The active drug, levetiracetam, isn't new, but FDA approval of Spritam to treat certain forms of epilepsy guaranteed a spot in biopharma history for Aprecia Pharmaceuticals Co., which became the first company to bring a drug product using three-dimensional printing (3DP) through the approval process. Aprecia is wagering that development of its Zipdose technology platform, which uses 3DP to produce a porous drug formulation that disintegrates rapidly with just a sip of liquid, will transform the dosing of central nervous system (CNS) and other drugs associated with high rates of noncompliance and other challenges, such as swallowing difficulties.

The FDA approved oral Spritam levetiracetam (Keppra, UCB SA) as adjunctive therapy to treat partial onset, myoclonic and primary generalized tonic-clonic seizures in adults and children with epilepsy. The Zipdose technology developed by Aprecia – the middle section of the company's name alludes to its focus on "precision" manufacturing – enables the delivery of a drug load of up to 1,000 mg in a single dose, enabling administration of the largest approved strengths of levetiracetam with just a sip of liquid. Each Spritam dose is individually packaged, eliminating the need to measure liquids or count pills.

Success didn't exactly occur overnight. Aprecia began operations in 2004, and some of the management team worked together even earlier at a predecessor company focused mainly on medical device development and funded by a consortium that included Johnson & Johnson, Advanced Tissue Sciences Inc. and Tredegar Corp., which manufactures plastic films and other products.

The core technology involved a patent estate developed at the Massachusetts Institute of Technology (MIT) in the late 1980s for using an aqueous fluid to stitch together multiple layers of powder, resulting in a process that could potentially generate a wide range of products.

"The consortium wanted to explore how this technology platform might be used across different areas within health care – primarily tissue engineering and pharmaceuticals," explained Don Wetherhold, Aprecia's CEO.

Although pharmaceutical applications included potential uses for novel dosage formulations, the company never tackled some of the bigger challenges, such as gaining regulatory approval for the 3DP manufacturing process and scaling up for commercial launch. Eventually, Tredegar acquired the holdings of the other investors and then sold off the company and its tissue engineering applications.

Pharmaceutical uses in the patent estate reverted to MIT, however, prompting Aprecia's founders to seek an exclusive global license for those applications, which became the basis for the company's platform.

Aprecia is unusual in another respect. Over the course of its 10-year existence, the company has been sustained largely by a single investor: Tom Arington, who serves as chairman of the board. Arington also is founder, chairman and former CEO of Prasco Laboratories, an authorized generics manufacturer based in Mason, Ohio, and former chairman and CEO of Duramed Pharmaceuticals Inc., of Cincinnati. Duramed was picked up in 2001 by generics drugmaker Barr Pharmaceuticals Inc., of Montvale, N.J., which was subsequently acquired in 2008 by Teva Pharmaceutical Industries Ltd., of Jerusalem.

Arington "saw the technology platform when it was really just a desktop concept," Wetherhold said. "We feel very fortunate and blessed to have had one investor who has taken us to this point, where we now have an approval."

PLENTY OF 'POTENTIAL PRODUCT OPPORTUNITIES' IN CNS

Aprecia's team spent several years examining a range of applications for the 3DP platform before developing a long-term strategy. The company's Zipdose technology overcomes the "dose ceiling" associated with other products designed to dissolve quickly, Wetherhold said. Zipdose "breaks the bonds" created during the 3DP process, allowing for rapid disbursement through the gut once the product comes in contact with liquid, although the rate of absorption is comparable to the reference drug.

"Patients and caregivers are surprised by how quickly these large dose loads can disappear," Wetherhold said.

The 3DP technology can be used with other formulation platforms, offering development options that Aprecia will likely explore in the future. But epilepsy stood out as an initial indication due to issues with nonadherence in the "high dose zone" and management challenges for patients with significant co-morbidities such as stroke and Alzheimer's disease.

"Noncompliance is one of the biggest causes of breakthrough seizures," Wetherhold pointed out. "One skipped dose can put a patient with epilepsy at risk for reoccurrence." Patients who consider their medication regimen as unpleasant are the most likely to skip, postpone or otherwise avoid taking their prescriptions, he added.

"We think we can change the experience for those patients who have difficulties swallowing the large tablets," Wetherhold told BioWorld Today.

Aprecia has not disclosed the remainder of its pipeline, but the company sees "a lot of potential product opportunities in the CNS area," he added.

Spritam was advanced through the 505(b)(2) pathway without a single efficacy study, notwithstanding a good deal of hand-holding with the FDA. The company started the conversation some years ago with a "lunch and learn" to familiarize agency staffers with the 3DP manufacturing process and Zipdose platform technology. Prior to filing its new drug application (NDA), Aprecia also engaged in type B correspondence with the agency and held face-to-face meetings to discuss the clinical plan and manufacturing process control. The dialogue continued during the NDA review, and FDA officials gave the manufacturing process a clean bill of health during the pre-approval inspection.

"The key was to show that even though this was a new way to make pharmaceutical products, we very much operate in a manner similar to traditional manufacturing and have in place the same kinds of process controls and data," Wetherhold said.

Aprecia plans to launch Spritam in the first quarter of 2016. The company, which has offices in East Windsor, N.J., and manufacturing operations in Blue Ash, Ohio, completed validation batches and is now building launch inventory using proprietary equipment in a brand new plant acquired from Actavis plc (now Allergan plc). Aprecia partnered with Inventiv Health on marketing strategies for Spritam and plans to recruit and train a professional detailing team to educate physicians about the product. Prasco is handling the drug's distribution.

Aprecia conducted extensive research on reimbursement prospects, "and we do anticipate that we will get formulary coverage by commercial insurers and the government," Wetherhold said. To maximize coverage and patient access, the company plans to price Spritam in line with other branded anti-epileptic drugs.

With its first FDA approval in hand, Aprecia also is beginning to look at other markets that might benefit from the 3DP approach to high-dose drug formulation, although ex-U.S. efforts likely will be advanced through partnerships.

Long term, the company plans to launch a steady stream of products, and its operational strategy matches that goal. Over the past year, the company has ramped up head count, now at 80, and expects to nearly double its work force again over the next three years.

"We're on a pathway where, every 10 to 12 months, we could be in a position to introduce another product," Wetherhold said.

As for the financial wherewithal to accomplish that goal, "all of the usual options are available to us to raise additional money," he added. "In the meantime, our initial investor is committed to continuing to move the ball down the field and making sure we can execute our plan."