteria for approval (the Phase 3 study is a pharmacokinetic study – you weren’t thinking libido were you?):
Average concentration:At least 75% of patients who, at steady-state conditions, have an average concentration of serum total testosterone (Cavg) within the normal range (300 to 1000 ng/dL).
Maximum concentration:No patient should exceed a testosterone concentration of 2500 ng/dL, no more than 5% of patients should exceed a concentration of 1800 ng/dL, and no more than 15% of patients should exceed a concentration of 1500 ng/dL
The product that was licensed was testosterone undecanoate, 1000 mg injected once every 12 weeks.
Indevus submitted the NDA for NEBIDO on August 28, 2008 with an expected PDUFA user date of June 27, 2008. According to the company, the NDA (presumably 505(b)(2), but undisclosed) efficacy and safety information was based on “six clinical studies in which over 400 patients received at least one dose of NEBIDO, with over 300 of these patients treated for more than one year. In total, over 3,000 injections of NEBIDO have been given to hypogonadal males during the clinical development program. In addition, the NDA includes post-marketing data from safety reporting through June 2007, reflecting the world-wide experience from over 260,000 injections of NEBIDO.”¹
Indevus performed one Phase 3 clinical study for the NDA submission beyond that performed by Bayer. The study was a two-arm trial, with a total enrollment of 237 male hypogonadal patients, 117 patients in the 1000 mg arm and 120 patients in the 750 mg arm. The drug was administered every 12 weeks for 1 year (total of 5 injections). It’s not quite clear to me from the study summary, but it appears that 97 men completed the 1000 mg arm and 102 men the 750 mg arm. Thus, the total injections are about 485 (1000 mg) and 510 (750 mg). The reader is encouraged to click the link to see the outcome of the study, but, suffice it say the primary (Cavg and Cmax) and secondary endpoints were met.
Apparently, what was not disclosed in the study summary above, is that the steady state took a long time to achieve. Moreover, despite meeting the Cmax criterion, they came uncomfortably close. Time for a new study.
On January 22, 2008, Indevus announced the submission of a new study examining a 750 mg dose in which hypogonadal men were given an initial injection of 750 mg of NEBIDO, followed 4-weeks later by an additional 750 mg loading injection and then 750 mg injections every 10-weeks thereafter. The company asked the FDA for approval of this regimen instead of the previous studies regimen. In this new study, 117/130 completed data collection (duration is not stated). Study results were not reported in as much detail as the previous study, but it appears that the Cavg criterion was about the same and the Cmax criterion was better met. Note that the company stated “the spectrum of adverse events reported were comparable to other injectable hypogonadism treatments reported in the literature.”
Whew, a lot of information! Where does that leave us – our hypothetical FDA reviewer? I’m supposed to approve the new regimen. I have a nice safety database of men treated at 1000 mg and many at 750 mg (I don’t believe the spontaneous reports in Europe to be of much help, we know they’re under-reported over there and in the U.S.). The studies done in Europe show the potential of a reaction – its on the European label. Is the site reaction related to dose? The sponsor believes it due to the oil matrix and poor injection technique – thus not patient or drug related. The dose is 4 ml for the 1000 mg strength and 3 ml for the 750 mg strength. Thus, it may be related to the dose of oil . The product in Europe is 1000 mg with a recommended 12-week injection. The previous regimen had a total of 5 injections per year. This new regimen has 7 injections in the first year, followed by 5-6 per year. Thus due to more injections there more potential for reaction. I only have 117 patients at the proposed regimen. Conclusion, I have insufficient information and must ask the sponsor for more information.
Indevus is now preparing to conduct a new study. They state that it will take 18 months to complete and file and 6 months for FDA review. We’ll follow the progress of this application because it gives insight into what FDA (at least this division) believes is an adequate safety database.
1. Indevus press release Nov. 1, 2007. FDA Accepts New Drug Application for NEBIDO(R) Submitted by Indevus.