Celldex - Impfstoffe gegen Krebs - Die letzten 30 Beiträge
neuester Beitrag 29.06.15 15:29:58 von
HAMPTON, N.J., June 29, 2015 (GLOBE NEWSWIRE) -- Celldex Therapeutics, Inc. (Nasdaq:CLDX) today announced that an independent Data Safety and Monitoring Board (DSMB) recommended continuation of the Phase 3 ACT IV study of RINTEGA® (rindopepimut) in patients with newly diagnosed glioblastoma.
The ACT IV study is a randomized, double-blind, placebo controlled study of rindopepimut plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled into ACT IV to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of overall survival as well as analyses of progression-free survival, safety and tolerability, and quality of life. The timing of the overall survival primary endpoint data is event-driven. Interim analyses assessing safety, futility and efficacy conducted by an independent DSMB were prespecified at 50 percent and 75 percent of events.
As previously announced, the second interim analysis is expected to occur in late 2015/early 2016.
Zitat von Aurum2010CLDX ende Monat auch auf der ASCO, wenn die Märkte nicht crashen müsste es hier bis dann nach oben gehen.
Sieht intakt aus der mittelfrisitge Aufwärtstrend...heute kamen zudem positive News und die ASCO steht ja vor der Tür.
Habe meine Position erhöht nachdem der Nasdaq Biotech Index am ATH arbeitet. Celldex ist ein guter Biotechstock. So long...
Rintega Phase-III-ACT-Studie wird Interimsdaten in Mitte 2015 veröffentlichen.
Seine BTD macht beschleunigte Zulassung durchaus möglich.
Basisszenario für Markt ist Ende 2016, kann aber auch früher geschehen.
3 Jahre zurück, als ich zum ersten Mal über Celldex (NASDAQ: CLDX ) auf Motley Fool, die Aktie gerade stieg von $ 5 bis $ 20 auf der Rückseite der hervorragenden Ergebnisse aus Rindopepimut. Allerdings habe ich, wie andere auch, konzentrierten sich mehr auf ihre CDX-1135 DDD (dichte Ablagerung Krankheit, einer ultra-seltene Nierenerkrankung) Kandidaten.
an der Gesellschaft für eine beschleunigte Zulassung.
Ich ziehe mich hier auch wieder zurück, wünsche aber weiterhin viel Glück
und gute Studienergebnisse.
Seit geraumer Zeit wird auch in diesem allgemeinen Thread über CLDX berichtet:
Thread: Biotech Depot - verschiede Werte und Strategien (der Anfang des Threads ist nicht relevant)
von Freitag wieder realisiert. Vielleicht bleibt ein Teil der Aktien
auch langfristig noch in der Firma liegen, mal sehen. Immerhin haben
sie noch Daten der "compassionate use" mit Rindopepimut rausgehauen, die
auch nicht schlecht sind. Allen Investierten
weiterhin viel Glück und allen, die den Trade am Freitag mitgemacht
gefunden. Wie aus dieser
Präsentation hervorgeht war die experimentelle Gruppe
vor Einschluss etwas besser dran als die Kontrollgruppe:
Mehr OPs und etwas mehr Patienten mit erstem (anstatt zweitem)
Rezidiv. Mist. Das könnte den Effekt des Medikaments zumindest
teilweise erklären. In der Präsentation ist zwar auch ersichtlich,
dass gerade Patienten OHNE OP einen Benefit von Rindopepimut
hatten, ob dies die FDA aber überzeugen wird das ganze ohne
Phase III durchzuwinken, würde ich anzweifeln. Sind zwar trotzdem
vielversprechende Resultate aber leider nicht ganz so positiv
wie ich initial angenommen hatte.
Beste Grüße an alle Mitinvestierten.
