Therapeutic Focus - Pfizer grabs sickle cell therapy but novel approaches far off

Pfizer’s $340m deal to license phase II sickle cell disease treatment GMI-1070 from privately held GlycoMimetics highlights continuing interest in orphan drugs, but points out some truths about treatments for this specific genetic condition.

Like many of the drugs in mid- and late-stage development, the GlycoMimetics product aims to prevent episodes of pain and organ damage caused by blood vessel blockages rather than addressing underlying biological processes. A look at the other products in development suggests a true disease modifying remedy is many years away (see table below).

Painful episodes

Sickle cell disease is a genetic condition affecting largely people with African and Mediterranean descent – about 60,000 in the US have it. Its main trait is the deformation of red blood cells into a distinctive crescent shape, reducing their oxygen-carrying capacity and increasing their tendency to get stuck in small blood vessels and break into small pieces, impairing normal blood flow.

The condition is marked by episodes called crises, which can cause pain in the abdomen, bones and chest, as well as causing organ failure and strokes. Drugs on the market today largely address symptoms.

Cancer drug hydroxurea was the first approved drug in the indication, approved to prevent crises and blood tranfusions; its mechanism of action is not clear, but known pharmacological effects include increasing foetal haemoglobin levels, a type of haemoglobin found in both children and adults, which is believed to prevent the red blood cells from deforming, and altering cells’ adhesion to blood vessel walls.

Phase III has just two products: the first is ANX-188, a form of the surfactant poloxamer 188 that sponsor Adventrx believes will prevent clotting and blockages. Adventrx, which acquired the compound with its acquisition of SynthRx, has reported that it will be meeting with the FDA in the fourth quarter of 2011 to discuss phase III trial design and development plans, a potentially crucial event on that company’s calendar (Trial SNAFUs prove to be Adventrx's Waterloo, August 10, 2011). The product has been on the shelf for quite a while – a phase III trial was listed to start back in 1997, according to

The second product is the nutritional supplement NutreStore, which is the amino acid L-glutamine, now recruiting patients for a significant 48-week, 225-patient trial aimed at reducing the frequency of sickle cell crises, which is scheduled to complete in December 2012. NutreStore is already on the market for short bowel syndrome in combination with recombinant human growth hormone.

Selected sickle cell development projects
Product Generic Name Pharmacological Class Company Originator Trial ID
Phase III ANX-188 - Poloxamer ADVENTRX Pharmaceuticals CytRx
NutreStore glutamine Gastro-intestinal agent Emmaus Medical Cato Research NCT01179217
Phase II GMI-1070 - Selectin antagonist Pfizer/GlycoMimetics GlycoMimetics
LentiGlobin - Haemoglobin gene therapy bluebird bio bluebird bio
HQK-1001 - Short chain fatty acid HemaQuest Pharmaceuticals HemaQuest Pharmaceuticals NCT01322269
Zolinza vorinostat Histone deacetylase (HDAC) inhibitor Merck & Co Sloan-Kettering Institute/Columbia University NCT01000155
Phase I MP4CO carboxy hemoglobin (pegylated) Haemoglobin-based carbon monoxide carrier Sangart Sangart
SelG1 - Anti-P-selectin MAb Selexys Pharmaceuticals Selexys Pharmaceuticals
Cord Blood Cells - Stem cell therapy Celgene Celgene
Effient prasugrel hydrochloride Platelet ADP antagonist Daiichi Sankyo/Eli Lilly Sankyo/UBE Industries NCT01430091
LBH589 panobinostat Histone deacetylase (HDAC) inhibitor Novartis Novartis NCT01245179
Pre-clinical Aes-103 5-Hydroxymethylfurfural Anti-sickle cell disease agent AesRx AesRx
Grara - Anti-anaemic ERYtech Pharma ERYtech Pharma


Phase II products range from targeting improved blood flow to gene therapy. As mentioned, the GlycoMimetics product hopes to prevent blockages, doing so by reducing the stickiness of deformed red blood cells. Bluebird Bio, on the other hand, is trying something more ambitious: harvesting stem cells from patients’ bone marrow, altering the genetic makeup and re-implanting the cells, in the hope they turn off the underlying biological malfunction.

In between those two approaches are HemaQuest Pharmaceuticals’ HQK-1001 and Merck & Co’s blood-cancer drug Zolinza. HemaQuest has fully enrolled and expects results soon from a 50-patient trial of HQK-1001, a short-chain fatty acid derivative; short-chain fatty acids have been studied for many years as a therapy for increasing foetal haemoglobin. Likewise, Zolinza, a histone deacetylase (HDAC) inhibitor, has been shown in treatment and research studies to increase foetal haemoglobin levels. That trial, led by the Dana-Farber Cancer Institute, is still recruiting, according to

Early stage

In phase I and earlier is a mix of approaches. Like Merck, Novartis is testing an HDAC inhibitor in LBH589. Eli Lilly and Daiichi Sankyo have tested blood thinner Effient.

More novel approaches include Selexys Pharmaceuticals, which announced earlier this year it has begun enrolling patients in a phase I study of its monoclonal antibody SelG1, which targets the protein P-selectin implicated in adhesion of blood cells to sites of inflammation. Sangart, which raised money to test MP4CO, aims to deliver therapeutic levels of carbon monoxide to patients experiencing a sickle cell crisis.

Pre-clinical candidates include AesRx’s Aes-103, a small-molecule designed to increase the affinity of sickle haemoglobin to oxygen, which the privately held company says can prevent their deformation. Erytech Pharma’s Grara aims to increase oxygen release to tissues.

As an orphan condition, promising sickle cell therapies will continue to attract interest from big pharma and biotechs alike as they seek high-value indications with lower development costs. However, the thin pipeline suggests patients are a few years away from truly novel approaches that will reverse the biological triggers that cause the condition.

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