Having resolved issues with its manufacturing supply chain and conducted an additional phase III study over and beyond requirements set by the FDA in two previous complete response letters (CRLs), Heron Therapeutics Inc. is confident the finish line is in sight for lead product Sustol (granisetron injection) to prevent delayed-onset chemotherapy-induced nausea and vomiting (CINV) following administration of moderately or highly emetogenic chemotherapy (MEC/HEC) agents.

Rebranding of the Redwood City, Calif.-based company, previously A.P. Pharma Inc., was more than skin deep, according to CEO Barry Quart, who joined Heron in 2013 after leading Ardea Biosciences Inc., of San Diego, to a $1.26 billion buyout by London-based Astrazeneca plc. (See BioWorld Today, April 24, 2012.)

Since then, Heron has bolstered its manufacturing capacity from an output of 1,500 to 2,000 syringes at a time to lots of 50,000 at a time. The additional phase III MAGIC (Modified Absorption Granisetron In the Prevention of Chemotherapy induced nausea and vomiting) study, now fully enrolled, is designed to help differentiate Sustol in the CINV marketplace.

Using its bioerodible drug delivery technologies, including its polymer Biochronomer platform, Heron also added three follow-on candidates to its pipeline, which was a flat line in 2013.

Sustol has been the company's lead product "for quite a while," Quart observed. Indeed, trials of the drug date back a decade, according to Cortellis Clinical Trials Intelligence. In a randomized, multicenter, observer-blind, actively controlled, double-dummy, parallel group phase III study that enrolled 1,395 patients, the sustained-release formulation of granisetron failed to show superiority over the approved 5-hydroxytryptamine type 3 (5-HT3) antagonist, Aloxi (palonosetron hydrochloride, Eisai Inc.), in preventing CINV, although the drugs were comparable in efficacy and safety. (See BioWorld Today, Oct. 1, 2008.)

The trial was structured to compare Sustol, dosed at 5 mg and 10 mg, with palonosetron across four primary efficacy endpoints: noninferiority to palonosetron to prevent acute and delayed CINV in patients receiving MEC agents, and noninferiority and superiority to palonosetron to prevent acute and delayed CINV, respectively, in patients receiving HEC. Because palonosetron is not approved by the FDA to prevent delayed-onset CINV in patients who receive HEC, the company was seeking to prove Sustol would be superior to palonosetron to obtain a corresponding label claim.

The 10-mg dose of Sustol achieved complete response (CR) rates that were numerically higher than palonosetron across all four assessments, demonstrating noninferiority across the four endpoints, but fell short of the superiority endpoint for the HEC assessment.

In 2009, the company forged ahead with its new drug application (NDA) anyway, filing under the 505(b)(2) pathway. The FDA accepted the NDA for review but, in March 2010, delivered a CRL, raising concerns about the drug's two-syringe administration system, including potential issues with the transfer of material from one syringe to the other before administration, certain components used in the dosing system and the potential risk of improper administration. Regulators also cited deficiencies in the contract manufacturing facility and requested clarification and revision of certain analytical specifications proposed in the application.

The FDA did not request additional efficacy studies, although it requested the reanalysis of certain phase III data along with bioavailability and metabolism studies.

The company resubmitted the NDA in 2012, which again was accepted by the FDA and in 2013 resulted in a second CRL, with the agency once more seeking additional data analysis and citing deficiencies found at a manufacturing facility.

That's when Quart came onboard and took the bull by the horns.

"From a regulatory point of view, the obstacle to getting this drug approved really was the manufacturing process," he told BioWorld Today. "The FDA did not request that we do this additional study."

'THIS IS A VERY LARGE MARKET OPPORTUNITY'

The newly branded Heron set about to "completely revamp our manufacturing supply chain," Quart said, seeking not just to meet but to exceed FDA standards. On its own initiative, Heron decided to conduct the additional phase III to differentiate its product by demonstrating its thesis for Sustol in delayed-onset CINV after HEC – a market that still lacks an approved product.

Heron reported Thursday that it reached its enrollment target in the prospective, randomized, placebo-controlled, MAGIC study comparing Sustol plus the neurokinin-1 (NK1) receptor antagonist fosaprepitant and dexamethasone to standard of care in the indication. The study has enrolled approximately 900 patients receiving various HEC agents, as defined by 2011 American Society of Clinical Oncology guidelines, at approximately 200 U.S. sites. The primary endpoint is the proportion of patients who achieve a complete response, defined as no emesis and no rescue medications in the 24-hour to 120-hour period following chemotherapy.

The company expects to report top-line data and May and to resubmit the NDA in all four indications around midyear, with approval possible by year-end, Quart said. Heron's goal is to position the product as the premier 5-HT3 receptor antagonist for the treatment of CINV.

Deciding to design the trial to compare Sustol to standard of care rather than an inferior control group could provide "a helpful competitive advantage vs. Aloxi, which is the market leader in this space," Quart said. "We hope the data will also show the FDA that this product deserves a close look to help satisfy an unmet medical need."

Analysts generally fell in line behind that premise. In a company note two weeks ago, when Heron reported fourth quarter and full-year 2014 financials, Jefferies Group LLC analyst Biren Amin concluded the "third time could be a charm for Sustol," predicting the drug will be approved and launched next year, with a differentiated label to treat delayed and acute phase CINV in patients receiving HEC.

Aloxi had sales of $451 million last year, Amin pointed out.

"We think Medicare Part B reimbursement could drive Sustol market share," he wrote. "In addition, physicians may be attracted to the long-active five-day durable efficacy compared to shorter-acting CINV agents." Amin predicted a peak share of 24 percent of the CINV market in 2026, with revenues of $472 million.

In his earnings review, Brean Capital LLC analyst Jonathan Aschoff agreed that "this trial will succeed and that inclusion of delayed-onset CINV in HEC data and subsequent regulatory approval will make Sustol the first 5-HT3 antagonist approved for delayed-onset CINV in HEC."

And Leerink Partners LLC analyst Jason Gerberry observed in his earnings report that Heron's shares "have had a strong performance since Jan. 2, returning ~46 percent vs. flat growth for the S&P during the same time frame. We believe there is upside for investors not only ahead of the phase III data but ahead of a Sustol launch in '16."

Heron expects to take Sustol to market using a targeted sales force of fewer than 100 reps, according to Quart.

"This is a very large market opportunity, and we feel very confident that with a differentiated profile we should be able to garner a significant portion," he said.

Behind Sustol in CINV, Heron has the NK1 receptor antagonist, HTX-019, an injectable formulation of aprepitant, that could potentially be used alone or in combination with its Sustol. Importantly, HTX-019 does not contain the surfactant polysorbate 80, which can cause hypersensitivity and other adverse reactions.

HTX-019, also moving forward along the 505(b)(2) pathway with a market entrance as early as 2017, "would fit very beautifully into the bag the sales reps already offer" in CINV, Quart pointed out.

The company also has two pain programs. HTX-011, which uses Heron's Biochronomer drug delivery technology, is a long-acting formulation of the local anesthetic bupivacaine in combination with the anti-inflammatory meloxicam, initially targeting prevention of postoperative pain. In a phase I trial, HTX-011 achieved the desired pharmacokinetic profile for both bupivacaine and meloxicam, sustaining therapeutically relevant plasma bupivacaine levels for up to three days without the initial peak observed with existing formulations. The anesthetic effects of HTX-011 persisted through 96 hours, correlating with plasma bupivacaine concentrations, and HTX-011 was well tolerated with no serious adverse events.

Aschoff called the early findings on HTX-011 "highly encouraging," citing the drug's "impressive durability" and clean safety profile. Heron plans to move the drug into phase II development in the second quarter of 2015.

HTX-003, also based on Heron's Biochronomer technology, is a long-acting formulation of buprenorphine to manage chronic pain and opioid addiction.

On Thursday, Heron's shares (NASDAQ:HRTX) closed at $14.07, dropping 15 cents.