Perry Pharma Development Pipeline
Introduction:
Perry Pharma Research & Development (PP-R&D) has been investigating Selective Oestrogen Receptor Molecules (SERM) for potential development that will be effective in both breast and uterine cancer as part of its drug pipeline.
Early clinical testing of PKWT and PKWX, for which PP holds Australian patents (66633 –PKWT and 44455 – PKWX) for, indicates significant improvement in their selectivity, clinical outcomes and safety profiles when compared to the current SERMs. Thus, providing an assessment of the development considerations including efficacy, safety, therapeutic indications and potential market share would aid PP in making decisions concerning the development of these molecules.
This information is now vital due to a potential infringement of patent 66633 – PKWT, by HCH who manufacture ‘Tamax’, and are about to launch the successor ‘Pro-tam’. PP-R&D has analysed samples of ‘Pro-tam’, which has been identified as PKWT. Because of the impending launch, PP-Legal is including recommendations for dealing with this infringement within this review.
Selective Oestrogen Receptor Modulators
Cancers that grow in response to oestrogen are termed ‘ER-positive’. Oestrogen receptor positive cancers growth is modulated by oestrogen binding at the oestrogen receptor (ER). These ER are located in breast, bone, central nervous system and uterine tissues. SERMs action in the body 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 blocking of the action of oestrogen in a specific tissue such as the breast or uterus is responsible for anti-cancer action of a SERM (Fabian 2005, Maximov 2013).
PP is interested in developing PKWT and PKWX for these ER-positive cancers.
Treatment of ER-positive cancer:
ER 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, Sledge 2014). Compound choice is dependent on the patient population, and the associated treatment period may last up to 10 years (ACOG 2014, Sledge 2014).
In uterine and endometrial cancers SERMs are less utilized, (Burke 2003, ACS 2014b,c). Tamoxifen has shown some efficacy, however the Product Information does not list endometrial and uterine cancer within the indications; these are included in the Precautions section (eBS 2014, ACS 2014b, c).
Highly selective SERMs are being developed to reduce off target action and improve safety profile, through exploiting the receptor subtypes. (Jordan 2004, Maximov 2013). However biological agent based therapies for breast and uterine cancers (Fabian 2005) make the future for SERMs unclear.
Issues in the development of PKWT & PKWX:
Indications:
PP needs to be strategic in the selection of indications to pursue. This will dictate not only the size of the treatable population and the amount of clinical data required for the registration dossier but also potential return 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 have shown high selectivity as well as good safety and clinical outcomes in women of all ages compared to current SERMs and establish these compounds within an already crowded market.
First, PP can position development of a ‘one tablet for both breast and uterine indications for all ages’. Although this will mean a complex and costly clinical development plan, it entails a potentially a larger population to treat due to the wider indications.
Second, PP may take a different approach aiming for a specific indication such as the ER positive breast cancer in post-menopausal women, but limiting the treatable population. It is worth noting importantly that there are no SERMs with approved indications for uterine or endometrial cancer, despite phase II trials (Munster 2006), which indicates a potential gap in the market. PP could launch the first SERMs indicated for ER-positive uterine cancer. PP will need rates of ER positive uterine cancer to determine the available market to ensure return on investment and determine any potential competition through patent searches.
The third option is to enter the market leveraging the structural novelty of PKWX active metabolite, with improved outcomes and safety. This may provide a compelling case for prescribers to switch treatment options.
Efficacy
PKWT and PKWX have both shown good clinical outcomes for both breast and uterine cancer. They are 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 have been shown to be effective against osteoporosis, keeping lipid profiles favourable, aiding in the reduction in symptoms of menopause, cardio-protectivity and risk 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 loss 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 period of treatment to achieve clinical outcomes.
Safety
Due to the pharmacological action of SERM’s acting as either agonists or antagonists at the ER, negative secondary effects can occur. SERMs safety profile includes development of endometrial abnormalities, increased risk of endometrial cancers, pulmonary venous thromboembolism’s and increased incidence of stroke (Pickar 2010, Qin 2013).
PKWT & PKWX have been found to have better safety profiles, due to the higher selectivity for breast and uterine ER’s, both acting as antagonists at these receptors. Tamoxifen has agonistic properties at uterine tissue which is linked to its use increasing the risk of uterine/endometrial cancers (Yilmaz 2013).
However no information has been provided on the adverse event profile known to date and no animal data on long term use associated with treatment length of current SERMs.
Market Share and Market Advantage:
‘Tamax’ is a recognised brand, (first patented 1978) with an established market; it is now the preferred treatment for breast cancer in pre-menopausal women. ‘Pro-tam’ which has reportedly an improved safety profile over the originator ‘Tamax’, already has an established brand and market. PP may become a direct competitor and will require a significant point of difference to change prescribing habits of clinicians.
The market advantage 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-too’ compound.
As a SERM to treat uterine cancer specifically, it would be a first. PP should consider pursuing compounds specifically into this new market, especially if there is the added advantage of treating breast cancer.
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 to be obtained, so PP can determine if there are any 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 Costs
As 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.
Legal:
PP-Legal has flagged potential PKWT patent infringement by HCH. The associated legal proceedings may add significant costs to the development budget and also effect development timelines.
‘Pro-tam’: Potential Patent Infringement?
HCH is launching ‘Pro-tam’, a prodrug that is claimed to be metabolised into ‘Tamax’. PP-R&D have analysed the metabolite and found it to be PKWT. PP-Legal advises pursuing this as a potential infringement by HCH on the PKWT patent and to ensure appropriate legal action is taken to avoid any adverse impact on further development of PKWT.
PP-Legal have suggested undertaking the following steps:

