Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
The last study also has some empirical evidence; updated june this year. The use of growthhormone in the treatment of ALS with stemcells.
(...)OTHER NOTES: Kelly was on a high protein diet and taking a cocktail of medicines including the experimental drug IGF which he feels may have helped to make the stem cells more effective more quickly. When Kelly came for the treatment, he did not bring his IGF but was able to substitute HGH for it. HGH raises the level of IGF in the body. Soon after hearing that Kelly was taking HGH, the other ALS patients wanted it too.
http://www.stemcellschina.com/content/view/162/122/lang,en/
It appears that the combination of Grothhormone and stemcells is successfull is treating all kind of diseases.
IPLEX™ (mecasermin rinfabate [rDNA origin] injection) is an aqueous solution for injection containing a binary protein complex of human insulin-like growth factor-1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3), both produced by recombinant DNA technology. http://www.go-iplex.com/description.asp
or reverse:
rhIGF1/rhIGFBP3 = IPLEX
RTN would you be so kind to correct this on INSM/IHUB info page! One of the 1st lines.
Coincidence? 3 drugs & 3 execs?
* Neupogen ($976m sales)
* Neulasta ($2.9b sales)
* Epogen ($3.2b sales)
All 3 are produced by Amgen; named by Dr. Allan as possible 'follow on' drugs to be produced by Insmed.
* D. Farrar
* Mr. Glover
* D. Lanfear
All 3 are former Amgen execs and still working for Insmed.
http://yahoo.brand.edgar-online.com/people.aspx?cik=1104506
Mr. Lanfear was responsible for the success of EPOGEN.
http://businessweek.brand.edgar-online.com/EFX_dll/EDGARpro.dll?FetchFilingHTML1?SessionID=oQscj4St_...
http://www.secinfo.com/d14D5a.u4a4e.d.htm
Could be coincidence!?
What would you do if you were the boss of Amgen and there's a possibility that a $6b market is canabalized by a small biopharmaceutical, where 3 former execs of Amgen are wotking?
Sorry ED, ALS will not generate revenue:
"Insmed is currently supplying IPLEXTM on a cost recovery basis to these Italian patients under an Expanded Access Program. Data collected through the Expanded Access Program in Italy will be used to design future ALS clinical development studies with IPLEXTM."
http://www.insmed.com/PDF/News_Press_Release42507.pdf
Calypte did NOT supply additional data today!
"We expect to complete this trial and assemble the other required information on or before May 10, 2007, the date by which the SFDA requires our response." )page 32
http://tinyurl.com/2pmu6n
...Unless they did it secretly! If so, why? suppose to be a milestone. This will delay SFDA-approval.
D-day, May 10th!
"We expect to complete this trial and assemble the other required information on or before May 10, 2007, the date by which the SFDA requires our response." )page 32
http://tinyurl.com/2pmu6n
This is our 1st focus; expect Calypte to PR on this important milestone...if/when filed ticker starts for final SFDA approval!
Report was filed on 2nd of April; if needed data was given to SFDA in previous months, this phrase would not have been part of the 10K.
If Calypte succeeds to deliver this data on time (before 10th of May), I suspect that management values this event important enough to PR this.
Till now I assume, while no PR on this event, that they are still processing this data in an attempt to deliver it to SFDA before 10th of May.
Previous message puts it all in the right perspective! Fact based data needed!No "plans", "intentions", "expect" or other safe harbors...Hard data needed before 10th of May!
Approval is still far away! First is:
"We expect to complete this trial and assemble the other required information on or before May 10, 2007, the date by which the SFDA requires our response." )page 32
http://tinyurl.com/2pmu6n
No, unless you´re able to provide us with your source of this "rumour"!...Rumour started on this MB just an hour ago.
Approval is still far away! First is:
"We expect to complete this trial and assemble the other required information on or before May 10, 2007, the date by which the SFDA requires our response." )page 32
http://tinyurl.com/2pmu6n
TRANSCRIPT Q3-CC
"We undertake no obligation to update or revise the information provided in this call, whether as the result of new information,
future events or otherwise. Before I make the introductions, I would like to state that the patents litigation trials of Genentech
and Tercica vs. Insmed will begin in Oakland, California on Monday, November 6, in the Northern District Court of the U.S. Circuit
Court. Therefore, we will not be making any comments on this litigation.
It is now my pleasure to introduce you to the participants in today's call: Dr. Geoffrey Allan, the President and Chief Executive
Officer at Insmed; Kevin Tully, Chief Financial Officer; and Philip Young, Chief Business Officer. It's now my pleasure to turn the
call over to Dr. Geoffrey Allan for opening remarks. Geoff?
Dr. Geoffrey Allan - Insmed Incorporated - Chairman, CEO, President
Thank you, Jody. Good morning, everybody and thank you for joining the call this afternoon. Insmed has enjoyed a very
productive third quarter result as well as year-to-date for 2006. Let me briefly review some of the year's activities before passing
over to some of the management here for more detailed presentation.
Since we launched IPLEX to the pediatric endocrine market late in the second quarter, we have been gratified to witness a good
physician adoption for the growing number of children on therapy. Still, we'll update you on our progress in a moment.
We continued our label expansion studies for IPLEX and now we have ongoing clinical studies where we are evaluating the
value of IPLEX in several disease areas, such as severe insulin resistance, myotonic muscular dystrophy, AIDS [unintelligible]
dystrophy and we're about to initiate a new clinical study in children with Newman's Syndrome.
