Many preventive measures for cognitive decline and for preventing Alzheimer's
disease -- mental stimulation, exercise, and a variety of dietary supplements
-- have been studied over the years. However, an independent panel convened
this week by the National Institutes of Health determined that the value
of these strategies for delaying the onset and/or reducing the severity of
decline or disease hasn't been demonstrated in rigorous studies.
The panel's assessment of the available evidence revealed that progress to
understand how the onset of these conditions might be delayed or prevented
is limited by inconsistent definitions of what constitutes Alzheimer's disease
and cognitive decline. Other factors include incomplete understanding of
the natural history of the disease and limited understanding of the aging
process in general. The panel recommended that the research community and
clinicians collaborate to develop, test, and uniformly adopt objective measures
of baseline cognitive function and changes over time.
Although many non-modifiable risk factors have been examined, age is the
strongest known risk factor for Alzheimer's disease. Additionally, a genetic
variant of a cholesterol-ferrying protein (apolipoprotein E), has strong
evidence of association with the risk for developing Alzheimer's disease.
Although it is hoped that improved understanding of genetic risk factors
may ultimately lead to effective therapies, currently these associations
are primarily useful in the clinical research setting.
The panel determined that there is currently no evidence of even moderate
scientific quality supporting the association of any modifiable factor-dietary
supplement intake, use of prescription or non-prescription drugs, diet, exercise,
and social engagement-with reduced risk of Alzheimer's disease. The evidence
surrounding risk reduction for cognitive decline is similarly limited. Low-grade
evidence shows weak associations between many lifestyle choices and reduced
risk of Alzheimer's disease and cognitive decline.
Although there is little evidence that these interventions lessen cognitive
decline, some are not necessarily harmful and may confer other benefits.
However, the panel also emphasized the need for enhanced public understanding
that these proposed prevention strategies are currently, at best, only loosely
associated with improved outcomes. This means that carefully-designed randomized
studies may reveal that these modifiable factors enhance, detract, or have
no effect on preventing Alzheimer's disease and cognitive decline.
Software to Replace
Bill Gates’ $10 million investment in Schrodinger, a Portland-based drug
development software outfit, could give him a strategic position in the quest
to use powerful computers and state-of-the-art software to reengineer the
development of pharmaceuticals. Schrodinger is a company with a staff
of 140 and a mission to create software that can be used to simulate the
lab work that chemists perform during the discovery stage. The field
caught fire in the ‘90s but then burned and crashed to earth a decade ago.
The soaring cost of drug development, combined with a meager productivity
rate from Big Pharma pipelines, has focused new attention on the field. For
Gates, the key connection was meeting Schrodinger co-founder and Columbia
professor Richard Friesner while playing bridge.
In a radical departure from traditional research funding standards, the Bill
& Melinda Gates Foundation is handing out 81 grants of $100,000 each
to researchers who are thinking big about revolutionary new approaches to
protecting people from disease. And the Foundation's scientists know going
in that as many as 90 percent of the projects will fail. Based on nothing
more than a two-page outline with no requirement for data, researchers around
the world have been lining up for these Grand Challenges Explorations grants,
which come with the promise of $1 million more if the initial research proves
promising. Projects from 17 countries have been selected. They include work
on giving mosquitoes a cold to prevent them from biting people, developing
tomatoes that can therapeutically target viruses and using laser technology
to enhance the human immune response triggered by a vaccine.
In an open letter, the fulltime philanthropist promised to shell out $3.8
billion this year, seven percent of the foundation's wealth and a significant
increase over the $3.3 billion spent last year. Gates highlighted the
foundation's success in helping advance a late-stage malaria vaccine, an
ongoing effort on HIV/AIDS and an ambitiopus effort to rid the world of polio.
But Gates’ billions have earned criticism, as well.
