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

To: Alper H.YUKSEL who wrote (24300)	8/9/1998 5:55:00 PM
From: tonyt	Respond to of 32384

>Do you ever sleep ? As long as the white whale 'tonyt' swims throughout cyberspace Cap'n Ahab can never sleep!

To: Alper H.YUKSEL who wrote (24300)	8/9/1998 6:16:00 PM
From: Henry Niman	Respond to of 32384

Alper, I was catching my breath for Targretin, because of course, the off label use there is certainly the biggest current wild card and its potential is reflected in post #0 of this Ligand Breakout! thread (which I think is a proper title). Targretin really demonstrates the unrealized potential of LGND's most impressive pipeline (naysayers not withstanding). Targretin is slated for NDA filing around the end of the year. The two registration tracks are for topical and oral treatment of CTCL and the Phase II data are very strong. LGND's strategy was to initially target small patient populations for their in house products because such trials were manageable for a company that is obviously grossly under funded (even with the equity sales that so many naysayers moan and groan about). As mentioned earlier, Targretin is expected to be granted priority review for oral and topical formulations. I expect the NDA for the oral formula to be filed first because it will give LGND three distict products, injectable ONTAK, topical Panretin, and oral Targretin. I expect oral Targretin to be launched around 2Q of next year and by then there could be a great deal of clinical data to support off label use in some rather large markets. LGND has completed Phase II trials for oral Panretin for psoriasis and oral Targretin trials are wrapping up. I expect the data to be released by the end of the year. I think that the drug will show efficacy, but the wild card for psoriasis is side effects (most likely elevated triglycerides). Such complications have been seen previously for retinoids which react with RARs. Targretin does not activate RARs, but there does appear to be some in vivo conversion of rexinoids to retinoids, so at high doses elevated triglycerides are observed. If Targretin is effective without elevating triglycerides, the the potential application for psoriasis is quite large. By the time Targretin is launched for CTCL, LGND will have had time to publish Phase II data and be well into a Phase III registration track for psoriasis. With that scenario,I suspect that off label use will be quite substantial. However, as noted in post #0, Targretin has shown promise for the prevention and treatment of breast cancer and type II diabetes. There is clinical data for diabetes, but like the psoriasis data, it has not been released yet. I believe that the diabetes situation is similar to the psoriasis situation. LGND began treating at high doses, which proved to be effective for treating CTCL, and saw positive responses. However, they are now titering the concentration down in an effort to maintain the efficacy and reduce or eliminate the side effects (most likely elevated triglycerides). If successful, the diabetes data could be quite impressive by the time Targretin is launched next year. LLY is also slated to begin US trials with Targretin for type II diabetes. The design of such trials are almost certainly dependent on the European phase II data. US type II diabetes trials are likely to be extensive and complex. At the molecular level, Targretin activates RXRs which then complex with PPARs, which are activated by TZDs such as Rezulin and Avandia. Thus, Targretin could be used as mono therapy for patients at early stages of diabetes and in combination with a variety of diabetes drugs (insulin, Rezulin, Metformin, sulfanylureas) for later stages. If the European data is positive, and LLY has one or more US trails underway, then again the Targretin off label sales could be quite significant. In addition to showing efficacy for psoriasis and type II diabetes, Targretin has produced some very impressive pre-clinical data in mouse models of breast cancer. Targretin has been effective in preventing breast cancer as monotherapy or in combination therapy with Tamoxifen or Evista. In addition, the drug has worked well for treating breast cancer as monotherapy as well as in combination therapy with Tamoxifen and Evista. Moreover, it has been shown to be effective in treating Tamoxifen resistant breast cancer. Thus, the potential combinations for treating breast cancer are quite large. LGND plans to initiate breast cancer trials soon. I suspect that they will target Tamoxifen resistant breast cancer. This could create a huge off label market. Such a trail would certainly be high profile. Tamoxifen has been the hormonal treatment of choice for some time and its recent application for breast cancer prevention has been widely reported. However, there is clearly room for improvement and Evista (another SERM that also synergizes with Targretin) has also shown promise (and is now in a head to head breast cancer prevention trial with Tamoxifen being compared to Evista). If Targretin comes anywhere close to the animal data generated for breast cancer, off label sales could be very significant. Since advanced breast cancer patients (especially those who are Tamoxifen resistant) would tolerate elevated triglycerides, it should be possible to show efficacy at the high doses which are effective for CTCL. Targretin is also in several Phase II trails for larger cancer indications (lung, ovarian, kidney, prostate, and KS) and I think that some of that data (ovarian and prostate) will be released by year end. Of course if that data is positive, off label use for those indications would also be significant. In summary, Targretin oral has many off label possiblities. Of course all would not have to work to generate significant off label sales. Any one of the above would have a major impact on LGND's bottom line. Targretin topical is also in trials for actinic keratosis, which could be a significant off label application for topical Targretin, which should also be launched around the middle of next year.