Bord. Am Montag wird das hier sehr interessant,
da der US-Markt am Freitag Nachmittag wohl nicht
mehr mit dieser Studie hier gerechnet hat:
Das ganze ist ein richtig gutes Ergebnis, wenn auch von
der Firma sehr vorsichtig verpackt:
Overall Survival (!) beim Rezidiv-Glio mit Rindopepimut + Avastin mit einer HR von 0,47 vs. Avastin mono verbessert! 12 Monate vs. 8,8 Monate. Signifikanter Effekt bei p=0.0208. Funktioniert hat es zwar nur bei Patienten ohne Vortherapie mit Avastin, da das Rezidiv-Glio nun aber eine der schlimmsten
Erkrankungen überhaupt ist, dürfte die Chance nicht schlecht stehen, dass
die FDA das Zeug unter Auflagen VIELLEICHT(!) durchwinkt, wenn eine Phase III
nachgereicht wird. Letzteres bleibt zwar abzuwarten aber die Daten sind echt gut. Nur zur Ergänzung: Progression free survival zum Monat 6: 27% vs. 11%
Wenn ich nichts schwerwiegendes übersehen habe, dürfte der Kurs noch deutlich anspringen, ist zwar sehr verwunderlich, dass der Markt noch nicht adäquat reagiert hat, ich gehe aber davon aus, dass dies an der vorsichtigen Kommunikation des Press Release lag.
Beste Grüße an alle, die hier an Bord geblieben sind. Ich müsste mal in den
Archiven des Threads graben, wann ich hier den letzten Beitrag geschrieben hab.
Neben Isis pharma für mich ein Grün investment im Biotech-Depot.
Celldex Therapeutics Prices Public Offering of Common Stock
HAMPTON, N.J., Dec. 4, 2013 (GLOBE NEWSWIRE) -- Celldex Therapeutics, Inc. (Nasdaq:CLDX) today announced the pricing of an underwritten public offering of 7,000,000 shares of its common stock, offered at a price to the public of $24.50 per share for an aggregate offering of $171,500,000 of common stock. The net proceeds to Celldex from this offering are expected to be approximately $162,725,000, after deducting underwriting discounts and commissions and other estimated offering expenses payable by Celldex. The underwriters have been granted a 30-day option to purchase up to an aggregate of 1,050,000 additional shares of common stock.
Ich stelle mal diese Analystenmeinung hier rein:
(Fettungen von mir)
KOL highlighted the correlation of survival with immune response and patients stable for an unexpected period of time. KOL sees the 5.6 month median overall survival (OS) to be very encouraging for patients in a highly refractory population. KOL commented that response data in GBM are often not reliable and he would not focus on the responses of 1 or 2 patients. The KOL also highlighted new data and analysis presented at SNO that support EGFRvIII as poor prognostic factor.
SNO presentation highlights tail in rindo OS curves. Dr. Weller's overview on immunotherapy for GBM highlighted 3-year survival rate of 26% from ACT III (n=65), which he considered to reflect benefit of the drug. Pooled Phase II rindo studies on 105 patients updated during ReACT presentation showed 3, 4, and 5-year survival of 30%, 18% and 14% respectively. As with other immunotherapies, the survival benefit may be more notable in the tail of the survival curve and longer follow-up may be needed to detect long-term benefits.
Correlation with immune response suggests that the longer than anticipated survival may be due to a drug effect rather than patient selection. OS from single-arm studies is often difficult to interpret and could be due to patient selection. However, as shown in other rindo studies, ReACT data showed a robust immune response to rindo and importantly better survival in patients with the higher anti-EGFRvIII antibody titers.
Alles in allem sehe ich das so, dass durch die neuen Daten die Vermutung gestützt worden ist, dass Rindo wirkt. Die Wirkung wird - ähnlich wie bei ipilimumab - eher darin bestehen, das OS für einen Teil der Patienten signifikant zu verlängern. Auf PFS oder ORR-Daten sollte man hier kein gesteigertes Gewicht legen. Selbst das mediane OS sollte nicht als entscheidender Maßstab betrachtet werden.
Bedauerlich ist natürlich, dass sich die Rekrutierung für ACT IV noch länger hinziehen wird (eventuell Abschluss in Q1/2014). Andererseits kommt es da auf ein paar Monate hin oder her nun auch nicht mehr an. Dass Celldex diese Studie allein gestemmt hat, ist eine riesen Leistung.
Du wirst recht behalten. Vorbörslich ist der Kurs deutlich unter Druck. Minus 10% und mehr.
ich würde bei Rindo nur auf OS und nicht auf PFS oder ORR schauen wollen (analog Yervoy). Aus meiner Sicht verdichtet es sich immer mehr, dass Rindo einen positiven Einfluss auf das OS hat. Ich würde nicht mal unbedingt sagen, dass das median OS die alles entscheidende Größe sein sollte. Was mich beeindruckt ist vielmehr, dass in den alten ACT-Studien auch nach 4 oder 5 Jahren ein Teil der Patienten am Leben ist.
