Intellect Neurosciences Inc. (fka ILNS)

[montanus]

Nature Biotechnology 24, 595 - 596 (2006)
Published online: 2 June 2006 | doi:10.1038/nbt0606-595

Monoclonals expand into neural disorders
Brian Vastag1

Washington, D.C.

In April, Pfizer bought a Genentech spinoff, Rinat Neuroscience, for close to five hundred million dollars


Monoclonal antibodies are now being tested to treat ailments of the central nervous system, a new territory for this class of drugs.

In April, Pfizer bought a Genentech spinoff, Rinat Neuroscience, for “close to $500 million dollars,” according to one source. What drew Pfizer's interest to Rinat was its pipeline, in particular, two of its most advanced drugs. Both are monoclonal antibodies that Pfizer hopes to cash in on over the next several years. The deal demonstrates the increased interest in monoclonals in new indications, such as central nervous system (CNS) disorders.

David Pritchard, Rinat's chief business officer, says the S. San Francisco-based company offered its portfolio to eight large drug makers—and received nine offers. “The amount of interest was overwhelming,” he says, and Pfizer's offer topped the list.

Pfizer was drawn to Rinat's two top candidates. The first, coded RN624, treats pain by shutting down nerve growth factor (NGF). It demonstrated impressive early trial results in osteoarthritis patients in the third quarter of 2005 and is now in phase 2 clinical trials. RN624 drew interest because NGF “is the first new clinically validated pain target these companies have seen in decades,” points out Pritchard. The second antibody, RN1219, clears Alzheimer-causing plaque from the brains of mice, but has yet to enter human trials. “Half a billion seems a little high,” says Casey Lynch, managing partner at biotech investment advisor NeuroInsights. “But Pfizer has lots of money in the bank and their pipeline is running dry.”

Rinat's product 'is the first new clinically-validated pain target these companies have seen in decades.'

David Pritchard
Chief Financial Officer of Rinat Neuroscience
Although only one monoclonal antibody for a CNS application (Biogen-Idec's ill-fated multiple sclerosis treatment Tysabri; natalizumab) has been approved by the US Food and Drug Administration to date, the acquisition epitomizes growing excitement in applications of biotech in the 'neuro' area. A recent analysis of 450 companies by San Francisco, California-based consultants NeuroInsights concludes that the worldwide market for neurological disease treatments was $93 million in 2005, a 7% increase over 2004. A quarter of all life sciences venture capital invested in the US now flows into firms in this area. And NeuroInsights 'neurotech' index, which tracks 30 publicly traded companies with this focus, is up 85% since 2004, whereas the NASDAQ and Standard & Poor's 500 are up just 16%.

Pfizer was interested in the quality of Rinat's pipeline, despite its early stage. Rinat's RN624 is now in a phase 2 trial in 300 patients, with full results expected in the second half of 2007. “It does appear to be first in class,” Lynch says of RN624. “It's a good application for an antibody because it targets peripheral cells. It doesn't have to cross the blood-brain barrier.”

The mechanism of action of RN624 is quite complex, however. In embryos, NGF spurs neurodevelopment. But in adults, NGF's only role, apparently, is to drive acute and chronic pain in at least three different ways. “We know it works locally—at the site of injuries and so on—and immediately increases the sensitivity of pain-sensing neurons,” says David Shelton, who began development of RN624 at Genentech in the mid-1990s and is now senior director for biology at Rinat. Second, NGF induces immune mast cells to release inflammatory proteins. Third, NGF drives a feedback loop that upregulates the synthesis of substance P and other pain-related peptides, thereby “increasing pain signaling up the spinal cord,” explains Shelton.

By binding to NGF, RN624 prevents it from latching onto nerve cells. In mouse models, this action dampens incisional, visceral, neuropathic and metastatic bone disease pain. Clinical data released in early May at the American Society of Pain meeting in San Antonio, Texas, show that RN624 effectively reduces osteoarthritis knee pain after a single injection. “It's an unbelievably clean [safety] profile,” says Shelton. “Knock on wood.”

Half a billion seems a little high, but Pfizer has lots of money in the bank and their pipeline is running dry.

Casey Lynch
NeuroInsights
As for competition, Amgen is the only other company with an anti-NGF antibody in phase 1 clinical trials. Originally developed for neuropathic pain, AG403 is now being tested against osteoarthritis pain, too. “They'll keep us on our toes,” remarks Shelton.

