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Clinical Trials

mystery molecule

PT-100 (Talabostat) plus Rituxan

Date: July 27, 2003

by Chaya Venkat

Phase I/II Clinical Trial from Point Therapeutics, Inc.

Below is an announcement of Phase I /II clinical trials for CLL from a company called Point Therapeutics, Inc.. It claims that combination of their PT-100 with Rituxan shows increased effectiveness compared to Rituxan alone, since PT-100 enhances the production of neutrophils, natural killer cells (NK-cells), macrophages, and CTL (cytotoxic T-cell) activity, all of which are important in carrying out the actual killing of cancer cells tagged by Rituxan. PT-100 (renamed Talabostat somewhere along the line) is an orally available small molecule drug. That means it is can be taken as a pill, no injections or infusions. Small molecules drugs are becoming increasingly rare in immunotherapy. PT-100 is also being tested for acute anemia and neutropenia caused by chemotherapy and / or bone marrow dysfunction.

They are very cagey about the specifics of their drug PT-100, but here is what I have been able to learn so far, after a lot of surfing around. Some of you who have access to the top experts, it would be nice if you can ask a few questions about this drug, its chemical name is "dipeptidyl peptidase inhibitor". The URL to the company's science web document is: You will notice they are now calling the drug Talabostat.

Background on PT-100

The company claims that PT-100 has the ability to stimulate the growth of primitive hematopoietic progenitor cells. They believe that PT-100’s interacts with stromal cells to increase the production of certain hematopoietic growth factors, required for the development and differentiation of mature blood cells. For example, PT-100 is expected to stimulate the production of the growth factor  G-CSF, which is a protein involved in both the expansion of primitive hematopoietic progenitor cells and the differentiation of committed progenitor cells into neutrophils. 

In mouse studies, Point Therapeutics demonstrated that PT-100 significantly accelerated neutrophil recovery in mice following chemotherapy. They have also tested PT-100 in an animal model of acute anemia. Results of these tests demonstrated that mice pretreated with PT-100 developed less severe anemia due to significantly faster recovery of mature red blood cells than in the control animals. In addition, committed progenitors of red blood cells were substantially increased in PT-100-treated mice, which supports previous observations that PT-100 increases the primitive hematopoietic progenitor pool in the bone marrow of mice. 

I also tracked down an ASCO 2003 abstract that describes oral treatment of tumors in mice. They showed significant anti-tumor effect attributed to increased CTL (cytotoxic T-cells) activity, increased production of neutrophils and NK-cells and macrophages, all of which are involved in attacking tumor cells. These are all the cell types we have discussed many times before as the necessary part of Rituxan therapy. They are the cells that do the actual killing of cancer cells tagged by Rituxan. The abstract goes on to claim that in animal studies, combination of Rituxan plus PT-100 had increased effectiveness. This is the work that is the basis of the newly announced clinical trial for CLL patients, combining Rituxan with PT-100. 

Attached below is also an abstract for an article in a very recent Blood-online that describes the nature of PT-100. If all this biochemistry sounds like Dutch, not to worry, I have not been able to figure out much of this either. This is an entirely new area for me, tinkering with the stromal cells to improve formation of very early stage and primitive stem cells. Sounds interesting, but I have no clue at this point if this is good, bad or indifferent.


Dipeptidyl peptidase inhibitor PT-100: An anti-tumor small molecule that amplifies immunity.

Author(s): B. Jones, G. T. Miller, M. I. Jesson, T. Watanabe, B. P. Wallner, S. Adams

Point Therapeutics, Boston, MA; Kyushu University, Fukuoka, Japan; Biotransplant, Inc., Boston, MA; Point  'Therapeutics Inc., Boston, MA

