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

To: Alper H.YUKSEL who wrote (24288)	8/9/1998 3:16:00 PM
From: Henry Niman	Respond to of 32384

Alper, I try you questions one at a time. As far as products are concerned, the are two Tagretin NDAs that are planned (oral and topical). Both should be ready about the end of the year, but I expect LGND to do them one at a time. If the CTCL data is comparable, I suspect that LGND would go with oral Targretin first. Assuming that things go smoothly, they would then have an injectable (ONTAK) a topical (Panretin) and an oral (Tagretin) product (and oral Targretin could be used off label for cancer, psoriasis, and possibly diabetes). I asked about an approved CTCL product (ONTAK) slowing approval of Targretin (oral or topical). Since the drugs target different patient populations (ONTAK is more for the advanced CTCL patients, topical Targretin is for early disease, and oral Targretin is for patients in between, LGND expects all three drugs to receive priority review (and ONTAK and topical Panretin have already been granted priority review). Thus, I expect ONTAK to be launched next quarter, topical Panretin to be launched partially next quarter and a full launch 1Q, '99, oral Targretin launched in the middle of 1999 and Topical Targretin launched in the second half of 1999. Oral Panretin (for KS) could be launched by the end of next year. For each of the above, European launches would trail US launches by about 6 months.

To: Alper H.YUKSEL who wrote (24288)	8/9/1998 3:38:00 PM
From: Henry Niman	Respond to of 32384

As far as off label use is concerned, once a drug has been approved by he FDA, it can be prescribed by an MD for any condition that the MD believes that it will be useful to the patient. MDs are more likely to prescribe off label uses for more serious conditions, because the patient may not have the luxury of waiting for more data or FDA approval. In the past, companies could not promote off label uses. The new FDA modernization act does allow promotion and I'm not sure when the new law goes into effect (it may already be active). I believe that the new law allows companies to send unsolicited promotions for indications that have had clinical data published in a peer reviewed journals (and I think that there may be a 2 article minimum requirement). However, a recent Federal Court ruling indicated that a pharmaceutical's promotion of its product was covered by free speech, and promotion would be legal without a specific "off label" approval by the FDA.

To: Alper H.YUKSEL who wrote (24288)	8/9/1998 4:30:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

As far as off label use is concerned, there are many potential markets. I will go through with my understanding of the potential, but the likelihood will be dependent on the clinical data, and much has not been released yet. The first drug to be launched is ONTAK. It targets cell expressing IL-2 receptors and such diseases include many types of lymphomas as well as psoriasis plaques. The most likely off label use is non-Hodgkin's lymphoma. Phase I trials have shown promise and advanced patients who have failed other therapies are the most likely targeted population. LGND does plan on starting Phase II? trials for ONTAK treatment of non-Hodgkin's lymphoma, and I think that these trials are designed to increase the likelihood of off label use for this indications. As I said earlier, the $40,000 cost could produce significant income, even with low penetration of the 50,000 non-Hodgkin's patient population in the US. European approval for CTCL should be early next year, which of course allows for more on and off label use there. In addition to non-Hodgkin's lymphoma, ONTAK may have additional off label use for other lymphomas which express IL-2. However, I know of no such trials, and the cost may limit off label use in these areas. ONTAK also has potential for psoriasis. For some reason, there seems to be an association between CTCL and psoriasis. Because of cost and side effect consideration, I would expect ONTAK to be used in only the most severe cases of psoriasis, if at all. The next drug to be approved should be topical Panretin. Its registration track is for KS and the population is reasonably large (about 25,000 in the US and another 25,000 in Europe). Aggressive combination therapies has kept AIDS patients alive longer, and KS develops more frequently in the more advanced stages of the disease. A recent BioWorld article indicated that the number of KS patients was significant, contrary to some other article posted on this board. The topical treatment for KS is easy to administer and may have significant advantages over other treatments which must be intergrated with complex combination treatments that the patient is using to control AIDS. Off label use for topical is probably the most curious. Panretin is so named because it reacts with all 6 receptors (3 RARs and 3 RXRs). Thus, the RAR activities suggest that topical Panretin could be used for approved treatment for other retinoids such as tretinoin or isotretinoin. Tretinoin is the active ingredient in Retin-A (for acne), Renova (for wrinkles), and iso-tretinoin is the active ingredient in Accutane (for acne). Panretin (ali-tretinoin) has not been tested for any of the above, so I'm not sure that a physician would prescribe it because there is no clinical data. LGND does have clinical data for Panretin oral for the treatment of psoriasis, but I'm not sure why they have not done any clinicals using topical Panretin for psoriasis, acne, or wrinkles. LGND does plan on doing clinical trials for basal and squamous cell carcinoma, but a start date for such trials (which I assume would start at the Phase II level) has not been announced.

