Therapy focus – not quite the hammer for sickle cell disease

When it comes to serious diseases with virtually no treatments the US FDA has shown flexibility in approving new therapies, even if these have questionable efficacy. This could play out again when the agency decides on Emmaus’s Endari for sickle cell disease by July 7, especially as the project now has an adcom’s blessing.

The case of Endari is curious for several reasons, not least the fact that it has a cheaply available active ingredient and a data package flattered by statistical changes; its maker until recently looked like being taken over by the struggling Generex. Still, given how barren the industry’s sickle cell disease pipeline is, patients might welcome any advance, however speculative (see table below).

As such, the US adcom’s 10-3 vote in support of Endari’s risk/benefit profile is understandable. This came despite questions at the meeting about a high rate of dropouts, missing data in the project’s pivotal GLUSCC09-01 study, and doubts about the relevance of the primary endpoint – reduction of sickle cell crises over 48 weeks.

Perhaps most egregious of all was that Endari failed according to the trial’s planned analysis, yielding a non-significant p value of 0.063 versus the control comparator, maltodextrin. It was only when Emmaus amended the statistical method that it claimed success with a 0.005 p value (Upcoming events – Panel woes for Puma and statistical uncertainties for Emmaus, May 12, 2017).

A low bar

Still, if Endari is approvable, competitors might celebrate the fact that the bar in sickle cell disease has been set so low.

Perhaps the most important near-term challenge will come from Glycomimetics’ rivipansel, a pan-selectin antagonist, given that this was licensed to Pfizer, which is now in charge of a phase III trial called Reset.

Sickle cell disease is an autosomal recessive disorder caused by a simple mutation in the gene coding for haemoglobin, which affects haemoglobin’s ability to carry oxygen and causes it to polymerise. These haemoglobin polymers distort red blood cells’ shape and increase their rigidity, leading to anaemia, occluded blood flow and pain crises during severe episodes.

Sickle cell disease is curable with stem cell transplantation, but most patients do not have a matched donor to serve as the graft source. Two groups, Gamida Cell and Bellicum, are working on expanded grafts that might be used by non-matched or partially matched patients.

Clearly, this is complex, but unlike stem cells few small-molecule or antibody approaches will treat the disease’s underlying cause. The aim with rivipansel, for instance, is to reduce adhesion of red blood cells, thus making it harder for them to aggregate.

Also acting via anti-adhesive properties is Modus Therapeutics’ Sevuparin, a phase II asset that has been licensed to Ergomed. Endari is similarly a symptom-targeting agent, aiming to reduce oxidative damage to cells, while Eliquis is being studied for its anticoagulant effects.

In terms of potential cures the spotlight is on Bluebird’s gene therapy Lentiglobin, which aims to correct the disease’s underlying genetic defect. Both this and Global Blood Therapeutics’ GBT440, which inhibits haemoglobin polymerisation, have had rollercoaster developments, and updates will be presented at December’s Ash meeting.

It is also worth noting that data generated by Selexys’s crizanlizumab, an antibody targeting cell adhesion, were good enough to secure a buyout by Novartis (Ash delivers early for Selexys, November 21, 2016).

Will it sell?

All that said, in the near term Emmaus faces a more fundamental threat: it is by no means certain that Endari is a viable business proposition.

Its active ingredient is a pharmaceutical-grade form of L-glutamine, which is available over the counter; it is also available on prescription as Nutrestore for short bowel syndrome. Approval for sickle cell disease would lock out competitors on the basis of data exclusivity, but getting insurance coverage could be tricky, especially in a price-conscious political environment.

Then there is the mystery of Emmaus’s proposed takeover by the troubled oral insulin company Generex. This was to have involved Generex buying a 51% stake at a $441m valuation, under a letter of intent signed in January, but the deal was quietly terminated on May 16.

Among the unusual aspects of this transaction was the $500,000 cash advanced to Generex by its chief executive and a senior vice-president to cover the up-front fee under the letter of intent. Generex then raised $3m, and paid $3.5m to Emmaus in March, but scrapped the deal citing delays in its plan to eliminate warrants and preferred stock and carry out a reverse split.

Generex says it is now due a $4m refund. It seems that the group will not, after all, become a player in sickle cell disease.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter