The Perilous Development Of A Potential Biologic Blockbuster

By Matthew Pillar, Editor, Bioprocess Online

CytoDyn’s leronlimab is under FDA review for Breakthrough Therapy status. Its path from a forgotten molecule to near market readiness was riddled with financial and process challenges.

In May 2019, the U.S. FDA granted Fast Track Designation for a drug called leronlimab for use in combination with carboplatin for the treatment of patients with CCR5-positive mTNBC. Last month, the maker of leronlimab filed for Breakthrough Therapy status for the drug as a treatment for metastatic triple-negative breast cancer. The road it took to this point was bumpy at best.

CytoDyn, the maker of leronlimab, was resurrected from the ashes in 2008 by an immigrant teacher with a PhD in mechanical engineering named Nader Pourhassan.

At the time, Pourhassan had been teaching mechanical engineering at the Center For Advanced Learning, a charter school in Gresham, OR while nurturing a few ancillary business partnerships. One of his partners, a 72-year-old named William, was holding 750,000 shares of a company called CytoDyn, which was then trading at a nickel. William, half desperate to unload his stake in the failing company, urged Pourhassan to meet CytoDyn’s CEO and help him turn things around. Pourhassan bristled. “I didn’t even know what biotechnology meant,” he tells me. “I wasn’t about to get involved.”

Pourhassan’s wife changed that paradigm, as spouses often do. She was weary of his frequent trips to China to nurture his business interests. She was convinced the CytoDyn project brought with it an opportunity to do something altruistic, to change peoples’ lives. “If it fails,” she reasoned, “we can always teach.” Her support sealed the deal. William helped Pourhassan sell off their business interests, and he went all-in on CytoDyn. Pourhassan joined the brink-of-bankruptcy organization as COO and was charged with its turnaround. For a year, he took no salary. His wife funded his travel, most of which was to raise enough funds to keep the company in the game.

An Abrupt—And Risky—Change Of Molecular Course

At the time, the company’s lead molecule, cytolin, was being developed for HIV. That molecule was in a phase one clinical trial when it hit a snag. The FDA had put a hold on the trial, asking CytoDyn to humanize it. Pourhassan set to work, but soon his research led him to redirect his efforts. He caught wind that Progenics planned to sell off a molecule called PRO 140, a phase 2 product it was developing for HIV indication, so the company could focus on its cancer program. PRO 140, a humanized mAb directed against the molecular portal that HIV uses to enter cells (CCR5), is a viral-entry inhibitor intended to protect healthy cells from viral infection. The Progenics PRO 140 project that caught Pourhassan’s eye was underwritten in part by a $28 million award from NIH. It had received Fast Track designation per FDA findings that it was better than the standard of care in resistance, toxicity, compliance, and side effects. But, Progenics had already moved through $22 million of that NIH funding at the time of purchase. Some, including a handful of CytoDyn’s board members, called the product a high risk.

Where others saw risk, however, Pourhassan saw opportunity to advance a molecule that was closer to commercialization than CytoDyn’s own cytoline. He convinced his board to take that risk. With some notable dissent, and with the stipulation that he assume the role of CEO, he proceeded to raise $7 million from private backers in fewer than thirty days. On October 10, 2012, he wired three and a half million dollars to Progenics to acquire PRO 140. “Then,” he tells me, “I gave the remaining $6 million Progenics had been awarded back to the NIH.”

“Four of the five paths they forecasted led to between $2 million and
$3 million in annual revenue. The fifth path showed $20 million
per year. This from a project that Progenics spent $200 million
on, and which we anticipated spending another $200 million on.
It just didn’t make financial sense, and more than a
few on our board threw their hands in the air.”

Back to that dissent Pourhassan faced at PRO 140’s prospects. Two of his board members in particular—a pair of ex-Gilead guys—were less than impressed with what hired analysts deemed the molecule’s likely path to market as a combination therapy. “Four of the five paths they forecasted led to between $2 million and $3 million in annual revenue,” recalls Pourhassan. “The fifth path showed $20 million per year. This from a project that Progenics spent $200 million on, and which we anticipated spending another $200 million on. It just didn’t make financial sense, and more than a few on our board threw their hands in the air,” he says.

