IO list of checkpoints/agonists/TME modulators...

AGEN: CTLA4, PD1
INCY/AGEN: GITR, OX40, TIM3, LAG3
ARGX.BR: CD70, GARP
ARRY/VentiRx/CELG: TLR8
CCXI: CCR2, CCR4-6, CXCR2/7
CGEN: new IO targets
CLDX: CD27
FPRX: CSF1R, discovery (B7H3, B7H4,...)
HALO: (PEGPH20?)
INCY: IDO, JAK
IPH.PA: KIR, NKG2A, MICA, KIR3DL2
MDVN: PD1, (AR?)
MGNX: B7H3
NLNK: IDO, TDO
NKTR: IL2
PBMD: LAG3
SGEN: CD40
TRIL: SIRPaFc
TSRO: TIM3, LAG3, PD1, TIM3+PD1 bi, LAG3+PD1 bi

some rationale for Xtandi + pidilizumab combinations?

"Biological rationale to combine immunotherapy with hormonal therapy is "particularly strong". Immuno-oncology (IO) KOLs have suggested that the most compelling combination of checkpoint inhibitors may be with hormonal agents. Androgen blockade has been shown to activate thymic regeneration in mice and humans, therefore is an immunologically active intervention. In addition, androgen blockade was shown to traffic T-cells to the human prostate with 3 weeks of initiation. A recently published National Cancer Institute study with Xtandi specifically showed that Xtandi enlarged thymus and improved survival in combination with a cancer vaccine in a preclinical model.

We believe Xtandi's lack of requirement for concomitant steroid, which is at least suboptimal and potentially incompatible for use with immunotherapy, represents a fundamental differentiation vs. Zytiga in addition to other advantages."

ARQLs ESMO presentation - MARQUEE Met+ subgroup break down... mOS 9.3 vs 5.9, HR=0.7 (p=0.03)

http://files.shareholder.com/downloads/ARQL/2650277388x0x693826/f59dd69a-fcd1-4a02-8a40-93346b731bb8/ESMO%20MARQUEE%20Final%20Sat%20am.pdf

here are some ASCO notes from RBC...

PCYC (still the drug to beat; more data on Monday morning). We learned
more details of PCYC’s registration path, with two Phase III trials in relapsed
CLL (Ibrutinib monotherapy vs. ofatumumab and combination therapy with
bendamustine / Rituxan). A newly described potentially registrational Phase II
trial tests single-agent Ibrutinib in Velcade refractory MCL and could offer a
fast path to market. Competitive data from GILD and CELG still favors
Ibrutinib as the drug to beat, and while GILD plans a Phase III trial of
GS-1101 in combination with Ofatumumab in Q3:12, PCYC’s trial could
replace Ofatumumab in second-line CLL.

Genmab... recent comments by Ohad Hammer regarding anti-CD38 Daratumumab

Winners of ASCO 2012

Genmab – Potential breakthrough in myeloma

Genmab presented phase I results for daratumumab, an anti-CD38 antibody for the treatment of multiple myeloma. Daratumumab was given to very heavily pretreated myeloma patients, including patients with a history of 10 (!!!) or more previous treatment lines. Data included multiple objective responses as well as some dramatic reductions in myeloma cells in the bone marrow. Responses appear dose dependent, with 5 partial responses and 2 minor responses in the 12 patients who received the 4 highest doses (response rate of ~42%). This compares to no PRs and 2 minor responses among the 17 patients at the lower doses.

This type of activity is very rare in multiple myeloma, especially in such a challenging patient population. Importantly, daratumumab’s mechanism of action is distinct from the two classes of drugs that are active in myeloma: IMiD’s (Revlimid, pomalidomide) and proteosome inhibitors (Velcade, carfilzomib). Therefore, it is not a direct competitor of these agents and will probably be added to standard therapy.

In fact, daratumumab is the only antibody to date to show such a robust efficacy profile in myeloma. For example, BMS’ elotuzumab, currently in phase III in multiple myeloma leads to no responses as monotherapy. Even antibody drug conjugates such as Immunogen’s IMGN901 demonstrate a response rate of 5-8%.

The only issue with daratumumab was the fact that it was given with dexamethasone in order to minimize side effects. Dexamethasone is known to have activity in myeloma, but the extent of activity and the dose dependent response profile imply daratumumab has intrinsic activity.

Genmab’s results are good news for Immunogen and Morphsys, which also have anti-CD38 antibodies in clinical trials. Immunogen’s antinody is licensed to Sanofi whereas Morphosys fully owns rights to its CD38 antibody, MOR202. Sanofi is evaluating SAR650984 in several CD38+ blood cancers whereas Morphosys is focusing on multiple myeloma. CD38 antibodies could represent an important class of drugs with limited competition and a combined market opportunity of $2-3B in myeloma alone.

in line with other p38-inhibitor results they stopped development for all chronic inflammatory diseases...

Array BioPharma Stops Work on ARRY-797 Pan-Cytokine Inhibitor for RA Despite Good Early Data
July 16, 2009
by Janis Kelly

BOULDER, Colorado—Array BioPharma Inc announced that Phase 1b data from a 3-arm study of 28 rheumatoid arthritis (RA) patients ARRY-797 showed inhibition of C-reactive protein (CRP) levels during the first 3 weeks of dosing and a beneficial reduction in bone remodeling markers throughout treatment. There was also a trend toward lower pain scores over the 28-day course of the study. Nonetheless, the company is stopping development of ARRY-797 for RA and other chronic inflammatory diseases.

"In the 28-day RA study, ARRY-797 demonstrated a transient inhibition of the inflammatory biomarker CRP and a trend towards analgesic efficacy in the pain endpoint," said Kevin Koch, PhD, President and Chief Scientific Officer. "Since these results are similar to other p38 inhibitors evaluated in rheumatoid arthritis, these findings have led us to discontinue testing of ARRY-797 in chronic inflammatory diseases. We continue to believe that a p38 inhibitor holds promise in treating patients with cancer and sub-chronic pain."

Array has also stopped enrollment of new patients into a clinical trial of ARRY-797 in ankylosing spondylitis patients.

you can read it on slide 32 of their last Needham presentation...

http://investor.regeneron.com/phoenix.zhtml?c=119576&p=irol-presentations

REGN - Ilaris royalties

btw... REGN gets up to 15% royalties on all Ilaris sales

http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9ODI3NXxDaGlsZElEPS0xfFR5cGU9Mw==&t=1

Royalty agreement (June 2009)
- Opt-in rights cancelled
- Stepped royalty on worldwide sales in all indications
- Initial 4% royalty, reaches 15% of total sales if sales > $1.5B

*********

Novartis drug appears to compete with partner Regeneron (REGN)

June 19, 2009 · Filed Under Diabetes, General, fda
Novartis this morning said the FDA approved the sale of its Ilaris drug, one of the world’ s most expensive drug treatments, which targets a rare disease called cryopyrin-associated periodic syndrome (CAPS), and potentially some others.

That event may focus traders’ attention on Novartis development partner Regeneron Pharma (REGN), which has a competing treatment for the same CAPS disorder.

But what traders need to keep in perspective today is that CAPS is a tiny market; there are only about 7,000 known cases of it worldwide.

And CAPS is a gateway for both dugs to Novartis’ Ilaris and Regeneron’s Arcalyst to eventually target conditions that affect many more people . It’s very possible — if not likely — that the two drugs might not square off in the same large markets down the road, pending future FDA approvals.

Arcalyst is seen as a drug that can target acute illness such as gout. In contrast, Ilaris may be better suited to chronic diseases, such as diabetes and chronic obstructive pulmonary disorder.

ONXX sorafenib vs BAY 73-4506

patent WO/2005/009961 covers fluoro-sorafenib...
http://www.wipo.int/pctdb/en/wo.jsp?wo=2005009961&IA=US2004023500&DISPLAY=STATUS




obviously the chemical structure of nexavar is nearly identical...

[OT] nice $300 billion short squeeze



VW shorts scramble for exits as market cap swells

Auto maker becomes world's richest firm by market capitalization
By Steve Goldstein, MarketWatch

Last update: 12:00 p.m. EDT Oct. 28, 2008Comments: 88LONDON (MarketWatch) -- Short sellers of Volkswagen scrambled for the exits on Tuesday, briefly making the European auto maker the world's largest company by market capitalization and raising worries about the banks that sold Porsche Automobil Holding the options to build its stake in the Beetle maker.

The short squeeze sent Volkswagen shares up as much as 93% on Tuesday, extending Monday's massive rally that sent VW's common shares up 250%.

Volkswagen shares have been volatile over the past two months, leading to speculation that short sellers were desperate to cover positions.