Read more: http://www.fiercevaccines.com/story/bill-gates-plans-increase-spending-despite-heavy-losses/2009-01-28?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FBRV0#ixzz0mZyV95Mz
Big Pharma’s Love
Big Pharma's need to cut development spending and boost its presence in big
new markets is driving sizzling hot growth rates for China's contract research
organizations (CROs). There are at least 138 CROs in China. Frost
& Sullivan projects that China's CROs devoted to late-stage research
will boom along at an 18 percent annual growth rate, with revenue projected
to grow from $145 million to $240 million by 2012. The early work that
they offered in biology and chemistry is making way for more lucrative contracts
to undertake preclinical drug studies and human trials. The U.S.-based
CROs like Charles River are going to China. The company has already
built one facility in Shanghai and is now blueprinting a second.
The new crop of mAbs represents a resounding level of validation for the
HuMab transgenic mouse technology developed by Nils Lonberg, initially at
Palo Alto, California–based GenPharm, and then at Medarex, which acquired
GenPharm in 1997. The platform was further extended, after a cross-licensing
agreement with the Tokyo-based beer company Kirin, which had independently
developed a TransChromo mouse strain. UltiMab is based on so-called KM mice,
bred from these two lines.
The four 2009 approvals bring to six the total of fully human mAbs on the
market. Before 2009, Amgen's Vectibix (panitumumab), an inhibitor of epidermal
growth factor receptor approved for colon cancer, and Humira (adalimumab),
a TNF-α inhibitor marketed by Abbott Laboratories, of Abbott Park, Illinois,
for autoimmune disorders, were the sole representatives of this category.
Vectibix was generated by means of the XenoMouse technology developed by
Abgenix, of Fremont, California, and now owned by Amgen, of Thousand Oaks,
California. Humira's origins lie in the phage display technology developed
by Cambridge Antibody Technology, of Cambridge, UK, and now owned by AstraZeneca,
And there's more to come. “The four drugs approved in 2009 really represent
only the tip of the iceberg for our transgenic mouse platform. There are
a lot of exciting drugs behind these in clinical development, and we continue
to use the platform for drug discovery,” says Lonberg, now senior vice president,
biologics discovery at BMS. UltiMab's new owner is continuing to invest in
further development of the platform. “We continue to make new strains of
engineered mice that add to the basic platform, but, just as important, we
also continue to invest in the infrastructure necessary to characterize and
identify lead drugs derived from the mice. And we have developed our own
proprietary antibody-drug conjugate technology that extends the range of
applications for human antibody–based drugs,” Lonberg says. For example,
MDX-1203, an anti-CD70 antibody conjugated via a peptide-based linker to
a prodrug of CC-1065 (rachelmycin), entered phase 1 testing for advanced/recurrent
renal cell carcinoma and relapsed/refractory B-cell non-Hodgkin's lymphoma
Copenhagen-based Genmab is another beneficiary of UltiMab's recent coming
of age. Formed in 1999 as a European spin-out from Medarex, Genmab also holds
rights to the UltiMab platform, and it can lay direct claim to one of last
year's four antibody approvals, Arzerra (ofatumumab). It licensed the compound,
an anti-CD20 mAb, to London-based GlaxoSmithKline in late 2006. The entire
development process, from generating a hybridoma cell line to final approval,
took seven years, seven months and five days, says Jan van de Winkel, Genmab's
chief scientific officer.
All of the antibodies approved in 2009 are being commercialized by large
pharmaceutical companies. Ilaris (canakinumab), an interleukin-1β inhibitor,
was fully developed in-house at the Boston headquarters of the Novartis Institutes
of Biomedical Research (NIBR). Ilaris is not a first-in-class drug, as two
other IL-1β inhibitors already exist. Kineret (anakinra), a recombinant version
of the naturally occurring protein IL-1 receptor antagonist, was originally
developed by Amgen and is now marketed by Stockholm-based Orphan Biovitrum.
The fusion protein Arcalyst (rilonacept), an IL-1 trap that acts as a soluble
decoy receptor, is also marketed by Regeneron Pharmaceuticals, of Tarrytown,
J&J's Centocor Ortho Biotech arm can claim another two of the six biologic
approvals, one of which, Stelara (ustekinumab), is a first-in-class drug.