Positive data from our severe insular resistance study and our pivotal IGFD studies were presented at several [unintelligible] of
the Congress this last quarter and we hope to present top-line data from these new studies in the first half of 2007.
In the second quarter, we also submitted our European market application. THE EMEA has validated and accepted our application
and we anticipate working with this agency to gain approval in 2007. I am happy to say that we are making all of this progress
while staying within the financial guidance provided to you earlier this year and Kevin will provide more detail of our financial
performance in a moment.
So with that very brief overview, I will now pass on to Phil to present our business results. Phil?"
http://preview.tinyurl.com/y2hm6x
PY comments in more detail and is doing Q&A session with Osborne, as written in earlier post! Please read trial approved transcript!
Jody was NOT at R&R! PY was presenting! Only PY.
CF
FYI, This IS the transcript! It's even filed for the trial.
See link.
http://www.xs4all.nl/~surg3on/2006%20november%20INSMvsTRCA%20trial%20motions/847_20061110_main_docum....
During CC Young says:
We continued our label expansion studies for IPLEX and now we have ongoing clinical studies where we are evaluating the
value of IPLEX in several disease areas, such as severe insulin resistance, myotonic muscular dystrophy, AIDS [unintelligible]
dystrophy and we're about to initiate a new clinical study in children with Newman's Syndrome.
Positive data from our severe insular resistance study and our pivotal IGFD studies were presented at several [unintelligible] of the Congress this last quarter and we hope to present top-line data from these new studies in the first half of 2007.
(page 2)
In Q&A part:
The timing for the next data either from severe resistant myotonic muscular dystrophy, AIDS [like] dystrophy, when can we expect to see the next data?
Phil Young - Insmed Incorporated - Chief Business Officer
We expect to see it in early '07 for everything you just mentioned.
http://preview.tinyurl.com/y2hm6x
There's NO mention of PhII results. PY is expecting DATA on all studies somewhere during H1-2007.
CF
12/05/2006, 10.15AM
As you know, TRCA is claiming that their MAA was accepted for review in January 2006. The similar medicine question has delayed their review cycle by at least 4 months.
Clock started to tick again in May; CHMP meeting is around the 16th of November. I do not expect approval by then, but the December meeting will be tricky! (taking into account a 210 days review time)
CF
Young answered that progress on all stides will be touched upon in January 2007; he did not mention PhII results MMD.
Why would that be bashing? It's clear that during the trial process, INSM will not stress IPLEX and it's use for IGFD-market.
Just the non-hazardous zone; other indications.
CF
Due to lawsuit INSM is focussing on other indications! That's the reason!
MMD trial is still recruiting and INSM expects that study will start in January 2007!
CF
Old news! Was granted on January the 4th 2006, including PR.
Why issue a second PR on old news?
The University of Rochester, designated by the National Institutes of Health (NIH) as one of several "centers of excellence" for muscular dystrophy research, is receiving up to $1 million per year for five years in federal NIH funding and up to $500,000 per year for three years from MDA, for a total of up to $6.5 million, to identify potential muscular dystrophy therapies.
http://www.shareholder.com/insmed/ReleaseDetail.cfm?ReleaseID=183075
CF
"This study only affected the MDA-MB231 cell line of breast cancers. IGFBP-3 is however highly effective against HER-2-positive breast tumors."
From Leyland-Jones Summary (confirms study result of November study):
The anti-tumour activity of rhIGFBP-3 against
ER+ MCF-7 human breast cancer xenografts was compared
to effects in ER- MDA-MB-231 xenografts [84].
Mice with established MDA-MB-231 tumours were
treated for three weeks with rhIGFBP-3, taxol or a combination
of the two agents. In contrast to the effects
noted in MCF-7, rhIGFBP-3 inhibited tumour growth
in MDA-MB-231 by up to 40% of control as a single
agent, but failed to show synergy with taxol. Furthermore,
Western blot analysis showed that rhIGFBP-3
treatment had differential effects on PI3K-AKT and
MAPK signalling in MCF-7 and MDA-MB-231 cells
[84].
Recombinant human IGFBP-3 was also examined
for activity against herceptin-resistant breast cancer sublines
(MCF-7/HER2-18, SKBR3/IGF-IR and BT474/
HerR) with elevated IGF-IR levels. Treatment with rhIGFBP-
3 resulted in dose-dependent growth inhibition of
breast cancer cells. Moreover, the rhIGFBP-3 elicited a
strong dose-dependent increase in herceptin sensitivity
of SKBR3/IGF-IR and BT474/HerR, but showed a less
marked effect with MCF-7/HER2-18 in vitro [85]. Subsequently,
a related in vivo study was undertaken to evaluate
the anti-tumour activity of rhIGFBP-3 in a
xenograft model of herceptin-resistant breast cancer.
Mice bearing HER-2-transfected (MCF-7/HER2-18)
human breast carcinomas were treated for 21 days with
either herceptin, rhIGFBP-3 or a combination of the
two agents. rhIGFBP-3 displayed potent single-agent
activity superior to that of herceptin alone and modest
combinatorial activity with it [86]. Our data strongly
indicate that IGFBP-3 exerts antiproliferative and proapoptotic
effects as demonstrated with in vitro and in vivo
models of human breast cancer and that its therapeutic
efficacy should be tested in clinical trials.
CF
IGF-1/IGFBP3 complex: More recent results.
"These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...
Why?
It took INSM 6 months to train their sales reps in the US. Until now INSM does not have any sales reps in EU, nor do they have a partner who has a distribution network, that knows the ped-endo community.