Mir fehlt letztlich auch eine solide Vergleichszahl bei der Avastin-refractory-Gruppe. Aber wo soll man die auch herbekommen? Man kann ja nicht gegen eine Alternative testen, weil es keine gibt, oder?
Ich bin froh, wenn ACT IV mal fertig rekrutiert hat. Dann werden wir irgendwann OS-Daten bekommen und ich glaube daran, dass die gut sin werden. Celldex hat hier einen echten Kraftakt gestemmt, nachdem Pfizer gekniffen hat und ich denke, dass sie am Ende belohnt werden.
bist du dir sicher, dass es gute Ergebnisse sind? Die Reaktionen in Twitter sind im wesentlichen negativ. Zwar muss das kein Indikator sein, doch scheinen die Ergebnisse zumindest nicht eindeutig positiv zu sein.
Mögliche Probleme mit den Ergebnissen:
- Rindo+Avastin vs. Avastin... OS-HR 0.43 zwar okay, aber nicht signifikant (p=0.16)... insbesondere sind es nur Zwischenergebnisse mit 40 von 70 Patienten
- Avastin-refractory... nur Single-Arm(N=25): primärer Endpunkt (20% PFS>6mo) nicht erreicht mit 8%; OS=5.6 Monate... aber was ist der Vergleich? CLDX gibt einen historischen Wert von 3.6 an... ich habe aber auch Analystenkommentare gelesen, die mehr erwartet haben. Wie will man das bewerten?
mal sehen... ich kann mir auch vorstellen, dass morgen der Kurs negativ reagiert.
Ein mal mehr überzeugen auch die Updates der bisherigen ACT-Studien.
Die derzeitige Datenlage spricht wirklich dafür, dass Rindopepimut eine wirksame Immuntherapie ist, die das OS signifikant verlängert.
Es würde mich wundern, wenn es am Montag keine positive Kursreaktion gäbe.
Mag gut sein, dass Pfizer sich hier noch ärgern wird, das aus der Hand gegeben zu haben. Wer zuletzt lacht...?
Preclinical rationale is the strongest for the combination of a T-cell co-stimulatory agonist with PD1/PDL1 blockers. The KOL commented that PD1 represents a particularly good immunologic target; therefore it is unclear whether immunotherapy against other targets will be as successful. However the KOL sees several opportunities to combine PD1/PDL1 inhibition with other immuno-oncology targets. In particular, the preclinical data for the combination involving a co-stimulatory agonist (i.e., T-cell activators) like BMY's urelumab (41BB/anti-CD137), AZN's anti-OX40, and CLDX's (Celldex) CD1127 (CD27 agonist antibody) as these represent the only combinations that yield cure in preclinical models. He also noted strong preclinical data supporting dual checkpoint inhibition of PD1 and LAG3 (BMY entering Ph I in 2013) as well as TIM3. And while he was less enthusiastic for PD1 + lirilumab (anti-KIR), he believes natural killer cells could play an important role in improving responses to immunotherapy.
Ich übernehme hier auch einen Beitrag, den der User ipollit kürzlich im allgemeinen Biotech-Depot-Thread gepostet hat (wo auch viel zu möglichen Risiken gesagt wird):
CDX-1127 reiht sich ja in die neuen Immun-Krebstherapien ein. Während CTLA-4, PD-1 usw. die Unterdrückung des Immunsystems durch die Krebszellen verhindern soll und dies offensichtlich auch sehr gut funktioniert, ist z.B. CDX-1127, das über CD-27 wirkt, eher dafür gedacht, dass Immunsystem zu aktivieren, damit es sich stärker gegen den Krebs richtet. BMY hat hier mit dem CD137-AK Urelumab eine Eigenentwicklung in der PI, die theoretisch ein Kandidat für eine Kombi mit z.B. PD-1 wäre. Mehrere Studien mit Urelumab wurden allerdings abgebrochen. Wenn ich es richtig gelesen habe, so gab es erhöhte Leberwerte, so dass nun mit niedrigeren Dosierungen weiter getestet wird. CLDXs CDX-1127 hat solche Probleme bisher nicht.