It inhibits the pro-inflammatory cytokines IL-12 and IL-23 by binding the
p40 subunit common to each. That prevents their binding to the cell-surface
receptor chain, IL-12 β1, and triggers their respective immunological cascades.
The two cascades are ultimately distinct, as the IL-12 p35 and the IL-23
p19 subunits recognize different receptors and activate alternative inflammatory
pathways. IL-12 is associated with a T-helper (Th) type 1 response (Th1),
whereas IL-23, which has variously been described as the master switch in
both psoriasis and Crohn's, is associated with a Th17 response. Stelara has
gained approval initially as a treatment for plaque psoriasis, but studies
in Crohn's disease and psoriatic arthritis are also underway. However, the
molecule failed to demonstrate efficacy in multiple sclerosis4. Its long-term
safety profile is not well understood, either. The FDA approval required
J&J to put in place a Risk Evaluation and Mitigation Strategy to evaluate
and mitigate the risk of serious infection, malignancy and the development
of reversible posterior leukoencephalopathy syndrome, a neurological condition
associated with taking chemotherapy and transplant rejection drugs.
Simponi, J&J's second biologic to gain approval in 2009, is the fifth
TNF-α inhibitor to reach what is now a lucrative but crowded market. It is
going up against several mature product franchises, including Amgen's Enbrel
(etanercept), Abbott's Humira and Remicade, marketed in the US by J&J
and in Europe by Merck of Whitehouse Station, New Jersey, following its acquisition
of Kenilworth, New Jersey–based Schering-Plough. It is also pitted against
a more recent newcomer: Cimzia (certolizumab pegol), a pegylated Fab' antibody
fragment, marketed by UCB, of Brussels. Stelara, which is administered by
subcutaneous injection, can, like Cimzia, be self-administered by patients.
It also offers a more convenient dosing schedule than other TNF-α inhibitors,
as only five injections per year are necessary. However, it is not expected
to offer significant clinical advantages over its longer-established competitors5.
Judge Robert W. Sweet of the U.S. District Court for the Southern District
of New York ruled in favor of the plaintiffs on March 29, 2010 in Association
for Molecular Pathology, et al. v. United States Patent and Trademark Office,
et al, invalidating Myriad’s patents. The PTO currently grants patents on
nucleotide sequences provided that the sequences are "isolated" nucleotide
sequences and the isolated nucleotide sequence is novel (the particular sequence
had not been previously described), is non-obvious and is useful. According
to Judge Sweet, the basis of this policy was that nucleotide sequence was
being treated the same as any other chemical compound.
The Court highlighted the similarities between natural nucleotide sequence
and isolated nucleotide sequences: both are chemical substances and both
serve as physical carriers of information. According to Judge Sweet, since
the same structural and functional qualities are identifiable in both native
DNA and isolated DNA, isolated DNA is not "markedly different" from native
DNA and thus does not constitute patentable subject matter under 35 U.S.C.
§101. The Court acknowledged that "the identification of BRCA1 and BRCA2
gene sequences is unquestionably a valuable scientific achievement for which
Myriad deserves recognition, but that it is not the same as concluding that
it is something for which they are entitled to a patent." However,
the judge conveniently forgot that the human DNA existed for as long as humans
existed and nobody developed Myriad’s isolated sequences in the past several
millions of years to test breast cancer, and why humanity cannot grant monopoly
to Myriad’s cancer test for a trivial 20 years to incentivize such innovations,
particularly in this case the remaining life of the patents in question is
about 5 years only.
This is just the beginning of the debate on whether nucleotide sequences
and other molecules such as antibodies, vaccines etc constitute patentable
Industry and HealthCare Reform Law
On March 30, 2010, President Barak Hussein Obama made law of the final chapter
of health care reform when he signed the reconciliation bill (H.R. 4872,
the "Health Care and Education Affordability Reconciliation Act of 2010"
or "Reconciliation Bill") passed by both houses of Congress on March 25,
2010, which amended the landmark health reform legislation, H.R. 3590 (the
"Patient Protection and Affordable Care Act") signed by the President on
March 23, 2010.