Those board members—many of them pharma’s old guard—grew even more irate when Pourhassan, without an M.D. or more than a mere undergraduate course in biology, had the audacity to suggest a solution. At least one board member jumped ship. Other industry colleagues continued to pressure Nader to cut his losses, to abandon the product altogether, or take the path of lesser resistance and press on with PRO 140 as a potential combination therapy.

Pourhassan pressed on, proceeding to convince his board what a host of expert consultants—including a preeminent HIV authority in Dr. Robert Schooley and Progenics founder and discoverer of PRO-140’s interaction with HIV, Dr. Paul Maddon—had told him; if PRO 140 could find its way to approval as a monotherapy, it could change the HIV paradigm. As all of this played out, the company had yet to manufacture a single batch of the stuff.

Immediate Tech Transfer, Production Process Challenges

For a minute, let’s set aside the risk that PRO 140 might be a dud. On the immediate heels of the company’s acquisition of the molecule, CytoDyn couldn’t even produce it. “Progenics hadn’t manufactured the drug in five years. When we tried to duplicate the process, we couldn't find the molecule because the company that made it was out of business,” explains Pourhassan. “We brought some new partners on board who had introduced a new production process, but when you do that, the FDA wants every aspect of that production process to be presented from scratch again,” he laments. “The administration asked for 11 new assays to be developed.” In the end, rather than suffer the setback, Pourhassan says he “went through hell” to find, and subsequently hire, Dr. Nitya Ray, the man who developed the PRO 140 manufacturing process for Progenics. Ray, who now serves as Chief Technology Officer and Head of Process Sciences, Manufacturing & Supply Chain at CytoDyn, righted the wrongs and re-addressed the FDA with his original production processes. Crisis averted.

In 2014, CytoDyn engaged in what Pourhassan describes as a controversial trial of PRO 140, which it had by then named leronlimab, as a monotherapy in HIV patients. The intent was to demonstrate it could suppress the viral load of the disease. By December of that year, the company presented its trial data to the FDA. The Administration gave CytoDyn the greenlight, but with a caveat founded in HIV’s considerable resistance to antiretroviral therapy. For context, a 2010 study of HIV patients in India demonstrated more than 50 percent of participants with drug resistance mutations had two-class resistance and nearly 6 percent had three-class resistance, specifically to NRTIs, NNRTIs, and PIs. Due to that risk, pivotal trials of leronlimab were granted, but as a combination therapy. Move forward with pivotal combination trials, the FDA said, and CytoDyn could continue its work with the molecule as a monotherapy.

Concurrent Mono- And Combination Therapy Studies Produce Results

Last year, the company reported that ongoing refinement of its monotherapy program was paying off; a weekly, self-administered dose of 525 mg of leronlimab achieved 95 percent response rate after the first 10 weeks of monotherapy. After a total of nine phase 1, 2, and 3 trials as both a combined (phase 3) and monotherapy (entering phase 3) administered to more than 840 patients, leronlimab showed zero serious adverse events. The company is currently preparing its BLA filing for final approval of leronlimab as a combination therapy.

The U.S. alone sees nearly 40,000 new cases of HIV annually. New research from CytoDyn released in January 2020 posits that leronlimab could potentially reduce that number, not through its aforementioned suppressive mechanism, but through its observed prophylactic action in animal studies. The company says its preclinical study demonstrated that a single injection of leronlimab prevented intrarectal transmission of Simian-Human Immunodeficiency Virus (SHIV) in macaques, and it portends that these data support the potential of leronlimab as a pre-exposure prophylaxis (PrEP) treatment option.

Promise In GVHD, Triple-Negative Metastatic Breast Cancer

For all its potential on the HIV front, it’s the dozens of other potential indications for leronlimab that are getting the more recent buzz. Building on Pfizer’s recognition that its own CCR5 antagonist product revealed that the CCR5 receptor is an important mediator of GVHD, Pourhassan allocated $12,000 for an in vitro study on the effects of leronlimab on Graft Versus Host Disease. Based on the results of that study, CytoDyn sought Orphan Drug Designation for the therapy from the FDA, which recognized the unmet medical need.

“The FDA subsequently told us to take 32 mice, inject them all with human bone marrow, and give half of them leronlimab.” says Pourhassan. “If any of them lived for a hundred days beyond the study, we would be awarded orphan drug status.” Within nine days, the entirety of the control group was experiencing weight loss. Eventually, they all died. The test group, those that had received leronlimab, gained weight. They all survived the 100-day test. CytoDyn was granted a phase 2 clinical trial with orphan drug designation.