But covering activity took on renewed speed after Porsche announced over the weekend that it increased its equity stake in VW to 42.6% from about 35%, and more crucially, that it had options to buy another 31.5% of VW. See Monday's VW story.
Porsche hasn't disclosed the strike price of the options but said that it will lock in gains between whatever the market price of VW when it exercises the option and the strike price.

Porsche said over the weekend that it was acting, in part, because it was "clear that there are by far more short positions in the market than expected."

Porsche was able to build up its options position without detection because of relatively lax German disclosure rules that are due to be tightened next year.

The scramble for Volkswagen shares is particularly acute because its free float is estimated to be just over 5%, since Porsche holds VW shares either directly or indirectly that amount to 74% -- and the Lower State of Saxony, which is fighting both Porsche and the European Union to keep blocking control over VW, holds another 20%.

The massive gains for Volkswagen are raising worries whether funds which shorted the common stock will be able to survive -- and in turn about the banks that brokered the options and short sales transactions.

Banks ranging from Goldman Sachs to Commerzbank came under pressure on Tuesday.

VW's valuation

At its high on Tuesday, VW was worth 295 billion euros, or $367 billion, making it more valuable than Toyota Motor , Nissan Motors, Daimler, Renault and Ford Motor Co. combined -- not to mention the paltry 4.8 billion euro market cap of Porsche. Exxon Mobil closed Monday with a market capitalization of $343 billion.

Exxon shares have dropped about 30% this year as oil prices have plunged to the low $60-a-barrel level from $147.
The gains for VW come during a period of turmoil for Volkswagen.

Volkswagen last week said nine-month deliveries edged up 3.9% to 4.8 million vehicles, picking up market share vs. rivals, but said it was concerned about the "marked deterioration in the situation for our industry throughout the world."

DAX rally

The German DAX 30 rocketed more than its European peers as a result of the VW gains. See Europe Markets.

A spokesman for the Deutsche Boerse, which compiles the DAX, says that Volkswagen will stay in the top index so long as its free float is above 5%.

Stoxx Limited, which compiled indexes such as the Dow Jones Stoxx 600, said it will issue a statement tonight regarding treatment of Volkswagen.

Stoxx is a joint venture of the Deutsche Boerse, the Swiss Exchange and Dow Jones & Co. MarketWatch, the publisher of this report, is a unit of Dow Jones.

Micromet: Another Seal of Approval

http://seekingalpha.com/article/91907-micromet-another-seal-of-approval

posted on: August 21, 2008 | about stocks: MITI

There is always a debate regarding market efficiency and to what extent stock prices represent the available information about a company. Micromet’s (MITI) surge last week shows that in some cases, the market is far from being efficient. The spike of more than 35% in the last two trading sessions is attributed to the publication of a short article in Science Magazine, one of the world’s most prestigious scientific journals. The article contained clinical data from an ongoing phase I trial of Micromet’s lead candidate, MT103 (partnered with Medimmune). The data was spectacular, showing a strong, dose dependent response in concert with a good safety profile, exactly the kind of data that can put a small biotech in the spotlight. Ironically, the article contained data which has already been presented more than two months ago at the ICML in Switzerland.

Regardless of whether market reaction was justified, publishing clinical data at such an early stage in Science should be viewed as an indication for the scientific community’s embrace of Micromet and its BiTE platform. The BiTE platform relies on monoclonal antibodies for stimulating the patient’s immune system to attack cancer cells that have managed to evade or suppress the body’s immune response. Although most attention is given to the first product from the platform, MT103, it can generate an unlimited number of agents against a variety of cancers, making it a potential revolution in the way cancer is treated.

It still remains to be seen whether additional BiTE agents will be as promising as MT103, but examination of the clinical data leads to the conclusion that Micromet now has one of the most exciting technologies in the biotech industry. The BiTE platform represents a truly novel class of anti-cancer agents and is not like anything else out there. It facilitates the construction of bi-specific antibodies that simultaneously bind cancer cells and the body’s most potent immune cells (T cells), leading to a strong, long lasting and escalating immune response against tumors. In the past decades, there have been numerous attempts to create effective bi-specific antibodies, all of which failed. One exception may be a Biotest’s HRS3/A9, which showed promising efficacy but could not be produced in sufficient quantities for further clinical evaluations. The area of bi-specific antibodies has been long abandoned by the antibody industry and MT103 can be seen as the long anticipated breakthrough that overcame most of the hurdles. It seems that Micromet found the ideal formula for generating a potent yet safe anti-tumor response with bi-specific antibodies.

BiTE antibodies are small enough to get T- cells within sufficient proximity to cancer cells and unleash their lethal mechanisms in a targeted and specific manner. Their small size may also help them penetrate areas inaccessible for other agents. In addition, because the actual attack is done by the patient’s most potent immune cells, which can proliferate and multiply upon activation, it takes a tiny amount of BiTE antibodies for generating a systemic response. This may explain the incredibly low doses of MT103 that led to clinical responses in the phase I clinical trial. When compared to other antibodies and chemotherapeutic agents on a normalized basis, MT103 is certainly one of the most potent compounds to have ever been tested in humans, if not the most potent one.

Promising Data

The Science article reported data for thirty eight NHL (non-Hodgkin lymphoma) patients, who received various doses of MT103. The trial focused on two subtypes of NHL, follicular lymphoma [FL] and Mantle cell lymphoma [MCL], which together represent around 35% of the NHL market. There were 11 cases of objective response (four complete and seven partial), which appeared primarily in the cohorts who received the higher doses. Strikingly, all seven patients who received the highest dose responded to the treatment, two of whom had a complete response. As of the latest follow up (June 1st) all these responses were ongoing for a period of 1-8.5 months, on top of one response in a patient who had received a lower dose that was ongoing for more than a year. The issue of response duration is cardinal because many treatments, especially Rituxan containing regimens manage to achieve long lasting responses of more than a year in similar patient populations, so in order to be regarded as a viable alternative, MT103 must keep patients in remission for substantial periods of time.

It is important to understand that the significance of the data is not necessarily in the commercial opportunity of MT103 for these patient populations, which fortunately have a slower disease onset and enjoy an abundance of treatment options. The challenging competitive landscape leads to high entry barriers for new therapies for FL and MCL patients. Furthermore, there are additional antibodies in development that bind the same target MT103 binds, CD19. The most advanced of these agents is Sanofi-Aventis’ (SNY) SAR3419, based on Immunogen’s (IMGN) technology, which is currently in two phase I trials. Additional CD19 targeting agents are being developed preclinically in the hands of Genentech (DNA), Seattle Genetics (SGEN), Medarex (MEDX) and Xencor. MT103’s results are actually the first validation of CD19 as a target and are therefore likely to motivate these companies to advance their candidates into the clinic as soon as possible.

Hopefully, MT103 will find its way to the NHL market as the next line of defense for certain subsets of patients, but the real potential lies somewhere else. Because the BiTE platform is a universal and modular platform, it could be utilized to generate a plethora of candidates for indications with limited treatment options, primarily solid tumors. Solid tumors, such as lung and breast cancers are less sensitive to available treatments due to poor accessibility and are consequently responsible for over 90% of cancer related deaths worldwide. BiTE antibodies may have a competitive edge over other therapies due to their small size and certain properties of the immune cells they activate. They may also be advantageous for targets that cannot be hit by other antibody-based platforms, because they do not require internalization in order to be effective. For more on the mechanism by which BiTE antibodies operate and why they are considered so promising, click here. The first BiTE antibody for solid tumors, MT110, recently entered the clinic, and is expected to generate initial data next year.

Substantial Risks

Investors should be aware of the long list of risks associated with MT103 in particular and the BiTE platform in general. With respect to MT103, the data is preliminary and based on a limited number of patients, so it may turn out to be less effective in larger trials. In addition, the NHL market is full of promising compounds, some of which demonstrated comparable or even better efficacy in similar patient populations. A closer look at patient demographics reveals that patients in the highest cohort were younger and less heavily pretreated compared to patients in lower doses, which might explain the 100% response rate.

Despite the explosive potential of the BiTE platform, there is the obvious unpredictability associated with early stage drug development. There is no guarantee that additional BiTE antibodies will replicate MT103’s success, and even if some do, it might be after multiple failures, like is often the case with novel disrupting technologies.

Safety is also a concern, especially in therapies that manipulate the immune system, and until a compound is evaluated in large enough populations the fear of unexpected adverse events is always there. This explains Micromet’s decision not to escalate the dose in the MT103’s trial further, despite the fact that the maximum tolerated dose [MTD] was not reached. Because MT103 is the first product of the BiTE platform, safety issues can lead to delays or even jeopardize the entire platform. Therefore, when a dose escalation study reaches a sufficiently active dose, there is much more to lose from increased toxicity than to gain from better efficacy. In the case of solid tumors, however, it will probably take dose levels near or at the MTD in order to achieve the needed efficacy, so the risk there is obviously higher.

