Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

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

To: bob zagorin who wrote (29955)	1/8/2000 11:33:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Speaking of Targretin for CTCL, here's the text of the first patient to address the FDA advisory committee: MR. KUPSCH: Good morning. I am Barry Kupsch, a sufferer of CTCL. I'm voluntarily appearing this morning to share my experience with Targretin capsules. Ligand is not paying me to speak but are reimbursing for necessary expenses. Several years ago, I was afflicted with an unusual skin disorder and was seen by several dermatologists. Not one of them could come up with the diagnosis, just a guess. My body was covered with a very raised, red, itchy rash, accompanied by the enlargement of the lymph nodes in my neck and groin. The itchiness progressively worsened and I started getting large cracks in my hands, heels, and soles of my feet. Walking was an experience in pain every day with every step I took. The only way I could walk was to use crazy glue and glue the cracks together, hoping none would end up in the crevices. When I did walk, I would shuffle along at the same speed as an elderly person. During the following months, I was started on PUVA treatments in Edmonton. This was a trip twice a week and a drive of 2 hours one way. At first there seemed to be some improvement, then suddenly I reacted to it. My skin became very reddened as if I was severely sunburnt. After this, I was unable to tolerate the sun at all. The only way I could be outside was to cover my body with sunscreen and wear sun protective clothing. Shortly thereafter, I was admitted to the hospital twice with generalized swelling due to fluid retention. My skin started weeping fluid, especially from my legs and ears. At this time I was sloughing skin and my face looked like it was dipped in water, then oatmeal. The pain was very severe. Some of the medications which I was on were methotrexate and soralen which made my skin even more sun sensitive. The itchiness worsened, which was one of the side effects of this drug, and the pain remained constant. In March of 1996, I was started on interferon injections and a positive diagnosis of CTCL was made. I did start having some improvement in my hands and feet, but the itchiness remained. I took the interferon for a year and a half. The major side effects for me were depression, irritability, and constant flu-like symptoms. My arms and thighs were sore from all the needles. My condition was not improving and the itch was so bad I took a wire brush to my hands, desperate for some relief from the itch. Instead of sleeping at night, I would scratch till the early morning hours, and our bed sheets would be constantly covered with blood. Since my occupation is farming, I spend many hours outside. While doing my field work, I thought I was protected from the sun by the tractor cab. Much to my surprise, the sun rays were magnified by the glass, burning me even more severity. Thus, I was unable to do my farm work outside in the daytime. So, when other people were sleeping, I was out working. My condition was to the point of being unable to work, so I hired people to help me farm. There were many times I hated being around people, and people did not like being around me because I was constantly scratching. My sleep habits were messed up and my family was having a hard time coping with the miserable person I became. Since I could not see any light at the end of my tunnel, suicide did cross my mind just to end the constant itch and pain. In September of 1997, I was given the opportunity to partake in this Targretin study which was the only thing left for me to do. I found the Targretin easy to take and I noticed a change in my skin within a few days. I started shedding layer after layer of skin. The cracks all healed and my skin slowly started to look normal. After being on the Targretin for a year and a half, the itchiness had finally subsided. My skin is now a normal texture and color. My lymph nodes have decreased dramatically in size. The only side effects I have had are higher levels of cholesterol and triglycerides. I have been taking Lipidor to counteract this. I finally can live a normal life, work, and have fun outdoors, and feel there is a future for me and my family. In October, I decided to come off the Targretin temporarily just to give my body a rest from all the drugs, but plan to resume the treatment should any problems arise. Thank you.

To: bob zagorin who wrote (29955)	1/8/2000 11:37:00 AM
From: Henry Niman	Respond to of 32384

