Bristol Sacrifices Part Of Indication For Kidney Transplant Drug Belatacept

Bristol-Myers Squibb is willing to tailor the patient population for its kidney transplant agent belatacept by selecting for a biomarker and limit use by recommending the less intensive treatment regimen to try and avoid the risk of post-transplant lymphoproliferative disorder that was seen in clinical trials.

The company proposed these measures and a Risk Evaluation and Mitigation Strategy at the March 1 Cardiovascular and Renal Drugs Advisory Committee review of the BLA for prophylaxis of acute rejection in kidney transplant patients.

Safety concerns - specifically PTLD, which FDA reviewers identified as "the major safety signal detected in the belatacept trials" - were the prominent issue of the advisory committee review (¹ (Also see "Bristol Hopes REMS Proposal Can Overcome Safety Concerns About Belatacept" - Pink Sheet, 25 Feb, 2010.)). Another high-risk infection seen in the clinical trials was progressive multifocal leukoencephalopathy.

PTLD is a rare but well-recognized complication of organ transplantation, where patients in the weakened immune state develop B-cell lymphomas. It can be associated with Epstein-Barr Virus infection, and can be associated with significant mortality.

There were 14 cases of PTLD in the clinical trials, and 11 were severe enough to either result in death or require treatment with chemotherapy or radiation (another two were treated with rituximab). There were more cases in the more intensive treatment regimen and more in the EBV negative population. There also were two cases of PML in the clinical trials.

Bristol Came Prepared With REMS Proposal

To deal with these risks, Bristol drafted a REMS and proposed labeling that would limit the size of the market for belatacept - but could also ensure that the drug actually makes it to market.

Bristol's proposed labeling emphasizes the less intensive dosage regimen, which uses six days of dosing for the initial three-month period compared with eight days for the more intensive treatment, and then lower strength dosing for the maintenance period. It also would contraindicate patients whose EBV serostatus is negative or unknown, limit prescribing to experienced MDs and emphasize prophylaxis and diagnosis/detection for side effects.

The proposed REMS also includes such communication elements as a "Dear Health Care Provider" letter; educational material and a fact sheet targeting transplant centers, nephrologists, infusion centers and patients; and a Medication Guide that Bristol has already tested for patient comprehension. Bristol also is committed to monitoring the effectiveness of the REMS with surveys (and modifying if necessary) and to conducting post-marketing studies: pharmacoepidemiology studies in over 13,000 patients and long-term extensions of the clinical trials of up to seven years.

Brian Daniels, senior VP of global development and medical affairs at Bristol, presented the risk management proposal and a comparative risk-benefit assessment of belatacept versus cyclosporine, the current standard of care. Belatacept came out ahead. Daniels further stressed the treatment setting for belatacept, noting that transplant centers have extensive protocols and the very dosage regimen ensures that there will be frequent (monthly) visits and long-term follow up.

It's not unheard of for sponsors of a drug with known, clearly defined safety problems to proactively develop a REMS during the review process. However, it is not a guaranteed path to approval. For example, Novartis found that a post-market program it had designed to control Xolair (omalizumab) in the pediatric population ages 6 to 11 was not adequate to convince FDA or its Pulmonary-Allergy Drugs Advisory Committee to extend the indication for use in moderate to severe allergy/asthma patients below 12 years of age (² (Also see "Novartis Pediatric Post-Market Plans For Xolair Fall Short Of FDA Request" - Pink Sheet, 23 Nov, 2009.)).

FDA's PTLD Analysis Focused On CNS Immunity

In its presentation, FDA stressed the extent of the PTLD with central nervous system involvement and imbalance in deaths from CNS lymphoma that were weighted against belatacept. "Please note that that observation is consistent across both belatacept treatment groups, and among both EBV-positive and EBV-negative patients," FDA's Patrick Archdeacon said. But he also reported that the incidence of PTLD without CNS involvement was similar between the patients taking belatacept and those in the control group, who were taking cyclosporine.

