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Breaking into the oncology market

pharmafile | March 10, 2014 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | Boehringer, Cancer, NSCLC, edwards, gilotrif, oncology

In many ways, the US approval of Boehringer’s Gilotrif for patients with late-stage non-small cell lung cancer (NSCLC) last year was fairly innocuous, given that there are a number of drugs for the disease on the market.

But this was not just another approval for Boehringer, as the drug (known as Giotrif in Europe) represents the company’s first approved treatment for cancer rocketing the company into a complicated but potentially lucrative and rewarding market.

BI’s new drug is of course not the first to market and will directly compete with Roche’s established cancer pill Tarceva, which last May was approved by the FDA for first-line treatment of patients with NSCLC expressing the EGFR mutation, the same mutation Giotrif targets.

It already has a number of licences to treat late-stage patients – and as a second, third and maintenance therapy, Tarceva generated over $1.4 billion in 2012 sales. But whilst third to market, Giotrif represents an advance over its first generation EGFR rival in that it blocks a wider range of targets, and is the first irreversible erbB family blocker.

This means that BI’s drug could also be given to patients who develop a ‘resistance’ to first generation EGFR blockers (although this is currently not within its license), a common problem with personalised medicines, and the company hopes for blockbuster sales in the near future.

On new ground

Sarah Edwards, oncology medical and scientific affairs manager at Boehringer Ingelheim UK, tells Pharmafile: “We are a company that is relatively new to oncology so our experience has been one of firsts. Like all companies who are involved in oncology development and marketing, there are challenges with regards to timelines, delays or enhanced delivery with regards to pivotal trial results and results that may be different from Phase II to Phase III.”

She explains that the company and those working around Giotrif have learnt to be ‘flexible and agile’ in responding to these challenges, and also to be “patient and resilient when dealing with the unpredictability often seen in oncology development”.

For all pharma firms this includes a higher rate of failure than with most other medicines given their complicated nature, longer development cycles and resulting higher R&D costs, as well as cancer medicines regularly falling short of the efficacy hoped for.

But it has obviously been worth the time, money and effort for BI, which was granted a European approval for Giotrif late last year, just a few months after the drug’s US launch.

Edwards says: “Giotrif is just at the point of commercial launch in the UK and it has been a long journey. There was potential for a number of different indications within the EGFR mutation-positive advanced NSCLC indication based on the available data for Giotrif. This made planning for HTAs [health technology assessors] complex prior to license approval as different submissions and models had to be developed.”

Boehringer is certainly no stranger to HTAs such as UK watchdog NICE, but this will be the first time they have had to go through the body with a cancer medicine – a daunting task given that no cancer drugs were recommended by the regulatory body in 2013.

But echoing many in pharma, Edwards says that NICE and other HTA bodies ‘are essential’ to ensure appropriate access is granted to drugs such as Giotrif for patients.

“Our focus has been to work with all internal and external stakeholders to deliver a robust clinical effectiveness and health economic argument for use within the UK.” She adds that they will now await the outcomes of these submissions.

Outside of traditional HTA bodies, new systems are arising that essentially bypass them. The UK’s version of this system is the Cancer Drugs Fund (CDF), an initiative which injects hundreds of millions of pounds into the NHS to pay for drugs not yet appraised or rejected by NICE.

Edwards says that BI is supportive of ‘all appropriate initiatives’ which improve access to new cancer medicines for all patients. But she adds: “Our biggest concern currently is that the CDF provides such access to NHS patients in England only and that there are potential inequities and variability across the UK where access is not available through this route.” This is because the Fund has not been replicated across Scotland, Wales and Northern Ireland.

More to come

But Giotrif is not designed to be a flash in the pan for the firm, as BI has a number of other investigational cancer drugs in its pipeline. The company is applying its research into cancer biology to develop a wide range of potential treatments in areas of unmet medical need relating to both solid tumours and blood cancers.

Using technological advances and the latest science, the search for new cancer treatments from BI is currently focussed on the following areas of investigation: signal transduction, angiogenesis, cell cycle kinases, and immunotherapy.

