Does Roche Have The Hemophilia X Factor?

Aug. 09, 2017 9:48 AM ETRoche Holding AG (RHHBY)
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The hemophilia A market is turning into a fierce battleground, but some can see a winner emerging, at least in patients who have developed inhibitors. "We really need an effective medication to prevent bleeding, and I think [Roche's (OTCQX:RHHBY)] emicizumab has been shown to be that," Guy Young of the Children's Hospital Los Angeles tells EP Vantage.

Mr. Young is not alone in thinking that emicizumab can dominate the underserved inhibitor population - patients who have developed antibodies rendering front-line factor VIII clotting factors ineffective. But if the Swiss company really wants to take the fight to its rival Shire (SHPG), it will also need to impress in patients without inhibitors. With data from the phase III Haven 3 trial due in the fourth quarter, a showdown beckons.

Emicizumab is now under review at the FDA in patients with inhibitors and with breakthrough therapy designation in this indication it could get the go-ahead by the end of the year. It is currently unclear whether it will first need to face an advisory committee.

Unmet need

Dr. Young, a lead clinical investigator in Roche's Haven program, believes that because of the unmet need in patients with inhibitors, emicizumab has a good chance of approval.

Current therapy for patients who have developed inhibitors includes bypassing agents like Shire's Feiba, which can be given as a rescue therapy or prophylactically. However, "with Feiba prophylaxis alone, patients have at best about a 50% reduction in bleeding", Dr. Young notes, versus a reduction of 87% in the Haven 1 trial of emicizumab (Roche brings new blood to hemophilia A, June 26, 2017).

The non-inhibitor population, however, will be harder to penetrate. These patients are already well treated with factor-replacement therapy including Shire's market leader, Advate. "Non-inhibitor patients have fantastic and very effective drugs, and can lead pretty much a normal life, with the exception of needing intravenous infusions," he says.

Emicizumab's prospects here will depend on data from the Haven 3 trial. If results are positive Roche will be expected to capitalize on the advantages of its product, which include once-weekly subcutaneous delivery; prophylactic factor VIII therapy is administered intravenously several times a week.

"A sizable minority of patients have problems with venous access," says Dr. Young. As a result these patients - who include the very young and very old - do not receive adequate treatment and can subsequently have bleeding issues.

Even those able to receive intravenous therapy might choose emicizumab for its convenience. "By the time it takes a patient to open a box of factor, do the mixing and draw it up in a syringe, they will already be done with the emicizumab injection," Dr. Young says.

Of course, Roche's candidate must first show that it can match the safety and efficacy of factor VIIIs. "If it does, there's quite an opportunity in the non-inhibitor community," he says. "Ultimately we need to wait for data and then we can have a more robust discussion."

Johannes Oldenburg of the University of Bonn, who ran the Haven 1 study, adds that, all else being equal, uptake in the non-inhibitor population will also depend on how Roche chooses to price the product. On this point the Swiss company has shown that it is not afraid to undercut the competition, launching its multiple sclerosis drug Ocrevus at a discount earlier this year - a strategy that appears to have paid off (Roche prices Ocrevus for maximum disruption, March 29, 2017).

However, Stifel analysts believe that the number of well-controlled non-inhibitor patients switching to emicizumab will be lower than the market is expecting, noting that the hemophilia segment is notoriously conservative - probably not helped by previous safety scandals.

Shire's chief executive, Flemming Ornskov, does not seem too concerned. He admitted during a second-quarter media call that he expects emicizumab to take share in the inhibitor population, but added that, with this market worth around $800m, it is a relatively small chunk of the overall hemophilia sector.

However, Feiba, which was the fifth-biggest hemophilia A product last year with sales of $722m, is not forecast to even make the top 10 by 2022. Meanwhile Novo Nordisk's NovoSeven, another rescue therapy for patients with inhibitors, is also set to see sales shrink after emicizumab enters the market, according to EvaluatePharma consensus.


