View source for Avicine

<!--Definition and medical uses-->
'''Avicine''', tested and developed by [[Sarepta Therapeutics|AVI BioPharma]], and also known as '''CTP-37''' was trialled as a possible [[cancer vaccine]] to treat a number of different [[cancer]]s.<ref name=":0">{{Cite journal|last=Adis Insight|date=15 January 2007|title=Cancer vaccine - AVI BioPharma|url=https://adisinsight.springer.com/drugs/800009467|journal=Adis Insight}}</ref> These included [[colorectal cancer]], [[pancreatic cancer]] and [[prostate cancer]].<ref name=":0" /> The treatment was trialled as and intended to be induced via [[intramuscular injection]]<ref name=":0" /> into the bloodstream, the location dependent on the treatment area.<ref name=":1">{{Cite web|last=Lilly|date=7 January 2001|title=AVI BioPharma Announces One-Year Survival Results from Phase II AVICINE Cancer Vaccine Study; Study Shows 'Substantial Survival Benefit|url=https://investor.lilly.com/news-releases/news-release-details/avi-biopharma-announces-one-year-survival-results-phase-ii|access-date=30 May 2020|website=Lilly}}</ref>
<!--Side effects and mechanism-->
Common [[side effect]]s during [[clinical trial]]s included [[fever]] and [[chills]] as experienced with many other conventional [[vaccine]]s.<ref name=":0" /> The vaccine operated by eliciting [[Antibody|antibodies]] against [[human chorionic gonadotropin]] (hCG) a cancer associated [[protein]] expressed by most [[cancer cell]]s, with the goal of prolonged survival for those affected.<ref name=":2">{{Cite web|last=Biopress Online|date=11 December 1998|title=AVI BioPharma announces additional data from multi-center phase II study of AVICINE in advanced colorectal cancer.|url=https://www.bioprocessonline.com/doc/clinical-trials-roundupweek-of-12477-0001|access-date=30 May 2020|website=Biopress Online}}</ref>
<!--History, society and culture-->
Avicine was originated by AVI BioPharma in the [[United States|USA]],<ref name=":2" /> who licensed the product to SuperGen.<ref name=":3">{{Cite web|last=Speits|first=Keith|date=12 April 2017|title=Sarepta Therapeutics Stock History: A Biotech Roller-Coaster Ride|url=https://www.fool.com/investing/2017/04/12/sarepta-therapeutics-stock-history-a-biotech-rolle.aspx|access-date=30 May 2020|website=Motley Fool}}</ref> However, due to delays in [[Clinical trial|clinical testing]], as a result of research difficulties, the owners of Avicine were forced to direct their attention to other areas being the investigation and treatment of cardiovascular and infectious disease indications.<ref name=":0" /><ref name=":3" />
== Medical Uses ==
Avicine never reached the [[Medical treatment|commercial treatment]] phase as research was discontinued on 15 January 2007.<ref name=":0" /> The cancers Avicine was designed to manage were, [[Pancreatic cancer|pancreatic]], [[Colorectal cancer|colorectal]] and [[prostate cancer]]. In a one-year, [[Phase II clinical research|Phase II]] Avicine cancer vaccine study, a group of [[patient]]s were treated with Avicine alongside the combination of [[Gemcitabine]] (Gemzar),<ref name=":1" /> the results yielding that Avicine could be induced alongside [[Gemzar]], in the [[prostate]] region. As the [[Phase III clinical research|3rd]] and [[Phase I clinical research|4th]] clinical trials were not done this was never done as a commercial treatment.<ref name=":0" />
== Contraindications and drug interactions ==
Patients who were [[Pregnancy|pregnant]] were not to be treated by Avicine, as it elicits [[Antibody|antibodies]] against [[Human chorionic gonadotropin|hCG]],<ref name=":0" /> a cancer associated [[Oncofetal antigen|oncofoetal protein]] that is also prevalent during the development of a child in the [[womb]].<ref name=":4">{{Cite journal|last1=Moulton|first1=Hong M.|last2=Yoshihara|first2=Paul H.|last3=Mason|first3=David H.|last4=Iversen|first4=Patrick L.|last5=Triozzi|first5=Pierre L.|date=July 2002|title=Active Specific Immunotherapy with a Beta-Human Chorionic Gonadotropin Peptide Vaccine in Patients with Metastatic Colorectal Cancer: Antibody Response Is Associated with Improved Survival1|url=https://pubmed.ncbi.nlm.nih.gov/12114402/|journal=8|volume=8|issue=7|pages=2044–2051|pmid=12114402|via=Clinical Cancer Research}}</ref>
As of 2007, due to the discontinued state of Avicine research, drug interactions have not been studied.<ref name=":0" />
== Adverse Effects ==
Results from a [[Multicenter trial|multi-center]] phase II study in test subjects with [[Colorectal cancer|metastatic colorectal cancer]] in USA exposed that of 64 patients some experienced [[fever]]s and [[chills]]. Overall, the [[vaccine]]s were tolerated well by the patients. 69% (55 of the 73 patients).<ref name=":4" />
== Key Development Milestones ==
=== Colorectal Cancer ===
