A New Clinical Test..Higher Dosage

The speculation that Arena will receive a CRL rather than approval on October 22, led me to thinking that if a new Clinical test is contemplated, perhaps a higher dosage per day would provide advantages to both efficacy results and to dispelling any lingering heart valve concerns of the review panel.

The max dosage tested in Bloom and Blossom Clinical Tests was 20 mg/day. What would happen if that were increased to 30 mg/day" Some posters on Yahoo ARNA believe that Arena was thorough and has some unpublished internal data that justifies their choice of 20 mg/day? However, I worked within a big company and know that research strategy and marketing strategy often do not agree and aspects of the latter are often foisted on the first.

I tend to think that Arena researchers were thorough, but am still left with the question of what would a higher dosage result in.

The clinical tests were designed to evaluate either 10 or 20 mg of Lorcaserin per day. The 20 mg dosage resulted in a higher weight loss than the 10 mg dosage:

"BLOSSOM evaluated 4,008 patients with an average BMI of 35.9 and baseline weight of 220 pounds. The Week 52 completion rate wi 10 mg
twice daily (57.2%) and 10 mg once daily (59.0%) compared to patients on placebo (52.0%). Discontinuations for adverse events wer
twice daily (7.2%), 10 mg once daily (6.2%) and placebo (4.6%)."

" Patients treated with 10 mg of lorcaserin dosed twice daily (BID) who completed the 52-week trial according to
protocol demonstrated the benefit of long-term treatment with lorcaserin:
• 63.2% of patients lost at least 5% of their body weight (p<0.0001);
• 35.1% of patients lost at least 10% of their body weight (p<0.0001);
• Patients lost an average of 17.0 pounds, or 7.9% of their body weight; and
• The quartile of lorcaserin patients with the greatest weight loss (among those with a Week 52 weight
recorded) lost an average of 35.1 pounds, or 16.3% of their body weight.

For the patients treated with 10 mg of lorcaserin dosed once daily (QD) and completing the 52-week trial according to protocol,

53.1% lost at least 5% of their body weight, and
26.3% lost at least 10% of their body weight.
The average weight loss in the lorcaserin 10 mg once daily group was 14.3 pounds, or 6.5%.

As with the higher dose, all results were highly statistically significant (p<0.0001 compared to placebo)."

http://www.sec.gov/Archives/edgar/data/1...

It seems possible that 30 mg per day would have resulted in better weight loss. While this seems to fly in the face of the cancer issue, it is not that much of a stretch to increase the daily dosage by 50%, and could be the way to redo some animal tests using this as a base dosage and therefore, put this concern to rest.

I was also intrigued by the drop in rate of weight loss after the first 38 weeks. This is obvious in the weight loss vs time graphs shown in many investor presentations. It was also true in the Qnexa results reported, the mid-dose Qnexa had results very similar to high-dose Lorcaserin. Therefore to an outsider to pharmacology, it seems possible that a higher-dose Lorcaserin could look more like the high-dose Qnexa.

The absence of serious side effects with Lorcaserin also leaves some room for a higher dosage. Perhaps, some side effect might become more manifest, but many such as headaches, repiratory infections, etc. are treatable by over the counter medications.

From the same 8K on Blossom test filed with the SEC:

"The most frequent adverse events and their rates for patients who took lorcaserin twice daily, lorcaserin once daily or placebo, respectively, were as follows:
upper respiratory infection (12.7%, 14.5%,
12.6%);
nasopharyngitis (12.5%, 11.7%, 11.8%) and
headache (10.0%, 10.5%, 7.6%)."

There has been speculation that Arena should have tested and reported on a Lorc-Phen combination, but Jack Lief assured the FDA that they would not pursue that avenue, but concentrate on a monotherapy approval. Jack has also commented that Lorcaserin has an advantage of not requiring titration.

In the case of Qnexa, titration seemed to be necessary to get patients acclimated to the side effects and to give physicians time to assess the interaction of the drugs with each individual patient. However, a secondary effect of adding titration with Lorcaserin may be to "tune" the agonist effect in the hypothalmus for each patient. Some patients may respond to 10 mg/day and not need advancement to higher dosages, others at 20 mg/day, and finally some agonist resistant people would benefit from advancement to 30 mg/day. It would not be possible for a physician to predict that without prescribing a titration approach.

Choosing to not test the Lor-phen combination and to not evaluate titration could have been primarily marketing strategies to clearly separate Lorcaserin from Qnexa (a topiramate-phen combo requiring titration), and the earlier fen-phen combo. Receiving a CLR may also provide the internal fuel to change their marketing strategies.