TRCA and IPSEN are EAGER to get revenue in as soon as the MAA-application is approved (by april 2007) by CHMP and EC-approvel by July 2007.
INSM will probably gat aproval by CHMP in late january 2007 and EC approval in april 2007.
TRCA/IPSEN do have a big competitive advantage compared to INSM and that is the fact that, there are already IPSEN sales reps in EU. They only need to be trained...so what would prevent TRCA/IPSEN to do so (they probably are doing it right now) in order to get revenue in from the moment EC-approval is in?
CF
NEWS!! Diabetes Type I & Prostate cancer results!
WHAT A GREAT DAY!!
Diabetes:
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2265.2006.02600.x
Conclusions Seven days treatment with IGF-I/IGFBP-3 complex enhanced overnight insulin sensitivity and reduced GH levels, but there was no effect on glomerular hyperfiltration or albumin excretion rate
Prostate Cancer:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16983336&...
Together, these studies provide the first evidence that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis providing an additional mechanism by which it exerts its tumor suppressive effects and further supporting its development for clinical use in the therapy of patients with prostate cancer.
Dunger & Iplex involved in the Diabetes study and Shiry & Pinchas Cohen in the Prostate cancer study!
Both studies are not published yet!
CF.
It's clear that some parties DO know more! Was wondering why the 'unfair practice' trial was postponed till 2007, two weeks ago.
Guess that the answer is becoming more and more clear! DNA is preparing a nice deal (including settlement) with INSM, in order to stay ahead of the competition (GSK & NVA).
Any NEGATIVE publication(s) about a lost trial (for TRCA/DNA), would raise the pps for INSM instantly!
(reminder: The Federal Circuit reversed. The court held that three requirements must be met before a non-inventor's recognition of the utility of an invention can inure to the benefit of an inventor. "First, the inventor must have conceived the invention. Second, the inventor must have had an expectation that the embodiment tested would work for the intended purpose of the invention. Third, the inventor must have submitted the embodiment for testing for the intended purpose of the invention." Since Genentech did not submit the fusion protein to the outside consultant for the purpose of determining whether it promoted growth, the three requirements were not met, and the consultant's recognition of utility did not inure to Genentech's benefit.)
No Offend! It's the abstract of Gene to Cure Conference in Feb 2006.
17.25 - 17.45
O.17 Recombinant Human Insulin-like Growth Factor-Binding Protein 3 (rhIGFBP-3) has Single Agent Anti-Tumor Activity and Enhances Letrozole Effects in Postmenopausal Breast Cancer Model
A.N. Alami, Montreal, CAN
http://www.eurcancen.org/GenetoCure06/programme.htm
Purpose of this article is showing the possible interest of NVA in INSM, like they have for CTIC.
CF
This was published in february 2006. Did not make any headlines sofar...Today NVA showed what they are interested in...deal with CTIC.
Cancertreatment development...The research showed convincing results with a combination of Letrozole (NVA) & rhIGFBP3 (INSM).
Insmed was/is actively involved, as well as Leyland Jones...
CF
NVA to announce deal with INSM as well?
Results with combination of RhIGFBP-3 & Letrozole (NVA) is very convincing!
L.Shiry (INSM)
Leyland Jones ( http://www.medicine.mcgill.ca/oncology/pubs/Leyland-Jones/Leyland-Jones_2005_02_EssentialRoles.pdf#s... )
http://www.eurcancen.org/GenetoCure06/abstracts/0.17.pdf
O.17
Recombinant Human Insulin-like Growth Factor-Binding Protein 3 (rhIGFBP-3) has Single Agent Anti- Tumor Activity and Enhances Letrozole Effects in Postmenopausal Breast Cancer Model.
A.N. Alami1, K. Banerjee, V. Page, Z. Li, R. Audet, L. Macedo, L. Shiry, A. Brodie, B. Leyland-Jones
1McGill University,Oncology, 3655 Sir William Osler, # 717 MONTREAL, Canada
Estrogen and insulin-like growth factors (IGFs) stimulate the proliferation of human breast cancer (BC). Both
hormones have been shown to act through an interactive cross-talk between estrogen and IGF signaling
pathways, resulting in subsequent activation of the downstream signaling cascades, such as the PI3-kinase and
ERK pathways. IGF-binding proteins (IGFBPs), predominately, IGFBP-3, bind to IGFs regulating their
bioavailability and preventing their interaction with the IGF-IR, thereby inducing growth inhibition/apoptotic
effects. Studies have shown that increased levels of IGF-I and/or reduced levels of IGFBP-3 are associated with
increased risk of BC.
Despite substantial improvements in the efficacy of endocrine therapy in estrogen-receptor positive (ER+) post
menopausal BC patients following the introduction of aromatase inhibitors, de novo or subsequent resistance
remains a major limitation. In the present study, we used a postmenopausal breast cancer model developed by
Brodie et al to investigate the effectiveness of targeting both estrogen and IGF by combining the non-steroidal
aromatase inhibitor, letrozole, and rhIGFBP-3.
Ovariectomized, athymic mice bearing subcutaneous tumors of ER+ estrogen-receptor positive human breast
cancer cells stably transfected with the aromatase gene (MCF-7 Ca) were used. All mice received ∆-4-
androstenedione (100 µg/day) subcutaneously (s.c.) from days 1 through 28, along with one of the following
treatments: rhIGFBP-3 at 10 or 30 mg/kg, s.c., twice daily, letrozole (2 or 5 µg/ day), s.c., or their combination at
the lowest doses.
