Selective Oestrogen Receptor Molecules (SERM)

selective oestrogen Receptor Molecules (SERM)Lucy PerryPerry Pharma Development line of creditIntroductionPerry Pharma Research Development (PP-RD) has been investigating Selective oestrogen Receptor Molecules (SERM) for authorisation breeding that testament be effective in both(prenominal) breast and uterine genus malignant neoplastic disease as fragmentize of its medicate pipeline.Early clinical testing of PKWT and PKWX, for which PP holds Australian opens (66633 PKWT and 44455 PKWX) for, indicates significant improvement in their selectivity, clinical topics and natural rubber profiles when comp atomic number 18d to the certain SERMs. Thus, providing an assessment of the education circumstances including efficacy, safety, therapeutic indexs and capableness securities industry sh ar would aid PP in making decisions concerning the development of these molecules.This entropy is now vital due to a potential infringement of letters visible 66633 PKWT, by HCH who m anufacture Tamax, and are about to launch the successor Pro-tam. PP-RD has analysed samples of Pro-tam, which has been determine as PKWT. Because of the impending launch, PP-Legal is including recommendations for dealing with this infringement within this demarcation lineed review.Selective oestrogen Receptor ModulatorsCancers that grow in solvent to oestrogen are termed ER- ap dappleed. Oestrogen sense organ imperious crabby mortals growth is modulated by oestrogen cover song at the oestrogen sensory receptor (ER). These ER are located in breast, bone, central nervous system and uterine tissues. SERMs action in the proboscis is through agonism or antagonism at the ER, leading to both positive and negative effects depending on the tissue site. Antagonism of the ER and cube of the action of oestrogen in a circumstantial tissue much(prenominal)(prenominal) as the breast or uterus is trustworthy for anti- pubic louse action of a SERM (Fabian 2005, Maximov 2013).PP is inte rested in developing PKWT and PKWX for these ER-positive malignant neoplastic diseases.Treatment of ER-positive cancerER positive cancers are one of the most common forms of breast cancer subtype (ACS 2014a). SERMs are used as primary, combination or adjuvant therapy for cancers expressing the ER receptor (Yilmaz 2013, ACOG 2014, maul 2014). Compound choice is dependent on the patient population, and the associated handling period may last up to 10 days (ACOG 2014, Sledge 2014).In uterine and endometrial cancers SERMs are less utilized, (Burke 2003, ACS 2014b,c). Tamoxifen has shown rough efficacy, however the Product Information does non list endometrial and uterine cancer within the indications these are included in the Precautions surgical incision (eBS 2014, ACS 2014b, c). exceedingly selective SERMs are creation developed to reduce off address action and improve safety profile, through exploiting the receptor subtypes. (Jordan 2004, Maximov 2013). just biological agent b ased therapies for breast and uterine cancers (Fabian 2005) make the future for SERMs unclear.Issues in the development of PKWT PKWXIndicationsPP needs to be strategic in the selection of indications to conform to. This give dictate non hardly the size of the treatable population and the amount of clinical information required for the registration dossier but also potential event on investment. It will also play a significant part in whether the compounds are listed on the Pharmaceutical Benefits Scheme (PBS)PKWT and PKWX both stand shown high selectivity as well as good safety and clinical moments in women of all ages compared to current SERMs and establish these compounds within an already crowd mart.First, PP can position development of a one tablet for both breast and uterine indications for all ages. Although this will mean a Byzantine and costly clinical development plan, it entails a potentially a big population to treat due to the wider indications.Second, PP may take a contrasting approach aiming for a specific indication much(prenominal) as the ER positive breast cancer in post-menopausal women, but limiting the treatable population. It is outlay noting importantly that in that respect are no SERMs with approved indications for uterine or endometrial cancer, despite phase II trials (Munster 2006), which indicates a potential spreadhead in the trade. PP could launch the initiative SERMs indicated for ER-positive uterine cancer. PP will need place of ER positive uterine cancer to determine the available market to hold return on investment and determine some(prenominal) potential competition through patent searches.The third option is to enter the market leveraging the structural novelty of PKWX active metabolite, with