In the last couple of days a news report was put out on APOBEC3C and APOBEC3D.....two enzymes that cause problems for Lilly's gemzar (gemcitabine) in pancreatic cancer
Starpharma's DEP platform could possible solve this problem with Enzymatically Cleaved Linkers. It is possible to preferentially release a drug molecule at the location where a specific enzyme occurs by connecting the drug to the dendrimer with a linker that is subject to enzymatic degradation. Such locations include tumours where certain enzymes are commonly over-expressed.
As we all know DEP® gemcitabine is ready to go forward into phase 1 clinical trials, however due to Starpharma focus on conserving funds......the trial has been put on hold for the time being
Below is a post from some time ago that gives you some historical background on the drug
Sep 30, 2010
Starpharma Holdings Limited (ASX:SPL, OTCQX:SPHRY) today announced the signing of a collaborative research agreement with leading US pharmaceutical corporation Eli Lilly and Company.
The new agreement relates to a co-development program for one of Starpharma’s dendrimer-drug conjugates. Under the agreement Lilly will receive an option on the conjugate, will pay research fees to Starpharma and will conduct studies in animal models to advance the compound. The identity of the conjugate cannot be disclosed at this time due to confidentiality restrictions.
This latest announcement follows on from two previous agreements between the companies. In February 2010, Starpharma announced that its dendrimer drug delivery technology will be applied to enhance compounds in Lilly’s human pharmaceutical portfolio.
In May 2009 Starpharma and Lilly’s animal health division, Elanco, signed an agreement to develop new animal health products with enhanced properties.
“We are delighted that Lilly has chosen to expand the scope of its partnership with us once again,” said Dr Jackie Fairley, CEO Starpharma. “The agreement follows on from an initial evaluation in animal models of this conjugate by Lilly. Starpharma now looks forward to developing the compound as rapidly as possible with Lilly.”
Below is an announcement made by Starpharma in regards to it’s Dep version of Gemzar
Oct 31, 2019
DEP® gemcitabine outperforms Gemzar® in human pancreatic cancer model
Starpharma advances a new internal DEP® candidate, DEP® gemcitabine, into development
DEP® gemcitabine demonstrated significantly enhanced anti-tumour activity compared with Gemzar® (gemcitabine), both alone and in combination with Nab‑paclitaxel (Abraxane®, in a human pancreatic cancer model
Gemzar® (gemcitabine), used alone or in combination with Abraxane®,is the current standard of care therapy for pancreatic cancer
A patent has been filed for Starpharma’s proprietary DEP® gemcitabine, providing coverage to 2040
Starpharma) today announced results for its next internal development candidate, DEP® gemcitabine.
Starpharma’s proprietary DEP® gemcitabine demonstrated significantly enhanced anti‑tumour activity compared with Gemzar® (gemcitabine), both alone and in combination with Nab-paclitaxel (Abraxane® in a preclinical human pancreatic cancer model. This data has formed the basis of a new patent application, which will provide coverage over DEP® gemcitabine to 2040. DEP® gemcitabine is one of several internal DEP® candidates under preclinical development by Starpharma.
DEP® gemcitabine is a DEP® version of Lilly’s Gemzar® (gemcitabine) - a well-established anti-cancer drug, which had peak sales of US$1.7 billion. Gemzar® (gemcitabine) is one of the leading chemotherapeutic drugs used to treat pancreatic cancer. It can be administered as a monotherapy or in combination with other therapies such as Abraxane®.
DEP® gemcitabine demonstrated significantly improved anti-tumour activity, compared to Gemzar®, the standard form of gemcitabine, in the human pancreatic cancer xenograft model (p<0.0001). When used in combination with Abraxane®, DEP® gemcitabine significantly outperformed a combination of Gemzar® (gemcitabine) and Abraxane (p<0.005).
Pancreatic cancer is a leading cause of cancer death, with a 1-yr survival rate of 20%, and a 5-yr survival rate of only 7%, with current therapeutic approaches (gemcitabine and Abraxane® having significant bone marrow toxicities. An important attribute of DEP® products is a lack of bone marrow toxicities in both preclinical and clinical studies.