All treatments were effective in suppressing tumor growth as compared with the control (P < 0.001). Both
rhIGFBP-3 and letrozole, as single courses, showed dose-dependent tumor growth inhibition. rhIGFBP-3
showed significant antitumor activity at both 10 & 30 mg/kg and induced a tumor growth inhibition (TGI) of 43
and 55% at day 28, respectively. Letrozole caused a TGI of 63 and 71 %, at 2 and 5 µg/day, respectively. The
treatment with rhIGFBP-3 (10 mg/kg) and letrozole (2 µg/ day) elicited an enhancement of letrozole anti-tumor
activity (TGI = 78%) and was more effective than letrozole alone even at the highest dose tested. Moreover, this
combination regimen resulted in tumor regression to the initial level at day 18. Tumor regression continued
throughout the treatment period, with no apparent toxicity, whereas tumors in the letrozole treated groups (2 & 5
µg/day) were not reduced to the initial level up to day 28.
Western blots analysis of representative tumors are undertaken to explore the effect of the cross-talk between
ER and IGF-IR signaling and the downstream cascades on tumor growth inhibition.
Our results demonstrate, for the first time, the antitumor activity of rhIGFBP-3 against established MCF-7 Ca
post-menopausal human breast cancer model and that its combination with letrozole at sub-optimal doses is
proved superior to treatment with letrozole as first line treatment.
CF
<<There has always been a question regarding TRCA's clinical trials and maybe the EU would ask for additional info. considering the known risks of naked IGF-1.>>
And this new study will not help TRCA's approval process!
First Editor’s Comment: This is the first study comparing 2 doses of GH in short children with SGA and the effect on growth and IGF-I levels. The issue is important since there is a theoretical risk of cancer after prolonged exposure to higher circulating levels of IGF-I and IGF-I/IGFBP3 ratio. This has led to repeated recommendations for the evaluation of circulating IGF-I levels, at least yearly, during GH treatment. The present data document precisely the effect of the 2 most frequently prescribed doses of GH and provide unique data for an appropriate comparison at 6 months of treatment. However, the study does not elucidate the question whether the dose-related increase of IGF values remains the same at a later time, when the high-dose GH does not produce a higher growth rate anymore.
http://www.gghjournal.com/volume22/3/ab04.cfm
CF
New research confirms treatment Diabetes:
Insulin-like growth factor I: a predictor of long-term glucose abnormalities in patients with acute myocardial infarction.
Wallander (M). Brismar (K). Ohrvik (J). Rydén (L). Norhammar (A).
Journal: Diabetologia 49(10) 2006 8 29
AIMS/HYPOTHESIS: Low levels of IGF-I are associated with increased risk of cardiovascular disease and type 2 diabetes. The aim of this study was to investigate the IGF-I system in patients with acute myocardial infarction (AMI) without previously known diabetes. MATERIALS AND METHODS: One hundred and sixty-eight AMI patients were classified before hospital discharge by means of an OGTT as having NGT, IGT or newly detected type 2 diabetes. Age- and sex-matched subjects from the background population (n=185) served as the control group. The associations between fasting levels of IGF-I and IGF binding proteins 1 and 3 (IGFBP-1, IGFBP-3) and glucose metabolism during a follow-up period of 12 months were studied. RESULTS: At hospital discharge, age-adjusted IGF-I (IGF-I SD) was significantly lower in patients with abnormal glucose tolerance (AGT=IGT or type 2 diabetes) compared with patients with NGT (p=0.014) and control subjects.
http://www.heartzine.com/pmdisplay.php?pmid=16955207#more
...And on top of that, INSM is also involved (unrestricted educational grant from Insmed, Inc) in providing online, webbased training; given by Dr's we all know:
Clinical Syndromes of GH and Insulin Resistance: New Opportunities for IGF-I Therapy
• One-hour on-demand slide presentation with audio
• Includes PDF slide handouts, suggested reading list, and references
• Registered participants have unlimited access to the presentation
• Convenient, timely and useful information
• Accredited for CME / CE credit for physicians, nurses and pharmacists.
Please refer to the accreditation section for complete information
• Associated monograph with case study to be released Fall 2006
Program Agenda
Introduction and Welcome
Dr. Reiter, Faculty Chair
IGF-Based Therapies for Conditions with Growth Hormone Resistance
Presented by Dr. Savage
Pharmacologic Properties of rhIGF-I and rhIGF-I/rhIGFBP-3
Presented by Dr. Clemmons
IGF-Based Therapies for Conditions with Insulin Resistance
Presented by Dr. Dunger
Professors' Pearls
Questions and answers with each faculty member
http://www.growingdevelopments.com/index.php
CF
Childhood and Adolescent Diabetes
Dunger DB, Regan F, Acerini C
Cianfarani S, Clemmons DR, Savage MO (eds): IGF-I and IGF Binding Proteins. Basic Research and Clinical Management. Endocr Dev. Basel, Karger, 2005, vol 9, pp 107-120 (DOI: 10.1159/000085761)
Article (PDF 95 KB) Free Preview
Opens in a new window Medline Abstract (ID 15879693)
Abstract:
Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of free IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of ‘free’ IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.