Three Main Events

For the remainder of the year, there will be three important events for Micromet.

Most importantly, the company will publish additional data in December at the Annual Society of Hematology [ASH] annual meeting. The data set will include an update from the ongoing trial in NHL patients as well as preliminary results from a phase II study that evaluates MT103 in Acute lymphoblastic leukemia [ALL]. Choosing ALL as a second indication makes sense because it is estimated that over 90% of ALL cases express CD19.

The data from the NHL trial is very important not only because it will include additional patients and an update on the durability of the responses, but also because data from Sanofi-Aventis’ SAR3419 will be presented. This will give investors the opportunity to assess the BiTE platform relatively to competing platforms.

The ALL study has important implications as well, because it represents an attractive route for commercialization for MT103. ALL is an aggressive blood cancer with a dismal prognosis and very few treatment options, in contrast to the NHL subtypes in the phase I trial. If MT103 demonstrates sufficient activity against ALL, this indication represents a faster route to market, with very little competition upon approval. In addition, the ALL study is very significant for the future development of MT103, because it represents a different treatment modality. The study does not evaluate MT103 as a primary treatment, but as consolidation in patients who receive chemotherapy but still have leukemia remnants in their bone marrow. The company views this study as a probe for the utility of MT103 as a secondary treatment as well as for the potential of the compound for other aggressive blood cancers.

The second event, which is supposed to take place before ASH, is rumored to be a partnership deal for one of Micromet’s pre-clinical programs or a technology licensing deal with a major pharmaceutical company. Such a development will serve as another validation of Micromet’s potential, provide highly needed cash infusion and decrease the overall risk.

The third event will be some sort of a capital raising deal, which will probably happen sooner rather than later given the recent stock movement. This may put some pressure on the stock in the coming months.

I have been getting a lot of questions from investors with respect to Micromet’s target price. My answer is that the huge potential of the company warrants holding it as long as the BiTE platform continues to produce impressive clinical results. Nevertheless, with a market cap of $220M and a year to date return of over 170%, Micromet is not a cheap stock. The recent jump following the Science article, coupled with the anticipated round of financing might imply that now is a good time to take some gains off the table with the purpose of waiting for a lower entry point down the road, prior to the ASH annual meeting.

Disclosure: Author is Long MITI, IMGN, SGEN

Re: >Am i missing something?<

perhaps... it's confusing to compare increases vs placebo and baseline. In the VEGF Trap Eye PII there isn't any placebo group...



The mean change from baseline in visual acuity, a key secondary endpoint of the study, also demonstrated statistically significant improvement (all groups combined, increase of 5.7 letters, p<0.0001). Preliminary analyses at 16 weeks showed that the VEGF Trap-Eye, dosed monthly, achieved a mean gain in visual acuity of 9.3 to 10 letters (for the 0.5 and 2 mg dose groups, respectively).

with the highest dosing 9.3-10 letters after 16 weeks ...9 letters after 52 weeks. from my point of view that's comparable to lucentis... 11.3 letters after 52 weeks (also the highest dose) in ANCHOR, 6.6 letters after 2 years in MARINA.

LEVP/VPHM - is the possibility of prophylactic use a competitive criterion?

>>Companies line up for hereditary angioedema market

Brady Huggett

At the end of this month, the first therapeutic for hereditary angioedema (HAE) could receive approval for marketing in the US. By end of next year, there could be as many as five biotech products on the HAE market from separate companies. Being first to receive approval in a small, niche indication will ensure a competitive edge, but differences in mode of action, delivery and eligibility for orphan status for the different therapies, as well as the heterogeneity of the patient population itself, might mean later entrants could still be successful as the market becomes segmented.

Berlin-based Jerini is poised first in line to receive a decision from the US Food and Drug Administration (FDA). The company's Icatibant, a synthetic peptidomimetic drug licensed from Paris-headquartered Sanofi Aventis, has a Prescription Drug User Fee Act date of April 26. Approval is by no means certain, however, as the HAE field has a history of late-stage regulatory setbacks (Box 1).

HAE is caused by low serum levels of C1 esterase inhibitor (C1-INH). As well as inhibiting components of the fibrinolytic, clotting and kinin pathways, C1-INH also blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s (sub-components of C1). Low levels of C1-INH lead to unchecked complement activation that is important in inflammation and the clearance of pathogens from the body. There are two types of HAE patients: most are type 1 and have levels of C1-INH <35% lower than normal; those with type 2 have normal or elevated levels of C1-INH, but the protein is nonfunctional. Either way, both types suffer attacks that swell the hands, feet, larynx, facial features and genitals, with gastro-intestinal swelling that sometimes causes vomiting, diarrhea and severe pain. The condition is rare but autosomal dominant.

One key problem for drug developers is how to estimate the HAE market size. A "pretty standard" estimated prevalence is 1 person with HAE in every 30,000 people, says Samir Singh, president of US operations at Pharming (headquartered in Leiden, The Netherlands). This suggests about 10,000 people in the US and 22,000 people in the Western world with HAE. "When you look at the US, Europe and Japan, that's total treatable attacks of 200,000 [annually]," he estimates.

All the players think the market is set to grow and that the disease is often mis- or underdiagnosed. Cambridge, Massachusetts–based Dyax's general counsel and executive vice president of administration, Ivana Magovevi-Liebisch, says diagnosing the disease can take as long as ten years, as patients repeatedly leave hospitals after the attack resolves without a physician fingering HAE as the culprit.

"Patients look like they are having an allergic reaction," she says, and even as they suffer vomiting and diarrhea, doctors "can't find anything wrong." Eventually an allergist suggests HAE, and the patient begins mining the family history to discover a pattern of illness in relatives.

Once diagnosed, there is no consensus on whether those individuals should receive acute or prophylactic care, mostly because the frequency of attacks is also unclear. CSL Behring of King of Prussia, Pennsylvania, already markets its C1-INH product Berinert in Germany, Austria and Switzerland, where the drug has been administered >300,000 times. Published data from these European patients point to about seven attacks per year, though many assume it's higher and Pharming's Singh says certain surveys have it pegged as high as 20 annually.

If people with HAE are having 20 or more attacks yearly, then "one could make a case for prophylactic use," says Singh, though personally he's doubtful. In fact, only New York-based Lev is developing its product, Cinryze, to include the prophylactic market. Dyax's executive vice president and chief business officer, Gustav Christensen, doubts that market exists. Prophylactic treatment could mean two injections a week, driving the cost per patient to $250,000 annually, so insurance carriers would probably begin pushing cheaper acute treatment as preferred.

Three of the five drugs vying for approval aim to address HAE by supplementing the individual's endogenous C1-INH with a functional version of the human protein (Table 1). Lev and CSL Behring are both developing a purified plasma protein version, whereas Pharming has developed a recombinant C1-INH produced in transgenic rabbits.

The other two companies—Dyax and Jerini—are developing proteins aimed at dampening the inflammatory cascade. Dyax's recombinant protein DX-88 (ecallantide) inhibits kallikrein, an enzyme that liberates bradykinin, which causes fluid to leak from blood vessels into the tissues. Jerini's Icatibant attacks one step further down the line; it's a competitive bradykinin B2 receptor antagonist. All five drugs are deemed comparably efficacious (though there have been no head-to-head clinical trials to help determine this), which means it's difficult to predict which product will have the competitive edge.

One differentiating factor is delivery. DX-88 is just 60 amino acids long and can be administered subcutaneously, as can Icatibant, but the C1-INH products must be given by intravenous (i.v.) infusion. Jerini CEO Jens Schneider-Mergener says that, based on feedback from physicians, his firm sees "a big advantage" in the subcutaneous route over the i.v. one. Bret Holley, analyst with New York-based Oppenheimer, which covers Lev but receives no compensation from the firm, tends to agree, venturing that i.v. infusion can be seen as a "killing handicap." But Holley also argues that attacks are foreseen by people with HAE, much like migraines, allowing them time to seek a physician for an infusion, and he points out that Dyax's DX-88 needs to be refrigerated anyway. So far, Jerini boasts the only subcutaneous administration that does not need to be refrigerated—the company has data showing sterility exceeding 18 months at room temperature. Dyax is working on a room-temperature formulation.

The final uncertainty is orphan drug status—all have it except CSL Behring. The FDA makes the final decision here, but it is assumed DX-88 and Icatibant will be viewed as independent molecules and thus each drug's orphan drug status will not block another from entering the market. Pharming's Samir says that his company's C1 inhibitor should stand alone, as it is a recombinant molecule. Whether the plasma-derived C1 inhibitors will be viewed as the same molecule isn't clear.

