Having built a heritage on the discovery of breakthrough medications in oncology, immunology and tissue growth and repair, Genentech is now turning its sights to tackling diseases in two new therapeutic areas: neuroscience and infectious disease.

The South San Francisco biotech announced its intention to expand drug development into two new areas during an investor meeting in New York City March 14.

"We take the decision to add a new focus area very seriously and carefully," CEO Art Levinson told investors. "We only do it when we think the science has progressed to the point where we think we can make a meaningful contribution."

"We now believe that we are in a position where we have enough scientific understanding like we did in the early 1990s with cancer [and] late 1990s with immunology to make a serious effort in two new areas: neurobiology and infectious disease," he said.

Early Plans For New Therapeutic Areas Revealed

Citing the unmet medical need in neuroscience, Exec VP-Research Richard Scheller said Genentech will soon hire a VP to lead drug development in the area.

In neuroscience, Genentech will focus on three areas of research: degeneration (Alzheimer's disease and Parkinson's disease), physiology (pain, depression and schizophrenia) and restoration (stroke and spinal cord injury).

One of the first projects to move forward will be in the Alzheimer's disease space. Genentech plans to file an IND this year to initiate clinical studies of a beta antibody for treating the disease.

While cancer is a significantly higher cause of death in the U.S. than Alzheimer's disease and other neuro-disorders, the disease burden on society of neuro-psychiatric disorders like Alzheimer's ranks higher, Levinson pointed out.

In the areas of pain, depression and schizophrenia, Genentech's research will focus on synapse connections in the brain and modulating the neurotransmitters that are released. In restoration, the company will focus on nerve damage, and in particular examining why peripheral nerve damage can be repaired, but central nerve damage in the spinal cord or brain cannot, Scheller said.

"We're trying to understand the difference of why this occurs peripherally, not centrally, and kind of trick the [central] nerve into re-growth," he said.

Genentech's move into infectious disease is based on high unmet need, scientific opportunity and the company's existing strength in the area of protein and antibody engineering, said Andrew Chan, Senior VP Research-Immunology and Antibody Engineering.

"As we've done with our anti-CD20 platform, where we have been able to engineer into both our second generation and third generation anti-CD20 antibody specific properties that are tailored to both immunologic or oncologic indications, we will also tailor into the infectious disease therapeutic antibodies specific host defense mechanisms that are beyond what a standard antibody actually does," Chan explained.

Leading research in the area is Eric Brown, who joined Genentech at the end of 2006 to establish a group focusing on microbial pathogenesis. He previously worked as chief of infectious disease at Washington University and headed the host pathogenesis program at the University of California-San Francisco.

Opportunities Emerging In MS and Lupus

In the nearer term, Genentech could see progress on efforts to expand its immunology franchise into multiple sclerosis and lupus. Genentech, with its partner Biogen Idec, is developing both Rituxan (rituximab) and a second generation anti-CD20 molecule for MS and lupus.

In MS, Genentech has programs ongoing in both relapsing-remitting MS, the more common form of the disease, and primary-progressive MS. The company recently released positive Phase II data showing treatment with Rituxan reduced the number of inflammatory brain lesions seen on an MRI and the number of relapses in patients with RRMS.

A Phase II trial evaluating the second generation anti-CD20 in RRMS will enroll 200 patients, with the first patient expected to initiate treatment in the second quarter, Product Development President Susan Desmond-Hellmann said.

In the primary progressive form of the disease, data from a Phase II/III trial, Olympus, evaluating Rituxan in 439 patients is expected in the second quarter.

"If Rituxan were to show a benefit in this condition, it would meet a devastating unmet medical need," the exec said. Unlike patients diagnosed with RRMS, those with PPMS tend to get the disease when they are older, on average at age 39, and it takes on a more relentless course, according to the company. There are currently no effective treatments for PPMS.