After successfully completing a [[Phases of clinical research|Phases I and II]] trials for the use of Avicine in [[colorectal cancer]], a [[Phase III clinical trials|phase III]] licensing trail began to investigate Avicine as a first line treatment for [[colorectal]] patients alongside [[chemotherapy]] in January 2001.<ref name=":0" /> The trial was randomised where the patients would either receive Avicine in combination with chemotherapy or chemotherapy unaided. However, Phase III was discontinued as of 15 January 2007.<ref name=":0" />
=== Pancreatic Cancer ===
A [[Multicenter trial|multi-centre]] [[Phase II clinical research|Phase II]] clinical trial of Avicine was conducted by [[Sarepta Therapeutics|Avi Biopharma]], including 55 patients in the US. The trial was conducted 10 patients with [[pancreatic cancer]] saw positive results in a pilot phase II trial of Avicine.<ref name=":1" />
A plan was proposed to begin a phase III trial for patients with pancreatic cancer. However, in 2003 it was reported in order to do so an additional [[Corporate|corporate partner]] was needed for the trial to be instigated. Research was discontinued on 15 January 2007 as an additional corporate partner was found and phase II was still not complete.<ref name=":0" /><ref name=":1" />
=== Prostate Cancer ===
A phase I trial of Avicine was completed by Avi Biopharma in patients with [[prostate cancer]], however after this stage research was discontinued on 15 January 2007.<ref name=":0" />
== Drug Properties and Chemical Synopsis ==
[[Route of administration]]: [[Intramuscular injection|IM]]<ref name=":0" />
[[Pharmaceutical formulation|Formulation]]: unspecified<ref name=":0" />
[[Drug class|Class]]: [[Cancer vaccine|Cancer Vaccines]]<ref name=":0" />
[[Mechanism of action|Mechanism of Action]]: [[Immunomodulator]]; [[Immunostimulant]]<ref name=":0" />
[[ATC code|WHO ATC code]]: L03A-X (Other immunostimulants)<ref name=":0" />
[[Anatomical Therapeutic Chemical Classification System|EPhMRA code]]: L3A (Immunostimulating Agents Excluding Intereferons)<ref name=":0" />
== Chemistry of Avicine ==
The [[Chemical property|chemical]] and [[Physical property|physical properties]] of Avicine can be highlighted in the table below:<ref>{{Cite web|last=National Library of Medicine|date=24 April 2020|title=Compound Summary: Avicine|url=https://pubchem.ncbi.nlm.nih.gov/compound/Avicine#section=Computed-Properties|website=PubChem}}</ref>
{| class="wikitable"
!Property Name
!Property Value
|-
|[[Molecular-weight|Molecular Weight]]
|332.3 g/mol
|-
|XLogP3-AA
|4.4
|-
|[[Hydrogen bond|Hydrogen Bond Donor Count]]
|0
|-
|[[Hydrogen bond|Hydrogen Bond Acceptor Count]]
|4
|-
|Rotatable Bond Count
|0
|-
|[[Monoisotopic mass|Monoisotopic Mass]]
|332.092283 g/mol
|-
|[[Mass (mass spectrometry)|Exact Mass]]
|332.092283 g/mol
|-
|Heavy Atom Count
|25
|-
|[[Topological Polar Surface Area]] Count
|40.8 Å2
|-
|[[Formal charge|Formal Charge]]
|1
|-
|[[Complexity]]
|530
|-
|[[Covalent bond|Covalently Bonded Unit Count]]
|1
|-
|[[Canonicalization|Compound is Canocalized]]
|Yes
|-
|[[Isotope|Isotope Atom Count]]
|0
|-
|[[Stereocenter|Defined Atom Stereocenter Count]]
|0
|}
== Pharmacology ==
Avicine (CTP-37) is a peptide fragment of [[Human chorionic gonadotropin|Human chorionic gonadotropin (hCG)]], an [[Oncofetal antigen|oncofoetal protein]] expressed by most [[Cancer linearis|cancer lines]], the significant role of hCG being to ward off the [[immune system]], the same way cells of the developing [[foetus]] ward off the immune system. In some studies expressions of hCG in colorectal cancer has been positively correlated with reduced survival rates.<ref>{{Cite journal|last1=Kido|first1=A.|last2=Mori|first2=M.|last3=Adachi|first3=Y.|last4=Yakaya|first4=H.|last5=Ishida|first5=T.|last6=Sugi Machi|first6=K.|date=1996|title=Immunohistochemical expression of beta-human chorionic go-nadotropin in colorectal carcinoma.|url=https://pubmed.ncbi.nlm.nih.gov/9017956/|journal=Jpn. J. Surg|volume=26|issue=12|pages=966–70|doi=10.1007/BF00309954|pmid=9017956|s2cid=7330722|via=PubMed}}</ref> Two [[epitope]]s can be found in CTP-37 one of which is dominant and can elicit anti-bodies against hCG.<ref name=":0" />
By employing this ideology Avi Biopharma created a modulated form of CTP-37 (Avicine) containing an extra [[Peptide bond|peptide domain]], more specifically denoted as a loop peptide.<ref name=":0" /> The modulation of the earlier formulation was done to force the immune system to act against multiple epitopes, with the aim of improving the survival rate of individuals with cancer. The moderated formula of Avicine was built on the basis of a study that indicated patients exhibited prolonged survival when they responded to more than one vaccine epitope.<ref name=":4" />