There is general consensus, however, on what's at risk: a $500 million-a-year market. The small patient population and unmet medical need means the community will tolerate a "Genzyme-like pricing," Holley says, referring to the empire Cambridge, Massachusetts-based Genzyme has built by developing niche products for rare diseases. The HAE market, Holley believes, will be shaped in much the same way as the one formed around Genzyme's products.

"Patients will be treated on a physician-by-physician basis," he says, so the first step is to "get a therapy out there." Only then, as patients choose the product that works best for them, physicians become comfortable and usage is bent to individual needs, will there be hints as to how these products will settle out.<<

>>Hope Mixes With Doubt For Alzheimer's

http://www.forbes.com/business/2008/06/17/alzheimers-pharmacuticals-bapineuzumab-biz-healthcare-cx_mh_0617alzheimer.html

Matthew Herper and Robert Langreth 06.17.08, 5:35 PM ET

A promising new treatment for Alzheimer's disease helped some patients but may have harmed others, according to a preliminary study of 240 patients released today by the drug's makers.

Still, Elan (nyse: ELN - news - people ) of Dublin, Ireland, and Wyeth (nyse: WYE - news - people ) of Madison, N.J., said they were encouraged by the results, and the stock prices of both companies' shares rose in early trading. The companies have already started studies in thousands of people in order to get the drug approved, but those will take at least two years.

Bapineuzumab is one of the most-watched experimental treatments among drug and biotech investors. It was designed to attack and remove what some researchers believe is a root cause of Alzheimer's, the tell-tale amyloid plaques that build up in patients' brains. If it works, sales could reach $5 billion a year, according to Wall Street forecasts. But some scientists say bapineuzumab is based on a flawed conception of what causes Alzheimer's, making its chances of working far from assured.

The new results shed only a little light on the debate. According to a press release, the study failed to meet its pre-stated goal of helping patients do better on any of several questionnaires and tests designed to measure Alzheimer's severity.

But a subset of patients who did not have a genetic variant called APOE4, showed statistically significant improvements across four different tests for Alzheimer's symptoms, Wyeth and Elan said, when compared to a control group of patients who did not get the drug. They also appear to have lost less brain volume, according to MRI scans.

Meanwhile, in patients who had the APOE4 gene variant, which increases the risk of developing Alzheimer's by as much as tenfold, the drug had little benefit and increased risk of brain swelling due to leaky blood vessels, called vasogenic edema. Roughly half of Alzheimer's patients have the APOE4 gene variant.

"In my view, these results are very, very slightly hopeful, but not more than this," says John Hardy, a University College, London, neuroscientist and geneticist who was among the first to point to a link between amyloid, the protein bapineuzumab attacks, and Alzheimer's. He says because the companies didn't decide to divide patients into those with and without APOE until after the study finished, there is a meaningful risk that the positive results are due solely to chance.

Other researchers are more optimistic. "This is exactly what you would want to see to justify going to a big phase III program," says Steven Ferris, director of the NYU Langone Alzheimer's Disease Center and a paid adviser to Elan. "These are pretty good results." He noted that those without APOE4 also showed less brain shrinkage on MRI scans as well as on cognitive tests. That, he says, is exactly what would be needed for the drug to be approved by the Food and Drug Administration as a disease-modifying agent, not just a treatment of symptoms.

Lon S. Schneider, a psychiatrist and Alzheimer's disease expert at the University of Southern California Keck School of Medicine, adds: "I don't think this is particularly earth shaking. The basic thing they are saying is we looked at our data and it continues to give us faith to go ahead."

The news release is also notable for what it does not include. It doesn't say how many patients were in the subset that appeared to benefit or what the magnitude of the benefit was. The news release also does not reveal whether higher doses of the drug showed more or less of an effect than lower doses. The news release also does not say how many different subsets of patients were analyzed, which is particularly important because the more subsets you analyze, the more you are likely to have a positive result merely by chance.

The big question behind bapineuzumab is whether it is targeting a cause of Alzheimer's or a symptom. The dominant explanation of Alzheimer's disease contends that the massive brain cell death is due to the buildup of plaques containing a protein called beta amyloid built up in the brain. Bapineuzumab is an antibody that attacks beta amyloid. Eli Lilly (nyse: LLY - news - people ) and Pfizer (nyse: PFE - news - people ) are among numerous other companies testing similar approaches.

One big mystery is why hitting amyloid with a drug would benefit people without the APOE4 gene but not those with it. There are few clinical differences, experts say, between those with APOE4 and those without it once they develop the disease.

That difference is "unexpected but not inexplicable," says Zaven Khachaturian, president of Keep Memory Alive in Las Vegas and former head of Alzheimer's research at the National Institutes of Health. Alzheimer's is probably caused by a complex interaction of many genes, and it is possible those with the APOE4 gene are less able to repair their injured brains. These patients tend to have more amyloid built up in their blood vessels, not just in their brains.

For investors, the huge potential of bapineuzumab and the very real risks create a very big betting opportunity. Wall Street analysts differ on the chances that the drug eventually proves effective and is approved. Timothy Anderson at Sanford C. Bernstein wrote in a note to investors that he models only a 30% chance of approval but still sees Wyeth as worth buying because of the valuation of the stock.

James Kelly, the pharmaceuticals analyst at Goldman Sachs, wrote in a note that the results should slightly increase Wall Street's view of bapineuzumab's chances. However, he said, the new data should cool hopes that the drug could be approved in this mid-stage. Barbara Ryan at Deutsche Bank wrote that the results were "as good as could be expected at this time," and that shares will trade up for now. But she advises investors to be careful because of other disappointments that could hit the company.

David Amsellem and Jacob Rasmussen of FBR Capital Markets called the data "underwhelming." They write that even in the subgroup of patients without the APOE4 gene, the results were statistically significant only for one of two primary endpoints, and note that unspecified imbalances mentioned in the news release could skew the results.

The last experimental drug to generate sales forecasts as big as the ones analysts are ballparking for bapineuzumab was torcetrapib, a Pfizer pill designed to reduce heart attacks. Torcetrapib actually increased the death rate and was canned.

James Nicoll, a neuropathologist at the University of Southampton, performed autopsies on nine patients who received a plaque-removing vaccine Elan and Wyeth tried in an earlier trial. (Side effects torpedoed that approach.) He found that the vaccine patients had dramatic reductions in plaque compared to a control group. Yet eight of nine still developed end-stage dementia.

Nicoll called the news release this morning "tantalizing." However, he added: "There is quite a lot of information you would like to see that isn't there. If there is efficacy, it is not of a very large magnitude."<<


*********************

http://foodconsumer.org/7777/8888/D_rug_N_ews_50/061712222008_Wyeth_s_Alzheimer_s_drug_shows_promise.shtml

>>The drug called bapineuzumab helped some Alzheimer's patients reduce loss in cognitive functions by 2 to 2.5 points during an 18-month follow-up as measured by a test.

Normally, Alzheimer's patients would otherwise lose 6.5 points over 18 months.

Ian Sanderson, senior research analyst for Cowen & Company was quoted by the New York Times as saying that “Anything north of a 2 point spread would be considered clinically significant.”<<

Final survival data from the SPARC trial are "all we're waiting for now," and those results are due around the end of the year, Doyle said.

Published June 26, 2007

http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forc...

GPCB - (ASCO) Satraplatin+Taxol 1st-line NSCLC PII data

Phase II trial of satraplatin and paclitaxel in the first-line treatment of advanced non-small cell lung cancer.
Sub-category: Non-Small Cell Lung Cancer
Category: Lung Cancer
Meeting: 2007 ASCO Annual Meeting

Abstract No: 18073
Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 18073
Author(s): D. Shipley, D. R. Spigel, C. Cavanaugh, Y. Moore, J. D. Hainsworth, S. Jones, H. A. Burris, L. Sade, D. A. Yardley, F. Greco
Abstract: Background: Satraplatin (S) is a novel oral platinum analogue that has shown promising activity in a number of solid tumor settings. Our center previously conducted a phase I trial combining S and paclitaxel (P) in patients (pts) with refractory malignancies, establishing safety for this combination. This single center community-based trial was designed to examine the role of S/P in pts with newly diagnosed advanced non-small cell lung cancer (NSCLC). Methods: The primary endpoint is the objective response rate (ORR). Eligibility criteria: newly diagnosed and unresectable stage IIIB/IV NSCLC, measurable disease, ECOG PS 0-2, and informed consent. Treatment: S 80 mg/m2 PO days 1-5 and P 200mg/m2 IV day 1, every 28 days for a maximum of 6 cycles. Pts were restaged every 8 weeks. Results: 28 pts were enrolled from 2/06 to 12/06 (trial ongoing, n = 40 planned). Data are available on 24 pts for analysis. Baseline characteristics: median age 67 years; male/female, 58%/42%; and ECOG PS 0/1/2, 25%/63%/12%; adenocarcinoma/squamous/large cell/unspecified, 33%/42%/1%/24%. The ORR was 17% (95% CI 5%-37%). 10 pts (42%) had stable disease (SD) and 5 pts (21%) had progressive disease. The disease control rate (ORR + SD) was 59%. 5 pts were not evaluable due to: death (3 pts - 1 possibly due to treatment-related sepsis), and physician/pt preference (1 pt each). With a median follow-up of 8.3 months, the median time to progression is 4 months. Grade (G) 3/4 non-hematologic toxicity occurring in = 5%: infection (29%), nausea, vomiting (17% each), anorexia, hyperglycemia (13% each), and fatigue (8%). G3/4 hematologic toxicity: leukopenia (21%), neutropenia (41%), and thrombocytopenia (29%). Conclusions: In this preliminary analysis, S/P appears to have comparable activity to other platinum-based regimens. In an effort to reduce myelosuppression this trial has been amended to a S dose of 70 mg/m2. Additional accrual and follow-up are needed to better assess the safety and efficacy of this combination regimen.