copyright © 2006 S. Karger AG, Basel
http://tinyurl.com/jsk86
CF
The Insulin-Like Growth Factor System and Its Pleiotropic Functions in Brain
V. C. Russo, P. D. Gluckman, E. L. Feldman and G. A. Werther [/]
Actually the last study you are citing, concerning brain development & rhIGF-1 is also presented at ESPE 2006:
Saturday, July 01, 2006
Session: Clinical Focus 1 - GH/IGF treatment (Click here for session schedule)
Date: Saturday, July 01, 2006
Time: 12:00 - 13:00
Room: Willem Burger Zaal
Moderator: Bessie E. Spiliotis, Patras, Greece
Moderator: Gerhard Binder, Tübingen, Germany
Save session to Outlook calendar
Remove from Planner Partial IGF-I deficiency demonstrates the critical role of IGF-I in growth and brain development
Netchine, Irène (presenting); Azzi, Salah; Houang, Muriel; Seurin, Danielle; Daubas, Claudine; Ricort , Jean-Marc; Legay , Christine; Perin, Laurence; Heirich, Robert; Godeau, François; Le Bouc, Yves
France
CF1-95
Monday, July 03, 2006
Session: Poster Session 3 - IGF / IGFBP (Click here for session schedule)
Date: Monday, July 03, 2006
Time: 13:45 - 14:45
Room: Expo Hall
Moderator: Ragnar Bjarnasson, Reykjavik, Iceland
Save session to Outlook calendar
Remove from Planner Comparative catch-up growth of height, foot and brain in children with Laron syndrome (LS) treated by IGF-1 to that of children with IGHD treated by HGH
Silbergeld, Aviva; Lilos, Pnina; Laron, Zvi (presenting)
Israel
PO3-610
CF
The study of Letrozole (NVS) in combination with rhIGFBP-3 (INSM), which was presented in the Netherlands in February this year, and which was done by INSM as well as by NVS-sponsored researchers.
This was posted a few days ago:
Posted by: Digdeeper
IHUB
Letrozole/rIGFBP-3 = Novartis/Insmed, 78% inhibition.
"Why oh why has there NOT been an announcement about the SUPERIOR results on the treatment of Breast Cancer, by a combination of drugs from Novartis & Insmed?"
* Letrozole (Novartis)
* rIGFBP-3 (Insmed)
(...)Our results demonstrate, for the first time, the antitumor activity of rhIGFBP-3 against established MCF-7 Ca post-menopausal human breast cancer model and that its combination with letrozole at sub-optimal doses is proved superior to treatment with letrozole as first line treatment.
This research was/is done at the Mc-Gill university by Dr. Leyland-Jones who has been granted $10 million by the Department of Defense to find new treatments against Breast Cancer where rIGFBP-3 was selected as a Candidate Agent.
Breast Cancer Center of Excellence Awarded $10 Million Department of Defense Grant; rhIGFBP-3 Selected as a Candidate Agent in Clinical Trials
RICHMOND, Va., May 13, 2004 (BUSINESS WIRE) -- Insmed Incorporated (NASDAQ:INSM) announced today the Department of Defense has granted a group of leading oncologists $10 million to support therapeutic individualization for breast cancer treatment in a translational research project. Insmed's rhIGFBP-3 has been selected as one of the candidate therapies for study. The lead investigator for the trials with rhIGFBP-3 is Dr. Brian Leyland-Jones of McGill University, former Head of Developmental Chemotherapy at the National Cancer Institute. The consortium of physicians collectively called the Breast Cancer Center of Excellence will use the emerging technologies of genomics, proteomics, and pharmacogenetics to predict individual response to therapeutic agents in advanced breast cancer. The desired outcome of the study will be to maximize patient benefit while minimizing the toxic side effects of standard therapies on the market today.
Geoffrey Allan, Ph.D., President and chief executive officer of Insmed added, "We are very pleased that the Department of Defense and the Breast Cancer Centers of Excellence have supported the selection of rhIGFBP-3 as a potential treatment for breast cancer and have provided significant funds to validate this novel therapeutic approach in future trials."
The presentation of this study (with a combination of Letrozole/rIGFBP-3) has taken place in February 2006 in the Netherlands at a conference called ' From Gene to Cure'.
(...)The treatment with rhIGFBP-3 (10 mg/kg) and letrozole (2 µg/ day) elicited an enhancement of letrozole anti-tumor activity (TGI = 78%) and was more effective than letrozole alone even at the highest dose tested. Moreover, this combination regimen resulted in tumor regression to the initial level at day 18.(...)
"It is suprising that Insmed nor Novartis have presented these SUPERIOR results at ASCO 2006. Novartis has done a presentation about the treatment of Breast Cancer with Letrozole, but the results were not as good as expected...
"Could it be that Novartis nor Insmed will give ground to speculation about a possible upcoming partnership in the future? What is going on here? The results (78% inhibition) justify a more then decent PR!"
http://www.eurcancen.org/GenetoCure06/abstracts/0.17.pdf
http://www.medicine.mcgill.ca/oncology/pubs/Leyland-Jones/Anti-InsulinLikeGrowth Factor.pdf
"Curious about the how and when, the results will be communicated to the investor community, whether by Novartis or by Insmed!"
**********************************************
See what Novartis presented on Letrozole at ASCO 2006 (page 10-15)
http://www.novartis.com/downloads_new/investors/NVS_ASCO_06.pd
Nothing has changed...Still positive opinion...Review time was referring to the time it took to review...
* Treatment of primary insulin-like growth factor-1 deficiency due to molecular or genetic defects
* Treatment of patients with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH
CF
Coinstarz, That message was posted around 07:00 AM this morning; I was suprised that it was erased a few hours later (I thought to be honest that it was erased by you, but could not figure out why)...cos I thought that it was a great find!
Mpetisth1 copied it from Ihub to YMB:
http://finance.messages.yahoo.com/bbs?action=m&board=1600811390&tid=insm&sid=1600811390&...