modify outcomes and safety. This may abide a compelling case for prescribers to switch intercession options.EfficacyPKWT and PKWX stick both shown good clinical outcomes for both breast and uterine cancer. They a re also highly selective, which is an important consideration so that off-target action is minimised which responsible for the safety profile of the current SERMs (discussed in safety section)A consideration for prescribers is the secondary effects of oestrogen treatment. SERMs rent been shown to be effective against osteoporosis, retentiveness lipid profiles favourable, aiding in the reduction in symptoms of menopause, accountio-protectivity and essay prevention of cancer (Maximov 2013, Munster 2006, Pickar 2010). PKWT and PKWX must show some of these positive secondary effects to be competitive. Prescribers will not switch to SERMs which can lead to the same outcome but leave a patient worse off e.g. from button of bone minerals or exacerbation of menopausal symptoms.Length of treatment with SERMs such as Tamoxifen can be up to 10 years to ensure optimal clinical outcomes for patient (ACOG 2014). PP needs to investigate whether PKWT or PKWX requires the same significant peri od of treatment to achieve clinical outcomes.SafetyDue to the pharmacological action of SERMs acting as all agonists or antagonists at the ER, negative secondary effects can occur. SERMs safety profile includes development of endometrial abnormalities, increased risk of endometrial cancers, pulmonic venous thromboembolisms and increased incidence of stroke (Pickar 2010, Qin 2013).PKWT PKWX have been rear to have better safety profiles, due to the higher selectivity for breast and uterine ERs, both acting as antagonists at these receptors. Tamoxifen has laboured properties at uterine tissue which is linked to its use increasing the risk of uterine/endometrial cancers (Yilmaz 2013).However no information has been letd on the unfavorable event profile known to involution and no animal data on long term use associated with treatment length of current SERMs.Market Share and Market AdvantageTamax is a recognised brand, (first patent 1978) with an established market it is now the p referred treatment for breast cancer in pre-menopausal women. Pro-tam which has reportedly an modify safety profile over the agent Tamax, already has an established brand and market. PP may become a betoken competitor and will require a significant point of contravention to change prescribing habits of clinicians.The market emolument within the breast cancer treatment arena may be the improved safety and clinical outcome however PP needs to consider whether it wants to produce a me- similarly compound.As a SERM to treat uterine cancer specifically, it would be a first. PP should consider act compounds specifically into this new market, especially if there is the added advantage of treating breast cancer. once again PP should consider the structural novelty of the PKWX metabolite as well as improved safety and clinical outcome as a market advantage to attract clinicians and gain some ground in the ER-positive breast cancer market.Regions in which Tamax has been launched needs t o be obtained, so PP can determine if there are each new markets, and if there are regional specific factors such as the PBS. Pricing strategy and treatment indications will be important in these markets.Investment CostsAs part of the review process there needs to consideration of the level of return on investment. PP need to be sure that if development goes forward they have a treatable population and potential to gain market share or market advantage.PP may wish to consider attempting to out-license the compounds if the development costs prove too much of an investment.LegalPP-Legal has flagged potential PKWT patent infringement by HCH. The associated reasoned proceedings may add significant costs to the development cipher and also effect development timelines.Pro-tam Potential Patent Infringement?HCH is entry Pro-tam, a prodrug that is championshiped to be metabolised into Tamax. PP-RD have analysed the metabolite and found it to be PKWT. PP-Legal advises pursuing this as a p otential infringement by HCH on the PKWT patent and to ensure appropriate legal action is taken to avoid either perverse impact on further development of PKWT.PP-Legal have suggested undertaking the following stepsReview the Pro-tam precedency date to ensure that it is dated after the PKWT priority date (25 April 2002).If the Pro-tam patent does have a priority date prior to 25 April 2002PP-Legal will review the Pro-tam patent to determine any grounds to challenge its validity or navigate around the patent.Applying for a patent on PKWT for uterine cancer. This