Alexion: aiming to break new ground in ultra-rare therapies

Martin Mackay, head of R&D at Alexion, talks to pharmaphorum about the company's research pipeline for severe and ultra-rare diseases.

Alexion has become hugely successful in recent years thanks to its focus on treating severe, life-threatening and ultra-rare diseases – earning billions of dollars annually from treating just a few hundred patients around the world.

The foundation stone for the company is Soliris (eculizumab). Developed in-house and first launched in 2007, the drug is on track to earn $2.5 billion this year through treating two life-threatening and ultra-rare disorders: paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS).

Since its launch, Soliris has also been known as the most expensive prescription drug in the world, costing around $440,000 for a year's treatment – a price justified by Alexion because of the very few patients it treats, and its ability to transform their lives.

Despite this, the high price of Soliris, and other ultra-rare disease drugs, continues to be a source of controversy, and there are already signs that the cost ceiling has been reached.

Alexion does still have headroom to expand Soliris sales by helping to uncover more undiagnosed patients with these conditions, as well as expanding into other rare disease indications. Analysts Evaluate Pharma forecast that Soliris will hit sales of $5.46 billion by 2020, which would confirm its place as the biggest-selling non-oncology orphan drug on the market.

The Cheshire, Connecticut-based company wants to consolidate its status as the leader in the ultra-rare therapy field, but there are plenty of challengers. Sanofi's rare disease division Genzyme and deal-hungry Shire are both major players in the field, and others such as Vertex and BioMarin are poised for significant growth with major new products.

In September, Alexion hit a major milestone when it gained European approval for not one but two major new drugs, Kanuma (sebelipase alpha) and Strensiq (asfotaste alpha). US FDA approval followed for Strensiq in October, with Kanuma following just a few days ago.

This will help transform Alexion, moving it away from being a single-product company to one with broader interests. However neither of the new drugs will match Soliris in terms of revenues, forecast to earn around $1 billion each within five yaers. The firm will need to generate even greater growth if it wants to retain its lead – Shire is currently stalking Baxalta, which, if the merger goes through, would create a rare disease leader with sales of around $20 billion by 2020.

Today sees Alexion host an investor day in which the company's leadership will highlight early- and late-stage pipeline projects, as well as indicate its long-term growth strategy for its existing portfolio in complement and metabolic diseases.

Martin Mackay

I spoke to Martin Mackay recently about Alexion's pipeline, and the firm's approach to R&D. Mackay joined Alexion in May 2013 after a big pharma career culminating in research leadership roles at Pfizer and AstraZeneca (AZ).

He says Alexion has a very clear, focused philosophy for targeting areas of unmet need.

"We call it 'How bad and how good': we only work on diseases that are truly devastating. And we aim only for major advances – we have to believe the treatments that we develop can be truly transformative. There's nothing wrong with incremental benefit, but it's just not where we work."

He states that this approach invariably leads the research to rare diseases, but points out that the firm remains agnostic in terms of therapy area and modality, open to working on small molecules, antibodies or proteins.

One of the most eye-catching projects in Alexion's early-stage pipeline is a collaboration with Moderna, which works on messenger RNA therapeutics, a hotly-anticipated technology.

"Philosophically, you have to bring to bear a spirit of collaboration, because we could never build all of that knowledge internally, whether it is with Moderna or another company. The [research] group here really are very collaborative."

This collaborative approach is, of course, the norm in R&D, and necessary because of limits to research spending. Indeed, Mackay has far less to play with at Alexion than at somewhere like AZ: Alexion's annual R&D budget will be $480 million in 2015, a fraction of a typical big pharma budget.

Its small-scale approach has paid off handsomely for the firm so far, with returns on its R&D outstripping the average big pharma many times over.

But the firm has relied on M&A for its two new approvals, Strensiq and Kanuma. Strensiq was gained as part of the $470 million deal for Enobia in 2011, while Kanuma came through the $8.4 billion purchase of Synageva in June this year.