And the questions raised in this message are valid!...Nobody seems to wonder why this has not be released in a kind of PR...Like NVS did this morning with 'Early Clinical Results' on Leukemia treatment.
CF
GH Resistance in Noonan Syndrome: From Cause to Clinical Outcome
Volume 22, Issue 2, June 2006 - Table of Contents
Proportionate short stature (SS) occurs in more than 70% of individuals with Noonan syndrome (NS), an autosomal dominant disorder found in 1:1000 to 1:2500 live births. NS is also characterized by typical facial dysmorphisms and cardiac defects, especially pulmonic stenosis and hypertrophic cardiomyopathy. Although prior growth hormone (GH) studies in these patients have shown mixed results (some normal, some abnormal, some suggesting neurosecretory deficiency), in general classic GH deficiency is a rare finding.
A causative gene for NS was identified in 2001: PTPN11 (protein tyrosine phosphatase, nonreceptor type 11), which encodes Src homology region 2-domain phosphatase-2 (SHP-2). About half of individuals with NS harbor heterozygous missense mutations of SHP-2, the majority of which involve the amino SH2 (N-SH2) or the protein tyrosine phosphatase (PTP) domains (exons 3,8, and 13). Both N-SH2 and PTP normally interact, keeping the ubiquitously expressed, cytosolic SHP-2 in a closed, inactive conformation. SHP-2 is activated upon binding of N-SH2 to a phosphotyrosine residue, such as those on activated receptors for GH, cytokines and other growth factors. By chronically stabilizing the SHP-2 open, and hence active, conformation, the missense mutations of NS would be expected to cause gain of function of this negative regulator of receptor signaling. SHP-2 can not only dampen signaling through dephosphorylation of the receptor itself, it can also dampen downstream signals like dephosphorylating STAT5. Thus, SHP-2 mutations would be expected to cause GH resistance in patients with NS. Three recent papers studied this proposed hypothesis.
Mild GH Resistance
Binder and colleagues recruited all 29 children who presented to their center during the past 5 years with SS and at least 3 typical anomalies of NS or pulmonic stenosis. Blood lymphocyte DNA was extracted for PCR amplification and sequencing; 11 different missense mutations of PTPN11 were found in 16 children from 14 unrelated families (55% of patients). Of these 11 mutations, 8 occurred in exons 3, 8 or 13. Comparing the mutation-positive (mut +) vs mutation-negative (mut -) subgroups, the former were found to have a higher incidence of pulmonic stenosis (81% vs 15%) and septal defects (63% vs 15%), and younger mean age at presentation (5.1 ± 2.7 vs 10.3 ± 5.2 years). Minor anomalies and height (−3.15 ± 0.92 vs –3.01 ± 1.35 SD) did not differ significantly, and all children were approximately 1 SD shorter in height than the mean for NS. While the higher spontaneous overnight and arginine-stimulated GH levels did not reach statistical significance, insulin-like growth factor (IGF)-I (−2.03 ± 0.69 vs –1.13 ± 0.89 SD) and IGF binding protein (BP)-3 (−0.92 ± 1.26 vs 0.40 ± 1.08 SD) were significantly lower in the mut + group.
A subgroup of 11 prepubertal children received recombinant human (rh) GH for one year. Mean change in height SDS in the 8 mut + children (+0.66 SD) was significantly lower than that in the 3 mut - children (+1.26 SD). However, the mut + children received a lower mean rhGH dose (0.042 mg/kg/d vs 0.05 mg/kg/d).
Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11 mutations are associated with mild growth hormone resistance in individuals with NS. J Clin Endocrinol Metab. 2005;90:5377−5381.
Response to 3 Years of rhGH Treatment
Ferreira and colleagues retrospectively analyzed the 14 children (10 male) followed at their Endocrinology Unit for NS; all had presented with SS (mean height –3.5 ± 0.9 SD) and were treated with (0.033−0.05 mg/kg/d) after a 6-month observation of baseline growth velocity. Eight of the children had been treated for 3 years, 4 for 2 years, and 2 for at least 1 year at the time of analysis. At the start of treatment, mean age was 12.3 years, bone age 9.8 ± 2.7 years, and 10 were prepubertal. Seven children initiated puberty during treatment, and one received concomitant gonadotropin releasing hormone (GnRH) analog therapy. Treatment with rhGH was discontinued during the second year in one patient for increasing ventricular wall thickness; this patient had mild left ventricular hypertrophy before starting rhGH, and cardiac function continued to worsen afterwards despite cessation of rhGH.
Gene sequencing revealed 5 different, de novo heterozygous PTPN11 missense mutations in 7 (50%) patients, 3 of whom were also seen among the children in the above Binder paper. At the start of treatment, the 7 mut + and 7 mut - patients did not differ in their GH secretory capacity (all had normal peak responses to clonidine stimulation; mean 13.1 ± 7.1 ng/mL), nor in their low IGF-I levels (−2.0 ± 1.4 SD). However, the rhGH-stimulated increment in IGF-I was significantly smaller in the mut + patients, as was the improvement in growth velocity, such that by the end of the third year of treatment, the mut + group had a significantly smaller gain in height SDS (+0.8 ± 0.4 vs +1.7 ± 0.1 SD; p<0.01). Bone age advancement did not differ between the 2 groups.
Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with NS. J Clin Endocrinol Metab. 2005;90:5156−5160.
