OrBec Future In Doubt: Cmte. Calls For Further Study, But Firm Is Out Of Funds

With FDA's Oncologic Drugs Advisory Committee one set of concluding that another clinical trial is necessary to prove a benefit of DOR BioPharma's orBec , the graft-versus-host disease drug may have reached the end of the road as the company says it does not have the funding for an additional trial.

The user fee action date for orBec (oral beclomethasone dipropianate, BDP), which was submitted based on a single pivotal trial that failed to meet its primary endpoint, is July 21.

At its May 9 meeting, ODAC voted 7 to 2 that there was not substantial evidence of orBec's efficacy to support the proposed orphan indication for treatment of graft-versus-host disease (GVHD) involving the gastrointestinal tract in conjunction with an induction course of high-dose prednisone or prednisolone.

FDA and committee members took issue with several inconsistencies in the pivotal Phase III trial for the anti-inflammatory corticosteroid, and were hopeful that a better designed study could foster more robust efficacy results.

However, DOR President and CEO Christopher Schaber said that further pre-market studies were not financially feasible for the firm.

"For a company our size, we've put a lot of time, effort, money and resource into this study to go after an indication that quite honestly, big pharma didn't want to touch because it is a very small patient population. ... To move forward from here and start over is really economically not feasible for us with this product," Schaber said.

One way forward could be a treatment IND, FDA's Robert Justice, director of the Division of Drug Oncology Products, suggested. "There are alternative mechanisms to get a drug out to people while [it is] further being studied. One of them would be a treatment IND," he said, "and that can be a very large treatment single arm trial."

Justice added that some costs of developing and manufacturing the drug could be recouped by the company. "Under the treatment IND mechanism, which is a special type of expanded access program, there can be some cost recovery on the part of the sponsor and we would entertain, in a situation such as this, that type of program," he said.

Committee Chair Maha Hussain, University of Michigan, pointed out that orBec failed to meet the primary endpoint in the pivotal trial - typically a "fatal flaw" for a drug hoping to receive FDA approval. Thus, she asked, "barring some surprising phenomenal benefits in survival ... what would be the point in bringing these discussions forward?"

Justice said the meetings provided for discussion of points that may have been missed by the FDA reviewers. "Personally, this drug, because of this discussion - irrespective of the vote - had a much different impact in my mind. So we will have discussions internally on this drug and discuss the points that were presented here," he said.

In addition to failing its primary endpoint, FDA reviewers found other problems with data from the two trials - one major (ENT 00-02) and one supportive (875).

ENT 00-02 was a Phase III, multi-center, placebo-controlled trial of BDP in conjunction with an induction course of high dose prednisone in 129 patients with grade 2 GI GVHD following allogeneic transplant performed for a variety of hemotologic disorders. Though BDP did not meet the primary endpoint of a decrease in time to GVHD treatment failure through Study Day 50, it met a secondary endpoint of time to treatment failure at day 80. Other secondary endpoints included days 10, 30, 50, and 60.

Study 875 was a single institution, placebo-controlled, Phase II trial conducted from 1994 to 1996 in 60 patients with a similar background. The primary endpoint was the ability to increase oral caloric intake to 70 percent or more of the patient's estimated daily caloric requirements at day 30.

FDA analysis found an imbalance in treatment arms in the major study based on the types of transplant - the percentage of patients who received a non-myeloablative conditioning regimen was approximately two-fold higher in the BDP group compared to placebo, and the percentage of patients who had bone marrow as the source of their transplant, rather than peripheral stem cells, was higher in the BDP group compared to the placebo group.

The agency also did not support the company's post hoc proposal to pool data from the two trials, as the studies had different primary endpoints, objectives, designs, dosing regimens/schedules, and procedural circumstances.

Some committee members expressed concern over the counterintuitive and unexplained differences in survival benefit among the patient subgroups. A higher survival benefit was seen in the subgroup of patients who had previously received non-myeloablative transplants, which are less aggressive transplants given to patients too sick to tolerate a myeloablative transplant.

"All of the benefit in terms of the one-year survival, is in the non-myeloablative group ... I would have intuited, actually, the people who are going to get the sickest, who had the most intensive preparative regimen, are more likely to get bad GVHD and they would be the most likely to benefit, so this is the opposite result," committee member Michael Link, Stanford University, said.

DOR BioPharma Medical Monitor Timothy Rodell pointed out that there was a small data set: 15 patients in the placebo arm and 26 in the BDP arm at one year. "So we probably shouldn't over-interpret the degree of differences between the groups," he said.

OrBec inventor George McDonald, Fred Hutchinson Cancer Research Center, speculated that the differences in survival among subgroups "may well be related to underlying disease characteristics," noting that though the primary cause of death was relapse of leukemia, the study was not stratified for relapse risk.

This was one of the aspects of the trial that FDA medical officer Nancy Scher said the company should have designed differently. "If we're looking at a trial with a survival endpoint, it seems to me that you would also focus on the baseline hemotologic disorder ... one might want to prospectively define relapse risk if one were devising a survival trial, rather than collecting the very important disease-specific data post hoc and then aligning time to look at where the risk fell," Scher said.

Discrepancies in subgroup efficacy led some committee members to doubt the merit of moving to a secondary endpoint as evidence of efficacy.

"For me, I think what's important is that when one moves away from the primary endpoint to other supporting endpoints, the story has to be really consistent and very robust," committee member David Harrington, Dana-Farber Cancer Institute said.

"Once one ... moves to an endpoint like one-year post-randomization survival ... as strong evidence for the agent, then it becomes important to understand exactly how that recommendation would be written," he said. "I agree that the people on the non-myeloablative group seem to be helped quite a lot ... the data are compelling, but the corresponding story is that the people in the myleoablative side weren't helped at all."

FDA medical reviewer Ann Farrell said that although, in this case, moving to the secondary endpoint was merely an extension of time from study day 50 to day 80, it was important to look at the NDA as a whole.

"The sponsor has said that they failed the day 50 endpoint because they had bad luck - the patients in the BDP arm just happened to fail during the time they were on prednisone, so ... clinically the day is okay, but I think you have to look at the totality of the package, and that's just one point," she stated.

The committee and FDA agreed that further studies need to be done on BDP to ascertain its effects. "The only way to get an answer for this drug is to do an appropriately designed trial. ... I don't think the main factors have proved the point, and while it may be helpful in some, it hasn't proved its efficacy overall," committee member Michael Perry, University of Missouri, said. "We simply need a better trial."

Hussain said a prophylaxis trial sounded like a "very attractive" option. "We've thought about a prophylaxis trial," DOR's McDonald said, but he noted "that's a different indication, though. This indication is for the treatment of acute GVHD and a prophylaxis trial is for prophylaxis of acute GVHD." He added, however, that it would be easier to enroll patients in such a trial, as they would not be ill.

"The hope there is that one would, with effective prophylaxis, take what would ultimately be stage four, turn it into stage three, take stage three, turn it into stage two, make them into being stage one - so I think that's a feasible thing," he said.

- Jamie Hammon ([email protected])