First and Only Biologic OA Treatment Unblinds Phase 3 Data

In 2015 the director of trauma research at Swedish Medical Center in Englewood, Colorado, Dr. David Bar-Or posed the following provocative, if dense, hypothesis for interrupting, possibly reversing the effects of osteoarthritis (OA) in human knees.

“By examining the effect of the anti-inflammatory prostaglandins 15d-PGJ2 and 12-PGJ2, we propose that new therapeutic agents for this disease [osteoarthritis of the knee] could facilitate the transition from the COX-2-dependent pro-inflammatory synthesis of the prostaglandin PGE2 (catalyzed by mPGES-1) to the equally COX-2-dependent synthesis of the aforementioned anti-inflammatory prostaglandins. This transition could be instrumental in halting the breakdown of cartilage via matrix metalloproteinases (MMPs) and aggrecanases, as well as promoting the matrix regeneration and synthesis of cartilage by chondrocytes. Another desirable property of new OA therapeutics could involve the recruitment of mesenchymal stem cells to the damaged cartilage and bone, possibly resulting in the generation of chondrocytes, synoviocytes, and, in the case of bone, osteoblasts.”

Dr. Bar-Or’s audacious idea was put to the test repeatedly—including in a 12-week randomized, double-blind, controlled phase 3 clinical trial conducted at 13 sites including at Dr. Brian Cole’s lab at Rush—and, based on the recently unblinded data, may become the first and only biologic treatment for osteoarthritis of the knee approved for sale in the U.S. by the FDA.

On March 2, 2022, the clinical study sponsor, Ampio Pharmaceuticals, Inc. unblinded the Phase 3 clinical study data and in the accompanying press release announced that researchers had found that the treatment (brand named AmpionÔ) demonstrated a statistically significant reduction in pain (p=0.042) and trended favorably toward improvement in function versus saline control.

In a later press release Ampio provided additional information about the impact of COVID-19 pandemic on the clinical study and the modified Intent-to-treat (mITT) population (more about that later).

Ampio CEO Mike Martino said, “We believe that the AP-013 data confirms the results from AP-003-A and supports the safety and efficacy of Ampion for the treatment of pain from severe OAK [osteoarthritis of the knee].”

“Earlier this year we submitted a Type C meeting request to FDA. FDA acknowledged our request and confirmed they will provide written responses to our questions as the next step. To support our position and inform FDA’s response, we recently submitted a detailed briefing package. I believe we are on track to provide clarity on AP-013 acceptance as the second pivotal trial by FDA by the end of the first half of this year.”

If Approved, Biologics Like Ampion Represent a New Approach to Knee Osteoarthritis

The promise of using a biologic like Ampion to treat knee osteoarthritis is that it could:

• Reduce inflammatory cytokines, including TNF-a, responsible for pain, tissue damage, and inflammation
• Decrease vascular permeability (an upstream event in inflammation)
• Attract and differentiate bone marrow-derived mesenchymal stem cells into normal chondrocytes
• Protect cells from apoptosis (programmed cell death) and autophagia
• Up-regulate both COX-2 mRNA and COX-2 protein in human immune cells and in synovial fibroblasts, human normal and osteoarthritic chondrocytes.
• Lead to increased production of the anti-inflammatory prostaglandins PGD2 and its metabolite 15-d-PGJ2.
• Shift the differentiation of inflammatory macrophages (M1) to the anti-inflammatory macrophage (M2) phenotype
• Decreases osteoarthritic inflammatory damage to the knee and restore healthy chondrocytes and normal cartilage accretion.

Knee osteoarthritis is treated with over-the-counter pain medications, cold therapy, hyaluronic acid (HA) injections, corticosteroid injections, prescription pain medications and, finally, total knee replacement surgery.

Where along that continuum of palliative care would a treatment which interrupts, and reverses arthritis fit? Likely somewhere between over-the-counter meds and corticosteroid or HA knee injections. In short, it could change the standard of care for severe osteoarthritis of the knee.

AMPION

Ampion is a low-molecular-weight filtrate of human serum albumin (HSA). It is a blood-derived cyclized peptide with various small molecules. It functions by suppressing inflammatory cytokines while simultaneously activating anti-inflammatory proteins.

Martino explained to OTW, “Ampion is a biologic, and it consists of a cyclized protein and two small molecules that have anti-inflammatory effects. It’s the first medication specifically [developed] to target severe osteoarthritis in the knee…and, to the best of our knowledge…would be the first new medication approved—if it’s approved—to treat osteoarthritis in about 25 years.”

Ampio’s Tortuous Pathway to FDA Approval

Ampio has been developing Ampion for nearly a decade—since 2013. In 2014, the company completed its first pivotal trial, AP-003-A. For OTW’s coverage of the first trial’s results, see “Ampion Trial Results Impressive for Severe Knee OA.”

Since that time, Ampio has completed a second clinical trial where data from the modified Intent-to-Treat (mITT) population in the company’s AP-013 study demonstrated sufficient power to reach statistical significance.