Prospective Study of 2 years of rhGH Treatment
Limal and colleagues prospectively recruited 35 patients (19 boys) with NS and growth retardation (height <−2 SD), excluding those with severe congenital heart malformations and/or hypertrophic cardiomyopathy. The 25 prepubertal children at study start (mean age 10.4 ± 3.1 yr) were given rhGH 0.30 mg/kg/wk while the 10 pubertal children (mean age 14.7 ± 1.7 yr) were given rhGH 0.46 mg/kg/wk to compensate for their late treatment start.
Distribution of PTPN11
Distributioin of PTPN11 missense mutations identified in 20 of the 35 NS patients. Mutations that have never been described are marked by an asterisk. The number of patients carrying the same mutation is indicated in parentheses.
Reprinted with permission Limal JM, et al. J Clin Endocrinol Metab. 2006;91:300-306. Copyright © 2006. The Endocrine Society. All rights reserved.
Sequence analysis revealed 12 different heterozygous PTPN11 missense mutations in 20 children (57%) (Figure), 10 of which were previously reported; all but one occurred in exons 3, 8 or 13. The mut + subgroup had a higher frequency of small-for-gestational age (SGA [32%]) than the mut - (13%), though birth weight and head circumference were normal in all. At age 6 years, the mut + group was significantly shorter, as was their mean target height. Starting at age 10.4 ± 3.1 years, 2 years of rhGH resulted in less catch-up growth among the prepubertal mut + children than the prepubertal mut - children; their end heights were –3.1 ± 1.4 SD (vs −2.0 ± 0.9 SD; p<0.05) and deficit from target heights were –2.5 ± 0.9 SD (vs –1.1 ± 0.7 SD; p<0.01). At initiation, peak GH level following pharmacologic stimulation was 15.4 ± 6.5 ng/mL (5 –34.3) in all 35 children, though 5 of the mut - had peaks of 5 ng/mL to 10 ng/mL. Of the 19 patients studied (11 mut + and 8 mut -), all had normal IGFBP-3, but they had IGF-I at or below the lower limit of normal, and acid-labile subunit (ALS) levels were extremely low in all 10 patients (5 mut +) tested at rhGH initiation. There was no difference between the 2 genetic subgroups in rhGH-stimulated increases in IGFBP-3 and IGF-I.
Limal JM, Parfait B, Cabrol S, et al. NS: Relationship between genotype, growth and growth factors. J Clin Endocrinol Metab. 2006;91:300−306.
Editor’s Comment: These 3 related papers offer intriguing glimpses into a possible mechanism of growth failure in NS. There are clearly additional mechanisms involved, since mut - patients frequently also have SS. Nonetheless, as a group, these papers suggest new directions.
Mechanism
In the idiopathic SS age of non-GH deficient growth failure, the quest has been on for molecular causes of post-receptor GH resistance. The search for individuals who harbor mutations in the signaling cascade directly downstream of the GH receptor has yielded fruitful results: novel GH receptor mutation that impairs GH receptor/STAT5 signaling but maintains normal STAT3 signaling,1 mutations of STAT5b itself,2 IGF-I gene partial deletion,3 singe copy number of the IGF-I gene,4 and IGF-I receptor mutation.5
Yet these papers on NS serve as a reminder that a signaling cascade can be turned off (or down) not just by mutations from within, but also by mutations affecting molecules from without; gain of function mutations of negative regulators of a cascade, such as SHP-2, can serve to augment the normal checks and balances and overly suppress the signaling cascade. This is not the first time that such possibility was shown. In 2001, 8 years after the FDA approved rhGH treatment for SS associated with chronic renal insufficiency, the molecular mechanism underlying the GH resistance was discovered. Comparing rats status-post partial renal ablation (chronic renal failure) and sham-operated, pair-fed rats (controls), Schaefer and colleagues found the former to have blunted hepatic induction of IGF-I expression by GH treatment despite unchanged GH receptor protein levels and GH binding to microsomal and plasma membranes.6 Normal protein levels of JAK2, STAT5, STAT3, and STAT1 completed the cascade. Instead, these authors6 found a 75% reduction in GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3, due to over-expression of SOCS (suppressor of cytokine signaling)-2 and -3. The SOCS proteins normally function as a cellular internal feedback loop; they are induced by GH and in turn, inhibit GH-stimulated GH receptor/JAK2 complex activation to turn down the GH sensitivity of the cell.
The over-expression of SOCS in chronic uremia and the gain of function mutations of SHP-2 in NS may be just the beginning. Further search may reveal additional conditions involving augmented negative regulators, as well as loss of positive stimulators and enhancers, of the GH receptor/JAK/STAT signaling cascade. Thus, the quest for non-GH deficient causes of growth failure just got a whole lot broader.
Clinical Implications
The increased GH resistance of PTPN11 mut+ vs mut- patients reported in these papers suggests that a genotype-driven approach may be more effective for ameliorating the SS associated with NS. Two treatment strategies may be plausible, and additional studies designed to test these approaches will be needed to determine their relative efficacies and safety.
First, to overcome the increased GH resistance, rhGH therapy may require higher doses, and an approach titrating rhGH dose to achieve desired IGF-I levels rather than a standard weight-based dosing scheme, may be the best way to gauge clinical requirements of mut+ vs mut- individuals. Thus, we may discover 2 different optimal dosing levels based on genetic subtype.
On the other hand, we may discover that the degree of GH resistance in the mut+ individuals is so great that cranking up the rhGH dose really cannot compensate effectively or may be associated with undesirable side effects.