Dr Jackie Fairley, Starpharma CEO, commented: “We are delighted to be progressing yet another internal candidate through development and to have achieved such impressive results in this important cancer type with otherwise limited options for patients.”
Study Results
DEP® gemcitabine vs Gemzar® alone
DEP® gemcitabine showed significantly enhanced tumour inhibition as compared to standard gemcitabine (Gemzar® in this human pancreatic cancer (CAPAN-1) xenograft model (p<0.0001; figure 1).
Figure 1: Enhanced efficacy of DEP® gemcitabine, compared to standard gemcitabine, in a human pancreatic cancer model (CAPAN-1) DEP® gemcitabine + Abraxane® vs Gemzar® + Abraxane® combination
The anti-tumour effect of the DEP® gemcitabine + Abraxane® combination was significantly better than for the Gemzar® (gemcitabine) + Abraxane® combination (P<0.005).
Figure 2: Enhanced efficacy of DEP® gemcitabine + Abraxane®, compared to standard gemcitabine + Abraxane®, in a human pancreatic cancer model (CAPAN-1) Study Methods
The mouse xenograft study used CAPAN-1 human pancreatic cancer cells and was conducted for Starpharma by an internationally recognised translational cancer group. A xenograft study uses human cancer cells, which are then implanted in a mouse, and is a well‑established means of assessing efficacy of anti-cancer therapies before clinical trials.
Balb/c mice were inoculated subcutaneously with the human pancreatic cancer (CAPAN-1) cells (10 mice/group). Mice were dosed with saline (vehicle), DEP® gemcitabinemce-anchor[1], standard gemcitabine (Gemzar® (120 mg/kg) and Abraxane® (40mg/kg) IV on days 1, 10 and 18.
Tumours were measured twice weekly using electronic callipers. Tumour volume (mm3) was calculated as length (mm)/2 x width (mm)2. Tumour growth inhibition data was analysed in GraphPad Prism and statistical analysis of treatment groups v vehicle control was one-way ANOVA with Dunnets multiple comparison test. Statistical analysis between different groups was conducted via a one-way ANOVA with Sidaks multiple comparison test. The tumour volume data represent the mean ± standard error of the mean (SEM). Note: If error bars do not display on the graphs, they are not visible because they are shorter than the height of the symbol. About Gemzar® (Gemcitabine)
Gemzar® (gemcitabine) is a chemotherapy drug used to treat cancer of the pancreas, bladder, ovary and breast, and non-small cell lung cancer. Gemcitabine is used as a first-line treatment alone for pancreatic cancer, and in combination with Abraxane® for the treatment of metastatic Adenocarcinoma of the pancreas. Gemcitabine also has a role in the treatment of metastatic bladder cancer, advanced or metastatic non-small cell lung cancer, ovarian cancer and breast cancer. Myelosuppression is the principal dose-limiting toxicity with gemcitabine.
As you can see from the figures below once the patent expired for Gemzar annual revenue fell in a heap
For obvious reasons Lilly stopped reporting annual sales for 2012 onwards
GEMZAR REVENUE FOR LILLY IN US$ MILLIONS
Note that there are multiple generic versions of gemcitabine in the market today
Below is the list
Market research indicates CAGR (compound annual growth rate) of Gemcitabine to be in the order of 6-7%
If this is indeed true
A non generic version of Gemcitabine (Starpharma’s DEP® gemcitabine), based on calendar year 2022.
Assuming over the period of 2009 -2022 if there was no competition (ie no generic versions)
History lesson
Gemcitabine was first synthesized in Larry Hertel's lab at Eli Lilly and Company during the early 1980s. It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.
During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival time significantly, and it was approved in the UK in 1995 and approved by the FDA in 1996 for pancreatic cancers. In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved for metastatic breast cancer.