Satraplatin - PDUFA Aug 15?

>The FDA this month scheduled an Aug. 15 decision on Spectrum's application to market satraplatin.<
http://www.ocregister.com/ocregister/money/homepage/article_1662827.php

>it is based on the log-rank test<

sorry, dew... i see you don't take me seriously... the p-value has nothing to do with my question. without a null hypothesis you can't calculate any significance values... p-values are only supportive (and supportive only in a well defined context)... and you know that.

DNDN - >One can reach all kinds of strange conclusions by playing with median values the way you did.<

1.) all OS numbers published by DNDN are median survival values (50th percentile)... the whole provenge BLA is based on median survival

2.) from my point of view i didn't played with median numbers... but i've tried to adjust the official KM survival curve by take out the taxotere treated patients (on the assumption of the linear decreasing KM curve of this subgroup showed in the above slide). the resulting curve gives you not only the 50th median value but also 10th, 20th or whatever you want...

3.) the question for me was... what influence has taxotere treatment (or chemo) on the official survial values of D9901 or D9901+D9902A by taking into account that the median survival of tax+provenge (34.5 months, N=51) from both studies was nearly the full study timespan of 36 months. In the case of the integrated D9901+D9902A results the OS(MS) numbers go down from 23.2 to 19 months - that tells me the adjusted KM survival curve...

what is provenge worth without taxotere? Can you tell me?

DNDN - provenge WITHOUT taxotere 19 months median survival?

or am i wrong?

two slides from Petrylaks provenge+chemo presentation
http://www.mssmtv.org/player/player.php?id=111006ada_petrylak

provenge+taxotere subgroup (D9901+D9902A)




subtract provenge+tax from the the integrated provenge arm (increasing red line)... and you get approx 19 months median survial integreted provenge without taxotere.

19 months MS are about 6 month lesser than the 25.4 months in the taxotere without provenge subgroup!!!

taxotere (without provenge)... 25.4 months MS (N=31)
provenge (without taxotere)... 19 months MS (N=96)

can anybody verify this?

greetings!

sorry, i see no difference, do you?

but i think you know what i have meant...

"substantial evidence of efficacy"...



mmmmmmm?!

DNDN - mere chance?

the 10 patients (8% of all patients) excluded from 9901 cox os analysis are surprisingly not in favour of provenge... provenge reduced the median survival time in these patients from 22.1 to 19.7 months. you can find the same effect in 9902A: 10 patients excluded from cox and a reduction from 20.9 to 13.2 months.

and why there is no difference in the KM-survival curve up to 24 month between the two arms in the nearly 100 patients study 9902A? why the huge drop in the 9901 placebo patients OS curve in the last 2 months? After 36 months the provenge curve drops too... if you had seen that the other way around, provenge 36-months survival benefit would be much lesser in 9901 (perhaps zero)...

"since no imputation approaches was pre-specified, anyone would tend to select her/his favorite one as the primary intentional or unintentionally."... and thats why blinded pre-specified studies are the better way!

re: SPPI, GPCB abstract

-> #43238

satraplatin - SPARC PSA and pain RR

Pain and PSA Responses in Metastatic Hormone Refractory Prostate Cancer Treated with Satraplatin: Results of the SPARC Phase III Trial

Introduction & Objectives:

Treatment of metastatic hormone refractory prostate cancer (HRPC) focuses on not only prolonging survival but also alleviating bone pain that afflicts 85% of patients (pts). Taxanes are usually part of 1st-line treatment but little data exist about which drugs should follow once they fail. Satraplatin (S) is a novel oral platinum (IV) complex with demonstrated activity in platinum-sensitive malignancies. A global, double-blind, placebo-controlled randomized trial (SPARC) evaluating S as 2nd line therapy for HRPC has recently completed accrual.


Material & Methods:

The primary objective was to compare progression free survival (PFS) in pts with progressive HRPC, randomized to either S + Prednisone (P) or placebo + P at a ratio of 2:1. Pain diaries and analgesic use were obtained during the entire observation period. A pain response was defined by a reduction in weekly PPI score (>= 2points from BL over >= 5 consecutive weeks) or stable/decreasing weekly analgesic score (<= 25% from BL). Progressive events as well as PPI and analgesic scores were reviewed centrally and blindly. Prostate-specific antigen (PSA) response was analyzed based on consensus criteria: A decrease of PSA level by >= 50% since onset of treatment and confirmed not less than 4 weeks later. Eligibility included: Pts with stage D2 HRPC, progressive after 1 prior cytotoxic regimen for metastatic disease. ECOG <= 2. Treatment: P 5mg po bid combined with active S or placebo 80mg/m2 po x 5 days, q35 days until disease progression or occurrence of unacceptable toxicity.


Results:

A total of 950 patients entered the study. Pts in the S+P arm had a 40% reduction in the risk of disease progression (HR = 0.6; 95% CI: 0.5-0.7) compared with the placebo+P arm. There was a statistically significant increase in PFS for S+P pts which became more pronounced at the 75th percentile (36 vs 19 weeks). A greater proportion of S+P pts experienced a statistically significant pain response of 24.2% compared to placebo+P of 13.8% (p<0.005). The analysis for PSA showed a 25.4% response rate in pts treated with S+P compared to 12.4% in the placebo+P group (p<0.001). Pts are still being followed for OS. Most common toxcities observed were generally mild to moderate myelosuppression (thrombocytopenia, neutropenia) and GI toxicity (nausea/vomiting, diarrhea).


Conclusions:

Satraplatin is an efficacious and well tolerated oral platinum agent for the treatment of HRPC.

GPC Biotech Launches Expanded Access Program for Oncology Drug Candidate Satraplatin in the U.S.
Wednesday February 21, 4:20 am ET

MARTINSRIED/MUNICH, Germany, WALTHAM, Mass. and PRINCETON, N.J., Feb. 21 /PRNewswire-FirstCall/ -- GPC Biotech AG (Frankfurt Stock Exchange: GPC; TecDAX index; Nasdaq: GPCB) today announced that the Company has launched the Satraplatin Expanded Rapid Access protocol (SPERA) in the U.S. Expanded Access Programs (EAPs) are intended to give patients access to investigational drugs to treat serious or life-threatening diseases or conditions for which there are no adequate therapies available. Under the SPERA program, satraplatin will be provided to patients free of charge.

"There is an important medical need for treatments for hormone-refractory prostate cancer patients whose first-line chemotherapy has failed," said Martine George, M.D., Senior Vice President, Clinical Development, GPC Biotech. "We look forward to working with clinicians to make satraplatin available through the SPERA program to these patients who currently have no approved treatment options for their disease."

U.S. physicians interested in receiving more information about SPERA can contact 1-800-349-8086 or www.speratrial.com.

GPCBs presentation at the same conference... prospects of satraplatin in prostate cancer...

http://www.corporate-ir.net/ireye/conflobby.zhtml?ticker=GPCBF&item_id=1466847

dew, are there any chances to expand the us patent protection beyond the 2015 time frame? for example new patents... ?

greetings,
ipollit77

SPPI $1M are flying straight to JM...

Spectrum said the FDA has up to 60 days to decide whether or not to formally accept the application. Upon a formal acceptance, the company is entitled to a $4 million milestone payment. In 2002, the company licensed global rights to GPC Biotech.

