Just three years old, Braeburn Pharmaceuticals is assembling a pipeline of drugs using a tried-and-true recipe: The company is applying implantable and injectable technology to reformulate off-patent drugs and bring them to market using the 505(b)(2) pathway.

The neuropsychological indications the company selected are not your mother's apple pie, however. They include opioid dependence, pain and schizophrenia – each with distinct challenges. Even the pathway isn't a given, observed Behshad Sheldon, Braeburn's president and CEO, who previously was responsible for marketing, alliance management and early development strategy in the U.S. for Tokyo-based Otsuka Pharmaceutical Co. Ltd., where she served on the board of directors of the company's R&D organization. Sheldon wryly called the 505(b)(2) "the occasionally abbreviated FDA pathway."

Braeburn, of Princeton, N.J., was founded in 2012 and is wholly owned by venture firm Apple Tree Partners. Its first asset was Probuphine, a long-acting subdermal implant designed to deliver a six-month dosage of the pain drug buprenorphine hydrochloride following a single treatment. In December 2012, Braeburn licensed exclusive commercialization rights to the drug in the U.S. and Canada, from Titan Pharmaceuticals Inc., of South San Francisco, in return for a nonrefundable up-front payment of $15.75 million, to $50 million upon approval by the FDA to treat opioid dependence, up to $130 million in sales milestones and up to $35 million in regulatory milestones for additional contemplated indications, including chronic pain. Titan also is eligible for tiered, double-digit percentage royalties on net sales.

Titan had filed the new drug application (NDA) for Probuphine just weeks earlier, but the drug stumbled out of the gate. Probuphine appeared off to a good start, garnering a generally favorable review during a meeting of the FDA's Psychopharmacologic Drugs Advisory Committee, which voted 10-4, with one abstention, in favor of approval. (See BioWorld Today, March 22, 2013.)

Two months later, however, the agency delivered a complete response letter, requesting additional clinical data demonstrating both the ability of Probuphine to show opioid blockade of relevant doses of agonists and the effect of Probuphine at higher doses than studied to approximate blood plasma levels associated with daily 12 mg to 16 mg sublingual doses of buprenorphine. (See BioWorld Today, May 2, 2013.)

Last July, based on what Braeburn called "clear guidance" from the FDA, the specialty pharma initiated a randomized, double-blind, double-dummy phase III study that enrolled 180 clinically stable patients with opioid dependence who were receiving maintenance treatment with an approved sublingual formulation containing buprenorphine at a daily dose of 8 mg or less.

Patients were randomized either to four Probuphine implants or to continue daily sublingual buprenorphine therapy. To maintain blinding, those receiving Probuphine implants also took daily placebo sublingual pills and those randomized to sublingual buprenorphine pills received four placebo implants. All patients are expected to be treated for six months, and the primary analysis will be a non-inferiority comparison of responders in the two arms.

The fully enrolled study is nearly complete, Sheldon said, with data expected to read out in the next few months, followed by an NDA filing in the second half of the year. The company hopes Probuphine will gain FDA approval in the first half of 2016.

'IT'S IMPORTANT TO TREAT PEOPLE'S PAIN'

In the meantime, Braeburn expanded its reach into long-acting buprenorphine injectables by inking a license with Camurus AB, of Lund, Sweden, for weekly and monthly subcutaneous buprenorphine injection products (CAM2038) to treat opioid addiction and pain. Braeburn obtained exclusive rights in North America and option rights in Japan, Korea, Taiwan and China in return for an up-front license fee of $20 million to Camurus plus $35 million and $21 million, respectively, in development milestones for opioid dependence and pain. Camurus also is eligible to mid-teen royalties on Braeburn product sales and can receive up to $75 million in sales milestones.

The companies are working together on a phase III development program for opioid dependence and expect to begin registration trials this year, following by applications next year for marketing approval in the U.S. and the EU. Braeburn and Camurus also plan to co-develop buprenorphine injection depot products for pain.

Earlier this month, Braeburn added a new ingredient to the mix by acquiring an implantable, six-month formulation of the second-generation antipsychotic, risperidone, from Endo Pharmaceuticals plc, of Dublin, to treat schizophrenia. That deal included global rights to other potential applications of the platform technology known as the Medlaunch implant program.

At the same time, Braeburn licensed from Oncothyreon Inc., of Seattle, the development and commercialization rights to ATI-9242, an atypical antipsychotic compound also designed to treat schizophrenia. The compound originally was designed by Aryx Therapeutics Inc., of Fremont, Calif., to have many of the benefits of clozapine without the drug's adverse effects.

In keeping with its business strategy, Braeburn plans to develop long-acting formulations of both drugs. A phase III study of the risperidone six-month implant is expected to begin by year-end, following meetings with the FDA. ATI-9242 was previously studied in a single ascending dose phase I trial, and additional formulation development and a phase II trial are planned for this year.

"When you do a 505(b)(2) and you go for a reformulation strategy, the key is what products you pick and what therapeutic areas," Sheldon told BioWorld Today. "We have two really successful molecules – buprenorphine and now risperidone – and we're in therapeutic areas where long-acting implants or injectables are not just a nice-to-have but essential to improving treatment outcomes."

In addition to the unmet medical need in treating opioid addiction and the enormous effort to prevent deliberate or accidental overdoses "we also realized that pain is pretty interconnected," Sheldon said, with a subset of these patients treated with opioids and many of those also becoming addicted.

Although schizophrenia is in an entirely different class, the need for an effective long-acting formulation is no less pressing, according to Sheldon, who was involved in the development and commercialization process for Abilify (aripiprazole, Otsuka/H. Lundbeck A/S), whose extended-release formulation still requires monthly injections.

"We know the space really well and have a great appreciation for what happens to patients when they stop taking their meds and relapse," she said. "We think we have a great synergistic portfolio that will allow us to leverage technology across the different therapeutic areas."

Braeburn's approach is to address pain without pretending that the potential for abuse will go away. Using buprenorphine, a partial agonist, as the base molecule dramatically reduces the potential for abuse while adding potentially beneficial mood and other effects.

"You can't overdose on buprenorphine by itself because it has a ceiling effect, so it's a great molecule for pain as an alternative to a full agonist," Sheldon explained. "But the part that takes us a whole level higher is our platform to use injectable and implantable formulations, which can't be used for pill mills, which can't be diverted and which can't get into the hands of children. Of course it's important to treat people's pain, but at the same time there are public health issues to deal with. This gives us almost the perfect scenario."

In the next 12 months, Braeburn plans to start four additional studies of its candidates, and Sheldon said the company remains on the lookout for additional long-acting technology. "In central nervous system disorders, there are almost an unlimited number of opportunities from a clinical standpoint," she observed.

On the marketing front, Braeburn plans to go it alone on its addiction products, which will target the North American market, but remains flexible on the broader commercialization opportunities in pain and schizophrenia.

And Braeburn has the luxury of making these decisions without constantly returning to the orchard to pluck its next financing round.

"We're funded through commercialization by Apple Tree Partners," Sheldon said. "We don't have to look at anything else. We're quite happy with the way things are, but of course we'll keep our options open and see where the markets go."