Despite encouraging data shared earlier by Nymox Pharmaceutical Corp., a pair of phase III studies with NX-1207 for benign prostatic hyperplasia (BPH), known as NX02-0017 and NX02-0018, failed to meet their primary endpoints in top-line results, and the company blamed a strong placebo response – stronger than was seen in previous experiments.

"The drug got to where we expected it to, but the placebo was not sufficiently distant from it," said CEO Paul Averback during a conference call with investors after the markets closed. "There are a number of approaches that people take to try and dampen placebo effect, by run-ins and this sort of thing," he added, but none were attempted in these two studies, known as NX02-0017 and NX02-0018.

"We had never encountered any problems before and we didn't want to further complicate our studies, because they took long enough to do," Averback said. "Nobody has ever successfully enrolled 1,000 people for an injectable [year-long] prostate study where you had to do placebos before, and the more barriers you put in the more difficulty there would have been to enroll such a large number of people in the U.S."

Placebo patients "fill out reports and funny things can happen," he said, adding that the company still believes strongly in the drug. "Some of the placebo responses are clearly troublesome, so off the dial it's hard to imagine there's any validity to them," Averback said.

One investor found them especially so. "I've got some cash in my retirement plan, and it's gone to hell," he said, in a voice that sounded shaky at times. "I've lost a lot of money. You're commenting on everything but the money part. You can't give me any assurance about what I should do?" Averback said he couldn't, adding that officials "accept it and respect your question, and trying to give answers as best we can."

Shares of Hasbrouck Heights, N.J.-based Nymox (NASDAQ:NYMX) closed Monday at 93 cents, down $4.21, or 82 percent, as onlookers speculated about what the failure could mean for Sophiris Bio Inc., of La Jolla, Calif., which in early September said it had completed enrollment in its first of two necessary phase III trials with PRX302 (topsalysin) for BPH. Sophiris expects an interim analysis around the end of this year, with a complete analysis in the second half of 2015.

Sophiris' stock (NASDAQ:SPHS) closed Monday at $2.58, down 6 cents. Comparison has never been easy, since Nymox has kept its protein drug's mechanism of action close to the vest, saying only that the compound promotes apoptosis. Injected NX-1207 has an advantage over daily pills, since urologists administer the compound during an office visit and trials have shown that men maintain improvements three months after a single dose.

Sophiris' injected therapy is designed to provide the same upside over pills – alpha blockers, 5-alpha-reductase inhibitors, and phosphodiesterase-5 inhibitors – and the company is testing PRX302 as a single shot. In phase IIb experiments, the recombinant proaerolysin produced a clinically significant improvement in the subjective symptom score (International Prostate Symptom Score, or IPSS) and the objective measure of mean peak urinary flow (Qmax) rate sustained over 12 months.

Native proaerolysin binds to glycophosphatidylinositol-anchored proteins found on the surface of most mammalian cells. It contains a carboxy-terminal inhibitory domain that is cleaved by membrane-bound proteases such as the furins, turning out aerolysin, rapidly oligomerizes and makes its way into the plasma membrane to form highly stable pores that cause rapid cell death.

Sophiris has been much more forthcoming about PRX302, noting that the compound has been genetically modified to replace the furin-cleavage sequence with a prostate specific antigen-selective sequence.

PLACEBO 'BETTER THAN SURGERY'

Leerink Partners analyst Paul Matteis pointed out that, since Nymox disclosed no numerical details regarding the absolute reduction observed on the IPSS and did not include "p" values in its reporting of the trials' outcomes, analysis remains difficult. "Nonetheless, anecdotally, the large placebo-effect observed in the Nymox phase III study is consistent with what was also observed in the PRX-302 phase II trial, in which the placebo cohort (who also underwent an intraprostatic injection but with an inert vehicle) showed larger IPSS reductions than the placebo group had in any previous BPH trial that studied oral medications."

Sophiris contended that the big IPSS knockdown in the phase II placebo group could mean that "multiple injections into the prostate may be marginally therapeutic even in the absence of drug by incurring small amounts of cell death in the prostate transition zone," Matteis wrote in a research report, "and the failure of the Nymox phase III studies seems to lend support to this theory."

While the Nymox's result-foiling placebo response might suggest a hurdle for Sophiris, though the latter's first phase III trial is powered at 90 percent to show a statistically significant benefit even if the effect size is only around 2.5 points. "The failure of the NX-1207 phase IIIs paves the way for PRX-302 to be the only intraprostatic injection available for BPH if Sophiris' phase III program is successful," in Matteis' view.

The Nymox fizzle, though it helps Sophiris gain ground, also may do away with the potential for a pre-paved regulatory pathway in BPH therapies given by injection.

Nymox held out hope for NX-1207, described as a protein with pro-apoptotic properties, in low-grade localized prostate cancer, where phase II results showed evidence that treatment had a positive effect on biopsy results and clinical as well as biochemical progression. Endpoints in further trials in that indication should be more reliable.

"We wouldn't be subject to the disastrous confluence of events that happened in these pivotals, where placebos were reporting 25-point improvements, which is twice as good as surgery," Averback said. "It's absurd."