However, Spectrum licensed the drug from Johnson Matthey PLC, and must pay that company $500,000 in Spectrum shares for the complete submission and $500,000 cash upon FDA acceptance of the filing.

phrm - satraplatin

latest estimates of a german bank are peak sales of $877MM for the on-label 2nd-line HRPC indication and $450MM for 1st-line HRPC.

i don't think gpcb/phrm seeks an on-label use because time is running with loss of us-patent protection in 2015 and probably 2018 in europe

additional off-label indications for satraplatin are mainly unmet need indications without much competition from other platinum compounds. e.g. 1st-line use for NSCLC in combination with tarceva is limited to patients older than 70 years of age (one third of all NSCLC cases): "patients >= 70 years of age with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) frequently do not receive systemic cytotoxic chemotherapy due to concerns regarding their inability to tolerate treatment."

actually there are successful phase II studies for ovarian, SCLC and breast cancer.

other aspects... flexible sequential dosings could improve the efficacy with less toxicity. satraplatin as a IV-platinum compound acts like a prodrug with in vivo reduction to the cisplatin-like highly cytotoxic II-platinum metabolite JM118. this allows oral administration and gives satraplatin the ability to partially overcome cisplatin/carboplatin resistence (during treatment all cancer cells develop resistance to platinum). and finially oral-oral cancer treatments are the future... we will see...

greetings,
ipollit77

AGIX - CART-2?

Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial

Received 7 September 2006; revised 20 November 2006; accepted 30 November 2006. Available online 9 January 2007.

Abstract
Background
The antioxidant AGI-1067 was shown to reduce experimental atherosclerosis. The present study originally intended to study restenosis as a primary endpoint but was subsequently modified to primarily investigate the effects of AGI-1067 on coronary atherosclerosis.

Methods and results
This placebo-controlled randomized trial assessed the effects of AGI-1067 280 mg qd started before percutaneous coronary intervention (PCI) and administered for 12 months after PCI on atherosclerosis progression as assessed by coronary intravascular ultrasound (IVUS). Among patients with IVUS examinations considered technically adequate both at baseline and follow-up upon central laboratory assessments (n = 232), plaque volume was not significantly modified with placebo (least squares mean change: −0.4 mm3, P = 0.85 versus baseline), but was significantly reduced by −4.0 mm3 at end of treatment in the AGI-1067 group (P = 0.001 versus baseline, P = 0.12 versus placebo). LDL-cholesterol varied by −9% and +4% in the placebo and AGI-1067 groups, respectively (P < 0.05 between groups), and HDL-cholesterol was reduced by 1% with placebo and 14% with AGI-1067 (P < 0.05 between groups). Plasma myeloperoxidase was reduced by 6% with AGI-1067 (P < 0.05) but hs-CRP was not significantly different between groups.

Conclusions
Atherosclerosis regression (−4.0 mm3) was observed in patients treated with AGI-1067, although this was not significantly different from placebo. The anti-inflammatory effect of AGI-1067 is supported by reduced levels of myeloperoxidase.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T12-4MSHTGY-2&_user=10&_handl...

SPPIs legal action against GPCB

GPC Biotech Responds to Arbitration Claim by Spectrum Pharmaceuticals
Wednesday December 13, 1:32 am ET

MARTINSRIED/MUNICH, Germany, WALTHAM, Mass. and PRINCETON, N.J., Dec. 13 /PRNewswire-FirstCall/ -- GPC Biotech AG (Frankfurt Stock Exchange: GPC; TecDAX 30; Nasdaq: GPCB) announced that on December 12, 2006, the Company was informed by Spectrum Pharmaceuticals, Inc. that Spectrum has filed a Demand for Arbitration and Statement of Claim with the American Arbitration Association to resolve a dispute under the co-development and license agreement for satraplatin. GPC Biotech firmly believes that Spectrum's claims are made in bad faith, are inconsistent with the license agreement, and are completely baseless and without merit.

In its arbitration claim, Spectrum's main allegation is that it is entitled to a payment from GPC Biotech of approximately euro 9.0 million (approximately US$ 12 million). This claim is in connection with an approximately $18 million reimbursement for past development expenses, an approximately $19 million payment for ongoing and future development costs and an additional approximately $22 million commitment for future development related expenses from Pharmion GmbH under the co-development and license agreement between GPC Biotech and Pharmion entered on December 19, 2005. Spectrum also alleges, together with two other claims, that GPC Biotech has not used commercially reasonable efforts to obtain regulatory approval and to promote the distribution of satraplatin in Japan. GPC Biotech will respond to the filing by seeking an affirmative declaration that the Company has not defaulted on any material obligation under the license agreement, will assert various counterclaims against Spectrum in connection with its wrongful conduct, seeking, among other things, damages and attorneys' fees, and will pursue all remedies available under the law. Although Spectrum is seeking a declaration that GPC Biotech's alleged breach provides a basis for termination, GPC Biotech is confident that the dispute will not result in a termination of the co-development and license agreement.

"We believe that the claims made by Spectrum are made in bad faith and are completely baseless and without merit," said Bernd R. Seizinger, M.D., Ph.D., Chief Executive Officer of GPC Biotech. "We will vigorously defend ourselves against these allegations and seek every remedy available to us under the law. We are confident that the dispute will not jeopardize our rights to satraplatin. We therefore are continuing to work aggressively towards completion of the NDA filing in the U.S. by the end of January and will move forward, together with our partner Pharmion, on the application for marketing authorization in Europe. We will also continue to expand our clinical program for satraplatin and to build our commercial infrastructure."

GPCB - MHCII-mAb is #2 in the pipeline - with 2 ongoing PI-trails...

btw... whats your opinion about the satraplatin offlabel potential? for example 1st-line HRPC mono based on the EORTC-PIII-trial, 1st-line NSCLC 70+ tarceva+satraplatin based on hopefully positive PII results or perhaps ovarian cancer, if the successful BMS-PII is adequate...

greetings,
ipollit77

GPCBs mAb against NHL

I think this could be a good alternative to the CD20 target, isn't it?

GPC Biotech Presents Preliminary Clinical Data on Anticancer Monoclonal Antibody 1D09C3 at ASH
Monday December 11, 4:11 am ET

MARTINSRIED/MUNICH, Germany, WALTHAM, Mass. and PRINCETON, N.J., Dec. 11 /PRNewswire-FirstCall/ -- GPC Biotech AG (Frankfurt Stock Exchange: GPC; TecDAX index; Nasdaq: GPCB) today announced the presentation of preliminary clinical data on its anticancer monoclonal antibody 1D09C3 at the 48th Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida. 1D09C3 is currently in a Phase 1 clinical program that is evaluating the antibody in patients with relapsed or refractory B-cell lymphomas, who have failed prior standard therapy. The objectives of the Phase 1 program are to determine the maximum tolerated dose and to establish a recommended dose for a Phase 2 efficacy trial.

The poster entitled, "Two Phase 1 Open-Label Studies of the Fully Human IgG4 Monoclonal Antibody 1D09C3 in Patients with Relapsed and/or Refractory B- Cell Lymphoproliferative Neoplasias on a Weekly and Bi-Weekly Dosing Scheme," (Abstract #2730) presented initial results from the ongoing Phase 1 clinical program. These preliminary data from 25 patients suggest that 1D09C3 is well tolerated in this heavily pre-treated patient population. A maximum tolerated dose had not yet been reached. Hints of antitumor activity were observed in two patients.

"We are pleased with the initial clinical data from our antibody program," said Marcel Rozencweig, M.D., Senior Vice President, Drug Development and Chief Medical Officer. "Importantly, 1D09C3 seems to be well tolerated by this heavily pre-treated patient population. The early signs of anti-tumor activity are encouraging at these low doses. We expect to see the final results from our Phase 1 clinical program in mid 2007. Should the data continue to be promising, we anticipate moving into Phase 2 testing thereafter."

Dr. Rozencweig continued: "While good progress has been made in recent years in treating lymphoid cancers with antibodies, there remains a major need for additional therapies to treat patients who have relapsed or become resistant to currently available treatments. 1D09C3 has key attributes differentiating it from marketed therapies; thus, it could hold the potential to become an important new therapy for treating lymphomas and leukemias."

New preclinical data under the title "Interferon-Gamma Enhances the Anti-Myeloma Activity of the Fully Human Anti-HLA-DR Monoclonal Antibody 1D09C3" (Abstract #656) will also be presented. The findings suggest that interferon-gamma induces up-regulation of HLA-DR, the target of 1D09C3, resulting in a potent enhancement of the in vivo anti-myeloma activity of 1D09C3.

greetings,
ipollit77

GPCB - anti HLA-DR mAb 1D09C3

some preliminary data of two ongoing p1 studies...