Top five hemophilia A products in 2022
Global sales ($m)
Product Company Mechanism Status Inhibitor/non-inhibitor population 2016 2022
Advate/Adynovate Shire Factor VIII Marketed Non-inhibitors 2,381 2,464
Emicizumab Roche/Chugai Anti-factor IXa/X bispecific MAb Filed/phase III Inhibitors/non-inhibitors - 1,427
Eloctate Bioverativ/Swedish Orphan Biovitrum Factor VIII Marketed Non-inhibitors 544 1,386
Kogenate Bayer Factor VIII Marketed Non-inhibitors 1,290 893
NovoSeven* Novo Nordisk Factor VII Marketed Inhibitors 1,167 634
Total hemophilia A market 8,311 10,249
*Also used in hemophilia B; Source: EvaluatePharma.

As for the non-inhibitor segment, Mr. Ornskov says the market dynamics are "totally different. Factor VIII treatment is well established and the unmet need is much less."

This might be true, but an appetite for more novel therapies is also apparent: only the more recent launches are forecast to grow this market.

And the prospect of a new rival has spurred Shire into action: last month the group licensed a bispecific antibody from Novimmune that, like emicizumab, targets factors IXa and X. However, it will be a while before it can compete, as the candidate is still at the preclinical stage.

In the meantime, Roche is pressing home its advantage with emicizumab, and recently presented positive results from the Haven 1 and 2 trials, in inhibitor patients, at the International Society on Thrombosis and Hemostasis (ISTH) Congress.

Safety

Haven 1 showed impressive efficacy in adults, although the detailed data did little to assuage concerns about the risk of thromboembolic events.

There were no such events in Haven 2, which enrolled patients under 12. Indeed, there was only one bleed in the 19 subjects included in the interim analysis - admittedly over a relatively short follow-up of 12 weeks, admits Dr. Young, the lead investigator.

Like many others, Dr. Young and Professor Oldenburg believe it was the combination of emicizumab and Shire's bypassing agent Feiba that caused the thromboembolic events, putting the blame specifically on high doses of Feiba over a prolonged period of time.

Professor Oldenburg notes that these events were only seen in patients receiving Feiba for more than 24 hours at dose of more than 100 units per kg of bodyweight.

And the lack of such events in Haven 2 could be explained by the low bleeding rate. "If patients don't bleed, they're not going to need the bypassing agent, and they're not going to have any safety concerns," Dr. Young says.

However, Shire disagrees with this explanation and has obtained a preliminary injunction in Germany to address "misleading statements" by Roche.

Both Dr. Young and Professor Oldenburg think it should be possible to manage the risk of thromboembolic events if emicizumab is approved. One option would be "to use Feiba but at much lower doses, so you're not getting into this critical window", Professor Oldenburg says.

Dr. Young concludes: "If there are some very well-stated and well-distributed educational materials that explain how to manage bleeding events, and also what not to do, then I don't think we'll have a significant problem with those events once the drug is licensed."

Coming down

Excitement over emicizumab is not what it was - the EvaluatePharma sellside consensus forecast for 2022 has halved since last September, and now stands at around $1bn. Most if not all of this figure is likely accounted for by the inhibitor population - Morgan Stanley analysts' current prediction only includes these patients, while success in the non-inhibitor population would add another CHF2bn ($2.1bn) to their estimate.

"I think adverse events have a way of muting peoples' enthusiasm," says Dr. Young by way of explanation for the fall in expectations. However, he believes that there is an "enthusiasm gap" between physicians who have used emicizumab and those who have not.

"Once the drug starts getting prescribed in the inhibitor population and word spreads about how amazingly patients are doing, that will take away all these pre-licensure concerns, because patients are going to be demanding the drug."

"This is the biggest breakthrough in the 20 years I've been doing hemophilia," he says. If the data in non-inhibitor patients are as impressive, Shire could soon be up against some serious competition.


Study Trial ID
Haven 3 NCT02847637

Editor's Note: This article discusses one or more securities that do not trade on a major U.S. exchange. Please be aware of the risks associated with these stocks.

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