By 2008, Lilly's worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009. The first generic launched in Europe in 2009, and patent challenges were mounted in the US which led to invalidation of a key Lilly patent on its method to make the drug. Generic companies started selling the drug in the US in 2010 when the patent on the chemical itself expired. Patent litigation in China made headlines there and was resolved in 2010
FYI
It was about at the same time Lilly’s patent were just about to expire for Gemzar that Starpharma began a collaboration with them
Up until 2017 Lilly were mentioned with announcements by Starpharma in all of it’s news
However since then nada
One can suspect the human cancer drug Stapharma were working on in collaboration with Lilly was in fact Gemzar
Wonder what happened. Why did it go hush hush all of a sudden
Anyway Starpharma is just about to begin it’s 4th in house trial with this new formulation and I would not hesitate to suggest combinations as well
Or possibly with a partner
a list of some of the generic versions of Gembcitabine HCL
Some information on report put out on APOBEC3C and APOBEC3D.....two enzymes that cause problems for Lilly's gemzar (gemcitabine) in pancreatic cancer
MARCH 18, 2024
Editors' notes Researchers pinpoint issue that could be hampering common chemotherapy drug
by Anika Hazra, University of Toronto
Genome-wide CRISPR–Cas9 screens reveal modulators of gemcitabine sensitivity. Credit: Nature Cancer (2024). DOI: 10.1038/s43018-024-00742-z
Researchers at the University of Toronto's Donnelly Centre for Cellular and Biomolecular Research have found two enzymes that work against the chemotherapy drug gemcitabine, preventing it from effectively treating pancreatic cancer.
The enzymes—APOBEC3C and APOBEC3D—increase during gemcitabine treatment and promote resistance to DNA replication stress in pancreatic cancer cells.
This, in turn, counteracts the effects of gemcitabine and allows for the growth of cancer cells.
"Pancreatic cancer has proven to be very challenging to treat, as it is usually diagnosed at stage 3 or 4," said Tajinder Ubhi, first author on the study and a former Ph.D. student in biochemistry in U of T's Temerty Faculty of Medicine.
"It is the most lethal type of cancer in Canada, with an average survival time of less than two years. While chemotherapy with gemcitabine has increased survival by a few months in clinical trials, options for treatment of pancreatic cancer remain limited."
The findings were published in the journal Nature Cancer.
Replication stress is the key process by which gemcitabine stops cancer cells from continuing to multiply. It involves the dysregulation of DNA replication, which occurs when cells divide. Replication stress can transform a healthy cell into a cancerous one, but can also be activated within cancer cells to eliminate them.
Gemcitabine has been used for nearly three decades to treat a wide variety of cancers, including pancreatic, breast and bladder cancer. However, a downside of using gemcitabine to target dividing cells is that it can produce toxic side effects in tissues that aren't being targeted for treatment.
Ubhi and other members of Professor Grant Brown's lab at the Donnelly Centre have been trying to understand the possible causes of replication stress and its impacts. One way to do this is by studying the stress response mechanisms in cancer cells treated with gemcitabine.
"We conducted a genome-wide CRISPR screen to find genes that could increase the sensitivity of pancreatic cancer cells to gemcitabine," said Brown, professor of biochemistry at the Donnelly Centre and in the Temerty Faculty of Medicine, who is the principal investigator on the study.
"We were excited to identify APOBEC3C and APOBEC3D because other enzymes in the APOBEC3 family can cause cancers to eventually become resistant to treatment. We discovered a more direct role for the enzymes, where they actually protect pancreatic cancer cells from gemcitabine therapy."
Neither enzyme is naturally found in high concentrations within healthy or cancerous cells. The catch is that the replication stress the drug causes in pancreatic cancer cells in turn triggers an increase in both enzymes. The research team found that removing either APOBEC3C or APOBEC3D kills pancreatic cells by stymieing DNA repair and destabilizing the cell genome.
"What is most exciting is that the removal of just APOBEC3C or APOBEC3D is enough to stop the replication of gemcitabine-treated pancreatic cancer cells," said Ubhi. "This indicates that the enzymes could be effective new targets for treating this form of cancer." More information: Tajinder Ubhi et al, Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells, Nature Cancer (2024). DOI: 10.1038/s43018-024-00742-z
Provided by University of Toronto monkey brain during everyday tasks
MAR 15, 2024
, in a human pancreatic cancer model
(20min delay)