Trials are also ongoing with Rituxan and the second generation anti-CD20 in patients with systemic lupus erythematosus and lupus nephritis. Results from the Phase II/III EXPLORER trial, evaluating 260 SLE patients following treatment with Rituxan, are due in the second quarter. The Phase III BEGIN trial evaluating the second generation product is underway.

In lupus nephritis patients, the LUNAR Phase II/III trial evaluating Rituxan is due to report results in early 2009. BELONG, a Phase III evaluating the second generation product, enrolled its first patient in Q1.

Near-Term Focus Is On Line Extensions

The second generation anti-CD20 molecule is one of only two NMEs in Genentech's Phase III pipeline. The other is pertuzumab for metastatic HER2-positive breast cancer.

Facing a shortage of new molecular entities in Phase III, Genentech's short-term focus will be on line extensions and bringing forward NMEs in Phase I and II development.

"We know that we have a gap in terms of NMEs, but between now and 2010, we have 23 possible line extensions," Exec VP-Commercial Ian Clark told investors.

Genentech has managed to develop quite an expertise with maximizing the potential for existing products.

Avastin lifecycle management is (and has been) a key component of Genentech's short-term growth strategy, with the company pursuing several new indications for the vascular endothelial growth factor inhibitor, including brain cancer and adjuvant colon cancer.

The company plans to file an sBLA for Avastin (bevacizumab) for the treatment of refractory glioblastoma multiforme in 2008, Senior VP-Clinical Hematology/Oncology David Schenkein said.

Genentech reported positive results from a Phase II trial last year demonstrating that Avastin in combination with irinotecan improved six-month progression-free survival in patients with relapsed disease, with 51 percent of patients experiencing six months of PFS, compared to historical controls of about 15 percent PFS at six months (¹ Also see "Avastin Growth Not Limited To Breast Cancer In 2008, Genentech Says" - Pink Sheet, 21 January, 2008., p. 6). The company also will initiate a Phase III first-line glioblastoma multiforme confirmatory trial.

Another important opportunity for Avastin could be a move into adjuvant colon cancer. Two Phase III trials are underway: NSABP C-08, enrolling 2,710 patients and comparing a regimen of FOLFOX6 plus Avastin for six months followed by Avastin alone for six months versus FOLFOX6 alone for six months; and AVANT, enrolling 3,450 patients into three regimens: treatment with FOLFOX4, FOLFOX4 plus Avastin or XELOX plus Avastin.

Final data from both trials are anticipated in 2010, but an interim look at the C-08 trial will occur in the second quarter of 2008. Levinson indicated the interim look could yield statistically significant results, noting, "We might get data in 2008. We're not expecting it at all, but it could be a potential upside."

In February, FDA cleared Avastin for treatment of first-line metastatic breast cancer on the basis of progression-free survival, rather than overall survival (² Also see "With Avastin Approval For Breast Cancer, Will More Patients Hit Price Cap?" - Pink Sheet, 3 March, 2008., p. 16). Avastin already is approved for first- or second-line treatment of patients with metastatic colorectal cancer, as well as for non-small cell lung cancer.

During the investor meeting, Clark said the opportunity for Avastin in breast cancer is large, but cautioned investors not to be overly bullish. Avastin has been used off-label in the breast cancer patient population, and is estimated already to have penetrated about 25 percent of the market, he noted.

Other labeling expansion opportunities in Phase III development include studies for Rituxan in follicular non-Hodgkin's lymphoma, lupus and primary-progressive multiple sclerosis; Lucentis for diabetic macular edema and retinal vein occlusion; and Xolair for pediatric asthma.

Despite the lack of new drugs in Phase III, the number of NMEs in Genentech's clinical pipeline overall has risen dramatically, Desmond-Hellmann pointed out. The number of NMEs in clinical development has increased from seven in March 2005 to 21 now.

- Jessica Merrill (j.merrill@elsevier.com)

Next For Genentech: Tackling Neuroscience And Infectious Disease

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