AKs, die das Immunsystem aktivieren, können zu schweren Nebenwirkungen führen, wenn das Immunsystem überreagiert. Vor mehreren Jahren gab es mal eine deutsche Firma in der Presse, bei der die Probanden in einer PI mit einem ähnlichen CD-28 AK nur knapp überlebt haben. CLDX betont, dass ihr CD-27 AK bisher sehr sicher war und es keine Anzeichen für derartige schwere Nebenwirkungen gegeben hat.
Allerdings habe ich in den folgenden Artikeln gelesen, dass agonistische (d.h. verstärkende) AKs auf CD-27 zu konträren Ergebnissen führen können. Es könnte auch sein, dass ein solcher AK das Krebswachstum beschleunigt und eher ein hemmender AK den Krebs verringert. Positiv ist allerdings eine mögliche Wirkung des CD-27 AKs auf Blutkrebs-Stammzellen... das sind quasi schwer zerstörbare Krebszellen, die dazu führen, dass es immer wieder zu Rückfällen kommt. In diesem Fall z.B. bei CLL usw...
"From “magic bullets” to specific cancer immunotherapy"
...In addition, T cell co-stimulatory receptors such as CD28 and the TNF receptor family members CD137, OX40, GITR and CD27 may serve as potential targets for agonistic mAbs in order to activate anti-tumoural T cell responses ... Current evidence supports the view that CD27-signalling improves anti-tumoural immunity as well. However, these findings are controversial. Some pre-clinical studies demonstrate that agonistic anti-CD27 mAbs effectively activate immune cells to control or eliminate lymphomas, leukemia and solid tumours. ...In contrast, we could recently document in a murine tumour model that activation of CD27 induces progression of solid tumours by inducing regulatory Tregs.
Cancer stem cells (CSCs) are a subpopulation of cancer cells that are thought to drive the growth of tumours,... Cure of cancer implies the elimination of CSCs. However, CSCs display increased resistance against chemotherapy, irradiation and even targeted therapy. Several factors favour CSC resistance, such as the expression of high levels of ABC pumps that expel small molecules and the localisation in hypoxic niches, preventing the accumulation of reactive oxygen species after radiotherapy. Therefore, new therapies that selectively destroy CSCs are needed... Recent work from our laboratory demonstrates that LSCs may be targeted by blocking CD27 signalling. The TNF-receptor family member CD27 is expressed on CML LSC and CD27 signalling activated the canonical Wnt pathway, induced LSC proliferation, increased differentiation to malignant granulocytes and promoted disease progression...
"CD27-signaling promotes tumor growth"
Naja, dabei handelt sich zwar nur um Tiermodelle, trotzdem besteht offensichtlich ein Risiko, dass CDX-1127 genau gegenteilig wirken könnte. Andererseits sind die Erwartungen wohl auch sehr niedrig.
There Is A Lot To Like About Celldex Therapeutics
For some time, rindopepimut was the major reason why many have invested in Celldex Therapeutics (CLDX). However, late last year, Celldex generated a great deal of excitement after the final results from the company's Phase 2b metastatic breast cancer study of CDX-011 were released. The results were so good that the company plans to initiate a randomized trial suitable for accelerated approval in patients with triple negative breast cancer in the second half of 2013.
In addition to the CDX-011 accelerated approval study, Celldex plans to initiate new clinical studies and expansion studies for four other Celldex programs this year.
Celldex's primary focus is in oncology. There are four programs currently in clinical development for treatment of several cancers, and additional oncology programs are progressing toward clinical development. Celldex also expects data from three clinical studies by year end, including results from its Phase 2 study of rindopepimut with Avastin (bevacizumab) in refractory glioblastoma. The company also hopes to complete enrollment in the Phase 3 rindopepimut ACT IV registration trial in frontline glioblastoma.
Celldex's expertise is the design of new therapeutics and treatment regimens that maximize the beneficial aspects of the immune system, and counter its negative elements that are exploited by cancers and pathogens. These innovative programs include:
APC Targeting Technology, a new class of vaccines based on Celldex's proprietary antibody-targeted vaccine technology that is used to generate an immune response against cancer and other diseases;
Therapeutic Antibody Programs, a well validated approach to using antibodies that target cancer and other diseases directly or by interfering with the disease; and
Immune System Modulators, drugs that activate or suppress specific parts of the immune system, including such molecules as Toll-like receptor (TLR) agonists that can activate patients' innate and adaptive immunity.