Here's the second patient: MS. GROBLUSKI: Good morning. My name is Gaetana Grobluski. I'm here to speak voluntarily regarding my use of Targretin capsules as treatment for my CTCL. I am not receiving any payment for being here except for expenses directly related to my travel. About two and a half years ago, I developed symptoms on my body which were red, very itchy, skin pealing. My hands were like claws. I couldn't open them. Fissures were deep. And doctors didn't know what was happening at first. I was being treated for eczema. I was being treated for psoriasis. They gave me prednisone. Prednisone just made my body swell up and did nothing. After being introduced to the doctors at NYU Medical, they put me on something called cyclosporine. Cyclosporine didn't seem to help to do anything. I was introduced to my current doctor who, after substantial treatments -- or I should say, after trying to find out what was wrong with me, he put me on something called interferon A. Interferon A did nothing for me except make like a zombie. I was lethargic. I had no interest in life. I didn't want to get out of bed. It was a major decision whether to have a cup of soup to eat or a plate of spaghetti. I describe it as a zombie like feeling. After approximately three months of being on interferon A, they tried methotrexate. Methotrexate had a reaction to me which made me like a crazy lady. I'd be scratching and pulling at my body. I'd go through chills and completely uncomfortable. After methotrexate, we tried what they call PUVA treatments. PUVA treatments I felt did nothing for me except give me a very lovely tan. I got lots of compliments on what a beautiful looking tan I had, and that was about it. After discussing with my doctor, we decided to try this Targretin. I've been on it for a little over two years now. Targretin I feel has given me back my life. The fissures are gone. The scaling has gone. I used to get up in the morning and my skin used to just peal off. I felt like a snake shedding its skin. Today my skin is smooth again. I have a life. I do experience some side effects with Targretin, but nothing I can't overcome and control. I take some Tricor and Lipidor and Synthroid. In addition, I have such experience as losing hair and some weight gain. Those I feel I can overcome. But my experience with Targretin has been lifesaving as far as I'm concerned, and I'm happy to be in the program and hope to continue using it. And I thank you for listening to me.

To: bob zagorin who wrote (29955)	1/8/2000 11:40:00 AM
From: Henry Niman	Respond to of 32384

Here's the third patient: MS. BORCHERDING: My name is Nancy Borcherding, and I'm excited that I have the opportunity to talk to you today. I came here voluntarily to tell you my story. Before I begin, I want to make it clear that Ligand has not paid me to speak here today, but they have only reimbursed me for my expenses so that I could be here. I was diagnosed about 18 years ago with CTCL. Since then, I have tried many treatments, the same that have been told to you by others today, Accutane, methotrexate, prednisone, PUVA, UVB, UVA. All of these treatments did help me for some time, but they eventually became intolerable and also ineffective, producing itching and sometimes added skin lesions. Two and a half years ago, I thought my only option was interferon. Again, the two people who spoke to you today had mentioned that. I was terribly frightened by that drug. I had had a friend who was on it. I do lead and have always led a very active life. I work full-time and I work out every day. I knew that on this drug none of that would be possible and that my life would change. Fortunately for me, my doctor who had been treating me, who was a man of great compassion and a person who had kept in very close contact with all kinds of studies and things that were going on with this disease, suggested that I enter this study of Targretin. I began by using the topical Targretin, which at the beginning again gave me relief, but again only temporarily, and after a year Dr. Deborah Brenneman suggested that I go on the Targretin capsules. This drug has improved my condition dramatically. The skin lesions have faded. The itching has stopped, and everything almost has virtually disappeared. How could anybody ask for more than that? I do have some side effects. I do have raised triglycerides, lower thyroid, and my white blood count also is lowered. But all of these have been able to be treated with medication. The side effects certainly can't compare to how wonderful the treatment has been on the Targretin capsules. I feel that I am a very, very fortunate person. I have been on the capsules for two and a half years, and I continue to take them as I speak to you today. My CTCL is 95 percent cleared, and the side effects are all under control. I guess more importantly the fact that I'm here today, that I'm happy and alive and have a wonderful quality of life is more than I can say. I can't complain about just popping a pill to get me to that level. I hope that through my appearance today that I will be able to help other people who have the same disease as I do, and I just thank you for the opportunity of being here.

To: bob zagorin who wrote (29955)	1/8/2000 11:42:00 AM
From: Henry Niman	Respond to of 32384

Here's the fourth: MR. CARTER: My name is John Carter. I'm 75 years of age and I'm a retired surgeon, having retired the 4th of July of this year. I was a clinical professor of surgery at the Albany Medical College prior to my retirement. I come here voluntarily. I have nothing whatsoever to do with Ligand Corporation. They've paid my way down and they're paying for the hotel expenses. In the winter of 1997, I began to have a terrible itch. I went to see several dermatologists, all of whom told me I had dry skin, and they gave me all kinds of salves to work and try with. None of them seemed to work. As time went on, my dry skin and itching worsened. I began to develop generalized adenopathy. I had many biopsies, and finally a positive biopsy was obtained in the summer of 1998. At that time, I was referred down to Yale, and at Yale they started me on PUVA, supplemented by photopheresis. Both of them tended to make things worse. I developed edema, large lymph nodes throughout my body. I had so much edema in my left leg that I thought that I had a deep phlebitis, and I had an ultrasound done, proving that my veins were clear. At that time I also had biopsies done which showed only a chronic inflammation. At that time I was asked if I would be willing to go on the Targretin study, and I said, sure, and I went on it in August of 1998. I've been on it since that time, 8 capsules per day. No problem taking the capsules. Within a short period of time, my itching disappeared. I might say that the itching didn't bother me particularly in the operating room, but it had a terrible effect upon me at night. I was unable to sleep, and the lack of sleep began to show in my work. Anyway, when I went on the Targretin, the itching soon disappeared and everything became fine again. I've had no bad side effects from the Targretin. My triglycerides went up a little bit, but they're down to normal with Lipidor, 10 milligrams a.m. and p.m. Although I had no clinical symptoms of hypothyroidism, my thyroid function test deteriorated a bit, and I'm on 0.05 milligrams of Synthroid per day to control that problem. I have had no problems with the disease. I think Targretin is a fine drug, and I hope that you people will approve it for the rest of the people in this country who might be suffering from T-cell cutaneous lymphoma. Thank you for listening.