[2730] Two Phase I Open-Label Studies of the Fully Human HLA-DR-Specific IgG4 Monoclonal Antibody 1D09C3 in Patients with Relapsed and/or Refractory B-Cell Lymphoproliferative Neoplasias on a Weekly and Bi-Weekly Dosing Scheme. Session Type: Poster Session, Board #908-II

Alessandro M. Gianni, Carmelo Carlo-Stella, Anna Guidetti, Michael Hallek, Carmen Schweighofer, Clemens Wendtner, Michele Ghielmini, Erica Lerch, Sabine Sperka, Douglas Greene, Oliver Krieter, Faith Nathan, Michael Petrone Medical Oncology, Istituto Nazionale Tumori, Milan, Italy; Medical Clinic I, University of Cologne, Cologne, Germany; Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; GPC Biotech AG, Munich, Germany; GPC Biotech Inc, Princeton, NJ, USA

Background: Lymphomas are increasing in frequency and represent the fifth most common cancer diagnosis in the United States. 1D09C3 is a fully human anti-HLA-DR monoclonal antibody (mAb) derived from a human combinatorial antibody library (HuCAL) that has consistently demonstrated activity against various lymphoid tumors, both in vitro and in vivo (Nat Med 2002;8:801-7). Therefore 1D09C3 may offer a novel therapy to patients with B-cell lymphoma who have failed therapy. Two phase I studies are ongoing to determine i) the maximum tolerated dose (MTD) and phase II recommended dose (RD), ii) the pharmacodynamic (pd)- and pharmacokinetic (pk)-profile and iii) the immunogenicity of 1D09C3 given within a bi-weekly and weekly schedule in this patient population.
Material and methods: Patients with relapsed/refractory B-cell lymphoproliferative diseases are included in the two studies. 1D09C3 dose escalation is performed using modified Fibonacci increments with a minimum of 3 patients (pts) per dose level. It is administered once every week or every other week by a 2-hour intravenous (iv) infusion at escalating dose levels of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 10 mg/kg/day for either 4 or 8 weeks. All toxicities are assessed according to the NCI CTC version 3.0. Blood samples are collected at different times in the study to determine pd- and pk- parameters and to assess immunogenicity of 1D09C3.
Results: 19 pts have been enrolled into both protocols to date (13M/6F), median age 58 (range 30-76), pts with Hodgkins lymphoma (5), non-Hodgkins lymphoma (8) and chronic lymphocytic leukemia (6). The 4th dose level (2.0mg/kg/day) has been completed within the bi-weekly dosing scheme and accrual is ongoing until the MTD and thus the phase II RD will be determined. The safety profile was positive, with only few and mild treatment-related side-effects such as fatigue noted, although one dose limiting toxicity (DLT) was seen at the bi-weekly dose level 0.5 mg/kg/day.
Pk analysis of intravenous 1D09C3 indicated the drug to be cleared rapidly from blood circulation. 2 pts have been tested positive for human anti-1D09C3 antibodies (HAHA) at the 2nd and 3rd dose level, respectively; no allergic reactions were noticed. Clinical benefit was observed in 3 out of 14 evaluable pts who experienced partial response (PR), whereas 8 had no changes (NC) and 3 progressive disease (PD). After study completion an independent response evaluation team (RET) will review the information provided and determine individual treatment responses for the overall study.
Conclusion: Two phase I dose escalation studies of the anti-HLA-DR mAb 1D09C3 are currently open in three sites for accrual of pts with relapsed/refractory B-cell lymphoproliferative diseases to determine the MTD and phase II RD for a weekly and bi-weekly schedule. Preliminary data suggest that 1D09C3 is well tolerated within this heavily pre-treated patient population. Pd- and pk-data, development of HAHA and clinical responses will continue to be evaluated.
Abstract #2730 appears in Blood, Volume 108, issue 11, November 16, 2006
Keywords: Phase I|Monoclonal antibody|Lymphoproliferative disorder

Sunday, December 10, 2006 9:00 AM

Poster Session: Novel and Targeted Therapy of Non-Hodgkin Disease (NHL) (9:00 AM-8:00 PM)

********

[656] Interferon Enhances the Anti-Myeloma Activity of the Fully Human Anti-HLA-DR Monoclonal Antibody 1D09C3. Session Type: Oral Session

Carmelo Carlo-Stella, Anna Guidetti, Massimo Di Nicola, Cristiana Lavazza, Loredana Cleris, Paolo Longoni, Marco Milanesi, Michele Magni, Zoltan Nagy, Paolo Corradini, Antonino Carbone, Franca Formelli, Alessandro M. Gianni Medical Oncology, Istituto Nazionale Tumori, Milano, Italy; Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy; GPC Biotech AG, Munich, Germany; Hematology, Istituto Nazionale Tumori, Milano, Italy; Pathology, Istituto Nazionale Tumori, Milano, Italy; Medical Oncology, University of Milano, Milano, Italy

The fully human anti-HLA-DR antibody 1D09C3 exerts a potent anti-lymphoma activity both in vitro and in vivo in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. 1D09C3 is currently tested in phase I clinical trials in patients with relapsed/refractory B-cell malignancies. To investigate whether 1D09C3 might represent a treatment modality to target malignant plasma cells, we re-evaluated HLA-DR expression on CD138+ plasma cells. Additionally, we investigated the capacity of interferon (IFN-) to upregulate HLA-DR expression on myeloma cell lines, and tested in vitro and in vivo the anti-myeloma activity of 1D09C3 alone or in combination with IFN-. Bone marrow CD138+ cells were enriched using an immunomagnetic method from 60 multiple myeloma (MM) patients. Three-color flow cytometry revealed a highly heterogeneous HLA-DR expression on plasma cells. CD138+HLA-DR+ cells were detected in 31/60 patients (52%), with 15/60 patients (25%) having 20% CD138+HLA-DR+ cells (median, 50%; mean, 54%; range, 23 100), and 3 patients (5%) displaying 100% CD138+HLA-DR+ cells. Two thirds of HLA-DR+ patients expressed CD45 on CD138+ cells, suggesting that 1D09C3 might target self-renewing plasma cells. HLA-DR expression was not associated with distinct cytogenetic abnormalities. Since primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines (n = 6) with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin-V/propidium iodide double staining showed that 1D09C3-induced cell death strongly correlated with constitutive HLA-DR expression. Interestingly, induction of HLA-DR by IFN- restored the sensitivity of HLA-DR dim cell lines (i.e., RPMI-8226, KMS-11) to the cytotoxic activity of 1D09C3. As compared to controls, exposure of RPMI-8226 and KMS-11 cell lines to IFN- and 1D09C3 significantly increased cell death to 45% (P 0.0001) and 40% (P 0.0001), respectively. The in vivo activity of 1D09C3 was analyzed by xenografting NOD/SCID mice with the KMS-11 cell line. A significant increase of median survival over controls was detected in mice treated with 1D09C3 alone at either 3 mg/mouse (92 vs 48 days, P 0.0001) or 6 mg/mouse (89 vs 48 days, P 0.0001). The combined treatment with IFN- plus 1D09C3 (3 mg/mouse) resulted in a significant increase of median survival as compared to controls (147 vs 48 days, P 0.0001) or mice receiving 1D09C3 alone (147 vs 92 days, P 0.03). The better therapeutic activity of the combined IFN-/1D09C3 treatment over 1D09C3 alone was further demonstrated by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% vs 25%). No mice experienced any apparent treatment-related toxicity. In conclusion, our data demonstrate that: (i) one third of patients with MM express significant levels of HLA-DR on CD138+ cells; (ii) IFN--induced upregulation of HLA-DR results in a potent enhancement of the in vivo anti-myeloma activity of 1D09C3.
Abstract #656 appears in Blood, Volume 108, issue 11, November 16, 2006
Keywords: Apoptosis|Monoclonal antibody|NOD/SCID

Monday, December 11, 2006 3:45 PM

Simultaneous Session: Multiple Myeloma: Immunotherapy (3:30 PM-5:00 PM)

Satra - 1st line NSCLC tarceva combination

http://www.clinicaltrials.gov/ct/show/NCT00370383;jsessionid=28F72D0052E1F3657276E9D0A6525C9A?order=...

Study start: July 2006;
Expected completion: December 2007
Last follow-up: September 2007;
Data entry closure: October 2007

if positive P2 results enables an off label use in this indication, how about the market opportunity in 1st line NSCLC? one third of NSCLC patients are of age 70+...

"Platinum-based combination therapies are often used to treat patients with advanced non-small cell lung cancer. However, elderly patients are frequently not treated with standard chemotherapy due to concerns about their ability to tolerate treatment," said Marcel Rozencweig, M.D., Senior Vice President, Drug Development and Chief Medical Officer. "A combination regimen of satraplatin -- an oral, well-tolerated platinum-based compound -- in combination with another oral, well-tolerated drug such as Tarceva could, if effective, offer an important new treatment option for this under-served patient group."

greetings,
ipollit77

GPCB - Street Rewards Biotech After Positive Trial Results
BY PETER BENESH

INVESTOR'S BUSINESS DAILY

Posted 11/3/2006

When a little-known biopharmaceutical firm's stock shoots up in one day, it usually means the company has had convincing results for a prospective drug.

