Written by: Matt Killeen

SUMMARY
In June 2010, Bristol Myers Squibb and Pfizer announced that they are halting the Phase III AVERROES trial of apixaban for stroke prevention in atrial fibrillation (SPAF) due to the drug’s greater efficacy over aspirin. Results from this trial, which have not yet been disclosed, could trigger an earlier than expected filing for an AF indication in the United States and Europe, and alter the competitive landscape of the SPAF market.

ANALYSIS
Apixaban is one of a handful of agents in late stage development vying to fill the large unmet need of a safe and effective novel oral anticoagulant with significant benefits over warfarin. Warfarin’s effectiveness is offset by its drawbacks, which include a risk of bleeding, regular dose adjustment and patient monitoring. With its risk/benefit profile proven in the setting of VTE prevention, and its low renal clearance, apixaban has the potential to herald a new era in stroke prevention.

The aim of the AVERROES study was to assess the effectiveness of apixaban in AF patients who have failed or are unsuitable for warfarin treatment; these patients are typically assigned either aspirin alone or in combination with clopidogrel to reduce their stroke risk. The primary efficacy endpoint in AVERROES was stroke or systemic embolism, whereas the primary safety outcome was major bleeding.

BMS/Pfizer very recently announced that they would be halting the AVERROES study because an interim analysis of the study “revealed clear evidence of a clinically important reduction in stroke and systemic embolism in patients with atrial fibrillation considered intolerant of or unsuitable for vitamin K antagonist therapy.” As a result of this development the companies could seek approval for an AF indication earlier than expected, and BMS’ CEO is reportedly considering whether these data will be adequate for U.S. regulatory approval.

We do not consider approval of apixaban for an AF indication at this stage to be a likely scenario for a number of reasons. Firstly, from a regulatory standpoint, we do not expect that positive data from AVERROES alone will be sufficient for approval in an AF indication. AVERROES was a relatively small trial with only 5,600 patients enrolled; Pradaxa’s RELY trial studied over 18,000 patients. Additionally, given regulator’s experience with AstraZeneca’s Exanta, whose development was discontinued after liver safety signals were detected, we expect the FDA and European Medicines Agency to demand a considerable body of long term safety data from a much larger sample of patients.

Finally, an earlier approval could result in the drug competing with Pradaxa, and at this stage in apixaban’s development this will be difficult; Pradaxa’s strong results from the RELY trial, which studied the drug at low and high doses to yield superior safety and efficacy effects over warfarin, have fuelled physician enthusiasm for the drug. We also expect that BMS/Pfizer will face an uphill struggle in driving sales of the drug without any head-to-head warfarin comparator data (apixaban’s ARISTOTLE trial, which is a noninferiority trial against warfarin, is due to finish in April 2011), even in the warfarin intolerant sector of the SPAF market.

We expect BMS/Pfizer to seek approval of apixaban for SPAF upon completion of the large ARISTOTLE trial (this has enrolled 18,183 patients), and we anticipate a first launch of the drug in 2012. Combining data from AVERROES and ARISTOTLE will create a powerful value proposition for the drug by demonstrating its efficacy and safety across a broad spectrum of patients. In a market facing the entry of at least 8 novel oral anticoagulants for SPAF, product differentiation strategies will play an increasingly important role for the novel oral anticoagulants.

Written by: Ben Duncan

SUMMARY
At this year’s American Diabetes Association (ADA) conference we will be paying particularly close attention to Roche’s once-weekly injectable GLP-1 analogue, taspoglutide, AstraZeneca & Bristol-Myers Squibb’s SGLT-2 inhibitor dapagliflozin, and Novo Nordisk’s next generation insulin analogue, Degludec, in order to determine their positioning in the market.

ANALYSIS
Taspoglutide: Data from five pivotal Phase III trials for taspoglutide will be presented (T-Emerge 1, 2, 4, 5 and 7), which assessed the drug in a variety of different treatment contexts. With efficacy data comparable to other long-acting GLP-1 analogues, safety is a key focus; strong nausea data in particular will confer significant upside to our forecasts.

Dapagliflozin: Data from a late-breaking year-long Phase III trial for dapagliflozin in patients uncontrolled on insulin therapy will be presented. We will be concentrating on infection rates; if rates are pushing above 10% (placebo-controlled) this safety feature could become a significant drag to dapagliflozin’s market penetration.

Degludec: This year’s ADA will provide the first look at Novo Nordisk’s next generation insulin analogue, Degludec, in comparison to market leading basal insulin, sanofi-aventis’ Lantus. Phase II data reportedly demonstrates that Degludec thrice-weekly is comparable to Lantus over 16 weeks. This drug is therefore shaping up to be a potential blockbuster; further Phase III data is awaited with interest.