These compounds are being investigated across Phases I to III, and BI are looking at their potential to be effective in patients who are resistant to existing treatments, to improve the efficacy of established drugs in combination regimens, and to provide targeted therapies with more favourable tolerability profiles.

The most advanced is nintedanib, which the company showed off at the European Cancer Congress (ECC) in Amsterdam last October. The orally administered triple angiokinase inhibitor has been shown to extend life when added to chemotherapy in NSCLC patients after prior first-line chemotherapy.

The Phase III LUME-Lung 1 trial showed that nintedanib plus chemotherapy agent docetaxel lengthened overall survival by 2.3 months for advanced NSCLC patients versus placebo and docetaxel.

What makes the compound especially interesting is that it blocks three growth factor receptors: vascular endothelial (VEGFR 1-3), platelet-derived (PDGFR alpha and beta) and fibroblast (FGFR 1-3) – a range which could very well put it ahead of the field, and may give it applications in other therapy areas.

The investigational drug is currently being looked at in patients with various solid tumours including advanced NSCLC, but also ovarian cancer, liver cancer, kidney cancer, and colorectal cancer. The firm hopes that this drug, currently in the final stages of testing, will soon become the second treatment in its growing cancer portfolio.

Edwards says the company’s pipeline shows that BI “has a long-term commitment to deliver tomorrow’s cancer therapies by discovering and developing novel treatment options, both New Chemical Entities (NCEs) and New Biological Entities (NBEs), that combine ground-breaking science with high therapeutic value for patients”.

But whilst cancer is indeed becoming a bigger focus for the company, it still will reside as part of a larger, more diverse range of products. Edwards says that BI will continue to focus on five major areas, which include oncology, as well as its established therapies in cardio metabolic diseases, central nervous system diseases, immunology and inflammation, and respiratory diseases.

Mature versus emerging markets

There is a question for all pharma companies about whether a firm should focus primarily on traditional markets such as the US, Japan and Europe to market cancer medicines, or turn more to the emerging BRIC markets, which may become better guarantees of revenue growth for new oncology products.

Edwards adds that Boehringer’s goal is to provide appropriate access to its medicines for all patients who need them – “however, the simple answer to the question [for Boehringer] is both”.

She continues: “The emerging markets offer a definite opportunity to grow our products further and it is vital to support launches in these markets. It is worthwhile noting, however, that the more ‘traditional markets’ are still hugely important.

“The UK, for instance, may not offer the greatest revenue due to its small population, but the processes for reimbursement that need to be undertaken are incredibly robust, very challenging and are therefore referenced by many other countries.

“A positive NICE decision will not just impact the UK but will directly affect many other markets. Boehringer Ingelheim is committed to providing appropriate access to its medicines to as many people as possible who may benefit from them.

“In 2012 Boehringer Ingelheim reinvested 22.5% of net sales in our largest business segment, prescription medicines, on research and development.”

Digital initiatives

BI is well known in the digital space, being one of the first pharma firms on Twitter and Facebook, and the first to develop gamification in the industry, in the guise of the Facebook game ‘Syrum’. And with its new venture into cancer – and specifically lung cancer – the German firm has once again turned to the internet to help aid its marketing teams.

In October last year, just months after FDA approval, BI teamed up with the Global Lung Cancer Coalition (GLCC) to launch an online campaign called ‘Lung Cancer: We’re Listening’. This site gathers feedback from patients with the disease as well as carers, family members, friends, colleagues and healthcare professionals.

“By gathering insights and listening to real-life experiences from those directly affected by lung cancer, we can increase our knowledge and understanding of the challenges faced by patients,” said GLCC chair Dr Matthew Peters.

Boehringer added: “By learning more about their specific challenges with many topics, including those relating to changes in roles and relationships, stigmatisation, and difficulty communicating with their healthcare team, the campaign will help to improve the support and information available to them.”

Market potential

Boehringer UK has shown that the journey has been long, but the development of its first oncology drug – and one for one of the deadliest and most under-treated cancers in the world – has been the reward.

The firm must now face the potential minefield and frustrations of the HTA process, but it goes forth with much aplomb, armed with a belief in its product and the strength of its data.