In June 2010, Celldex stock crashed after Pfizer (PFE) decided to end its collaboration with Celldex for CDX-110. Celldex vowed to continue research and development of rindopepimut, also known as CDX-110. CDX-110 is a immunotherapeutic that targets the tumor-specific molecule, epidermal growth factor receptor variant III, or EGFRvIII.
EGFRvIII is a mutated form of the epidermal growth factor receptor, or EGFR, that is only expressed in cancer cells and not in normal tissue, and can directly contribute to cancer cell growth. EGFRvIII is expressed in approximately 30% of glioblastoma tumors, also referred to as glioblastoma multiforme, the most common and aggressive form of brain cancer.
Glioblastoma multiforme tumor cells show a high resistance to radiation and chemotherapy. These tumors spread and infiltrate tissue so quickly that eradicative surgery is often impossible with recurrence occurring within months of the initial treatment.
According to the US National Cancer Registry, approximately 28,000 new cases of malignant gliomas are diagnosed in the United States and the European Union each year. The current standard of care involves surgery, followed by radiotherapy and chemotherapy. The relative survival rate for adults diagnosed with glioblastoma is less than 30% within one year of diagnosis. According to the Central Brain Tumor Registry of the United States, only 3% of patients live longer than five years after primary diagnosis. The median overall survival does not exceed 15 months despite surgical resection, radiotherapy, and chemotherapy even in selected clinical trial populations.
The research firm, GlobalData, estimated that the global glioblastoma multiforme therapeutics market was valued at $370 million in 2010. GlobalData forecasted that the market will grow at a compound annual growth rate of 2.4% to reach $449 million by 2018. This low growth rate is primarily attributed to the patent expiry of Merck & Co.'s (MRK) Temodal/Temodar (temozolomide) in Europe in 2009, and in the United States in 2014. GlobalData research found that the entry of low cost generics in Europe in 2010 led to a decrease in the market valuation.
According to the pharmaceutical industry research firm, Decision Resources, there is a significant opportunity for investigational glioblastoma drugs. Despite advances in treatment such as adjuvant radiotherapy in combination with Temodar/Temodal, prognosis remains poor as the majority of glioblastoma patients experience disease recurrence.
Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have granted orphan drug designation to rindopepimut for the treatment of EGFRvIII expressing GB. The FDA has also granted a Fast Track designation to the investigational drug.
On November 15, 2012, Celldex announced the presentation of three-year survival data from the Phase 2 rindopepimut clinical program in EGFRvIII-positive glioblastoma, a more aggressive form of glioblastoma typically associated with reduced long-term survival in comparison to the glioblastoma population as a whole. Across three Phase 2 studies of rindopepimut, survival data has remained consistent, suggesting that a substantial and continuing survival benefit exists in comparison to independent control datasets at the median and at three years.
In the multi-center Phase 2 ACT III study, the median overall survival was 24.6 months from diagnosis (21.8 months from study entry) and overall survival is 26% at three years. In the Phase 2 ACT II study, the median overall survival was 24.4 months from diagnosis (20.5 months from study entry) and overall survival is 23% at three years.
The long-term survival data across all three rindopepimut Phase 2 clinical trials was consistent and suggested that rindopepimut provided long-term survival beyond what is historically seen in this subset of EGFRvIII-expressing glioblastoma patients, a group that typically has more aggressive disease associated with a worse prognosis than the general glioblastoma patient population.
In addition to the presentation of updated survival data, Celldex also announced the presentation of data from a retrospective analysis of EGFRvIII expression status and associated clinical outcome in the Phase 3 Radiation Therapy Oncology Group's (RTOG) 0525 study. This analysis was conducted by the University of Texas MD Anderson Cancer Center in cooperation with RTOG to provide an assessment of the prognosis for patients with EGFRvIII-positive disease contemporary with the ACT III data.
"The results presented at SNO provide further validation for the rindopepimut clinical program," said Anthony Marucci, President and CEO of Celldex Therapeutics. "The median and long-term survival rates are impressive in comparison to both the MD Anderson and RTOG historical control datasets, with 23% to 33% of patients on rindopepimut surviving to the three-year mark versus 6% to 18% of patients in the historical control datasets. In addition, while the ACT II and ACT III data continue to mature, across all three Phase 2 rindopepimut studies, approximately 15% of patients are alive at five years compared to an expectation of 0%. These results support our belief that rindopepimut has the potential to dramatically alter the prognosis for patients with EGFRvIII-positive glioblastoma. To that end, we continue to actively enroll patients in the pivotal ACT IV study with more than 150 clinical sites around the world selected to participate and, to date, 118 of these sites actively screening patients."
