Riquent "Approvable" For Lupus; FDA Says Ongoing Study Could Be Enough

La Jolla Pharmaceuticals hopes running a parallel study alongside the ongoing confirmatory trial for its lupus agent Riquent will satisfy the requirements set out in FDA's Oct. 14 "approvable" letter.

FDA indicated that the current study appears to be sufficient, but also requested additional dose-response data on the effect of abetimus on antibody titers. The company is planning to meet with FDA soon to clarify the requests laid out in the approvable letter.

La Jolla has been attempting to gain accelerated approval for lupus nephritis based on the biomarker of reduction in anti-double-stranded DNA antibodies (¹ Pharmaceutical Approvals Monthly June 1, 2003, p. 12). However, FDA appears to be requiring more data before accepting the measure as a surrogate endpoint.

"Based on the letter, we plan to discuss with the FDA the possibility of assessing whether higher doses will result in further reduction of double-stranded DNA, or increase the impact on clinical benefit," CEO Steve Engle told an Oct. 15 analyst call.

"One could run a parallel study that would give you additional information on antibodies that you could then incorporate [as] an additional arm in the study you already have ongoing," he said. "We have brought that idea up to [FDA] in prior conversations, so it's certainly on the table."

Engle also raised the possibility that the dose-response data could be collected from the current study. "We tried to anticipate this when we designed the trial with FDA. The trial already has a 300 mg group in addition to the 100 mg and an arm that goes from 100 mg to 300 mg."

"We don't yet anticipate changes to the study," he indicated. "We do have a special protocol assessment for the study and the study is underway....But again, we're trying to listen to the agency and see what else - if anything, we don't know yet - needs to be considered."

"The question is, if you run an antibody trial you get antibody data, you don't get efficacy data on a clinical outcome. So our conundrum has always been do you put off doing clinical outcome trials in order to be able to gather antibody change data?"

"Our feeling was, based on the conversation we had at that time, that our current study was sufficient to answer the question and that the study will generate antibody data," Engle continued.

"We're open to the idea of having additional studies in parallel, but the idea here was that if they felt comfortable with the Subpart H approach to this, that we would be able to find a way to better finance doing those additional studies while that big Phase IV study was ongoing."

The firm assumes the SPA agreement will extend to cover any protocol amendments.

FDA's approvable decision implies that the agency is not acceding to La Jolla's request for review under Subpart H. The agency's letter specifically notes that abetimus must show a benefit versus placebo "on an endpoint of clinical benefit, such as time to renal flare." The ongoing trial "would appear to satisfy this requirement," the letter states.

The additional dose-response antibody data would be a step towards connecting the dsDNA biomarker to a clinical benefit.

The ongoing confirmatory trial uses time to renal flare as the primary endpoint. The randomized, placebo-controlled study is focusing on lupus patients with a history of renal disease who have dsDNA antibodies, the subgroup that appeared to respond to the drug in previous trials (² Pharmaceutical Approvals Monthly Aug. 15, 2004, In Brief).

"To be eligible for enrollment in the trial patients must have antibodies to double-stranded DNA and a history of renal flare within the last four years, and must not be receiving high doses of immunosuppressive agents," Engle said.

He noted "several enhancements" over the previous study's design: "First is the patients are not in more than 12 months, where in the last trial the patients could be in longer. We believe that there is a fatigue factor in the flare rate of patients after 12 months based on the last study - essentially people were not flaring after the last point."

"And secondly, we have doubled the number of patients from 300 to 600...and that alone on the last data set would have driven it to significance," he maintained.

Based on the rate of renal flares in previous studies, La Jolla predicts the pivotal trial will take approximately four years. However, "it could be accelerated based on getting more sites overseas," Engle said.

One way La Jolla could expand trial centers would be through a partnering arrangement.

While the company will ultimately need to enter a partnership to ensure funding for the ongoing trial, La Jolla indicated the initial priority is to clarify what will be necessary going forward.

"Partnering and fundraising…clearly is a key issue for us," Engle acknowledged. "We'd certainly want to have conversations with corporate partners, as we have had in the past, to see their interest….We think we have a pathway forward that a partner could be interested in."

The approvable designation for Riquent is not surprising, considering that the Cardio-Renal Division was specifically evaluating the drug's effect on renal flare, based on La Jolla's initial Phase III trial (90-05) and a follow-up study (90-09).

"Your study 90-05 was designed to show a clinical benefit (delayed time to renal flare) associated with treatment, but it failed to do so," the approvable letter states. "An unplanned analysis of patients with high affinity antibodies to dsDNA appeared to show benefit, leading to study 90-09, designed to study benefit in that high affinity subgroup. Study 90-09 also failed to show benefit, thus failing to support the hypothesis raised by the subgroup analysis in study 90-05."

"Whether these results indicate that the hypothesis that lowering anti-dsDNA antibodies slows disease progression is wrong or that the effect was too small to affect disease progression cannot yet be known. Only another, better powered outcome trial, perhaps with a larger dose, will resolve this issue."

La Jolla apparently submitted a combined analysis of study 90-05 and study 90-09, which FDA found "not a credible analysis as it is driven by the retrospective analysis of study 90-05," the letter says.

La Jolla has maintained a number of trial design issues contributed to study 90-09's failure, including being underpowered and the high rate of use of immunosuppressive drugs.

However, the company's recently presented data on the concomitant use of Riquent and immunosuppressive agents suggest that the drug remains effective when added to immunosuppressant therapy, as measured by dsDNA biomarker levels.

According to the study poster presented at the American College of Rheumatology and the American Society of Nephrology annual meetings in October, "patients treated with [Riquent] and who were on [mycophenolate mofetil or azathioprine] at baseline had a greater reduction in dsDNA [antibody] levels compared to placebo patients on MMF or AZA at baseline."

Lupus drugs have generally faced difficulties with endpoints and clinical trial design. The latest strategies have been to focus on biomarkers or surrogate measures that can signal a clinical response, and to target narrow patient populations with different organ manifestations.

In developing Prestara (prasterone), Watson and Genelabs have concentrated on women with systemic lupus erythematosus receiving glucocorticoids, using bone mineral density as the primary endpoint. Prestara recently failed a confirmatory Phase III trial (³ Pharmaceutical Approvals Monthly Oct. 15, 2004, In Brief).

FDA's Arthritis Advisory Committee recommended use of a composite of organ-specific endpoints for lupus nephritis trials at a Sept. 29, 2003 meeting. FDA's draft guidance on lupus drug development will address use of biomarkers (⁴ Pharmaceutical Approvals Monthly June 1, 2003, p. 15). The draft guidance is expected to be released imminently.