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DEVELOPMENT OF NOVEL HYPERGLYGOSYLATED TYPE 1 INTERFERONS: A STRATEGY TO IMPROVE PK PERFORMANCE WITHOUT LOSS OF BIOLOGICAL POTENCY
DEVELOPMENT OF NOVEL HYPERGLYGOSYLATED TYPE 1 INTERFERONS: A STRATEGY
TO IMPROVE PK PERFORMANCE WITHOUT LOSS OF BIOLOGICAL POTENCY
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Reported by Jules Levin
43rd EASL
April 23-27, 2008
Milan, Italy
There are several alternative interferons in development including this one and Albuferon which is now in phase III.
AUTHOR CONCLUSIONS
⇒ A need still exists for IFN-based products with novel biological properties
⇒ Addition of Glycosylation Sites
- Improved PK
- Maintained Biological Potency
- May Address HCV NR
- Additional applications in HBV and possibly HIV
⇒ Continuing optimization of glycosylation
- Optimization cell culture conditions will improve carbohydrate incorporation
- More glycosylation sites can be added if needed
⇒ Further Study is Warranted
GLYCOPROTEIN ENGINEERING OF INTERFERONS
This statement is from Alios BioPharma
Interferon
(IFN) alpha based products are approved worldwide for the treatment of
various malignancies as well as viral diseases such as chronic
hepatitis B hepatitis C, and human papillomavirus.
Although the clinical utility of both alpha and beta IFN has been
clearly demonstrated, there is a need for new molecules that address
the disadvantages of pegylated-IFN (PEG-IFN) and albuferon (interferon
alpha 2b/albumin fusion protein) products which have improved
pharmacokinetic (PK) characteristics but with significant loss of
biological potency. The need for new IFNs is most urgent for the
treatment of chronic hepatitis C where recent data show that the
addition of direct antiviral agents to treatment regimes still requires
the use of PEG-IFN and that patients who are null-responders (NR) to
PEG-IFN + ribavirin are unlikely to benefit from retreatment with
PEG-IFN + ribavirin and a direct antiviral agent. This lack of response
may in part be due to the fact that the addition of the PEG moiety to
the IFN molecule reduces the biological potency of the resultant
molecule by creating steric hindrance of the receptor ligand
interaction. These patients may however benefit from a more potent IFN
included in the drug cocktail.
Alios founding scientists have discovered, and hold exclusive worldwide
rights to, a method enabling the creation of highly potent IFN protein
therapeutics with improved PK characteristics without loss of
biological potency resulting in molecules with the potential for
improved therapeutic indices. This proprietary technology does not
require post-fermentation chemical modification of the IFN, a process
that dramatically reduces potency and increases cost of goods of
existing PEG-IFN products. The Alios technology involves introduction
of glycosylation sites into the IFN protein by modification of the
primary amino acid sequence of the IFN molecules thus increasing the
molecular weight and hydro-dynamic radius of the protein resulting in
improved PK characteristics with no loss of biological potency. It is
important to note that the glycosylation sites that can be engineered
into one IFN molecule can also be engineered into additional IFN
species. Thus, the Company is applying this technology to several IFN
alpha and beta species with the goal of developing individual products
optimized for the treatment of: viral diseases, cancer and MS. The
prototype molecule under development is called Glycoferon¨.
Glycoferon
The first product the Company is developing an optimized
hyperglycosylated consensus interferon (Glycoferon) as a broad
spectrum antiviral for treatment of HCV, HBV, HIV, avian influenza
virus and other viruses. The non-glycosylated form of consensus
interferon is currently being sold by Three Rivers Pharmaceuticals
under the trade name Infergen and generated approximately $50 million
in annual revenues during 2007. Consensus Interferon has also
demonstrated clinical efficacy in patients with SARS in a clinical
trial that was completed during the 2003 Toronto SAR outbreak. While
Infergen is more potent than either Pegasys or PegIntron, the two
leading interferon therapies, each generate revenues in excess of $1
billion per year, Infergen's three times per week and daily dosing
schedule puts it a commercial disadvantage to competing therapies. The
Company believes that Glycoferon will have equivalent if not improved
dosing over these leading therapies (at least once per week dosing)
with superior potency.
To produce the Glycoferon candidates, Alios scientists took the DNA
encoding sequence for consensus IFN and made amino acid modifications
to encode for several glycosylation sites throughout the protein. Two
sites were identified that were quantitatively modified by addition of
carbohydrate moieties. A single variant carrying both sites was
quantitatively modified at both sites. Glycosylation substantially
increased molecular weight with no resultant loss of biological
potency. In cell culture models, consensus IFN demonstrates increased
potency when compared to naturally occurring type 1 IFNs. Comparisons
of the antiviral potency of glycol-variants with the parent
non-glycosylated consensus IFN and PEG-IFN alfa 2a using the VSV on
A549 cells are shown in the table below:
Statistical analysis of the EC50 values
obtained demonstrated that all glycol-variants retain similar
biological potency when compared to the consensus IFN molecule and all
are approximately 3 logs10 more potent when compared to PEG-IFN alfa 2a
(P<0.001 for all observation). Preliminary assessment of the
pharmacokinetic characteristics of the glycosylated variants
demonstrates an approximate 4-fold improvement in plasma exposure for
AUC and a significant improvement in serum half-life. These data
indicate that hyperglycosylation is a viable strategy to create a novel
type 1 IFN with improved PK characteristics without subsequent loss in
biological potency.
Based on the stage of development for Glycoferon, the Company estimates
the time to entering the clinical for the treatment of chronic
hepatitis C is approximately 18 months. It is important to note that
clinical development in this setting is well established for IFN-based
therapeutics and early clinical trials can demonstrate the utility of
drug candidates. Due to these factors the company plans to move rapidly
into a population of chronic Hepatitis C patients who are PEG-IFN plus
ribavirin NR to demonstrate the potential for viral kinetic effects in
these patients who previously failed to have log10 reductions of HCV
RNA following PEG-IFN + ribavirin combination therapy. Demonstration of
significant viral kinetic reductions in this patient population would
be a value creating event for the Glycoferon product as early viral
load reductions in chronic hepatitis C patients are predictive of
sustained virological responses (SVR). |
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