Finding a drug that can re-educate the body's confusion in lupus has proven a puzzler for biotech firms for years, and opinion is divided on which companies might be getting close to a fix for the devilish disease. Is there a way to teach the immune system the difference it once knew between foreign antigens and its own?
Systemic lupus erythematosus (SLE) is the most severe and common of three types, comprising about 70 percent of all cases, and strikes major organs including the kidney - lupus nephritis - with about 20 percent of SLE cases worsening to end-stage renal disease. The other lupus types are cutaneous, or discoid, which is limited to skin, and drug-induced, caused by such therapies as the high-blood pressure drug hydralazine and the anti-arrythmic compound procainamide. The "why" of lupus is unknown, but the disease is 10 times more likely to affect women, so there have been suspicions about an estrogen link.
The illness is "widely seen as one of the new, sexy indications," noted Deirdre Gillespie, CEO of La Jolla Pharmaceuticals Inc., at a Needham & Co. conference last week. LJP's Riquent, she said, "is at the forefront."
Approved rheumatoid arthritis drugs might work against SLE. Genentech Inc. has Rituxan (rituximab) in a 250-patient Phase II/III trial called EXPLORER and a Phase III trial known as LUNAR. The first trial's endpoint is clinical response after one year, while LUNAR will examine renal response after the same time period. EXPLORER trial was finished enrollment earlier this year, and results are expected in the middle of next. LUNAR started in early 2006, and likely will finish enrollment before the end of this year. Genentech also said recently that it plans to kick off Phase III trials with a second-generation humanized CD20 antibody in SLE and lupus nephritis late this year or in 2008.
Big pharma's on the case, too. Bristol-Myers Squibb Co. has its RA therapy Orencia (abatacept) in Phase II trials against discoid lesions, pericarditis and pleuritis, with the primary endpoint an improvement on the British Isles Lupus Assessment Group index, an 86-question scoring system. Rituxan and the BMS drug - both anti-B-cell therapies - already are used off label for lupus.
B-cells' role in lupus became the topic of talk last Wednesday when LJP's stock slid about 9 percent - closing at $4.74 - on analyst skepticism about Riquent (abetimus sodium) for lupus nephritis. Terence Flynn of Lazard Capital Markets differed predicted failure of the ongoing Phase III trial, rated the stock "sell," and forecast the 52-week price target at a measly dollar.
Flynn wrote in a research report that the Phase III results likely will "mirror those of earlier Phase II/III trials and fail to meet the primary endpoint," and the monitoring board in charge of the study could shut it down due to futility. Orphan, fast-track Riquent, being tested under a special protocol assessment with the FDA, is designed to reduce autoantibodies to double-stranded DNA.
"A growing body of evidence indicates the importance of B-cells rather than autoantibodies in lupus; therefore, Riquent could be missing the more important target," according to Flynn, who pointed to shortfall interim results from the trial. At the International Congress on SLE in May, LJP reported data on the 100 mg, 300 mg and 900 mg treatment groups, noting reductions in median antibody levels between the Riquent groups and the placebo group at week eight of 30 percent, 40 percent and 58 percent, respectively - 10 percent to 16 percent lower than the company shot for, according to a slide show Flynn said he saw in September.
LJP says Riquent hits the less-than-1-percent of B-cells responsible for the autoantibodies, but Flynn doesn't believe it. Published research, he told BioWorld Financial Watch, has found that antibodies to double-stranded DNA came back when Riquent dosing quit. "That says to me, essentially, they are not having this anergic or apoptotic effect on the B-cells," Flynn said, adding that the only published work backing LJP's B-cell claim is an animal study from 1996.
"The drug definitely has an effect on the antibodies in the serum, but that's not going to be enough to get it over the finish line," he said.