Written by: Kiran Meekings

SUMMARY
With few treatment options and a poor prognosis, ovarian cancer represents a considerable opportunity for drug developers. Currently available chemotherapeutic agents have little impact on improving the prognosis of patients whilst ovarian cancer is one of the few indications with no approved targeted therapies.  However, this may be set to change following the presentation of positive clinical trial results at ASCO.  We anticipate Roche’s Avastin will be approved for the first-line ovarian cancer setting in 2011, adding $1bn to the drug’s sales, whilst encouraging results of Amgen’s AMG386, Eisai’s farletuzumab, AstraZeneca’s olaparib and Sunesis’ voreloxin call for further development.  If the early-stage promise of these first-in-class compounds is substantiated in Phase III, we would anticipate the ovarian cancer market expanding significantly during our forecast period.

ANALYSIS

• The much-awaited results of Avastin in ovarian cancer were presented yesterday in the plenary session at ASCO.  The results demonstrated that treatment of newly-diagnosed ovarian cancer with chemotherapy and Avastin, followed by maintenance Avastin, significantly improved progression-free survival (PFS): The risk of progression decreased by 28% compared to chemotherapy alone.
• We anticipate these results will pave the way for approval of Avastin in both the US and EU for induction and maintenance use in the newly diagnosed ovarian cancer population.  We expect that approval in this setting will add nearly $1bn in sales in 2016.
• Phase II results of Amgen’s first-in-class Ang1 and Ang 2-inhibiting peptibody, AMG386, were presented today, Monday, at ASCO.  Angiopoietin molecules are known to interact with Tie2 and are pivotal players in the angiogenic process.  Thus, inhibition of the angiopoietin-Tie2 interaction may be a new strategy in the fight against metastatic cancer.
• The results showed that AMG 386 combined with weekly paclitaxel was highly efficacious and tolerable, with a manageable safety profile.  PFS, the primary endpoint, significantly increased from 4.6 months with placebo to 7.2 months in the high-dose AMG 386 arm, suggesting further development of the compound was warranted.  Phase III trials are in planning.
• Final Phase II data of farletuzumab in platinum-sensitive relapsed ovarian cancer were also presented.  Farletuzumab is an antibody against folate receptor alpha, which is over-expressed in approximately 90% of ovarian cancers. The Phase II trial involved treating patients with both monotherapy and combination farletuzumab.  There was a marked response to the drug, with 89% of patients exhibiting normalization of their CA-125 levels and an overall response rate (ORR) of 70%.  The compound is currently being investigated in Phase III trials in the same setting.
• PARP inhibitors have been touted for their potential in BRCA-mutated and serous ovarian cancer.  However, all studies to-date have only shown an effect when combined with chemotherapy.  However, results presented at ASCO on Saturday demonstrated that monotherapy olaparib is also an active therapy in high-grade serous ovarian cancer, regardless of BRCA mutation status.  This was shown not to be the case in breast cancer, where monotherapy olaparib did not exert an efficacious effect.  This positive result has the potential to expand the PARP inhibitor market and provide another treatment option for ovarian cancer patients.
• Lastly, positive data was also reported for the first-in-class quinolone derivative voreloxin in platinum-resistant ovarian cancer.  The ORR of 11%, 12 week disease control rate of 48% and PFS of 84 days was in line with results produced by pegylated liposomal doxorubicin in the same setting.  Adverse events were manageable although a 9% rate of febrile neutropenia will require careful monitoring of patients.  However, the great unmet need in this population of patients and encouraging efficacy data encourages further development.

Written by: Kiran Meekings

SUMMARY
A wealth of data presented at ASCO is adding credibility to the idea of using Prolia as a superior treatment option to Zometa in the treatment of skeletal related events (SREs).  Over multiple studies, Prolia has consistently demonstrated superiority to Zometa in prostate cancer, breast cancer and multiple myeloma.  Current controversy surrounds the idea of using bone-resorption inhibitors as a therapeutic treatment option but positive data presented at ASCO showed Zometa to have a direct anticancer effect in multiple myeloma (positive data in breast cancer will also be presented tomorrow), which could be a positive indicator of the bone-resorption inhibitor class as a whole. Although we see little upside for Zometa, due to its near-term patent expiry, we note that approval of Prolia for in the coveted therapeutic indication; prevention of metastases, could add over $1bn to our current forecast for Prolia of $697 in oncology sales in 2016.

