Thrombolytic therapy needs innovation

Patent expiry of recombinant tissue-type plasminogen activator (t-PA) and its TNK-derivative commencing in 2005 did not lead to biogeneric competition in regulated markets. Combined net sales of Activase (t-PA) and TNKase in 2004 only were US$ 200 mln, far away from a blockbuster status. Reasons are 1) competition with low price veteran drugs streptokinase and urokinase which are purifed from cell cultures; 2) competition with mechanical recanalization of occluded coronary arteries in highly developed health care systems; 3) a narrow therapeutic index due to the risk of intracerebral hemorrhage; and 4) a time-limited therapeutic window in treatment of acute ischemic stroke. Ongoing developments focus on plasminogen activators with higher fibrin selectivity in combination with improved diagnostics and on innovative fibrinolytics directly lysing the main target fibrin. These results were found in a search conducted by La Merie Business Intelligence. The results were published in the October 31, issue 15 of R&D Pipeline News, edited by La Merie.

Drug developers in non-regulated markets such as Cuba, Argentina, Korea, India and China predominantly preferred to manufacture recombinant streptokinase, thus omitting old-fashioned purification of the protein from cell culture preparations. The only generic development in regulated markets refers to purified urokinase which is not yet approved and will face competition with recombinant urokinase developed as a consequence of manufacturing problems with the purified product. The recombinant product was investigated in occluded central venous access devices (CVAD).

More recent developments of 5th generation thrombolytics differ from approved thrombolytics and 4th generation plasminogen activators in advanced development in their mechanism of action. The novel thrombolytics directly lyse fibrin which - as a mesh - stabilizes the thrombus, without needing plasminogen the supply of which may be limited in longer thrombi such as in peripheral artery occlusion. Companies developing 5th generation thrombolytics avoid acute myocardial infarction as an indication and focus on peripheral arterial diseae, acute ischemic stroke and central venous catheter occlusion.


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