The high cost of the Synageva buy-out led some investors to say Alexion had overpaid – offering double the market value of the company – but it also reflects the growing competition for bankable orphan drugs.

The Synageva deal was the first major strategic move by David Hallal, who took over as chief executive in April from Leonard Bell, the company's long-standing chief executive and founder. Hallal has stressed continuity, and will be looking to build on the firm's lead in ultra-rare diseases in any way he can.

Alexion's research strategy

While further acquisitions are always a possibility, Martin Mackay is focused on maximising the returns from the firm's pipeline and science base, now enlarged with the addition of Synageva's researchers, who are located in Lexington, Massachusetts.

Martin Mackay says that, in order to make a transformative benefit, a deep understanding of the pathophysiology of the disease and the target space is needed.

"We do that work before we go into any area, and there are always questions to be asked in ultra-rare diseases that are poorly understood. And if you think about some of the diseases that we work in such as paroxysmal nocturnal haemoglobinuria (PNH) [the rare blood disorder that is one of Soliris' indications] and lysosomal acid lipase (LAL) deficiency [the condition that Kanuma targets], we have spent a lot of time understanding what impact the disease has on the patient."

Mackay explains this means Alexion does a lot of basic work with academics and key opinion leaders in these rare disease areas to understand and define the conditions better, which takes time and money.

On the other hand, as many are genetic diseases, the exact cause of the condition is usually clear, a contrast to diseases such as Alzheimer's or even diabetes or cardiovascular disease.

"The perfect example of that is hyperphosphotasia (HPP) – we know exactly why it is caused. Patients lack an enzyme called tissue non-specific alkaline phosphatase and asphotase alpha [Strensiq] replaces that enzyme. It does that in a very neat way, because it targets the bone, by dint of the fusion protein that we have built. We know that if you replace the enzyme you have got a good chance of making a meaningful difference."

Mackay says there is still more work to be done in understanding HPP, as it is a heterogeneous disease, with over 260 known mutations involved, creating many different manifestations of the condition.

Because it is an inherited disease, handed down from generation to generation, small isolated groups can be particularly badly affected. A lethal mutation affects a small group of patients in Japan, in whom Alexion has now located the precise mutation. The highest incidence of HPP anywhere in the world is a Menonite community in Manitoba, Canada, where one in every 25 is thought to be a carrier of the genes involved.

"These are what I call 'lethal hotspots', where our understanding is growing," says Mackay. "Over the rest of the world, there is this mass of genetic information that we're trying to understand better now. These details and nuances take a lot of research and a lot of time."

Key to helping these patients, and to Alexion growing its business, is the diagnosis of more patients around the world with these rare conditions. Almost by definition, the rarity of the diseases means they are harder to identify and take longer to get treatment than more common conditions. However earlier diagnosis can be vital for improving a patient's prognosis.

"Not surprisingly, the earlier you treat, the better. So we have had to work again with the academic community and physicians to really educate people to look for this disease."

Complement biology

Soliris works by targeting a problem in the complement system, a part of the immune system so-called because it helps, or complements, the ability of antibodies and phagocytic cells to clear pathogens from the body.

However in these rare diseases, the complement system becomes overactive, and attacks the body's own tissues and organs. Soliris is a terminal complement inhibitor and deactivates this process, blocking the C5 complement protein.

Alexion is investigating Soliris in late-stage trials in no fewer than four ultra-rare conditions in which this complement activation plays a part.

These include Neuromyelitis optica and refractory Myasthenia gravis in neurology and in transplant medicine, antibody mediated rejection (AMR) and delayed graft function (DGR).

Mackay says there is still much to understand about rejection, and Alexion is working with clinical and academic leaders on the pathophysiology and how best eculizumab can work for patients.

Alexion is extending its work in complement biology beyond C5 blockades – ALXN-1007 is a novel C5a inhibitor anti-inflammatory antibody, from which interim trial results in gastrointestinal graft versus host disease (GVHD) are expected soon.