The pattern of CNS involvement has not been seen previously with other immunosuppressive regimens. Archdeacon noted.

The occurrence of PML was also troubling. Literature suggests a background rate of one event for every 14,000 patient years. "Given that PML remains such a rare outcome among transplant patients, the two cases of PML together [one from the renal trial and one from a liver transplant trial] together constitute an appreciable safety signal," Archdeacon stated. Still, he commented that the PML "is sufficiently rare that it would not significantly affect mortality rates." And FDA has experience using REMS to mitigate the risk of PML (for Biogen Idec's Tysabri and Roche's Rituxan ).

Taken together, the safety signals of CNS PTLD and PML "suggest that perhaps belatacept has an effect on CNS immunity," Archdeacon stated. That possibility could actually smooth the way for approval because it offers a possible biological mechanism for the side effects and therefore helps reassure the agency that these are not inexplicable.

Committee Calls For Long-Term Studies

Panelist Richard Mann, Robert Wood Johnson Medical School, agreed that "there's some question ... about whether CNS immunity is altered overall when there's a propensity for more CNS infections," though he noted it was only seen in the more intensive, not the less intensive regimen. Mann also called for "more information, long-term numbers, to make sure this agent is safe," an opinion expressed by many other committee members.

"In my opinion, this study needs to be buttressed by maybe another protocol, perhaps, of 36 months or 48 months, because we're looking at giving our approval to a drug on the assumption that it's going to help people in the long run," Parmjeet Randhawa, University of Pittsburgh, said. "So we should be strict in terms of the data that is presented." He wanted protocol biopsies at 36 months and 60 months.

Some panelists found reassurance in the treatment setting and in the low number of PTLD events seen in the trials. "None of the medicines we use are safe. Realistically, they've all got potential adverse effects, some of which can be really bad," the Mayo Clinic's James Gloor said. "When you look at the absolute number of patients involved [in PTLD], it's a very small number," he added. "My opinion is that [belatacept's] safety is demonstrated sufficiently. I do think it will need to certainly be followed longer term to see just how big an issue this turns out to be. I'm nervous about it, but it would not, in my opinion, be a reason why I would say that this is not acceptable. I think it is."

The committee judged the risks acceptable due to convincing evidence from the clinical trials that the drug works, although a vocal minority expressed displeasure with the studies' non-inferiority design.

Efficacy And Risk Management Swayed Panel

FDA was not satisfied with the acute rejection endpoint used by Bristol, and reanalyzed the results with a modified composite endpoint of biopsy-proven acute rejection, graft loss, death, or loss to follow-up. FDA's analysis used biopsy-proven acute rejections instead of just clinically driven rejection, and the other elements allowed a better way to handle missing data with respect to the endpoint of acute rejection, FDA's Cheryl Dixon explained.

FDA's reviewers determined in the end that "non-inferiority based on a 20 percent margin of both belatacept regimens to cyclosporine was demonstrated for acute rejection," Dixon said. The less intensive belatacept regimen had a 15 percent margin to cyclosporine, although there were more acute rejections in the belatacept-treated patients than in the cyclosporine-treated patients, in absolute numbers.

Still, the case for belatacept's efficacy was strong enough, combined with Bristol's proposed restricted distribution, for the panel to vote 13-5 in favor of approval. Some panelists explained that it was the prospects for risk management that swayed their consideration.

Elaine Morrato, University of Colorado, called for "a registry kind of system in which we make sure there is good informed consent, that patients do understand and that's part of the distribution, as opposed to just totally letting it go open on the market."

"Following these patients closely using the proposed methods of mitigating the risk - restricting this to EBV-positive patients, using FDA's safety authority to hold the sponsor's feet to the fire about tracking these patients - is sufficient to assure that something really bad doesn't happen in the future," Douglas Hale, Vanderbilt University Medical Center, added.

- Martin Berman-Gorvine (³ [email protected])