will require negotiation of a licensing agreement with HCH.PP transfers its efforts to the development of the more novel PKWX.If the patent for Pro-tam was lodged after the priority date for PKWT,PP has grounds to pursue patent infringement and attempt to check the Pro-tam launch by lodging a request for an interlocutory injunction. This will grant PP to restrain the allegedly infringing actions by HCH until settled in a postrophize (IP Australia 2012).The justification would be based on the Pro-tam patent not coming together the novelty criteria as the chemical structure of Pro-tam is listed as part of the PKWT claim scope (IP Australia 2012). HCH legally can patent the prodrug, but at the point of metabolism, the PKWT patent is infringed. PP-Legal have previously determined PKWT does not exist in produce prior art.A patent on a prodrug and its metabolites is only valid if all conditions of patent validity are met. The Pro-tam active metabolite structures should indeed be captured in the claims. If the PKWT structure is not listed and the PP-RD can provide register that PKWT is the active metabolite, there are grounds to claim falsification of aspects of the patent, as HCH has not disclosed all claim details into the public domain, olibanum invalidating the patent (IP Australia 2012). Here the emphasis is on HCH proving the case otherwise.PP-Legal suggests creating a further portfolio of surro unding patents for maximum protection of PP capable property and allow for further development of the SERM pipeline.The Tamax patent has since lapsed, however, for completeness, PP-Legal have provided potential actions for PP to still patent PKWT if the Tamax patent was still valid.The reliable patent claimed a single isomer structure, which is not PKWT, nor was it described as racemic. The existence of other isomers was not common companionship at the time of the patent application so HCH were likely insensible that the structure listed in the claim scope had isomers.Between 1996 2000 journal articles were published discussing the discovery of isomers of compounds that may confer improved efficacy and safety profiles. disdain these articles being in the public domain, HCH did not move to patent any potential isomers of Tamax.If a compound is described as a racemic mess up in the aspects and that patent is challenged, court rulings in previous legal cases have stated that it is considered common knowledge that racemic mixtures may contain isomers with different properties and that it is manifest to try to separate these.Considering this information, PP could move to patent the PKWT isomer, on the basis that instauration of different isomers of compounds was not common knowledge at the time of the original Tamax patent so the argument of obviousness that the patent would cover the PKWT isomer cannot be made by HCH (IP Australia 2012). If HCH had claimed a generalised formula for Tamax type compounds, PP would be infringing (Harris 2013).Information on differences in efficacy and safety of undiscovered isomers has been in the public domain since 1996 and HCH still did not move to patent any isomers.Separation of isomers is possible by skilled practitioners since technological advancements have occurred.Conditions of patent validity can be met by PP PKWT is novel as it is not described in prior art, it is inventive in that it requires a person skilled i n the art (i.e. not obvious) to separate the isomers and it is potentially profitable in treating disease (IP Australia 2012).Development RecommendationsPP needs to consider which indications to pursue as it will affect the size and cost of the clinical development programme. The improved clinical outcome and safety, as well as selectivity, can provide market advantage in both indications. However, a breast cancer me-too drug may not be successful in obtaining a PBS listing which is crucial to success of a medicine in the Australian market.The PKWT patent infringement proceedings may affect development schedules and add significant cost. Whereas PKWX has a novel structure that is not subject matter to patent infringement, so this may be the better compound to pursue to avoid the legal routeWord Count 2118ReferencesAmerican Cancer Society (2014a) Breast Cancer http//www.cancer.org/ (Accessed Aug2014)American Cancer Society (2014b) uterine Cancer http//www.cancer.org/ (Accessed Aug2 014)American Cancer Society (2014c) Endometrial Cancer http//www.cancer.org/ (Accessed Aug2014)American College of Obstetricians Gynaecologists (2014) Committee Opinion Tamoxifen and Uterine Cancer. www.acog.org (Accessed Aug2014)Burke TW Walker CL (2003) Arzoxifene as therapy for endometrial cancer Gynaecologic Oncology 90 (2003) S40S46. (Accessed