If these results looks positive, it could open up a whole new pathway within the complement system. Mackay adds that there are a number of other parts of complement therapy in which Alexion believes it has leadership, but is yet to announce details.

There is also a next-generation follow up to Soliris in the pipeline, which Mackay says is 'very high priority'. ALXN-1210 is the lead programme, and is a modified version of eculizumab with the potential for an extended half-life, allowing for monthly injections rather than the fortnightly doses needed for Soliris.

Meanwhile in its metabolic portfolio, there is SBC-103 for Mucopolysaccharidoses IIIB (MPS IIIB) and ALXN1101 (cPMP Replacement Therapy) for Molybdenum Cofactor Deficiency (MoCD) Type A. As with many ultra-rare diseases, both these conditions affect young children, and both cause catastrophic disability within the first few months of life and premature death.

Mackay says working towards treatments which can transform the outlook for these patients is what drives everybody at the company.

"We are genuinely close to patients. In my office I have photos of people I've met with the diseases we work on. We know our patients, we know the devastation these diseases cause, and we know these medicines can transform people's lives.

"We have patients come in to meet us here, and I think these are the best days of the year – our people walk out to get back to their laboratories or offices with a real renewed determination."

The huge potential of messenger RNA, Moderna partnership

Undoubtedly one of the most exciting projects in Alexion's pipeline is its collaboration with Moderna. After many years of hope about messenger RNA therapeutics, there is belief that Moderna could be on the cusp of developing a ground-breaking treatment using the technology.

Messenger RNAi has the potential to help the body correct its own genetic flaws, directing it to produce the protein that is missing – often termed as allowing the body to be its own medicine factory.

Alexion is pursuing no fewer than seven programmes with Moderna, with the first expected to enter human trials in 2016.

Mackay says this is remarkable progress given that the work was begun only relatively recently. "It's relatively early technology, but it fits our bill completely – truly devastating diseases, small populations and, from a scientific point of view, such intriguing science – you can probably tell that I am just delighted with this collaboration!"

He adds: "We have a laboratory in Cambridge Massachusetts that has opened in the last few months, and our team works directly with Moderna colleagues – they are walking distance from the Moderna laboratories and are really hand-in-glove on all of these programmes.

The lead candidate is ALXN 1540, for patients with Crigler-Najjar Syndrome (CN-1). CN-1 is a chronic congenital condition of excessive serum bilirubin caused by mutations in the UGT1A1 gene that presents in newborns. CN-1 is associated with irreversible brain damage and premature mortality.

R&D integration and autonomy

Another major development for Alexion in 2016 will be the relocation of its R&D headquarters within Connecticut to New Haven.

This will make the company neighbours of Yale, the hospital and the university – the kind of co-location with academic excellence being practised across the industry, most notably in nearby Cambridge, Massachusetts. However there are no plans to merge the ex-Synergeva employees into the New Haven site – Mackay says he would "rather let them get on with the important work that they are doing, discovering and developing more new important medicines" than move them and disrupt this culture.

Mackay says he is happy to replicate many of big pharma's processes, while not burdening Alexion with layers of decision making, staying a "nimble, vibrant entrepreneurial" organisation.

Finally, 2016 will be important for the roll-out of Strensiq and Kanuma, with Alexion not yet declaring the US price of the latter. The company surprised analysts when it announced a lower-than-expected US price for Strensiq recently – $285,000 – significantly less than the $400,000 we have come to expect from rare-disease drugs.

This clearly reflects a change in the US market in particular, where opposition to rising drug prices has been inescapable in 2015. Alexion will need to negotiate this fine balance between prices, profits and serving patients as it pursues its mission in the increasingly competitive ultra-rare disease market.

Read Alexion's preview of today's pipeline presentation here.

Read more: Alexion expands its reach in ultra-rare disease

About the author

Andrew McConaghie is pharmaphorum's Managing Editor, Feature Media. He can be contacted via: andrew@pharmaphorum.com Follow him on Twitter

Read more from Andrew McConaghie Raising the bar: can Gilead's next challenge be even bigger than Hep C?