Onsolis' REMS Is Not Template For Long-Acting Opiates - FDA

FDA signaled it is moving ahead with action on short-acting opioid products - and their Risk Evaluation and Mitigation Strategies - on a case-by-case basis with the approval of BioDelivery Sciences International's buccal fentanyl product Onsolis for cancer breakthrough pain.

The July 16 approval should not be interpreted as a model for what a classwide REMS for the long-acting and extended-release products should look like, the agency stressed. The Onsolis REMS, the first ever REMS for an opioid product, "was specifically tailored to that drug," said Douglas Throckmorton, deputy director of FDA's Center for Drug Evaluation and Research.

Onsolis, a small dissolvable polymer film formulated with fentanyl for application on the inside of the cheek, is approved for management of breakthrough pain in patients with cancer, 18 years and older, who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. It will be available in five strengths, ranging from 200 micrograms to 1,200 micrograms.

FDA issued a "complete response" letter for the drug in August 2008 and sent BDSI back to the drawing board to sharpen up its REMS strategy (¹ (Also see "FDA: BioDelivery Sciences Should Improve “Safe Use” REMS Provisions For Oral Fentanyl Approval" - Pink Sheet, 28 Aug, 2008.)).

BDSI's commercial partner, Sweden-based international specialty pharma Meda, is set to launch the product early in the fourth quarter. Meda has used the year since the action letter to gear up a new specialty sales force that will detail the drug to oncologists and pain specialists, BDSI CEO Mark Sirgo said. Onsolis will be in "a primary detail position for the first two years, [which is] plenty of time to establish the product," Sirgo said.

The Onsolis approval foils predictions that the REMS Cephalon is working on for its competing buccal fentanyl product Fentora would gain FDA validation first and pave the way in the short-acting opioids space (² (Also see "Merck Commercial Model: Expand Customer Base, Tighten Marketing Spend" - Pink Sheet, 6 Oct, 2008.), In Brief).

Cephalon gained approval of Fentora in the cancer breakthrough pain indication with an old-fashioned RiskMAP, called SECURE, before the REMS requirement came into effect. The company now awaits the go-ahead from FDA to implement its REMS, which it originally called COVERS.

Once Cephalon has shown the plan to be effective in the oncology breakthrough indication, the agency will consider it as part of Cephalon's application to expand Fentora use to other kinds of breakthrough pain. But Cephalon is still "awaiting feedback" from the agency, the company said (³ (Also see "Fentora Expansion Awaits REMS Evaluation" - Pink Sheet, 15 Sep, 2008.)).

Cephalon changed the name of its REMS to "SECURE" because a lot of educational effort has gone into the RiskMAP by that name, and carrying it along will help the transition, a spokesperson said.

SECURE is likely not to look anything like COVERS or the original RiskMAP, BDSI's Sirgo said. "COVERS was something that was created really before FDA had a chance to even think through what they thought an appropriate REMS should look like," he said. "I'm not even sure the COVERS program is even relevant any longer, because FDA has taken time to think through this whole requirement themselves. FDA came up with something they shared with us, and I'm sure they shared the same thing with the other sponsors of fentanyl-based products."

FOCUS On Physician Education

The Onsolis REMS, dubbed FOCUS (Full Ongoing Commitment to User Safety), is heavy on education of physicians, who then ensure the patient understands how to use it for their breakthrough pain, Sirgo said. The key is that the patient has to already be on an opioid background therapy. "If you're on a background opiate for your chronic cancer pain, the likelihood of having any severe adverse events from adding Onsolis for the breakthrough component is really limited," he explained.

The product will be distributed through specialty pharmacies and delivered by courier to patients who have instructions on how to use it, when to use it and how often they can use it, Sirgo said. The physician gives verbal communication, and the company sends materials as well. Then, as a final backup, the patients have a call with a health care professional to double-check that the patient is appropriate and understands Onsolis' proper use, he said. The plan is set for assessment at 6 months, 12 months, and then yearly.

While the intense educational process involved with the REMS may initially slow uptake, it also eventually will drive usage, Sirgo said. Awareness of breakthrough pain among physicians is an obstacle in the space, and Meda has already launched an education program.

Meda Pursuing Non-Cancer Pain Indications

Meda has global marketing rights for Onsolis, except for Taiwan and South Korea. With the approval, BDSI is in line for a milestone payment of $15 million, on which Meda advanced the company $3 million in January, as well as another $15 million for manufacture of launch stocks of Onsolis. BDSI receives double-digit royalties on net sales as well as up to another $30 million in sales milestones. The company now will have cash on hand to last well into 2010, Sirgo said.

Among the therapies Meda currently markets. are Astelin (azelastine) nasal spray for rhinitis, and Soma (carisoprodol), a muscle relaxant used to treat acute pain. Meda also is actively pursuing a development program for Onsolis in non-cancer pain, such as neuropathic pain and osteoarthritis, set to enter the clinic in January.

"We're a revenue-producing company," Sirgo enthused. "We've graduated from the development state, and now on to commercialization."

Sirgo said BDSI, in Raleigh, N.C., would put its new revenue stream to work aggressively moving its new product pipeline, which includes a buccal formulation of buprenorphine, a less abuse and addiction-prone opioid, for broad application in acute and chronic pain. The drug currently is entering a Phase II proof-of-concept study in dental pain, with data anticipated by the end of 2009; Phase III studies in postoperative pain are planned for the first half of 2010.

BDSI plans a 505(b)(2) NDA submission for buprenorphine in the first half of 2011, but the product will be partnered long before then, Sirgo said. BDSI plans a partnering announcement in the second half of 2010 based on Phase II dat, that will "exceed what we've been able to achieve with Onsolis," he said.

- Shirley Haley ([email protected])