Rinat's Alzheimer antibody faces stiffer competition. It has yet to enter clinical trials and at least two dozen companies are also pursuing immunotherapies for Alzheimer. Most use active immunization, in which a small part of the beta-amyloid plaque is injected in hopes that it will recruit the immune system to attack disease-causing brain plaques. Rinat's RN1219 dodges the vagaries of the immune system by directly injecting an anti-plaque antibody. At least two other companies, Eli Lilly, of Indianapolis, Indiana, and the San Diego subsidiary of Elan Pharmaceuticals, of Dublin, are also pursuing so-called passive immunization against Alzheimer; both have antibodies in early clinical trials.

Elan generated a buzz in April when it released early clinical data from 30 patients receiving its monoclonal antibody bapineuzumab. The ten patients receiving the second of three doses showed statistically significant improvement in the mini-mental state examination 16 weeks after antibody injection. However, MRI scans of three of ten patients receiving the highest dose showed abnormalities that could indicate microhemorrhaging, says Dave Morgan, director of the Alzheimer research laboratory at the University of South Florida, Tampa. Morgan, who has no financial stake in Rinat or any other company, was stunned when he saw Elan's data, because he had published several articles showing small brain bleeds in mice receiving Rinat's antibody. “The human data parallels the mouse data perfectly,” he says. “When I first saw [microhemorrhaging] in my mice, I said, 'This is dead, this approach is over.' I was afraid Rinat was going to call me a lousy scientist. Instead, they wanted to see if they could correct it.”

Rinat cofounder and president, Arnon Ronsenthal, thought that a modified version of the antibody, one that didn't bind to glucose, might provide a cleaner safety profile. His team engineered such an antibody and shipped it to Morgan for mouse testing. In the May 17 issue of the Journal of Neuroscience (2006, 26 (20): 5340–5346), Morgan's team reports that the new, deglycosylated antibody clears beta-amyloid plaque as well as or better than the older antibody while causing less microhemorrhaging. The mice also performed better on a standard water-maze memory test.


Elan and others in the field are now eager to develop their own deglycosylated antibodies. But the standard method of deglycosylation uses a slow, expensive enzyme reaction. Here, Rinat has a head start—its latest antibody lacks the glucose-reaction site altogether. “They engineered it that way,” says Morgan. Citing confidentiality concerns, Rosenthal would not confirm this, but he did say that Rinat's antibody is “specifically designed to minimize” microhemorrhaging.

As for sneaking an antibody across the blood-brain barrier, no one can say for certain how the anti-Alzheimer antibodies manage the trick. Theories abound, but Rosenthal believes that, whatever, the mechanism, clinical data will drive the field. He says the company's first Alzheimer trial will begin this summer, although the company and its new owner are still debating whether to run it in Europe, Australia or the United States.

http://www.nature.com/nbt/journal/v24/n6/full/nbt0606-595.html



STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL

USAN PONEZUMAB
PRONUNCIATION poe nez' oo mab
THERAPEUTIC CLAIM Treatment of Alzheimer’s disease
CHEMICAL NAMES
1. Immunoglobulin G2, anti-(human ß-amyloid) (human-mouse monoclonal PF-04360365
clone 9TL heavy chain), disulfide with human-mouse monoclonal PF-04360365
clone 9TL light chain, dimer
2. Immunoglobulin G2, anti-(human amyloid beta A4 protein (Alzheimer disease amyloid
protein, ABPP, APPI, preA4, protease nexin-II)); humanized mouse monoclonal
PF-04360365 clone 9TL des-442-lysine(CH3107-K)-[325-serine(CH299A>S),326-
serine(CH2100P>S)]?2 heavy chain (130-219')-disulfide with humanized mouse
monoclonal PF-04360365 clone 9TL ? light chain, dimer (218-218'':219-219'':222-
222':225-225'')-tetrakisdisulfide
MOLECULAR FORMULA C6552H10158N1730O2090S52
MOLECULAR WEIGHT 148.3 kDa
TRADEMARK None as yet
MANUFACTURER Pfizer, Inc.
CODE DESIGNATION PF-04360365, RN-1219
CAS REGISTRY NUMBER 1178862-65-1

http://www.ama-assn.org/resources/doc/usan/ponezumab.pdf


http://www.iscd.org/wp-content/uploads/2012/10/PressRelease012609FINAL.pdf

http://www.drugs.com/news/intellect-neurosciences-inc-grants-license-certain-patents-patent-applications-wyeth-elan-pharma-8210.html

http://www.biospace.com/News/intellect-neurosciences-inc-grants-to-top-tier/112397

http://news.bio-medicine.org/?q=medicine-news-1/intellect-neurosciences--inc--grants-to-top-tier-global-pharmaceutical-company-license-to-certain-alzheimers-patents-and-patent-applications-33226