Abstract: PT-100 (Val-boroPro) has been shown to be a potent stimulator of hematopoiesis acting via the upregulation of cytokines. PT-100's targets are dipeptidyl peptidases, such as Fibroblast Activation Protein (FAP), which are involved in the regulation of polypeptide hormones and chemokines by cleaving N-terminal Xaa-Pro (Ala). Because FAP is present on stroma of lymphoid tissue and tumors, PT-100's effect on tumor growth was studied in vivo. Oral Treatment of tumor-bearing mice with PT-100 significantly  suppressed tumor growth and increased expression, in tumors and lymph nodes, of chemokines and cytokines that promote anti-tumor immune responses. Although CD26 is an alternative dipeptidyl peptidase target for PT-100 in the immune system, it was not involved, since PT-100's activity was undiminished in CD26-knockout mice. Mice that had rejected syngeneic tumors after PT-100 treatment became specifically resistant to secondary tumor rechallenge and had increased anti-tumor CTL activity. T cells play a major role in this anti-tumor effect, although T-independent activities also contributed greatly as was shown in immunodeficient mice (Rag-knockout and scid mice) where PT-100 treatment inhibited the growth of human tumor xenografts by 50-60%. The innate effector cells, neutrophils, NK cells and macrophages, are implicated in PT-100's activity because they are known to respond to the cytokines and chemokines upregulated by PT-100. These cells can function as killer cells in antibody-dependent cytotoxicity; therefore, the ability of PT-100 to augment the anti-tumor activity of specific antibodies was investigated. In a xenograft model of human B-lymphoma, PT-100 was shown to enhance anti-tumor activity of the anti-CD20 mAb, Rituxan. PT-100 is a small molecule with a unique mechanism of action and potential anti-cancer therapeutic application.

ASCO 2003, Abstract No: 860

Press Release:

Point Therapeutics Announces Enrollment Of First Patient In Combination Trial of Lead Product PT-100 and Rituxan(R)

BOSTON, July 8/PRNewswire-FirstCall/ -- Point Therapeutics, Inc. (OTC Bulletin Board: POTP.OB) today announced the enrollment of the first patient in a Phase 1/2 trial investigating combination therapy of PT-100 and Rituxan(R) for B-cell hematologic malignancies, including non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Rituxan(R) is a genetically-engineered monoclonal antibody directed against an antigen found on the surface of B-cells. The study will include patients whose disease has relapsed following chemotherapy and/or prior Rituxan(R) treatment. The Phase 1 portion of the trial is a multi-center, dose-escalation trial to determine the maximum tolerated dose to be studied in Phase 2. The Phase 1 trial will study up to 24 patients and is expected to be completed by the first half of 2004. 

Point has found that in pre-clinical animal tumor models, PT-100 stimulates the production of cytokines and chemokines known to promote both acquired and innate immune defenses against malignant tumors. The Company has demonstrated the anti-tumor activity of PT-100 in these pre-clinical models using a variety of tumor types. PT-100 is also currently being studied as a treatment for neutropenia in chemotherapy patients and may be developed as a potential treatment for a variety of hematopoietic disorders. 

Barry Jones, Point's Senior Vice President of Research, stated "The results published in the proceedings of this year's annual ASCO meeting showed that PT-100 has potent immuno-stimulatory activity in vivo in mouse models. We believe that PT-100 may provide an important and effective treatment option in patients with certain cancers. The pre-clinical results provided a compelling basis for the Company to initiate human clinical studies for the use of PT-100 for NHL and CLL in combination with Rituxan(R)." 

About Point Therapeutics, Inc.

Point is a Boston-based biopharmaceutical company developing small molecule drugs for the treatment of a variety of cancerous tumors and certain hematopoietic disorders. Point's lead product candidate, PT-100, has the potential to inhibit the growth of certain cancerous tumors. Point has initiated a Phase 1/2 human clinical study to test the safety and efficacy of PT-100 in combination with Rituxan(R) in patients with hematologic malignancies, such as NHL and CLL. Point is also developing PT-100 as a potential therapy for the treatment of hematopoietic disorders caused by chemotherapy treatments. Point is currently evaluating PT-100 in a human clinical study in which cancer patients undergoing chemotherapy are treated with PT-100 for neutropenia.


Blood. 2003 May 8 [Epub ahead of print].

Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies.

Jones B, Adams S, Miller GT, Jesson MI, Watanabe T, Wallner BP.

Point Therapeutics, Inc., Boston, MA 

In hematopoiesis, cytokine levels modulate blood cell replacement, self-renewal of stem cells, and responses to disease. Feedback pathways regulating cytokine levels and targets for therapeutic intervention remain to be determined. Amino boronic dipeptides are orally bioavailable inhibitors of dipeptidyl peptidases. Here we show that the high affinity inhibitor Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor cells in vivo, and accelerate neutrophil and erythrocyte regeneration in mouse models of neutropenia and acute anemia. Hematopoietic stimulation by PT-100 correlated with increased cytokine levels in vivo. In vitro, PT-100 promoted growth of primitive hematopoietic progenitor cells by  increasing G-CSF, IL-6, and IL-11 production by bone marrow stromal cells.