Review the ‘Pro-tam’ priority 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 2002:

PP-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 block the ‘Pro-tam’ launch by lodging a request for an interlocutory injunction. This will allow PP to restrain the allegedly infringing actions by HCH until settled in court (IP Australia 2012).

The justification would be based on the ‘Pro-tam’ patent not meeting 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 published 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 therefore be captured in the claims. If the PKWT structure is not listed and the PP-R&D can provide evidence 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, thus invalidating the patent (IP Australia 2012). Here the emphasis is on HCH proving the case otherwise.

PP-Legal suggests creating a further portfolio of surrounding patents for maximum protection of PP intellectual 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 original patent claimed a single isomer structure, which is not PKWT, nor was it described as racemic. The existence of other isomers was not common knowledge at the time of the patent application so HCH were likely unaware 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. Despite 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 mix 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 obvious to try to separate these.

Considering this information, PP could move to patent the PKWT isomer, on the basis that

Existence 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 in the art (i.e. not obvious) to separate the isomers and it is potentially useful in treating disease (IP Australia 2012).

Development Recommendations:
PP 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 to patent infringement, so this may be the better compound to pursue to avoid the legal route
Word Count 2118
References
American Cancer Society (2014a) Breast Cancer http://www.cancer.org/> (Accessed Aug2014)
American Cancer Society (2014b) Uterine Cancer http://www.cancer.org/> (Accessed Aug2014)
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) S40–S46. (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 23:1644-1655 (Accessed Aug2014)
Harris, T., Nicol, D., Gruen, N. 2013 Pharmaceutical Patents Review Report. Commonwealth 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_Issues_Paper_PharmaReview.pdf> (Accessed Aug2014)
Jordan VC (2004) Selective estrogen receptor modulation Concept and consequences in cancer. Cancer Cell Volume 5, Issue 3, p207–213. (Accessed Aug2014)
Maximov PY,Lee TM,Jordan VC (2013) The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol.2013 May;8(2):135-55 (Accessed Aug2014)
Munster PN (2006) Arzoxifene: the development and clinical outcome of an ideal SERM. Drug 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) 64–69. (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 premenopausal 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,Gönenç IM,Yilmaz E (2014) Genotoxicity of the some selective estrogen receptor modulators: a review. Cytotechnology.2014 Aug; 66(4):533-41.(Accessed Aug2014)
Personal Reflection
Starting this assignment I had no real knowledge of SERMs- I had a basic understanding 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 writing 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 oriented nature and love of deconstructing/reconstructing events and processes. I enjoyed the researching of case law and the practicalities of patents. I always enjoy doing the literature searches and review of papers, and the chance to delve into the legal terminology 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 liked 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 work sits strongly in the population health area, this early end of the development pathway is not really something that I am asked to consider 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.
Search Strategy

Keyword Wildcard Search: PubMed & Google Scholar

SERM, 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 Scholar

Pharmaceutical 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 of IP law and previous case law.
Referred back to Australian IP law to check proposal was sound.
Reviewed 9128 course notes to finalise ideas.