Editor

Genelabs Technologies Inc.'s $23.7 million financing at the start of October sparked renewed interest in its Phase III drug Prestara for lupus - and in the indication itself, for which a new therapy based on randomized, placebo-controlled trials has not been approved in more than four decades.

Prestara (prasterone), a synthetic form of the human hormone dehydroepiandrosterone, disappointed investors in 2004 with results from an intended confirmatory study, but the FDA has designated as approvable the compound's new drug application. Genelabs has a special protocol assessment deal with the agency for another Phase III trial, but that trial would cost about $25 million, and the firm vowed to use none of the recently raised cash on the lupus effort, focusing instead on its preclinical hepatitis C virus efforts.

"I think the company would like to run a pivotal program for Prestara," Kevin DeGeeter, analyst with Oppenheimer & Co., told BioWorld Financial Watch. "I know [the HCV push] is a priority. Let's say it's more of a priority with management than with investors."

The lupus space is heating up, and last week, Lazard Capital Markets published a 51-page report speculating that biotech and pharma might be on the verge of "slaying the wolf." Prestara wasn't mentioned, but plenty of other players made the grade, as the busy therapeutic area continues to evolve with new candidates. (See BioWorld Financial Watch, June 18, 2007.)

Would-be drugs for the most severe lupus type, systemic lupus erythematosus (SLE) and for lupus nephritis include varying approaches. Some attack cells, and others regulate interactions between cells. Some are immune-system modulators. Cytokines and interferon-alpha make up the targets of some.

Quite a few have reached pivotal trials or will begin shortly, including Rituxan (rituximab), the compound from Biogen Idec Inc. and Genentech Inc., already approved for rheumatoid arthritis and non-Hodgkin's lymphoma; ocrelizumab, in development by Genentech, Biogen, and F. Hoffmann-La Roche Ltd.; LymphoStat-B, from Human Genome Sciences Inc. and GlaxoSmithKline plc; Riquent (abetimus sodium), from La Jolla Pharmaceuticals Inc.; epratuzumab, from Immunomedics Inc.; atacicept, from ZymoGenetics Inc. and Merck Serono; and Orencia (abatacept), from Bristol-Myers Squibb Co.

Lazard is most excited about anti-CD20 antibodies Rituxan and ocrelizumab. The former has become part of the standard of care in CD20-positive NHL and chronic lymphocytic leukemia, and has two trials ongoing - one Phase II/III study called EXPLORER in SLE (due to report data in the first half of next year) and one Phase III study called LUNAR in lupus nephritis (due to report in the fourth quarter of 2008). One of Lazard's consultants described Rituxan as a "base hit for RA, but the drug has the potential to be a home run for lupus," and the firm projects Rituxan sales to hit $4.4 billion this year, thanks mainly to oncology growth, although "lupus could be the next growth driver of this franchise."

A Rituxan boost would be more than welcome to Biogen, which is entertaining buyout offers. The firm reported second-quarter revenues of $773 million and earnings of 70 cents per share, both beating analyst estimates. Most came from $462 million in sales of Avonex (interferon beta-1a) for MS, up 8 percent from last year. Revenues of $231 million from Rituxan, up 12 percent, helped, but both drugs' growth have been slowing in recent periods. Avonex faces challenges in MS from players that include Biogen's own Tysabri, which contributed about $48 million in revenues in the second quarter.

Genentech has ocrelizumab in the works for autoimmune indications where the immunogenicity of Rituxan could be a drawback, and the firm is expected to start Phase III trials with the compound in SLE by the end of this year, and in lupus nephritis the first quarter of next year.

Also in anti-CD20 monoclonal antibodies, Genmab A/S and partner GSK have ofatumumab (Humax-CD20) in Phase III trials for RA, and Immunomedics has veltuzumab in development for NHL, although none of the firms has disclosed plans to try their compounds against lupus.

There's also TRU-015, from Trubion Pharmaceuticals Inc., which saw its stock jump more than 30 percent in September when the firm reported preliminary data from its 276-patient Phase IIb with the compound in RA. Trubion said it was working with partner Wyeth to determine the next steps, but another trial likely will precede the Phase III program.

TRU-015 is described as small modular immunopharmaceutical that binds to CD20 and depletes B cells, much like Rituxan. The compound's structure resembles a monoclonal antibody but with shortened light chains, whereby Trubion intended to gain an advantage in ADCC (antibody-dependent cell-mediated cytotoxicity) over Rituxan, reducing the number of infusion reactions and proving useful against inflammation in cases where complement activation might be part of the problem. Trubion is expected to start signing up patients in a Phase Ib lupus nephritis trial soon.

Lazard is less thrilled about the likes of the Phase III-stage LymphoStat-B for SLE, from HGS and GSK, which is being tried to two studies under a special protocol assessment deal with FDA. The primary endpoint is response rate at week 52, with data expected in the second half of 2009 - but that endpoint in both trials is a novel composite endpoint based on a retrospective analysis of a failed Phase II SLE trial, there is no dose response for the drug and HGS already has reported "unimpressive" Phase II data with the compound for RA, noted the Lazard report.

LJP's Riquent drew little optimism as well, with Lazard's analysts predicting that results from the ongoing Phase III lupus nephritis will match those of earlier Phase II/III trials and fail to meet the primary endpoint of time to renal flare. Designed to reduce autoantibodies to double-stranded DNA and allow for B-cell tolerance, Riquent seems to work well in the first capacity but not so much in the second, Lazard said. A.G. Edwards analyst Albert Rauch, though, called the first data from the Phase III trial "compelling" and initiated coverage of LJP in April with a "buy/speculative" rating and an $11 price objective. The stock was trading at about $4.20 last week.

Combination-biologics therapy could be the wave of the future for "enigmatic" lupus, Lazard speculates, pointing to preclinical data from a trial testing Rituxan with BR3-Fc, the anti-BAFF fusion protein from Genentech and Biogen, in fibroblast-like synoviocytes isolated from RA synovial biopsies. Results were presented at the American College of Rheumatology meeting in 2005.