Two molecular targets of PT-100 are expressed by stromal cells: CD26/DPP-IV and the closely related fibroblast activation protein (FAP). Since PT-100 was active in the absence of CD26, FAP appears to be the hematopoietic target for PT-100. Interaction of PT-100 with the catalytic site seems to be required, because amino-terminal acetylation of PT-100 abrogated both enzyme inhibition and hematopoietic stimulation. PT-100 is a therapeutic candidate for treatment of neutropenia and anemia. The data support the increasing evidence that dipeptidyl peptidases can regulate complex biological systems by the proteolysis of signaling peptides. 

PMID: 12738665

Presentation by Point Therapeutics

Here is a link to a presentation made by Point Therapuetics. Some of the early slides are business related, but the bulk of the presentation thereafter is technical.

Remember, this is the company speaking, so you have to have the salt shaker handy. If these mouse study performance of PT-100 is reproduced in human clinical trials, this can be a very important development for us. If. 

We have just been discussing serious and potentially life threatening side effects such as neutropenia and anemia in CLL. And how Rituxan therapy does not work so well in non-chemo naive patients probably because the body is not able to do its part, supply the fire power to kill the cells tagged by Rituxan. If these guys at Point Therapeutics are right, even tough to treat patients pop a PT-100 pill every day along with the usual Rituxan infusion once a week, and they would get better responses to Rituxan. And at the same time, fix any little pesky problems the patients may have in terms of neutropenia and anemia.

What's wrong with this picture? Nothing really, except for the fact that there is precious little detail, this is early stage stuff, and there is no information on possible side-effects. It is encouraging that they are in clinical trials already, and in bed with IDEC and GENENTECH of Rituxan fame. (See my previous article for the company press release). I doubt IDEC&GENENTECH's huge staff of researchers and biochemists will easily allow their crown jewel to be contaminated with a real snake-oil con game, hopefully they saw good reasons for embarking on this clinical trial. The million dollar question: does it work, and does it work without killing the patient with side effects?

An Update

Those of you who are following the Point Therapeutics PT-100 clinical trial might find this update interesting. As you know, PT-100 is expected to enhance the effect of monoclonal antibody drugs such as Rituxan. The phase one trial is underway, at three centers: Houston, Detroit and Winston-Salem. Phase - II is expected to start early in 2004. I will follow up on this interesting technology and report back to you with any additional news. Its good to know that once in a while we get a responsive human being at the other end of a query from CLL Topics.


Dear Dr. Venkat:

I apologize that it has taken so long to respond. Your inquiry regarding PT-100 in CLL was recently forwarded to me. Firstly, I would like to compliment you on what I feel is the best disease-related website I have seen to date. It is very reader-friendly, and the content is very complete. You have obviously spent much time creating this very important resource for patients. 

I can tell you briefly about PT-100; I would refer you to our website, but it is out-of-date with respect to information on PT-100 in B-cell malignancies. The revised website should be active later this month with the non-confidential information of PT-100’s effects in both hematologic malignancies and solid tumors. So, please check in a week or so. In the meantime, PT-100 has immunostimulatory properties that, in animals, shows enhanced activity of rituximab in non-Hodgkin’s lymphoma. We believe this effect is mediated through ADCC. As you are aware, this disease is a “close cousin” (as you say in your website) to CLL, and many patients with Rai Stage III/IV have significant nodal involvement in their disease. We believe that PT-100 will have activity in later-stage CLL in combination with rituximab. 

The ongoing trial is a Phase 1 dose-finding study. We have completed enrollment into our first dosing cohort and plan to begin enrollment into the second cohort in mid-October. Depending on the dose that we select, we may be initiating our Phase 2 in early 2004. If you’d like to contact me toward the end of the year, I might be able to provide you with additional details regarding the study.

The study sites currently involved in the trial are the VanElslander Cancer Center in Detroit, MI, MD Anderson Cancer Center in Houston, TX, and Wake Forest University in Winston-Salem, NC. 

I commend you on your commitment to educating patients with CLL. My stepfather died two years ago of advanced CLL, and I am sure that he would have appreciated such a user-friendly resource. 

Best regards, 

Maggie Uprichard

Margaret J. Uprichard, PharmD
Vice-President, Clinical and Regulatory Affairs
Point Therapeutics, Boston MA




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