Martino told OTW, “AP-013 is actually the second pivotal trial that we believe confirms the results from AP-003-A which was the first pivotal trial, and those results were published in 2014.”

However, like almost every other sector, the trial was derailed by the COVID-19 pandemic. According to Martino, “[T]his trial was initiated in June of 2019 and a little more than half [of] the patients enrolled in time so that their 12-week efficacy visit occurred before the outbreak of COVID and the announcement of the COVID Public Health Emergency (PHE). A little less than half enrolled so that their 12-week efficacy follow-up visit occurred after that PHE announcement.”

“We looked at the data using FDA guidelines to determine sensitivity to COVID.” The sensitivity analysis revealed a statistically significant COVID effect. Ampio defined a mITT (modified Intent-to-Treat) population which included patients whose data was not sensitive to COVID.

Martino explained to OTW, “That results in an n of 618 patients in the modified Intent-to-Treat efficacy population. We have statistical significance in pain with a p value of .042. We did not hit statistical significance in function. We had a numerically higher number, but the p value is .111.”

Martino continued, “Frankly, the reason for that is the dramatic reduction in the n, from the over 1,000 patients that would have been required to hit statistical significance in function to now 618 patients which provides almost 90% power on pain but only about 73% power on function. A per protocol analysis of all enrolled subjects confirms statistically significant reduction of pain and function.”

Ampio’s Next Steps for Ampion

Ampio submitted a Type C meeting request to the FDA.

According to Martino, “[The request proposes] our modified Intent-to-Treat population and asks them [the FDA] if they agree. Ampio then proposes, based on the results of that modified Intent-to-Treat population, that AP-013 should be considered the second confirmatory trial to support a BLA [Biologics License Application].”

Martino continued, in part, “[W]e feel that they [the FDA] are considering our proposal, that they will consider it based on the merits of the data, and we’re just in wait and see mode now on that. We expect to have answers and clarity from them [the FDA] by the end of the first half of this year.”

New Management and a Cash Infusion

Over the past 24 months, the company has undergone a significant transformation.

Late in 2021, both Martino and Kevin Buchi joined the Ampio board. Martino and Buchi have significant experience. Martino took over as CEO, replacing Mike Macaluso, who took medical leave from the company. Martino’s 35-year career has been spent leading successful life sciences companies.

Buchi is the former president and chief executive officer of American biopharmaceutical company Cephalon, Inc. Over the course of his career, Buchi held other leadership roles in the pharmaceutical space.

Last month, Ampio announced another addition to its board, Elizabeth Jobes, Esq. Jobes has almost three decades of legal and compliance experience. She has held leadership roles at many biopharmaceutical corporations and currently serves as the senior vice president and global chief compliance officer at Amryt Pharmaceuticals Inc.

In addition to leadership changes, Ampio ended 2021 with the announcement of a successful fundraise with institutional investors. In a letter to stockholders, Martino reported the “successful completion of a $22.5 million registered direct offering.”

This funding came at a crucial time and is the reason that Ampio is even operating. Martino explained to OTW, “As a result [of the funding], we now have cash to operate into the second half of 2023. Which we think really gives us the flexibility to focus on these three objectives [discussed below] in parallel without worrying about cash in the short term.”

Focusing on the Future

With funding concerns behind the company (for now), it is free to focus on the future. What lies ahead for Ampio? The company plans to focus on the three objectives that Martino hinted at above.

Martino told OTW, “[T]he goals are pretty straightforward. Number one, getting clarity from the FDA. Number two, in response to what we believe will be a positive answer (we’re optimistic) we’re in the process of assembling a BLA so that we could be in a position to submit that and we believe that we could be in a position to do that—given current resources—in about a year.”

Martino went on to explain to OTW that Ampio’s third goal is to negotiate a partnership or partnerships to help globally develop and commercialize Ampion. Martino added that, ideally, Ampio would conclude one or more partnerships so Ampio would “have a partner’s capabilities and ideally cash to help us [Ampio] accelerate the BLA submission.”

Martino also added, “Then finally, we believe Ampion is a platform drug. We believe it has the potential to expand from treatment of osteoarthritis of the knee to treatment of osteoarthritis in other articular joints such as the shoulder, the hip, the wrist, the hand, the ankle. We believe that it has the potential to improve the treatment of other inflammatory diseases. We are working behind the scenes on our pipeline to determine what those next applications will be.”

Waiting for FDA

It is difficult to speculate on when Ampion will come to market. The only guidance Martino could provide was an assortment of milestones and timelines based on a number of factors. These factors include FDA approval in the U.S. as well as partnerships to assist with expansion into other geographies.

Even with an unclear timeline, Martino is optimistic and informed OTW, “We believe that the results of AP-013 confirm the results in AP-003-A and suggest that Ampion can be a safe and effective therapy for treatment of pain in patients with severe osteoarthritis in the knee. Of course, the FDA has to agree with that.”