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End of the road for La Jolla? As a futility analysis derails BioMarin and LJP's Phase III Riquent trial, Trista Morrison,, wonders if this is the end of Riquent and asks what the future holds for La Jolla Pharmaceuticals.

Pharmaceutical innovation is certainly not an easy road to follow. BioMarin Pharmaceutical Inc. and La Jolla Pharmaceutical Co. are stopping their Phase III trial of Riquent (abetimus sodium) in systemic lupus erythematosus after the first interim efficacy analysis determined that it would be futile to continue.

For BioMarin, the impact of the trial's failure is minimal. The Novato, California-based company just picked up a marketing option for Riquent last month, which means "a bit of egg on the face" for BioMarin, Credit Suisse Securities LLC analyst Michael Aberman wrote in a research note. But, from a financial perspective, BioMarin's clever structuring of the deal means the company has only shelled out $15 million upfront thus far--less than 3% of the $563 million in cash that it reported at the end of the third quarter. The deal could have been worth up to $289 million, but most of the milestone payments were triggered by events following the successful completion of the Phase III trial, and LJP was initially covering all trial costs. (1)

"While some may question the rigor of management's extensive due diligence that led to the collaboration just a month ago, we applaud their shrewd use of real options to limit financial exposure," wrote analyst Joseph Schwartz, Leerink Swann & Co. BioMarin spokeswoman Susan Berg confirmed that the company has no further plans for involvement with Riquent. BioMarin's shares slid marginally on the news. However, for La Jolla Pharmaceuticals--which has spent more than a decade advancing Riquent in the face of multiple setbacks--the latest Phase III failure was a crushing blow, and the San Diego-based company's shares plummeted to less than 50 cents.

Difficult Development

Developing drugs for lupus has never been easy. Patients with the autoimmune disease are treated with harsh regimens of chemotherapy and steroids. No new drugs have been approved for almost half a century--though plenty have tried. Among them are Phase III studies of Rituxan (rituximab, Genentech Inc. and Biogen Idec Inc.), Prestara (prasterone, Genelabs Technologies Inc.) and CellCept (oral mycophenolate mofetil, Aspreva Pharmaceuticals Corp.), as well as a Phase II trial of LymphoStat-B (belimumab, Human Genome Sciences Inc.).

Riquent, which is designed to suppress the production of antibodies to dsDNA in lupus, has suffered its fair share of setbacks too. In 1999, an interim analysis of a Phase II/III Riquent study failed to meet its primary endpoint of preventing or delaying potentially life-threatening renal flares in lupus patients. Partner Abbott dumped the drug, but LJP crunched the numbers and found statistical significance in a subgroup of "high-affinity" patients. (2)


Then, in 2003, a Phase III trial in high-affinity patients missed the mark in preventing or delaying renal flares. LJP saw good trends and pressed forward with a new drug application. The FDA accepted the filing and the company worked with the agency to design and initiate a trial that could serve to fulfil post-marketing requirements under a Subpart H accelerated approval. (3)

But, instead of accelerated approval, the FDA handed back an approvable letter asking for data from the ongoing trial, which was demoted from Phase IV to Phase III. (4) That Phase III trial, dubbed ASPEN (Abetimus Sodium in Patients with a History of Lupus Nephritis), evolved over time in an attempt to avoid the pitfalls that felled earlier trials. It enrolled more patients, looked at higher doses and tried to better control the use of background therapies. But the trial's independent data monitoring board determined after its first interim efficacy analysis that continuing the study would be futile.

In their news releases, BioMarin and LJP said they will stop the study and unblind the data. For BioMarin, the question now will be one of pipeline growth. The company markets Kuvan (sapropterin dihydrochloride) for phenylketonuria, Naglazyme (galsulfase) for mucopolysaccharidosis VI and Aldurazyme (laronidase), with partner Genzyme Corp., for mucopolysaccharidosis I. But its pipeline is earlier stage: 6R-BH4 is in Phase II for cardiovascular indications and sickle-cell disease, while PEG-PAL is in Phase I for phenylketonuria.

Recently, a Phase II trial of 6R-BH4 in peripheral arterial disease failed. Aberman wrote that he believes BioMarin will "continue to look externally to replenish the pipeline to sustain long-term growth." Berg confirmed that the company is interested in additional licensing opportunities.

For LJP, the question is one of survival. The company reported just $26.1 million in cash, equivalents and short-term investments at the end of the third quarter after posting a $17.1 million quarterly loss. The $15 million from BioMarin will provide a little padding, but LJP has only a preclinical anti-inflammatory program behind Riquent in its pipeline. The company said in a news release that it will provide guidance about strategic options in the 'near future.'


(1.) BioWorld Today (8 January 2009).

(2.) BioWorld Today (14 May 1999, 16 September 1999, 4 May 2000).

(3.) BioWorld Today (19 February 2003, 6 May 2003, 3 August 2004).

(4.) BioWorld Today (18 October 2004).
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Title Annotation:pharmaceutical innovation
Author:Morrison, Trista
Date:May 1, 2009
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