To: bob zagorin who wrote (29955)	1/8/2000 12:29:00 PM
From: Henry Niman	Respond to of 32384

Two case studies: DR. HYMES: Good morning. Thank you, Dr. Reich. I'd like to present 2 patients who were enrolled on the Targretin study in my institution not only from the perspective of an investigator, but also from the perspective of a physician who cares for a larger number of patients with cutaneous T-cell lymphoma. I have over 200 patients in my practice who I'm actively following with cutaneous T-cell lymphoma and see 1 to 2 new patients per week. The first patient I'd like to present is a 67-year-old woman with a history of stage IIB cutaneous T-cell lymphoma with a 10 and one-half year history of disease duration. There was 70 percent body surface area involvement with plaques, patches, and tumors, as well as three large cutaneous tumors, which the photographs will reflect. She's been refractory to previous treatments, including topical nitrogen mustard, as well as refractory to treatment with systemic interferon alpha 2B at doses of 7 and a half to 10 million units 3 times per week. This is the appearance of a large tumor on her right forearm at baseline. Following 12 weeks of therapy, there was significant flattening of the tumor. The bi-dimensional measurements of this area have not changed, but of course, there's actually a significant reduction in the total volume. At week 28, the skin had returned to normal texture with only some residual hypopigmentation. I would like to point out that based upon the very conservative composite assessment lesions, there would still be a tumor score despite the apparent major clinical response because of residual hypopigmentation. This is a lesion on the top of her scalp. If you notice, it's actually two large necrotic tumors which are communicating underneath a bridge of normal skin. This lesion is referred to in the letter which this patient submitted in the open public hearing. She described this tumor as being quite odoriferous to the extent that her grandchildren would not want to ride in the same automobile with her. I'd also like point out that because of the location, this would not be immediately apparent in hemi-body photographs. Nonetheless, the localized photographs show that at week 12 there was significant healing with a replacement of the tumor with granulation tissue. At week 41, the scar is barely visible under normal regrowth of her hair. If we're to look at the assessments based upon protocol endpoints, she achieved a 50 percent improvement, the definition for response based on physician's global assessment, and the composite assessment ratio determined independently at week 8. In summary, she had a 75 percent response, 75 percent improvement of her skin, with a duration of greater than 2 years. The body surface area involvement reduced from 70 percent to 12 percent. The three cutaneous tumors present at baseline all completely resolved. Interestingly, because dose reduction and concomitant medications were required to control hypertriglyceridemia, there was the appearance of a new tumor measuring 1.1 centimeters with dose reduction. This was in an area previously uninvolved with a cutaneous tumor. With dose increase, the tumor again resolved. The second patient I'd like to present is a 58-year-old woman with stage III cutaneous T-cell lymphoma. There was a 2-year duration of disease. She was erythrodermic with 100 percent body surface area involvement. There were two clinically abnormal lymph nodes, and her previous treatment included refractoriness to interferon, as well as refractoriness to high dose methotrexate with leucovorin rescue. Photographs of her arm showed thickening and erythema of the skin at baseline. By week 12, there was a reduction erythema. By week 36, the texture of the skin and the color of the skin had returned to normal. This improvement is not a photographic artifact. This was reflected in my personal clinical assessment of this patient. Similar improvement was noted on her back with the hypertrophic erythematous skin becoming paler and assuming more color and texture by week 36. There was good correlation between the composite assessment ratio and the physician's global assessment ratio, with the patient achieving a 50 percent improvement in both by week 16, and it being sustained and consistent improvement by up to 52 weeks on this slide. In fact, the patient has a 65 to 75 percent response based on the PGA and the CA over 2.2 years, and the patient continues on medication. Her complaints of pruritus, alopecia, and nail changes fully cleared. There were two nodes at baseline which completely resolved, as well as toxicity defined as elevated triglycerides requiring dose reduction and administration of medication. Since cutaneous T-cell lymphoma is a chronic, symptomatic, incurable, and relapsing disease, patients with this disease will require a sequence of multiple different therapies. Targretin is impressive because it has a very high single agent response rate in patients refractory to drugs which are ordinarily our only agents useful in this disease. The safety profile is qualitatively different from other treatments for cutaneous T-cell lymphoma, providing an advantage in avoiding cumulative and overlapping toxicities. The common toxicities, hypertriglyceridemia and hypothyroidism, can be easily controlled with medications that most physicians are familiar with using. The ease of oral administration eliminates the need for travel to centers for PUVA, electron beam therapy, or photopheresis. And the long duration of response is particularly impressive in this heavily pretreated group of patients.

