Market intelligence: Genentech's Rituxan fails late stage trials in Lupus

Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced today that a Phase II/III study of Rituxan® (rituximab) for systemic lupus erythematosus (SLE, commonly called lupus) did not meet its primary endpoint defined as the proportion of Rituxan treated patients who achieved a major clinical response (MCR) or partial clinical response (PCR) measured by BILAG, a lupus activity response index, compared to placebo at 52 weeks. The study also did not meet any of the six secondary endpoints. Genentech and Biogen Idec will continue to analyze the study results and will submit the data for presentation at an upcoming medical meeting.

The Phase II/III randomized, double-blind, placebo-controlled, multi-center study was designed to evaluate the efficacy and safety profile of Rituxan in patients with moderate-to-severe SLE on a background immunosuppressant. This study excluded patients with lupus nephritis (LN). A total of 257 patients from approximately 55 sites in the U.S. and Canada were randomized 2:1 to receive Rituxan plus prednisone or placebo plus prednisone in two infusions 15 days apart. The patients were retreated six months later with the same regimen. Patients were evaluated for efficacy every four weeks for 52 weeks. The majority of patients are being monitored to Week 78.

The primary endpoint of the study was the proportion of patients who achieved either a Major Clinical Response (MCR) or Partial Clinical Response (PCR) using the BILAG instrument at 52 weeks. Additional endpoints included: time adjusted area-under-the-curve minus baseline of BILAG score over 52 weeks; proportion of patients who achieve a MCR, and proportion of patients who achieve a PCR (including MCR) at Week 52; proportion of patients who achieve BILAG C or better in all domains at Week 24; time to moderate or severe flare over 52 weeks; change in SLE Expanded Health Survey physical function score from baseline at Week 52; and proportion of subjects who achieve a MCR with 10 mg prednisone per day from Weeks 24 to 52.

The news has not pleased investors and the stocks are diving as a result because the negative result has implications beyond Rituxan. The company has been developing a second-generation anti-CD20 antibody, ocrelizumab, which has the same mechanism as Rituxan, and is currently in Phase III for RA and Phase II for MS. This drug is being developed as a more benign version of Rituxan for use in patients witw non-life-threatening conditions, including the autoimmune diseases. Rituxan, a more potent drug, was unable to meet a single endpoint in this trial, and failed in MS, so the lupus news does not instill confidence in the prospects for the next-generation version, making investors wary and nervous about the future of the pipeline. In addition, there have been no new significant treatments for this debilitating disease for nearly 30 years.

Market intelligence - more layoffs, this time Wyeth

On Friday, Wyeth apparently announced to its employees that another 1,240 sales positions were being eliminated as part of an internal cost cutting program called "Project Impact".

These are troubled times in the Pharma industry and Wyeth appears to be no different. The FDA recently approved its Pristiq antidepressant, but company has experienced various challenges with its pipeline. Over the past year, the FDA has declined to approve a drug, demanded more data or required a new patient study.

In addition, its recently marketed new oncology product, Torisel, was third to market in renal cell cancer behind Nexavar and Sutent. Meanwhile, Wyeth expects generic competition for the Protonix, one of its biggest drugs with sales of $1.9 billion for heartburn. The outlook looks gloomier rather than optimistic so far.

Company market intelligence - GSK, Sirtris

GlaxoSmithKline have made an offer for Sirtris - $720 million, a hefty premium (84%) to what the company was trading for previously.

Sirtuins are emerging as potential therapeutic target to treat diseases such as aging, metabolism and stress tolerance. Amongst genes that have been shown to affect aging in model organisms, sirtuin genes are unique in that their activity level is positively correlated with lifespan (i.e. they are anti-aging genes).

For example, there are seven human Sirtuins (SIRT1-7) that display diversity in cellular localization and function. Growing evidence suggests that small-molecule activators of SIRT1 may counteract age-related afflictions such as type 2 diabetes. Inhibitors of SIRT2 may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Recent discoveries of small-molecule and protein modulators of Sirtuin deacetylation activity have provided insight into the biological and molecular functions of Sirtuins and have validated their potential as therapeutics.

Sirtuin 1 (SIRT1) in cells may have a role in regulating important aspects of mitochondrial biology. Mitochondria have been linked to aging, and also to diseases of aging. Thus, sirtuins might provide a key link between mitochondrial dysfunction, aging and metabolic disease.

Essentially, GSK are betting that this biochemical pathway will turn out to be critical for chronic aging diseases and therefore will generate future revenues by slowing the aging process.

While this novel concept may offer huge potential, it will also have some interesting challenges along the way for GSK and Sirtris to navigate. Imagine how might the FDA approach a a drug for aging and life extension? How would you design a Phase II trial for longevity? How long would it take? What are the clinical endpoints and measurables of clear benefit? Then it all starts to get very murky and uncertain from a regulatory perspective.

A cynic might, however, wonder whether GSK laid off a large number of employees so they could have this injection of cash (because as Dilbert's boss says "firing employees is like printing money") to bid for Sirtris.

The science I'm very impressed with, the corporate shenanigans considerably less so.

Company market intelligence - Merck

Hot on the recent Vytorin debacle comes another disappointment for Merck after the FDA issued a non-approval letter for Cordaptive (MK-0524A) yesterday. The good news, however, was that the EU authorities approved it, but the US market clearly remains sceptical. Merck did not elaborate on the reasons for the FDA's rejection.

Cordaptive is a combination drug that contains an extended-release form of niacin, a vitamin, and a chemical called laropiprant to stop flushing, a dilation of blood vessels that causes redness and an unpleasant burning sensation on the neck and face. Flushing is a common side effect of niacin-based drugs, and the biggest reason many patients stop taking current products, including Niaspan.

Given the failure of Pfizer’s torcetrapib, the current market news is hardly surprising. The Pfizer pill caused unexpected deaths, and a recent Cordaptive study revealed an increase in liver enzymes and had an impact blood sugar for diabetics.

Abbott are likely to be happy with the news - their related cholesterol medication, Simcor, was approved 2 months ago. Simcor was also a combination product, simvastatin and niacin; both components have separately demonstrated an ability to reduce heart attacks and death.

Amgen oncology franchise in free-fall?

Amgen announced their 1st quarter performance last week, and the results aren't pretty.

Sales of their growth factor franchise are suffering as Aranesp and Epogen revenues continue to decline since the FDA reviewed the risks associated with such therapies in March 2007.

There was a sequential (4Q07 to 1Q08) drop of $66 million and $84 million respectively. The FDA has yet to announce its new guidelines (read restrictions) on the use of the drugs on certain cancer patients who get fatigued from chemo, which could put even more pressure on sales. This is not good news for the already disgruntled shareholders.

The company is currently going through a major cost cutting and restructuring program. New product launches are needed to boost confidence and enthusiasm. The next likely candidate for approval, denosumab (D-Mab) for fracture data in postmenopausal osteoporosis, may contribute to the bottom line but whether it has the potential for blockbuster status remains to be seen.