Ampio Pharmaceuticals Inc. missed the primary endpoint in its second pivotal trial for Ampion, a candidate for treating osteoarthritis of the of the knee (OAK), tested under an FDA special protocol assessment (SPA). Nonetheless, with evidence of a consistent benefit for some of the worst-off patients in the indication, it plans to seek the agency's approval for the drug.

"In all the trials, we've seen Ampion work very well," Ampio's chief financial officer, Gregory Gould, told BioWorld Today. However, saline has also worked very well in some cases, turning in a much more variable performance in Ampio's studies than other controls in the OAK market.

Complicating matters, the Western Ontario and McMaster Universities Arthritis (WOMAC) osteoarthritis index, the FDA's favored endpoint for OAK trial, can be very subjective. "When you ask someone to tell you how they felt 12 weeks ago vs. how they feel today and rate that on a five-point scale, that can be tough for people to judge," Gould said.

In patients with the worst cases of OA, however, the picture has been clear, Gould said. Across three studies the company analyzed, Ampion provided those individuals – people with Kellgren Lawrence grade 4 OAK – the largest benefit relative to saline. Those patients, who have little other choice than knee replacement for relief, have been historically excluded from knee OA trials because of the advanced stage of their condition, the Englewood, Colo.-based company said.

A discussion of the trial, called PIVOT, is slated for a conference call to be held July 5, a day the company chose to reach the largest audience of investors in light of this weekend's holiday in the U.S. But investors, impatient for news, didn't wait to act, sending Ampion shares (NYSE MKT:AMPE) down 61.1 percent to a $1.29 close on Thursday.

It's the second time Ampio has endured a market drubbing following a phase III study that missed its endpoint. The last time was with STRIDE, a study that enrolled 338 patients to test multiple injections of Ampion for treating OAK. While Ampion did deliver some benefit, providing treated patients in STRIDE with a statistically significant reduction in pain compared to baseline, three intra-articular (IA) injections of the nonsteroidal therapy fell short of beating out the pain relief provided by saline, a partially therapeutic treatment used as a placebo in STRIDE and many other studies of osteoarthritis. Ampio said at the time that the saline control arm results varied "well out of a normal range" when compared to previous studies it had conducted and the published results of studies of other osteoarthritis drugs. (See BioWorld Today, April 21, 2015.)

During PIVOT, Ampio found that a single IA injection of Ampion successfully improved patients' OAK-related pain over baseline. However, it failed to provide better pain relief than a saline injection at 12 weeks, the study's primary endpoint. The double-blind trial included 480 patients. It measured pain using WOMAC index 3.1 and an overall global severity assessment.

The company said its analysis showed statistically significant improvements in WOMAC A pain (p = 0.016), Patient Global Assessment (p = 0.001) and responder status (p = 0.006).

PIVOT was the second pivotal trial testing a single injection of Ampion. It followed the 320-patient SPRING study, the results of which were reported during the second half of 2013. In SPRING, people with pain due to OAK were randomized to receive one of two doses (4 mL or 10 mL) of Ampion or corresponding saline control via intra-articular injection. Both doses showed a statistically significant reduction in pain compared to control, and there were no significant differences between the efficacy of the two doses. Patients who received Ampion during SPRING experienced, on average, greater than a 40 percent reduction in pain from baseline at 12 weeks. They also showed a significant improvement in function and quality of life, assessed using the PGA, compared to patients who received saline control at 12 weeks. (See BioWorld Today, Sept. 23, 2015.)

Ampion, or aspartyl-alanyl diketopiperazine, is an endogenous immunomodulatory molecule derived from the N-terminus of human serum albumin that appears to reduce inflammation by suppressing pro-inflammatory cytokine production in T cells.

Currently available OAK treatments include oral nonsteroidal anti-inflammatory agents, opioids, pain patches, IA corticosteroids and IA hyaluronic acid injections. The American Academy of Orthopaedic Surgeons has recommended NSAIDs but has found the evidence on opioids, pain patches and IA corticosteroids to be inconclusive. Evidence on hyaluronic acid's benefit has been mixed. If approved, Ampion would be the first nonsteroidal, non-hyaluronic-based IA treatment available for the treatment of OAK.

In addition to Ampion, the company continues to work on Optina (DMI-5207), an oral, low-dose repurposed formulation of danazol, for the potential treatment of diabetic macular edema. During 2014 and 2015, it conducted the Optimeyes multicenter, placebo-controlled, randomized, dose-ranging trial of oral Optina.

The 355-patient trial found the drug to be safe and well-tolerated with no drug-related adverse events and no differences in side effect rates between placebo and Optina groups. But it didn't meet its primary endpoint for all patients. Still, Ampio noted it believes it has successfully identified an optimal dose for a body mass index subgroup of patients refractory to current therapies and who also utilize RAS inhibitors to control their blood pressure. That subgroup showed a +6.2 letter improvement in visual acuity at three months.

At the end of March, Ampio had $11.1 million available to fund operations and $3.3 million in accounts payable and accrued compensation. That money should fund its currently planned operations through 2016 and into early 2017, it said.

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