To: bob zagorin who wrote (29955)	1/8/2000 12:31:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

More case studies: I'd now like to introduce Dr. Madeleine Duvic from the M.D. Anderson Cancer Center who will discuss her experiences with Targretin. DR. SCHILSKY: I'd just like to remind the sponsor that you've already exceeded your allotted time. So, I'd ask that you either abbreviate this presentation or move directly to your conclusions. Thank you. DR. DUVIC: Thank you. My name is Madeleine Duvic, and I've been involved with the care of CTCL patients at M.D. Anderson since 1985. We actively treat over 600 patients and evaluate 100 new patients per year, and 41 percent of my patients have been treated in the Targretin trial. I would like to share with you the dramatic and long-lasting improvement seen in four elderly patients. First was a 71-year-old man with stage IIA mycosis fungoides for 13 years who had failed 9 previous therapies, including several combinations of chemotherapy and pentostatin. He had 59 percent patch and plaque involvement. The patches are not shown well in the global photograph. But at 9 months, you can see he has a complete remission. However, there's an index lesion here that did not resolve and is shown in the next slide and remains to this day. Again, the CA in yellow and the PGA in green are back to back and show a response of 50 percent as early as week 4. This patient had a 98 percent response, disappearance of all cutaneous lesions, resolution of adenopathy and normalization of Sezary cell counts to 0 by week 12. He has had only triglyceridemia as a side effect, and he's been in almost complete remission for over 17 months. Secondly, an 81-year-old man with 7 years of CTCL and 7 previous therapies presented with 48 percent thick plaques on the body and adenopathy. He resolved with only residual hyperpigmentation on the trunk and on the extremities. His skin biopsy at baseline has shown resolution of the dermal infiltrate by week 8 and normalization of the epidermal changes. Again, the CA and PGA were similar confirming PR at 4 weeks and CR at 12 weeks. To summarize, this patient had a complete response confirmed by biopsy, resolution of nodes and Sezary cells which is ongoing at 17 months. Only mild side effects were present. The third case is a 63-year-old male with a 5-year history of CTCL who submitted a letter. He developed a large tumor with large cell transformation that relapsed on both CMED and ESHAP chemotherapies. This tumor resolved by week 4, leaving only an ulceration, and healing with normal skin that remains to this day. He also had clearance of 39 percent of his body involved with patch/plaque disease. Again, a biopsy comparing week 8 to week 0 shows resolution of the dermal infiltrate, resolution of the ulceration, and normalization. Again, his response was rapid, as shown by both the CA and the PGA, and he continues in almost complete remission ongoing at 2 years. Finally, we saw patients with exfoliative erythroderma such as this 71-year-old man with Sezary syndrome who had at baseline 100 percent body surface area and lichenified skin. He had failed interferon, photopheresis, nitrogen mustard. This patient was actually classified as a progressive disease in the study because lymphadenopathy noted prestudy was not appreciated at baseline and reappeared at week 4 evaluation. Since he had no index lesions, his assessment can only be determined by PGA, and it reached 50 percent by week 24 with sustained improvement shown at week 40 on the next slide. This man has skin like an alligator. It was thick, scaly, with lichenification of all his extremities, and over the course of therapy, his skin completely normalized, returning to normal color which remained after study. In summary, excellent clinical responses are seen for oral Targretin at all stages of this disease. As shown, the composite assessment was overly conservative and underestimated the clinical responses seen in some patients. Targretin has important advantages over other available agents. As an oral capsule, it does not require venous access or catheters. Patients do not get infections resulting from lines or from treatment. Targretin is not immunosuppressive. The responses to Targretin are rapid, dose-related, and durable. Side effects are reversible and can be prevented, treated, and monitored. From my experience, Targretin is an important new therapy for CTCL. Targretin would be helpful and a welcome addition for treating CTCL at all stages of the disease. Many of the patients I treat have run out of available or non-immunosuppressive options.