Aug2014)eBS (2014) TGA Nolvadex Product Information. Astra Zeneca 2013 https//www.ebs.tga.gov.au (Accessed Aug2014)Fabian CJ Kimler BF (2005) Selective Estrogen-Receptor Modulators for Primary Prevention of Breast. CancerJ Clin Oncol 231644-1655 (Accessed Aug2014)Harris, T., Nicol, D., Gruen, N. 2013 Pharmaceutical Patents Review Report. area Government of Australia.http//www.ipaustralia.gov.au/pdfs/2013-05-27_PPR_Final_Report.pdf (Accessed Aug2014)IP Australia (2012) Pharmaceutical Patents Review Background issues and suggested Issues Paper. Commonweath Government of Australia www.ipaustralia.gov.au/pdfs/Background_and_Suggested_Iss ues_Paper_PharmaReview.pdf (Accessed Aug2014)Jordan VC (2004) Selective estrogen receptor modulation Concept and consequences in cancer. Cancer cellular telephone Volume 5, Issue 3, p207213. (Accessed Aug2014)Maximov PY,Lee TM,Jordan VC (2013) The discovery and development of selective estrogen receptor modulators (SERMs) for clinical charge. Curr Clin Pharmacol.2013 May8(2)135-55 (Accessed Aug2014)Munster PN (2006) Arzoxifene the development and clinical outcome of an ideal SERM. dose Evaluation March 2006, Vol. 15, No. 3 , Pages 317-326. (Accessed Aug2014)McMeekin DS, Gordon A, Fowler J, Melemed A, Buller R, Burke T, Bloss J, Sabbatini P (2003) A phase II trial of arzoxifene, a selective estrogen response modulator, in patients with recurrent or advanced endometrial cancer. Gynecologic Oncology 90 (2003) 6469. (Accessed Aug2014)Qin T, Yuan ZY, Peng RJ, Zeng YD, Shi YX, Teng XY, Liu DG, Bai B Wang SS (2013) Efficacy andtolerability of toremifene and tamoxifen therapy in premen opausal patients with operable breast cancer a retrospective analysis. Curr Oncol, Vol. 20, pp. 196-204 (Accessed Aug2014)Pickar JH, MacNeil T Ohleth K (2010) SERMs Progress and future perspectives Maturitas Volume 67, Issue 2, Pages 129-138, October 2010 (Accessed Aug2014)Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ Wolff AC, (2014) Past, Present, and Future Challenges in Breast Cancer Treatment Journal of Clinical Oncology, Vol 32, No 19 (July 1), 2014 pp 1979-1986 (Accessed Aug2014)Yilmaz S,Gnen IM,Yilmaz E (2014) Genotoxicity of the some selective estrogen receptor modulators a review. Cytotechnology.2014 Aug 66(4)533-41.(Accessed Aug2014) individualised ReflectionStarting this assignment I had no real knowledge of SERMs- I had a basic reasonableness of the use of tamoxifen so building background knowledge was a prompt learning curve. However, such events are to be expected in all professional practice and simply enable improvement.When I think about the wri ting and the researching of this assignment, I can say that I found the intellectual property section the most challenging and intellectually stimulating area, as it resonated with my detail lie nature and love of deconstructing/reconstructing events and processes. I enjoyed the researching of case law and the practicalities of patents. I ever enjoy doing the literature searches and review of papers, and the chance to delve into the legal oral communication pushed me outside my comfort zone.The drug development side of the assignment was not so interesting to me. I would put this down to the word limit not really allowing for much exploration of the area. I would have wish to explore market share and the epidemiological basis and strategy of selecting an indication/s for these compounds in a much more detailed review.Because of my piece of work sits strongly in the population health area, this early end of the development pathway is not really something that I am asked to conside r often. However from the viewpoint of building a personal knowledge base and being able to provide answers to my direct reports regarding the drug development process in a more holistic manner, this assignment has been of help. reckon StrategyKeyword Wildcard Search PubMed Google ScholarSERM, oestrogen receptor modulator, ER breast cancer, ER uterine cancer, ER endometrial cancer, tamoxifen, hormonal cancer,Obtained literature centred on these wild card searches.Reviewed the literature to build a knowledge base to write the first half of the assignment.Reviewed 9128 course notes to finalise ideas.Keyword Wildcard search Google Google ScholarPharmaceutical Patents, enantiomer patents, isomer patents, isomer legal cases, patent portfolios, patent law Australia, pharmaceutical patent cases Australia, intellectual property law Australia, Obviousness, inventiveness.Obtained literature and websites centred around these wildcard searches,Reviewed the literature to build understanding o f IP law and previous case law.Referred back to Australian IP law to check proposal was sound.Reviewed 9128 course notes to finalise ideas.