The majority of the world's population have been vaccinated against diphtheria use [[diphtheria toxoid]] (DT), and was therefore used a [[Carrier-protein|carrier protein]] due to the significant data available on its effects as a vaccine. Also, the established [[immune response]] to DT was also believed to be important in encouraging an immune response to hCG peptides.<ref name=":0" />
== Therapeutic Trials ==
=== Colorectal Cancer ===
Phase I tests demonstrated a satisfactory [[safety profile]] of Avicine (CTP37-diphtheria toxoid/DT), whilst also establishing the [[Immunological|immunological activity]] of the drug.<ref name=":4" /> In the following Phase II study 77 patients with colorectal cancer were treated with Avicine using Active Specialised Immunization (ASI), the CTP37-DT, prompting [[Antibody|antibodies]] in patients experiencing cancers that expressed very high hCG levels.<ref>{{Cite journal|last1=Triozzi|first1=P. L.|last2=Gochnour|first2=D.|last3=Martin|first3=E. W.|last4=Powell|first4=J.|last5=Kim|first5=J. A.|last6=Young|first6=D. C.|last7=Lombardi|first7=J.|date=1994|title=Clinical and immunological effects of a synthetic beta-human chorionic gonadotropin vaccine.|url=https://pubmed.ncbi.nlm.nih.gov/21559734/|journal=Int. J. Oncol.|volume=5|issue=6|pages=1447–1454|doi=10.3892/ijo.5.6.1447|pmid=21559734|via=PubMed}}</ref> The patients were given the vaccine at week 0, 4, 10 and 16. Of the 77 patients 56 of those produced antibodies to [[Human chorionic gonadotropin|human chorionic gonadotrophin (hCG)]], in response to the vaccine. By [[intention-to-treat analysis]] it was observed that of the vaccinated patients the [[median]] survival was 34 weeks.<ref name=":2" /> The median survival of patients who those who did not produce antibodies from the vaccine was 17 weeks, whilst the patients who developed antibodies from the vaccine exhibited a median survival of 42 weeks.<ref>{{Cite web|last=Business Wire|date=5 May 2004|title=AVI BioPharma Announces First Quarter Financial Results|url=https://www.businesswire.com/news/home/20040505005299/en/AVI-BioPharma-Announces-Quarter-Financial-Results|access-date=30 May 2020|website=Business Wire}}</ref> Also, patients who developed median antibody levels (n=39) expressed higher survival rates than those who expressed antibody levels below the median value (n=38), where survival rates were 45 weeks and 24 weeks respectively (AVI BioPharma Inc.). Additionally, CTP-37 consists of two [[epitope]]s and those who responded to both epitopes demonstrated prolonged survival, with 65 weeks, compared to those who only reacted against one epitope who experienced a 39-week survival rate.<ref name=":4" /> Another randomised group was also given [[Pharmacia & Upjohn|Pharmacia-Upjohn's Camptosar]], where the subjects experienced a mean 35 weeks survival rate.<ref name=":0" /> Using this data AVI Biopharma formulated a new version of CTP-37 vaccine, which included another hCG peptide referred to as the loop peptide. Inclusion of the loop peptide is used primarily to modulate the dominance of the original substance, which would ideally force the immune system to react to the multiple epitopes, culminating with prolonged survival rates for colorectal cancer patients.<ref name=":4" />
=== Pancreatic Cancer ===
55 [[pancreatic cancer]] patients were included in a study which confirmed treatment with Avicine produces comparable survival rates to treatment with [[Gemcitabine]].<ref name=":1" /> A group was also tested with gemcitabine combined with Avicine, and expressed significantly better survival rates than those who were treated with either substance independently. Also, Gemcitabine did not affect the patients ability to have an immune response to Avicine's epitopes.<ref>{{Cite news|last1=Beauregard|first1=Colleen|last2=Fowler|first2=Andrew|date=2002|title=AVI BioPharma Announces 2001 Fourth Quarter And Full Year Financial Results|work=Waggener Edstrom Bioscience}}</ref>
Data from a [[Phases of clinical research|phase Ib]] study including ten patients with pancreatic cancer established the safety and value of the use of Avicine in the subjects.<ref name=":0" /> The patients survived for periods greater than 6 months, which were historical survival rates for patients with metastatic pancreatic cancer. During the phase II study, one patient survived greater than 20 months, three lived more than 11 months, and 4 out of 6 patients remaining exceeded the 5.3 month period of median historical survival for this disease in 2001.<ref name=":0" /> The median survival in the 10 pancreatic patients was equal to 33 weeks with the Avicine (CTP-37) vaccine.<ref name=":1" />
==References==
<references />
{{DEFAULTSORT:Avicine}}
[[Category:Vaccines]]
[[Category:Cancer vaccines]]
[[Category:Peptide vaccines]]