Therapy focus – Sickle cell therapies creep closer to market

Positive phase I/II data on Global Blood Therapeutics’ sickle cell disease therapy GBT440 line the project up for more extensive studies later this year, raising hopes for the first pivotal trial of a disease-modifying agent in this intractable condition. With Bluebird Bio also reporting glimmers of progress with its gene therapy, sufferers finally have two projects to watch closely.

Both remain several years from the market, but there are six therapies that address the symptoms of the disease in phase III; the impact of a new therapy to lessen pain and discomfort caused by vaso-occusive crisis should not discounted. Data on at least three of these should emerge later this year.

Patients with sickle cell disease and no appropriate stem cell donor have few options beyond painkillers for use during sickle crisis, in which the red blood cells stick to each other and to the lining of blood vessels. Hydroxyurea is the only approved therapeutic for the disease and is used in some cases to reduce the frequency of crises but the drug carries a signficant side effect burden, as well as increased risk of infections.

Dose response

As such, much hope rests with Global Blood's product, an oral molecule that works by increasing haemoglobin's affinity for oxygen. The stock took a bit of a beating late last year when interim data from the GBT440-001 study underwhelmed, with no dose response and a weaker treatment effect than had been seen previously.

The new data, also from GBT440-001, are more positive, with the elusive dose-response finally emerging. That said, the structure of the 001 trial is complicated, with three parts, five cohorts of subjects and 13 different dosing regimens. states that there are 128 patients in the trial, but it is not clear how many of these are in each part, cohort or dose group.  

GBT-440-0001 trial structure
Part Subjects Doses (mg) Number of subjects treated to date
Part A – single dose Healthy volunteers 100, 400, 1,000, 2,000 and 2,800
Sickle cell patients 1,000, placebo 8 in total for Part A
Part B – multiple dose Healthy volunteers 300 per day x 15 days Unknown
Healthy volunteers 600 per day x 15 days Unknown
Healthy volunteers 900 per day x 15 days Unknown
Sickle cell patients 500 per day x 28 days 10 on drug, 4 on placebo
Sickle cell patients 700 per day x 28 days 12 on drug, 2 on placebo
Sickle cell patients 1,000 per day x 28 days 6 on drug, 2 on placebo
Part C – multiple dose Sickle cell patients 700 per day x 90 days 6 on drug, 2 on placebo
Sickle cell patients 900 per day x 90 days Unknown

The new data focus on some of the patients in parts B and C of the trial. Importantly, over the 90-day period, there was a median 1.1g/dl increase in haemoglobin concentration with GBT440 treatment versus a 0.2g/dl decrease with placebo; over 28 days the haemoglobin response was variable, suggesting that this measure strengthens over time.

Other markers such as bilirubin and reticulocytes also showed strengthening reductions over time and by dose. GBT440 treatment was also linked with a 70% reduction in irreversibly sickled cells, compared with an increase of 15% with placebo.

The project was well tolerated, with the most common adverse event being headache, seen in both the placebo and treatment arms. There were no drug-related serious adverse events.

Leerink analysts say Global Blood now plans a pivotal trial with 900mg/day if the FDA gives its blessing after discussions later this year.

The company now must prove that the biomarker effects reported in this latest tranche of data – from a very small number of patients – will have an impact on hard endpoints, such as reducing the frequency of sickle cell crises, and indeed changing the course of the disease over the long term.


Shareholders, at least, considered the results positive, sending Global Blood’s stock up 9% on June 10. Bluebird, the closest competitor, saw a commensurate fall.

Being a gene therapy, Bluebird’s candidate LentiGlobin BB305 offers the prospect of a single treatment essentially to cure the patient, as opposed to the daily, lifelong therapy necessary with GBT440.

But results with LentiGlobin have been less than spectacular. The first patient treated in the phase II HGB-205 study achieved sustained levels of 5.5g/dl of antisickling haemoglobin at 12 months post-infusion, which analysts described as highly impressive. Data from two additional patients, though, disappointed (ASH – Bluebird and GBT hammered on sickle cell disappointments, December 7, 2015).

The next major update from the company is expected at the ASH conference in December; until then the future of this technique is hard to call.

Towards a cure

A cure is available in the form of stem cell transplantation, but this is rarely used owing to lack of donors and the cost and complications of the procedure. The final disease-modifying approach in trials is an attempt to improve on this approach: Gamida Cell's NiCord is a haematopoietic stem cell therapy produced by expanding umbilical cord blood.

Data from pilot studies are due early next year. The technology has attracted the interest of Novartis, which paid $35m for an equity stake in Gamida and an option to buy the Israeli group (Novartis builds on cell therapy investment with Gamida deal, August 20, 2014).

Disease-modifying sickle cell therapies – all phase II 
Project Company Pharmacology class Trial ID Notes
GBT440 Global Blood Therapeutics Sickle haemoglobin polymerisation inhibitor NCT02285088 -
LentiGlobin BB305 Bluebird Bio Haemoglobin gene therapy NCT02151526 Results due early 2018
NiCord Gamida Cell Haematopoietic stem cell therapy NCT01590628 Results due early 2017
CordIn Gamida Cell Haematopoietic stem cell therapy NCT02504619 Results due late 2017

Several assets are closer to market, but these are all aimed at treating or preventing the painful vaso-occlusive crises that characterise the disease. Mast Therapeutics’ vepoloxamer is most advanced and is in the largest-ever placebo-controlled clinical trial – 388 patients – in sickle cell. This binds to the damaged parts of blood cells' membranes, preventing them from sticking together and allowing cells to heal.

The Epic study is assessing vepoloxamer's ability to reduce the duration of vaso-occlusive crisis versus placebo; data should emerge by August.

Analysts forecast that Roche’s rivipansel will join vepoloxamer on the market in 2018. Mast’s chief executive, Brian Culley, strongly disagrees with this prediction, saying vepoloxamer has a two-year head start on rivipansel and that the company aspires to its drug becoming the standard of care for interventional treatment of sickle cell crisis. 

Leerink says there is room for many players in the sickle cell market, which is just as well as there are four other symptomatic treatments in phase III and two in phase II. Patients would surely welcome these – but their real hope remains with the disease-modifying approaches yet to make it to pivotal trials. 

Symptomatic sickle cell therapies 
Project Company Pharmacology class Trial ID Notes
     Phase III
Vepoloxamer Mast Therapeutics Poloxamer NCT01737814  Results due late 2016; launch expected 2017
Rivipansel Pfizer Pan-selectin antagonist NCT02187003  Expected launch 2018
Eliquis Bristol-Myers Squibb/Pfizer Factor Xa inhibitor NCT02179177  Results due mid-2016
Brilinta AstraZeneca Platelet ADP receptor antagonist NCT02214121 Results due mid-2017
NCT02482298 Results due late 2016
NutreStore Emmaus Life Sciences Gastro-intestinal agent NCT01179217 Trial concluded 2014; filing expected mid-2016
Docosahexaenoic Acid Sancilio & Company Omega-3 fatty acid NCT02604368 Results due early 2018
     Phase II
Sevuparin Dilaforette Adhesion proteins binder NCT02515838 Results due early 2017
Sanguinate Prolong Pharmaceuticals Anti-anaemic NCT02411708  Results due early 2017

To contact the writer of this story email Elizabeth Cairns in London at [email protected] or follow @LizEPVantage on Twitter

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