The Healthcare Reform Law imposes an annual fee on any "covered entity engaged
in the business of manufacturing or importing branded prescription drugs"
beginning in 2011. Branded prescription drugs and biologics covered include
(i) any prescription drug approved under section 505(b) of the Federal Food,
Drug, and Cosmetic Act; and (ii) any biological product for which an application
was submitted under section 351(a) of the Public Health Service Act.
"Covered entity" is defined broadly, and includes "any manufacturer or importer
with gross receipts from branded prescription drug sales." This annual fee,
for any individual pharmaceutical manufacturer (or importer), is based on
a calculation intended to reflect the market share of the manufacturer. "Branded
prescription drug sales" is defined to include sales of branded prescription
drugs to specified government programs (Medicare, Medicaid, the Department
of Veterans Affairs (VA), the Department of Defense (DOD), and the TRICARE
retail pharmacy program under 10 U.S.C. § 1074g) or "pursuant to coverage
under any of those programs."1 Significantly, based on the statutory language
and application to only "branded" drugs, sales of generic drug products will
not affect the calculation of the annual fee.
In determining the annual fee, the government programs that either purchase
or provide coverage for the branded drugs (i.e., Medicare, Medicaid, VA,
and DOD/TRICARE) will provide a yearly report to the Department of the Treasury,
indicating the prior year's sales (or units of drugs dispensed to beneficiaries
and corresponding payment amount) for each branded drug for all manufacturers
covered by the program. Dividing the industry into tiers of branded sales,
the Secretary of the Treasury will calculate the annual fee for each pharmaceutical
manufacturer or importer based on reports from other specified federal government
agencies based on a ratio of its branded drug sales to the branded drug sales
of all covered entities for the prior year (i.e., market share).2 The annual
fee is a step-wise annual increase, starting at $2.5 billion in 2011, increasing
to a maximum of $4.1 billion in 2018, and decreasing to $2.8 billion in 2019
In addition, section 10609 of the Healthcare Reform Law is intended to increase
access to lower-cost generic drugs by preventing brand name manufacturers
from delaying approval of generic products by making label changes to the
brand name or listed drug. Prior to the Law, the labeling of a generic drug
was required to match the labeling of the referenced brand name or listed
drug, or would not be approved. Under the new law, a generic application
can be approved despite last-minute changes to the labeling of the listed
drug, so long as the labeling change to the listed drug is approved 60 days
prior to the date of expiration of the listed drug's patent or exclusivity
period, and provided that the labeling change does not affect the "Warnings"
section of the listed drug's labeling.
Comparative Effectiveness: Drug manufacturers should keep abreast of comparative
effectiveness research activities initiated under the Healthcare Reform Law
and assess whether their products may be impacted. The law creates a new
public-private Patient- Centered Outcomes Research Institute tasked with
identifying comparative effectiveness research priorities, establishing a
research project agenda, and contracting with entities to conduct the research
in accordance with the agenda. Research findings published by the Institute
will be publicly disseminated. However, the law imposes restrictions on CMS's
ability to use such findings to make decisions related to coverage, reimbursement,
or incentive programs. Additional information on comparative effectiveness
will be available in a forthcoming Morgan Lewis LawFlash.
Fraud and Abuse: Drug manufacturers also will be affected by Healthcare Reform
Law amendments related to fraud and abuse, including amendments to the Anti-Kickback
Statute, False Claims Act, healthcare fraud criminal statute, and program
integrity provisions. Additional information on these amendments is available
in our March 31, 2010 LawFlash, "Healthcare Reform Law: Healthcare Fraud
and Abuse and Program Integrity Provisions," available at http://www.morganlewis.com/pubs/WashGRPP_PrgmIntegrityProvisions_LF_31mar10.pdf
Transparency Initiatives: Drug manufacturers will need to establish systems
and controls to ensure compliance with new transparency provisions, which
require reporting of (1) payments and other transfers of value to physicians
and teaching hospitals for values of $10 or more (or $100 aggregate in a
calendar year), and (2) physician ownership of or investments in drug manufacturers.
The statutory language is limited to applicable manufacturers of devices,
drugs, biologics, and medical supplies for which "payment is available" from
certain designated federal healthcare programs and does not appear to include
by its terms indirect payments or funding. The information reported will
be publicly available through an Internet website in a searchable format.
Additional information on the new transparency requirements is available
in our March 29, 2010 LawFlash, "Healthcare Reform Law Delivers New Transparency
Requirements for the Health Industry," available at http://www.morganlewis.com/pubs/WashGRPP_FDATransparencyRequirements_
Biosimilars: The Law authorizes FDA to create a new regulatory pathway for
biosimilar biological products, allowing licensure of biological products
as biosimilar or interchangeable to products with current licenses. Innovator
manufacturers of reference biological products are granted 12 years of exclusive
use before biosimilars can be approved for marketing in the United States.
Because it establishes a new regulatory pathway for biosimilars, this aspect
of the Healthcare Reform Law will have a broad impact on industry activities
for both innovator and follow-on biological products. Additional information
on the new transparency requirements is available in our April 15, 2010 LawFlash,
"Healthcare Reform Law: A New Regulatory Pathway for Biosimilar Biological
Products," available at http://www.morganlewis.com/pubs/WashGRPP_RegulatoryPathForBiosimilarBiologicalPro
Dawn Raids in Germany
Patent owners can obtain an ex parte order from a German court granting them
access to the premises of a competitor who is suspected of infringing their
patent. This covers in particular production facilities, laboratories, and
R&D sites, no matter how secret and protected the premises may be.
Such inspection proceedings or "dawn raids" are carried out by a court-appointed
expert, accompanied by a court marshal or sometimes even police officers,
and two to three attorneys as counsel for the patent owner, usually a litigation-focused
attorney and a patent attorney. This larger team can appear without prior
warning at the site that is to be inspected and enforce access, usually simultaneously
serving a court order on the management of the facility. The expert will
then proceed to inspect the allegedly patent-infringing device or process
and may take pictures, partially dismantle devices, and take samples. After
completing this inspection, the expert will summarize its findings in an
expert opinion, which will be admissible as binding evidence in subsequent
patent infringement proceedings….
The Federal Supreme Court has now, for the first time, confirmed that the
inspection procedure developed under case law is in accordance with German
law and balanced the interests of the patent owner and the suspected patent
infringer (BGH X ZB 37/08 – Lichtbogenschnürung). The Court confirmed
that a court order obliging attorneys to keep information confidential and
not disclose it even to their own clients is permissible, thus allowing the
release of expert opinions to plaintiff's counsel to comment on alleged business
secrets in such opinions. The same rules apply with respect to counsel's
observations during the inspection itself. With this ruling, the core structure
of the inspection procedure has been confirmed, thereby allowing plaintiff's
counsel to take part in the inspection. Furthermore, the Court provided a
clear set of rules that have to be met in order to qualify information as
a business secret, bringing the standard protection in line with long-tested
provisions of German criminal law.
To protect the interests of the alleged infringer, the Court ruled that it
is mandatory in every case to balance the interests of both parties. However,
the Court also clarified that even if business secrets were contained in
such expert opinion, they need not necessarily prevent the expert opinion
from being released, as the impact of their disclosure on competition may
in fact be more or less insignificant. It can be assumed that courts will
follow the approach developed under existing case law, where the outcome
of the expert opinion is a significant factor in determining the balance
of interests: The greater the likelihood that a patent infringement has occurred,
the greater the chance that the interests of the patent owner would prevail
over any concerns of secrecy raised by the alleged infringer.