To: Alper H.YUKSEL who wrote (24288)	8/11/1998 8:18:00 AM
From: Henry Niman	Respond to of 32384

When I gave the potential off label uses for LGND's products, I should have mentioned the initial data for treating advanced breast cancer with Rexinoids in combination with SERMs, like Tamoxifen and Evista. At the ASCO meeting in May, initial data on combining Panretin (9-cis retinoic acid, 9-cRA) with Tamoxifen (Tam) was presented. Although the report was just on the first 8 patients, 2 did respond to the treament with a reduction in their pulmonary metastases and remained on the treatment at 11 months and 14 months. The abstract doesn't give details on the status of these two responding patients with regard to Tamoxifen resistance, but 5 of the 8 patients in the trial had failed hormonal therapy (which I assume was treatment with Tamoxifen). Ligand IR had suggested that the Phase II Targretin trials on advanced breast cancer could initially target Tomoxifen resistant tumors. Here's the abstract: A PHASE I TRIAL AND PHARMACOKINETIC (PK) STUDY OF 9 CIS-RETINOIC ACID (9cRA, LGD 1057) AND TAMOXIFEN (Tam) IN METASTATIC BREAST CANCER PATIENTS. J.A. Lawrence, R.F. Murphy, R. Caruso, M. Shovlin, M. Noone, M. Kaiser, K.H. Cowan, P.C. Adamson, J. Zujewski, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD. The antiproliferative, differentiation, and apoptotic effects of retinoids have led to their development for breast cancer. The inhibitory effect of Tam is potentiated by the addition of retinoids in preclinical models. A phase I trial and PK study of 9cRA and Tam in metastatic breast cancer patients was performed. 9cRA was administered p.o. daily at 5 planned dose levels of 50 to 140 mg/m2/d. Following 4 wks of 9cRA administration, patients received Tam 20 mg q.d. Dose limiting toxicity (DLT) was defined as >/= to grade 3 non-hematologic toxicity, grade 4 neutropenia >3 days, or grade 4 thrombocytopenia. Maximum tolerated dose (MTD) was defined as the highest dose level that not more than 1/6 patients experienced a DLT. Eight stage IV breast cancer patients (6 ER/PR positive, age 49 to 64 y.o.) were entered. Prior therapy included hormonal (n = 5) and chemotherapy (n = 6). At 90 mg/m2/d, 3/5 patients experienced DLT prior to Tam administration: grade 3 headache (n = 1), grade 3 hypercalcemia (n = 1), and grade 3 pulmonary toxicity (n = 1). Hyperlipidemia was seen (n = 7) but not considered a DLT. One of 5 patients had an asymptomatic delay in the rod-cone break by Goldman Weekers dark adaptometry at 8 weeks. Two patients (dose 70 and 90 mg/m2) demonstrated improvement in their pulmonary metastasis and remain on therapy at 11 and 14 months. The peak plasma concentration of 9cRA following a 70 mg/m2 dose was 1.6 ñ 0.9 M. Plasma AUC decreased from 237 ñ 135 M on day 1 to 135 ñ 125 M by day 28. In the pt with a rod-cone break delay, retinol decreased to 25% of baseline levels. Additional patients are being evaluated at the 70 mg/m2/d dose level. A well tolerated combination of such agents may be useful in the management of metastatic breast cancer and in the development of chemoprevention strategies.

To: Alper H.YUKSEL who wrote (24288)	8/11/1998 9:11:00 AM
From: Henry Niman	Respond to of 32384

Alper, The positive clinical data for Panretin treatment of breast cancer is the first human data that addresses the question of Targretin's potential for treating human breast cancer. Both Panretin and Targretin showed promising results in preventing breast cancer in rats. A well established model was used, and both drugs were able to prevent breast tumors in rats that were pre-treated with a chemical that causes a high incidence of such tumors. Tamoxifen and Evista also produced promising results in that animal model. Of course Tamoxifen has been the hormonal treatment of choice for human breast cancer, and both Tamoxifen and Evista have produced promising data on the prevention of breast cancer in high risk humans. The government is currently sponsoring a breast cancer chemo-prevention trial that compares Tamoxifen to Evista. Panretin and Targretin not only prevent breast cancer in the same models that generated positive results with Tamoxifen and Evista, but both compounds were also shown to synergize with the SERMs, which led the government to sponsor at least two clinical trials combining Panretin with Tamoxifen to treat advanced breast cancer. In the animal studies, the compound that worked best in treating breast cancer was Targretin. It also synergized with Tamoxifen to eliminate tumors and importantly, it also was effective against Tamoxifen resistant tumors (tumors that grew in spite of Tamoxifen treatment). Although Tamoxifen is the hormonal treatment of choice for human breast cancer, many patients become resistant. I suspect that this population will be targeted by the Phase II Targretin breast cancer trials that LGND should be announcing soon. Targretin of course targets RXRs, which may allow use at higher levels without side effects. As noted in the ASCO abstract on Panretin combination therapy, patients did have a triglyceride rise, but the increase was not classified as dose limiting. The patients were in advanced stages of the disease, and the two that responded and remained on the treatment had metastases in their lungs. As noted on Sunday, positive results with Targretin on Tamoxifen resistant breast cancer would be very high profile, and help the street realize the potential of off-label use.