In this scenario (the second treatment strategy), treating with recombinant IGF-I and/or IGF-I/IGFBP-3 rather than rhGH, may be more appealing. These therapies have now become available and were recently approved by the FDA.
Growth, Genetics & Hormones is supported by an unrestricted educational grant from Insmed
http://www.gghjournal.com/volume22/2/ab01.cfm
CF
<<Professor Martin Savage, Dr Cecilia Camacho-Hübner and Dr Linda Johnston hold academic positions in Paediatric Endocrinology.>>
Dr. Linda Johnston
Senior Lecturer in Paediatric Endocrinology
Linda Johnston graduated with MA MB BChir from Corpus Christi College, Cambridge University in 1992, having undertaken clinical training at St Bartholomew’s Medical College, University of London. She undertook her clinical training in paediatrics subspecialising in endocrinology. In 2002 she was awarded a PhD in Medicine for the “Investigation of the Genetic Influences on the Small for Gestational Age (SGA) Phenotype”. This research was undertaken at Barts and the London School of Medicine with Professor Martin Savage and Professor Adrian Clark. She is now Senior Lecturer and Honorary Consultant Paediatric Endocrinologist at Barts and the London Queen Mary School of Medicine. Dr Johnston is Medical Coordinator for the international growth genomics programme NESTEGG which is funded by a programme grant from Pfizer (previously Pharmacia).
Research interests
* Dr Johnston has a broad interest in the genetic influences on fetal and postnatal growth, including pharmacogenomics.
o NESTEGG (networked European Studies of Genes in Growth) – families of children with idiopathic short stature and those with born SGA, with or without catch-up, have been recruited to perform both family and case-control studies.
o Pharmacogenomic – with NESTEGG the influence of GHRd3 is being studied in SGA short children.
* Dr Johnston has established a multidisciplinary growth clinic to support the needs of children with short stature born small for gestational age.
* Dr Johnston runs a clinic dedicated to the screening and management of children at risk of familial endocrine neoplasia syndromes
http://www.whri.qmul.ac.uk/staff/Linda.html
You'll find the whole EMEA & COMP process and the advantages it has on this link. http://www.eurordis.org/rubrique.php3?id_rubrique=24
http://www.eurordis.org/article.php3?id_article=440
Orphan medicinal product designation assigns orphan status based on a defined number of criteria. These can be resumed as:
- The product should be intended to be use for an indication concerning no more than 5 in 10 000 persons in the European Community.
- The disease concerned should be life-threatening, seriously debilitating or a serious and chronic condition.
- There should exist no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Community; or, if such a method exists, then the medicinal product will confer a significant benefit compared to the existing one.
The request for Orphan Medicinal Product designation can be made at any stage of drug development as soon as sufficient scientific evidence can be presented. The request for Orphan Medicinal Product designation can be made at any stage of drug development as soon as sufficient scientific evidence can be presented. The research may therefore be pre-clinical (not yet tested on human subjects) or may have reached the human clinical trial phase.
INSM received positive opinion from he COMP for Iplex as a treatment for:
- IGFD
- Noonan syndrome (even if phase II trial has not been finished yet)
CF
The Committee for Orphan Medicinal Products (COMP) is responsible for reviewing applications from persons or companies seeking 'orphan medicinal product designation' for products they intend to develop for the diagnosis, prevention or treatment of life-threatening or very serious conditions that affect not more than 5 in 10,000 persons in the European Union.
The COMP is also responsible for advising the European Commission on the establishment and development of a policy on orphan medicinal products in the EU, and assists the Commission in drawing up detailed guidelines and liaising internationally on matters relating to orphan medicinal products.
http://www.emea.eu.int/htms/general/contacts/COMP/COMP.html
CF
New ruling in EU! has been changed since March this year! Positive opinion to speed up the process of approval!
what is more important is that the second filing is for NOONAN syndrome! So they file for another 30,000 patients in EU with no treatment anymore!
Got also a positive opinion form COMP!!
http://www.emea.eu.int/pdfs/human/comp/18025106en.pdf
Mecasermin rinfabate, from Insmed Europe Ltd., for treatment of patients with growth hormone
(GH) gene deletion who have developed neutralizing antibodies to GH (review time: day 30)
From 10k:
Noonan Syndrome. Noonan Syndrome is a congenital disorder characterized by a deficiency in IGF-1, short stature, heart defects and variable dysmorphic features. Growth failure is a consistent feature of Noonan Syndrome and the response to recombinant human growth hormone therapy has been disappointing, particularly in children with an identified gene mutation.
With an incidence of approximately one in 2,000, we estimate that there are approximately 30,000 children in the United States with Noonan Syndrome.
CF.
Actually what Mr Young said is more positive, then what you mention. He said about 4 times... "Iplex-launch will be in the NEXT several weeks" which to my opnion refers to the start of a launching campaign, starting as of next week and continuing for the weeks after!
Otherwise he would have said, as in the Earinings CC, "Iplex will be launched in several weeks". Which, refers to a launch in 3-4 weeks, without being specific.
In what he said Mr. Young in R&R CC was more specific then in 8th of May CC.
The strategy of having a launching campaign, with a duration of several weeks, is in line with what Ketchum succesfully did with Enablex. This is what Ketchum did with Enablex of Novartis (winning campaign 2005)!
(...)During the launch week, the team conducted a national media blitz by targeting top-tier media, and by holding a 12-city SMT and RMT. It continued media efforts over the following month, targeting long-lead outlets such as Readers Digest.
http://www.prweek.com/us/events/awards/details/23653/healthcare+campaign+year+2006
CF