Making news earlier this month was Aspreva Pharmaceuticals Corp., which said the FDA granted fast-track designation for CellCept (mycophenolate mofetil, partnered with F. Hoffmann-La Roche Ltd.) in lupus nephritis. Enrollment in CellCept's Phase III study was completed in September. The trial has an induction stage and a maintenance stage, with the first comparing the drug to intravenous cyclophosphamide for 6 months, and the second is a comparing it to azathioprine for as long as three years. The primary endpoint is improvement in proteinuria and stabilization of serum creatinine, and preliminary data from the first stage expected at the end of this month, with a supplementary new drug application possible in the fourth quarter.
CellCept could pose a problem for Riquent, if the latter wins approval. LJP put a limit on baseline use of CellCept for patients taking part in the Phase III trial, which means most of the sites may be outside the U.S. (where patients can't get CellCept) - so doctors in the U.S. already treating patients with CellCept as a maintenance therapy won't know how Riquent might work with it, and might cringe at the cost of combining the drugs.
Mark Monane, analyst with Needham & Co., was more sanguine about Riquent, rating LJP at "buy" with a $9 price target in mid-May. Made of four short DNA fragments attached to a small carrier platform, Riquent's more-targeted approach gives Riquent an edge over shotgun methods that weaken the immune system and can open patients to infection, he wrote. About 320,000 patients in the U.S. and the Europe suffer from lupus nephritis - a multi-billion dollar market that hasn't seen a new therapy approve in more than 40 years, Monane pointed out. Needham, A.G. Edwards and others remain optimistic about LJP's drug.
Other late-stage possibilities against SLE include Human Genome Sciences Inc.'s LymphoStat-B (belimumab), an anti-B lymphocyte stimulator (BLyS) monoclonal antibody, and the subject of a partnership with GlaxoSmithKline plc. The compound is undergoing an 810-patient Phase III study, which started in December, and more trials are to start soon, all evaluating response rate after one year. The idea is that too much BLyS might crank up autoantibody production. "We cover HGS and we don't have much hope for LymphoStat-B, either," Flynn said, mainly because of the way apparently favorable Phase II data were analyzed retrospectively.
Moving ahead with Prestara (prasterone), purified synthetic dehydroepiandrosterone (DHEA), is Genelabs Technologies Inc., which this spring nailed down a special protocol assessment with the FDA for a Phase III trial that would go ahead when the company finds a commercialization partner. Prestara already has an approvable letter from the agency, and Genelabs wants to test 200 mg of the drug in about 500 women over a year's time. The primary endpoint would be the time to first severe flare on the SELENA-SLEDAI composite scale. The long acronym stands for Safety of Estrogen in Lupus Erythematosus National Assessment Trial-Systemic Lupus Erythematosus Disease Activity Index, and Genelabs is trying DHEA, long available as a health supplement, because the naturally occurring hormone turns up abnormally low in SLE patients.
ZymoGenetics Inc. has atacicept, a soluble fusion protein that links part of a cytokine receptor called TACI to the Fc portion of immunoglobulin, for SLE. The drug is the centerpiece of an exclusive co-development and commercialization deal with Serono SA, and is expected to launch in early 2011.
Like Riquent, more than a few lupus therapies have met stumbling blocks. Immunomedics Inc. and partner UCB SA have a monoclonal antibody targeting CD22 for SLE but have stopped two Phase III trials in the first quarter of this year and are putting together a new protocol. In a 14-patient Phase II study, though, 77 percent of drug-treated patients saw their BILAG scores drop by 50 percent or more.
Earlier stage, MedImmune Inc. has MEDI-545, a monoclonal antibody directed against interferon-alpha subtypes, in Phase I trials. The primary endpoint of the 45-patient study, which started in March 2006, is safety and tolerability.
"We like Rituxan, and we think those trials are going to be successful," Flynn said. While it's true that Rituxan patients are immunosuppressed for six months of therapy, he said, the currently used therapies - steroids and compounds used to prevent organ rejection - also weaken their systems.
Lupus remains a challenge. "We still don't know enough about the disease, in terms of all the parts of the immune system that are involved," Flynn said. "Each patient's disease is a little different from [the other's], and physicians tailor the treatment to each patient specifically."