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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: medsunman who wrote (21504)	5/28/1998 7:23:00 PM
From: Peter Singleton	Respond to of 32384

Medsunman, I'll pitch in on the Targretin diabetes issue, and look forward to Henry's thoughts. First, you are correct, my opinion is that Targretin may not become a product in diabetes. This is based on little data, and it's just a guess. But I suspect no one really knows at this point, including the folks at Ligand and Lilly. What we know is that it's a compound that shows promise in diabetes, and it's in PII testing. The fact that they are tweaking the dosing is not a big deal. It appears that LGND and LLY know they have a relatively safe compound, based on the side effect profile in cancer patients, who've been receiving much higher doses. There's no way they can predict, accurately and in advance, what the right dose is to start at, and it turns out they started a little high. No big deal. Nor is there any way they can predict accurately and in advance, what's the side effect profile at a given dosing. And finally, in a chronic metabolic disorder like diabetes, triglyceride elevation is a concern, so it's probably something the LGND and LLY are probably looking at very closely. And the goal of the PII trial dose de-escalation is to see if there's a dose range that appears to offer sufficient efficacy with satisfactory side effects, as relevant to this indication. LGND doesn't seem to be overly optimistic or pessimistic about Targretin in diabetes ... they just seem to be doing the job of drug development with a variety of compounds, across an array of indications. They seem to have a great deal of confidence that some of those products will work in some of those indications, and that some of those products will offer compelling benefits therapeutically and pharmaco-economically (e.g., they'll help patients and save healthcare dollars while doing so), while finding large markets. And I think their confidence is well placed. Finally, LGND has RXR and PPAR modulators under development that are extremely promising in diabetes ... whether or not LGND and LLY end up taking Targretin forward, I suspect they will be major players in a huge market within a few years. The net of it is, I've offered an opinion, based on minimal data ... and an opinion subject to change as I learn more and as new data comes out. And I could easily be wrong. How the market would react, if Targretin doesn't move forward in diabetes, I'm not sure. LGND is capable of generating a ton of significant, positive news in the next 6-12 months, which would have a big impact on the perceived (and real) value of the company. Peter As I mentioned earlier, the data I'm basing this on are: - acceptable therapeutic index not yet identified (in itself not necessarily significant, since this is drug development ... that's what you do clinical trials for) - the published, relevant pre-clinical data is more sketchy than that for 268, - the pre-clinical data for 268 is so promising, not only compared with Targretin, but in its own right as a potential diabetes compound.

To: medsunman who wrote (21504)	5/28/1998 8:09:00 PM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

medsunman, I wasn't at the shareholder's meeting, so I know even less about the current status of Targretin treatment of type II diabetes. The Phase II European trials were announced over a year ago. They were designed to test a range of concentrations in very small populations. This data appeared to be encouraging enough to convince LLY that a mega ($200 million) deal was warranted. Some of the cancer data has suggested that there may be some elevated triglycerides at high doses. This side effect is acceptable in cancer patients, but appears to be unacceptable for treatment of a chronic disease like Type II diabetes. I expected to see the European data by the end of last year. The side effects may have caused more concentrations at lower doses to be tested, leading to a delay in release of the data. The triglyceride problem may be due to activation of RARs, which is well documented for retinoids. Although Targretin reacts most strongly with RXRs, the specificity for RXRs appears to be higher for LGD1268 than Targretin. In the Nature study, more data was presented onLGD1268 than Targretin, possibly because it worked better, or possibly because LGND had seen Targretin side effects in cancer patients and assumed that more effort would be put on LGD1268 (and LGD1324?) for diabetes. As far as LLY is concerned, I think that new Phase II trials were slated for 2H, '98, so I'm not sure if they are on track or not. In summary, I really don't have enough data to comment on the likelihood of a Phase III Targretin trial for type II diabetes. I have not heard anything that indicated that such a trial would not take place, but I believe that LGND has said that the US trial will begin at the Phase II stage.