ANALYSIS

• With last week’s approval of Amgen’s Prolia for hormone-associated bone loss in the EU (approval pending in US) and last month’s filing in the US for the prevention of skeletal related events (SREs) in prostate cancer, all eyes were on the Prolia presentations and posters at ASCO in order to gauge its positioning in the market.
• Data presented today, Sunday, at ASCO positioned Prolia as superior to Zometa for the prevention of SREs in prostate cancer and will ensure rapid uptake upon launch. Decision Resources anticipates the drug will garner $697m in sales in 2016 for Amgen / Daiichi-Sankyo for the prevention and treatment of bone loss and SREs.
• In the study of nearly 2000 prostate cancer patients with at least one bone metastasis, Prolia significantly delayed the time to first-on-study SRE compared with Zometa by 18% (or 3.6months). The rate of adverse events was similar in both drugs; the largely publicised osteonecrosis of the jaw (ONJ) effect presented in 2.3% of those treated with Prolia, compared to 1.3% of those treated with Zometa.
• Although this trial was not powered to look at effect on overall survival and time to cancer progression, the two measures were similar between treatment arms, which may be indicative of a negative outcome for the much-awaited metastasis-prevention ‘147 trial; data from which is expected later this year.
• We note that a meta-analysis of two previously-reported studies investigating Prolia versus Zometa (one in advanced solid tumours and one in breast cancer) and results from a study looking at effects of the two drugs on health-related quality of life (HRQL) in breast cancer were presented on Friday and also position Prolia positively against Zometa.
• Other posters to be displayed tomorrow will demonstrate a significant lengthening of time to first SRE when comparing Prolia to Zometa in the treatment of bone metastases in patients with advanced cancer or multiple myeloma whilst another poster will show that Prolia prolonged time to pain worsening compared to Zometa in the same set of patients.
• We believe all this collective data cements Prolia’s as a superior treatment option to Zometa.
• An ongoing topic of discussion is whether bone-resorption inhibitors have a direct anticancer effect. Novartis filed Zometa in December 2009 for use in the adjuvant setting with the goal of preventing the development of bone metastases in pre-menopausal breast cancer patients.  Full mature data from the ABCSG-12 trial will be presented at ASCO tomorrow but initial data presented in the abstract show that overall, Zometa reduced the risk of death by 34% thus supporting a direct anticancer role.
• In support of an anticancer effect, an MRC-sponsored trial presented today demonstrated that Zometa exerted a direct anticancer effect in multiple myeloma (MM) and improved overall survival.  Compared to Bayer’s Bonefos (clondronate), Zometa significantly improved OS by 5.5 months (to 50 months) and PFS by 2 months (to 19.5 months). The OS benefit was maintained after adjustment for the direct deleterious effects of SREs on survival. Although we see little sales-upside for Zometa due to the product’s imminent patent expiry, these results add credibility to the idea of using bone-resorption inhibitors as a therapeutic treatment option.

Written by: Kiran Meekings

SUMMARY
Positive data reported today and yesterday at ASCO have expanded the market potential of Revlimid and Rituxan to include first-line maintenance settings in multiple myeloma (MM) and follicular lymphoma (FL) respectively.  Use of Revlimid is currently limited to the second-line MM setting whilst Rituxan is used in the first-, second- and second-line maintenance FL settings.  Approval of both compounds for first-line maintenance therapy will expand the respective drug’s sales bases, as well as the whole market due to a lack of current treatment options.

ANALYSIS

• Revlimid and Velcade currently dominate the treatment of multiple myeloma (MM).  While we believe that these two drugs will continue to be the standard of care in the medium term, we believe emerging data could change treatment patterns and sales of the respective drugs.
• Today at ASCO, positive data from two studies were reported demonstrating Revlimid is a beneficial treatment option for the 45% of newly diagnosed patients in the US and 30% in Europe that receive stem-cell therapy.  The first study, CALGB 100104, reported results from a second interim analysis, which showed that Revlimid significantly increased time to progression compared to placebo by 58% (13.8% of Revlimid-treated patients progressed at 12 months compared to 27.9% of placebo-treated patients).  The second trial, IFM 2005-02, was unblinded 24 months after randomization due to superiority of the Revlimid arm during an interim analysis.  In the treatment arm, patients received Revlimid consolidation post transplant followed by Revlimid maintenance whilst the control arm received placebo.  The results demonstrated that the Revlimid arm had a 54% reduction in risk of disease progression: The 3-year PFS improved from 38% with placebo to 68% with Revlimid.
• Celgene had already presented positive results of the MM-015 trial investigating Revlimid as a first-line and maintenance therapy in transplant ineligible patients at ASH in December 2009. The results supported the use of Revlimid as induction and maintenance therapy in newly diagnosed patients that do not receive stem-cell transplants.
• Although optimal maintenance duration of Revlimid is not yet known for either setting, it is likely to continue until progression.  Clearly this significantly increases the sales potential for Revlimid, but also expands the market as there is no current standard for maintenance therapy; Celgene’s Thalomid has given mixed results and Johnson & Johnson’s Velcade is less attractive in the maintenance setting as it cannot be given orally.  Furthermore, there is no evidence to support Revlimid maintenance following Velcade induction; therefore, if Revlimid is approved, we believe Velcade could lose market share to Celgene’s drug in the first-line setting. 
• Yesterday at ASCO, positive data of the PRIMA study investigating Rituxan as a maintenance therapy in follicular lymphoma was also reported.  The data showed that Rituxan reduced the risk of disease recurrence by 50% in newly diagnosed follicular lymphoma when given for 2 years in the maintenance setting. Although Rituxan is already indicated for the first-, second- and second-line maintenance settings, approval for first-line maintenance would provide further upside and completes Rituxan’s dominance of the FL arena.