It's even better if those results came in late-stage clinical trials that foreshadow regulatory approval. It's better still if the disease the developmental drug treats is one of the most feared and prevalent, such as prostate cancer. More than 230,000 new cases are diagnosed each year in the U.S., and about 30,000 men a year die from it.

So maybe it's not so surprising that shares of Germany's GPC Biotech (GPCB) rose sharply on Sept. 25, the day the firm announced positive results for satraplatin. The drug is aimed at late-stage, or hormone-resistant, prostate cancer that has failed to respond to earlier treatments.

Satraplatin binds to cancer cells' DNA and stops cell division, causing the tumor to stop growing. The drug could be on the U.S. market in late 2007, says Mirko Scherer, GPC Biotech's chief financial officer.

The company, which has operations in the U.S., got a Nasdaq listing in 2004 because that's where the biopharma action is, Scherer says.

He spoke with IBD.

IBD: If satraplatin gets approval in the U.S. and abroad, how big is its market potential?

Scherer: We estimate the global market for use of satraplatin in prostate cancer at about $500 million. But it could also have uses for other conditions for which we're conducting a number of additional trials.

If it were successful for other kinds of cancer, that number could be significantly higher. We're already running phase one and two trials for other sorts of cancers.

IBD: How did your firm come across the idea of satraplatin for prostate cancer?

Scherer: Back in the '90s, satraplatin was being tested for prostate cancer when Bristol-Myers Squibb (BMY) had the rights to the drug. Bristol-Myers did not proceed.

Often in the pharmaceutical industry a candidate product gets dropped and a few years later another company gets lucky with it.

We saw some of the raw data in 2002 and thought it looked interesting because treatment options for prostate cancer were limited. Also, there's been a change in insurance reimbursement. Nowadays all cancer drugs are reimbursed.

In the '90s, prostate cancer was not a market for therapy. That has changed too. Taxotere from Sanofi-Aventis (SNY) was approved in the U.S. and Europe for prostate cancer in 2004.

IBD: Satraplatin is seeking approval as a second-line treatment — that is, when other treatments have failed. What about it becoming a primary treatment?

Scherer: That's something we have in mind. Right now, Taxotere has become the standard of care in hormone-resistant prostate cancer. We're running phase one clinical trials combining satraplatin with Taxotere.

In cancer, compounds are often combined. Take Avastin and Herceptin from Genentech. (DNA) They're often used in combination.

We're looking at combinations of satraplatin with other drugs, for example with Tarceva, also from Genentech.

IBD: How prevalent is this late-stage, hormone-resistant prostate cancer?

Scherer: We reckon that 70,000 patients in the U.S. have it. Some 50% to 60% are being treated with chemotherapy.

Once it's metastasized there's no way to cure the patient. Then it becomes a question of prolonging the patient's life and maintaining his quality of life. With satraplatin we're not talking about cure. We're not promoting it as a cure for cancer.

By no means do we think it would be effective only on prostate cancer or lung cancer. We do have efficacy data from ovarian cancer and in small-cell lung cancer now.

IBD: How soon do you expect approval in the U.S. and Europe?

Scherer: Our goal is to file the new drug application before year-end. We have fast-track designation (in the U.S.) because this is an area of unmet medical need. We could have an approved drug if everything goes well by the middle of 2007, and could then begin selling in the U.S.

We licensed the European and Middle Eastern rights to Pharmion (PHRM) of Boulder, Colo., which already does business in Europe. They plan to file with European regulators in the first half of 2007 and could be on the market in 2008.

IBD: So GPC Biotech, a European company, has U.S. rights, while Pharmion, a U.S. company, has European rights?

Scherer: The U.S. is the bigger market and is to us the most interesting. Yes, we're a German company but half of our employees are in the U.S., in Waltham, Mass., and Princeton, N.J. We run the satraplatin program from Princeton.

IBD: Hence your Nasdaq listing?

Scherer: Half of our company is American. We wanted to support that from a capital markets perspective.Most importantly, the biotech industry will continue to be very American. That's where most of the competition is and most of the investors are.

Paion, RNVS & Co

drbio45, what do you think about axaron especially ax200?
http://www.axaron.com/pages/products/2/index.html
"Axaron is extremely excited about the potential for AX200, as work in pre-clinical models has shown that the drug has multiple modes-of-action and is not only capable of protecting brain cells from damage occurring during the acute phase of stroke, but also improves the functional performance thereafter."

the current market cap is something like 87 million usd...
"Heidelberg, July 6, 2006 – A specialized pharmaceutical company has emerged from Axaron Bioscience AG and LION bioscience AG. The new pharma specialist for central nervous system (CNS) diseases has funds of approximately EUR 51 million, of which EUR 21 million is being provided by the Hopp family. The majority shareholder of Axaron Bioscience AG, BASF Aktiengesellschaft in Ludwigshafen, will invest EUR seven million in the new company. A further EUR 23 million will come from LION bioscience AG. The company’s mission is to develop treatments for CNS diseases for which there are currently no or only limited therapeutic options. AX200, a product for the treatment of strokes, is the most advanced compound. It is currently being tested in a phase IIa clinical trial, which is expected to be completed by the end of 2008."
http://www.lionbioscience.com/press/release/latest_releases/dietmar_hopp_establishes_specialized_pha...

greetings,
ipollit77

PAION’S PHASE III STUDY ON TARGET TO BE FULLY ENROLLED BY
YEAR-END

Second of Three Planned Safety Analyses Successfully Completed

Aachen (Germany), 25 July 2006 – Biopharmaceutical company PAION AG

(Frankfurt Stock Exchange, Prime Standard: PA8), today confirmed that the
ongoing Phase III study DIAS-2 is on target to complete recruitment by the
end of 2006. Additionally, two of the study’s three planned interim safety
analysis have already been conducted, the second one just recently. No
safety concerns were raised by the Data Monitoring Committee and
continuation of the study was approved. Specifically, the rate of symptomatic
bleedings (sICHs) - which is a major concern of treating physicians - has been
below predefined levels.
The study explores the efficacy of PAION’s drug candidate Desmoteplase in
acute ischaemic stroke and was started in 2005 together with partner Forest
Laboratories Inc.. It is slated to enrol 186 patients in 80 centres worldwide who
are treated within 3 to 9 hours after the onset of acute ischaemic stroke. The
only clot-busting drug approved today has a label limited to application within
3 hours after stroke onset. Thus, significantly widening that time window with
PAION’s Desmoteplase to 9 hours would greatly enhance eligibility of causal
treatment for stroke patients.
“Thanks to the enthusiastic and diligent effort of our study investigators we
currently have already achieved almost two third of the enrolment completed”,
comments Dr Mariola Soehngen, PAION’s Chief Medical Officer. “Given the
recent recruitment rate we feel confident that we will complete enrolment on
time by the end of this year. Under this timeframe we would expect topline
results to be available not later than mid-year 2007.”
About stroke
Stroke is the third leading cause of death in the industrialised world and a
leading cause of serious, long-term disability. In the US alone, 700,000 people
suffer from a stroke attack each year, and around 20% of them die within four
weeks. For the US, the American Stroke Association expects the financial
burden of stroke due to in-hospital costs, long-term care programs and
productivity losses to be 58 billion dollars in 2006 alone.

Administration for the indication of acute ischaemic stroke. Desmoteplase is
partnered with Forest Laboratories, Inc. and H. Lundbeck A/S.
About PAION
PAION is a public biopharmaceutical company based in Aachen, Germany
(Frankfurt Stock Exchange, Prime Standard, ISIN DE000A0B65S3). It aims to
become a leader in developing and marketing innovative drugs for the
treatment of stroke and other thrombotic diseases for which there is a
substantial unmet medical need. PAION’s activities are focused on the
development of the three drugs Desmoteplase, Enecadin and Solulin.
Currently PAION employs more than 75 people.

potential way to overcome cytostatic drug resistance... EndoTAG - cytostatics encapsulated in cationic liposomes

MediGene´s EndoTAG technology aims at a novel method of cancer therapy by "starving out" tumors. The technology is based on the already approved and applied therapeutic principle of anti-angiogenesis (suppressing tumor vascularization), while adding another and unique alternative: the cutting-edge liposome transport system facilitates a novel application method of established cytostatic drugs (e.g. Taxane), intended to cause specific attachment and destruction of a newly developed tumor vascular system ("neovascular targeting"). Thus this treatment starts off at a very early stage of angiogenesis which is vital for tumor as well as metastases growth, which could permit an especially reliable efficacy. Moreover, the development of typical resistance to cytostatic drugs becomes very unlikely, since the toxic substance does not damage the tumor cells directly. These two specific factors may increase the efficiency of conventional therapies and alleviate their adverse effects. The EndoTAG technology is protected by extensive patents and provides a basis for the development of different cancer therapies.
http://www.medigene.com/englisch/EndoTAGTM.php