Deuterated drugs: chemical doppelgängers or life-cycle management tools?

Early last week, Concert Pharmaceuticals and GSK announced a deal concerning the deuterium analogues of various existing compounds that were in late preclinical development from the biotech company.

The word ‘deuterium’ comes from the Greek deuteros, meaning ‘the other of two’, and even in the words of Concert’s CEO, deuterium ‘does not change the physical characteristics of a drug’, but potentially it may change its metabolism. Is this therefore merely a cynical means of extending patent protected lifetimes, with little merit beyond the commercial; or, can it be combined with other approaches to life-cycle management in the deliverance of better therapies?

Specifically, the deal involves CTP-518, a deuterated version of BMS’s HIV protease inhibitor atazanavir (scheduled to enter Phase I this year), a preclinical compound in chronic kidney disease, and a third compound of undetermined structure. As reported on the In Vivo blog, the deal’s value is $35 million up front, half as an equity investment;  the  overall deal may deliver over $1 billion, including the success-based milestones, together with royalties. While the strategy will be quickly replicated by others, Concert have a taken lead on the competition that is likely to be attractive to other partners too.

Now that we have had a few days to see the dust settle, one of the common reactions to this announcement is that this represents the ultimate me-too strategy. Yet, if the deuterated compound behaves exactly the same as its hydrogen isotopologue, its patentability as well as its commercial rationale is substantially in doubt.

Concert has raised $110m, mainly from venture capital backers that were attracted by both the management’s success in prior biotech companies, and the low-risk nature of the proposition.  Yet two of the riskiest components to this company are not from the science, but from the patent and commercial angles.

Many chemists will regard the replacement of H by D as ‘obvious’, yet if it were so, why has it received so little attention up till now? Concert have pursued this strategy relentlessly since being founded in 2006, filing over 100 patents on various deuterated analogues of existing compounds, many based on a metabolic improvement relative to the H-based progenitor (and there are over 200 from Protia and around 60 from Auspex also based on D-analogues).

Since the C-H bond is weaker than the C-D (the deuterium atom is twice as heavy), metabolic reactions that rely on breaking such bonds in their rate-limiting step are slowed, even though in other chemical and pharmacological aspects there is no difference. The ‘deuterium isotope effect’ is taught routinely in undergraduate lectures yet drugs based on this have not hitherto been developed.

The key question is how much of an advantage can be achieved by this variation? Some of Concert’s patents evidence a significant decrease in metabolic rate and elongated pharmacokinetics. Others, though, show little or no difference. The patent examining offices are likely to focus on the advantage of the D-analogue during the prosecution process; it will also be a factor if and when these patents are challenged. Indeed, it is relevant that the deal with GSK followed swiftly after the reported grant of one of Concert’s patent applications. In the case of CTP-518, the hope is that the metabolic profile will be sufficiently improved to eliminate the need to include ritonavir into the HIV drug cocktail: not an insignificant advantage, but one that for other drugs could also be achieved through controlled release formulation technology.

There are other factors too to consider: impairing the rate of the major metabolic route by exhanging D for H, may actually lead to an alternative metabolic route becoming dominant, or at least significant.  The potential toxicity of alternative metabolites will clearly have to be considered in the development of the new drug.

But ultimately, it is differentiation from its progenitor that will govern how commercially successful this approach is, at least for its primary indication.  We have come across the similar considerations in the drug repurposing area.

There may be interesting cases, however, where the combination of a low-risk active based on this strategy can be combined with a new therapeutic use, and synergistically deliver a new product that is medically advantageous and significantly differentiated. The combination of these two orthogonal variables brings to mind the idea of combining new therapeutic uses with new presentations, which as we have pointed out previously, has led to some great commercial successes in the recent past.

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