Pourhassan says the results leronlimab was producing in HIV and GVHD cases began catching the attention of CCR5 experts, many of whom presented sound evidence that the drug would show promise in oncology. “We conducted an animal study that demonstrated 98 percent metastasis inhibition in a humanized mouse over 19 weeks,” he says. That finding earned the company yet another phase 2 clinical trial. In its first human application, Pourhassan credits leronlimab with shrinking tumors and thwarting metastasis in four triple negative metastatic breast cancer patients. One of those patients is Pourhassan’s own mother in law. These findings are what prompted last month’s Breakthrough Status application.

There’s also been an animal study on colon cancer. CytoDyn believes leronlimab to have 22 cancer indications. It’s currently pursuing a basket trial to study those. It also claims the drug reduced fatty liver deposits in NASH patients some 90 percent. And, of course, there are the aforementioned HIV and GVHD indications.

How Is CytoDyn Producing Enough To Meet Intense Clinical Demand?

With so much momentum—and clinical activity—in the works, Pourhassan acknowledges the demand that CytoDyn has plenty of product on-hand and is ready to go. In its bid for a contract manufacturer (its original provider couldn’t handle capacity), he says CytoDyn’s CMO of choice demonstrated the capability, but required a $70 million down payment. “When we showed them the potential of this product, they agreed to accept deferred payment, most of it after approval,” says Pourhassan, “which was a huge deal.”  With the financial portion of the puzzle largely handled, the company was again subject to approval to the tech transfer portion. “The FDA requires two manufacturing runs, and they need to inspect those while the runs are happening,” says Pourhassan. “That’s a logistical feat, because tech transfer from one manufacturing center to another is a one-year undertaking,” he says. Not to mention the fact that antibodies are in high demand. Most CMOs are booked for months, if not years. And, of course, scheduling these observations with the FDA isn’t as easy as getting a dentist appointment.

All that being said, Pourhassan admits the company is running short on clinical supply, though he anticipates replenishment by Q2 2020. He also acknowledges that dipping into the company’s $50 million stockpile of commercial-grade product could sustain its clinical trial needs through the end of 2020 if necessary. “No more than two percent of that supply would sustain our clinical trials for the year,” he says. Of course, dipping into commercial supply—which, as opposed to clinical supply, must demonstrate six months of stability, thus adding considerable time to the product’s market readiness—would be a last resort.

Preparations Underway For Commercial Scale-Up

Currently, CytoDyn is producing 2,000 liters per run, with immediate capacity to produce 12,000 liters per run. Upon approvals of leronlimab for its various indications, Pourhassan plans to leverage Samsung Biologics’ 180,000 liter-per-run capacity and Lonza’s 150,000 liter capacity to facilitate the product’s commercial scale-up. And while it’s currently filled to vials, he says the company is already planning the switch to prefilled syringes of leronlimab to meet commercial demand. “The transition to prefilled syringes is strategic for both patient centricity and supply chain efficiency,” explains Pourhassan. “The patient will simply remove the syringe from its box, self-inject, and dispose of the syringe per the instructions on the box. This will eliminate the waste of a significant amount of material.”

CytoDyn’s journey with leronlimab has certainly been a tumultuous one. It effectively took a back-burnered product deemed virtually worthless and re-discovered its promise. Pourhassan started with nothing more than a penny stock acquisition—CytoDyn was in a perilous Over-The-Counter Bulletin Board position when he came aboard—and through grit and determination, raised some $240 million to resurrect the company. $140 million of that came through multiple transactions brokered by Paulson Investment Company, LLC, while $100 million was generated from Pourhassan’s own relentless pursuit of private individual investments. “Rallying these funds was the most difficult thing I’ve ever done in my life,” admits Pourhassan. The most difficult thing up until now, perhaps, as he anxiously awaits the FDA’s ruling on CytoDyn’s Breakthrough Therapy Designation application for leronlimab. It’s an important milestone for a drug he believes has blockbuster potential. But if there’s one thing Pourhassan’s story makes clear in the interim, it’s this; should the FDA’s decision not fall CytoDyn’s way, it won’t be enough to temper the man’s tenacity.