We have decided this month to include comments on approaches to developing agonists drugs to stimulate these receptors with therapeutic potential. We will also broaden our review to cover the use of oligonucleotides as drugs, a subject we have touched on in earlier articles when we discussed RNAi, antisense and other approaches from companies such as Alnylam Pharmaceuticals (ALNY) and ISIS Pharmaceuticals (ISIS). It is worthwhile noting that IDP has a long history in the development of therapeutic oligonucleotides, being an early pioneer in antisense. The company changed course and name after well publicized clinical failures.
The first point to make is on the use of structure activity relationships [SAR] in the field of oligonucleotide drug discovery. In traditional small molecule medicinal chemistry each part of an active molecule is modified sequentially and the consequence of the modification on activity evaluated. The purpose of this approach is to find the optimal lead compound for further development. It has proved an effective drug discovery method for small molecule pharmaceutical development. An oligonucleotide, being a large polymeric molecule with over 1 million isomers in any batch, makes it impossible to use traditional SAR methods on these types of compounds. Any modifications to the structure are done less rationally and are based on scientific experience in the field.
One of the cornerstone modifications changed the linkages between bases in natural molecule into phosphorothioates; normally called first generation oligonucleotides. Second generation oligos have been developed with changes to the sugars on the backbone of the polymeric structure. There is still no real clinical proof that compounds based on these changes will be more successful in the clinic than the pure phosphorothioate. Modifications to the chemical bases, which form the distinctive component of the polymeric molecule, have proven problematic. When oligos break down into their constituent parts in the body the resulting molecules can have mutagenic effects especially those with base modifications.
The jury is still out whether the long term effects of base changes on the “metabolites” will have serious effects but short term toxicities have been shown in some areas. In its early days, Gilead tried base modified antisense compounds. They turned out to be toxic and Gilead (GILD) eventually abandoned its antisense program to focus on small molecule antiviral therapeutics. We are all glad they did!
What conclusions can be drawn by this review of the medicinal chemistry behind use of oligonucleotides in immunotherapeutics, antisense and the new gene silencing approach called RNAi? First, we do not believe that IDP’s modified chemistry is functionally superior to COLY’s, both being essentially phosphorothioate compounds. We are not certain that IDP’s proposed "modifications" will confer any advantage over Coley’s approach. In fact, the problems mentioned above with mutagenic effects of base modified metabolites may prove to be problematic.
In addition, manufacturing costs will be higher for the base modified oligonucleotides of IDP. The second comment is a broader comment on use of oligonucleotides therapeutically. The attempt to make oligos more “drug like” (with drug properties relating to absorption, metabolism etc), which includes oral bioavailability, has yet to prove itself. This is the case in antisense, where ISIS appears to have good results in a diabetes Phase II trial using a modified oligonucleotide but is still a long way from an approved product. RNAi is some way from proof of principle although there is some positive data from a Phase II trial from eXegenic’s (EXEG.OB) compound for wet AMD (see article in this issue). The biological effects of oligos continue to challenge with delivery issues remaining although attempts are being made to address this issue. This will apply for RNAi as well as other methods.
Returning to the use of oligos in immunotherapy we believe that other agonists, such as small molecules, as well as natural agonists, may prove superior agents than the use of oligonucleotides. A number of such agents are in late stage development and may prove tough competition for companies basing their programs on oligonucleotide agonists.
One venture capitalist we approached informed us that they are keeping clear of oligonucleotides. There also appears to be some reluctance on the part of large pharmaceutical companies to enter aggressively into these areas (but see below on Merck (MRK) deals). RNAi development has received a lot of attention from investors although we think that a number of the problems mentioned above apply to the smaller oligonucleotides used in this field. Merck has made investments in both RNAi and immunotherapies through its purchase of Sirna (RNAI) and the investment in IDP.
Our conclusion is that if a choice is possible as an antagonist or agonist it is preferable not to use oligonucleotide based therapeutics. We think there are still a number of disappointments in store for companies using oligonucleotides, even those with exotic modifications to make them more therapeutically effective, and investors should be smart in their longer term choices. The smaller the oligonucleotide the better, which is why the field of RNAi may have the most hope. However, it would be naïve to think this area will not be immune from challenges already seen in antisense, ribozymes and aptamers.