Researchers affiliated with The AMG 531 in Myelodysplastic Syndrome Study Group have reported that AMG 531 can reduce bleeding and transfusion events in patients with myelodysplastic syndromes (MDS). The details of this study were presented at the 2007 meeting of the American Society of Clinical Oncology (ASCO) in June.[1]

Thrombopoetin (TPO) or thrombopoetin-line drugs have had limited success for the treatment of thrombocytopenia, primarily due to antibody production. Currently, Neumega (oprelvekin) is the only FDA approved drug for treating or preventing thrombocytopenia and it has not been very widely used. The second generation of TPO-like agents has been developed by identifying peptides that bind the TPO receptor with high affinity. Because they bear no structural resemblance to TPO, but still bind and activate the TPO receptor, these compounds are called TPO mimetics.  Several peptides have been identified, and they have been further modified to both prolong their half-life in plasma as well as to increase their efficiency in activating the TPO receptor.  The theoretical advantage of these compounds over standard recombinant TPO is that they bear little structural similarity with native TPO, and should not trigger auto-immune anti-TPO antibodies like PEG-MDGF. 

AMG 531 is the most developed pharmaceutical in the peptide TPO mimetic category.  It is composed of several copies of the TPO receptor-binding peptide spliced into a recombinant antibody.  This peptide mimetic competes with TPO for binding to the TPO receptor, and activates the receptor in an identical fashion to endogenous TPO.  When administered subcutaneously to humans, AMG 531 produces a dose-dependent increase in platelets counts. Bussel et al. conducted a clinical trial published in the New England Journal of Medicine evaluating AMG 531 in the treatment of ITP (Immune (Idiopathic) Thrombocytopenia Purpura) among patients who had received prior treatment.[2] AMG 531 demonstrated platelet responses in 68% of these patients with no major adverse events reported. At ASH 2006, the long-term safety profile of AMG 531 was reported.[3]  These authors reported the outcome of 36 ITP patients who continued to receive weekly subcutaneous injections of the study drug. Twenty-nine patients received AMG 531 for longer than 48 weeks. Eighty-six percent of patients had a platelet response defined as at least double the baseline platelet count, and at least 50,000/µl.  Most of all of the responding patients had platelet counts greater than 150,000/µl. The most frequent adverse events were headache, upper respiratory tract infection, and fatigue. Overall, the results showed that long-term treatment with this TPO mimetic might be a viable therapeutic option for patients with refractory ITP.

The study of AMG 531 for the treatment of thrombocytopenia related to MDS was presented by Dr. Kantarjian from the MD Anderson Cancer Center. This was a phase1/2 study in patients with low-risk MDS. They enrolled 28 patients, 9 of whom were platelet transfusion dependent. Seventeen of the 28 patients continue on therapy with AMG 531. The only dose-limiting toxicity observed was an elevated platelet count in 2 patients. Sixty-one per cent of patients had a platelet response. The median baseline platelet count for responders was 25,000 with a peak response of 130,000 during 4 weeks of treatment. Almost half the patients achieved a durable platelet response for 8 or more weeks. These authors concluded that bleeding and transfusion events can be reduced in thrombocytopenic low-risk MDS patients.

Comments: The initial identification of TPO in 1994 has not led to a significant drug for the treatment or prevention of thrombocytopenia. This has been disappointing but possibly this second generation of TPO like agents will be more effective and may lead to effective drugs analogous to the success of EPO and G-CSF.