In December 2011, Celldex initiated ACT IV, a pivotal, randomized, double-blind, controlled Phase 3 study of rindopepimut in patients with surgically resected, EGFRvIII-positive GB. The primary objective of the study is to determine whether rindopepimut plus adjuvant GM-CSF improves the overall survival of patients with newly diagnosed EGFRvIII-positive GB after Gross Total Resection, or GTR, when compared to treatment with TMZ and a control injection of KLH. KLH is a component of rindopepimut and was selected due to its ability to generate a similar injection site reaction to that observed with rindopepimut.
The ACT IV trial will enroll up to 440 patients at over 150 centers worldwide to recruit approximately 374 patients with GTR to be included in the primary analysis. Celldex expects to complete patient accrual by the end of 2013 and anticipate receiving data 18 to 24 months after completing accrual. The company anticipates ACT IV to cost over $60 million during its duration.
In December 2011, Celldex also initiated ReACT, a Phase 2 study of rindopepimut in combination with Avastin in patients with recurrent EGFRvIII-positive GB. ReACT will enroll approximately 95 patients in a first or second relapse of GB following standard therapy. The study will be conducted at approximately 20 sites across the United States. Approximately 70 patients who have yet to receive Avastin will be randomized to receive either rindopepimut and Avastin or a control injection of KLH and Avastin in a blinded fashion. Another 25 patients who are refractory to Avastin having received Avastin in either the frontline or recurrent setting with subsequent progression will receive rindopepimut plus Avastin in a single treatment arm. We expect data from this study to be available in the second half of 2013.
In addition, researchers at Stanford University are conducting an investigator sponsored, pilot trial of rindopepimut in pediatric patients with pontine glioma. Patient enrollment is ongoing for this trial.
In June 2012, a survey of US oncologists surveyed conducted by the research and advisory firm, Decision Resources, found that they would prescribe CDX-110 to 36% of their newly diagnosed glioblastoma multiforme patients if the drug is approved.
Decision Resources predicted that CDX-110 would earn an 18% patient share in the US newly diagnosed glioblastoma multiforme market by 2020 because only about one-third of glioblastoma multiforme patients harbor the EGFRVIII variant targeted by the drug. The firm concluded that this limitation, combined with increased competition in the glioblastoma multiforme drug market, will limit the patient population eligible for the therapy.
CDX-011, also known as glembatumumab vedotin, is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor types, including melanoma, breast cancer and glioma. The FDA has granted Fast Track designation to CDX-011 for the treatment of advanced, refractory/resistant GPNMB-expressing breast cancer.
GPNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize, and to correlate with reduced time to progression and survival in breast cancer. The GPNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics' (SGEN) technology.
In June 2008, Celldex initiated a Phase 1/2 study of CDX-011 administered intravenously once every three weeks to patients with locally advanced or metastatic breast cancer who had received prior therapy. For all patients treated at the maximum dose level, tumor shrinkage was seen in 62% (16 of 26 patients) and median progression free survival (PFS) was 9.1 weeks. A subset of 10 patients had "triple negative disease," a more aggressive breast cancer subtype that carries a high risk of relapse and reduced survival as well as limited therapeutic options due to lack of over-expression of HER2/neu, estrogen and progesterone receptors. In these patients, 78% (7 of 9 patients) had some tumor shrinkage, 12-week PFS rate was 70% (7 of 10 patients), and median PFS was 17.9 weeks.
In December 2012, Celldex presented positive final results from the Phase 2b EMERGE clinical trial of CDX-011 in patients with both triple negative breast cancer and high GPNMB expression. In December 2012, Celldex announced final results from the EMERGE study which suggested that CDX-011 induced significant response rates compared to currently available therapies in patient subsets with advanced, refractory breast cancers with GPNMB over-expression (expression in greater than 25% of tumor cells) and in patients with triple negative breast cancer. The overall survival, or OS, and progression free survival, or PFS, of patients treated with CDX-011 was also observed to be greatest in patients with triple negative breast cancer who also over-express GPNMB and all patients with GPNMB over-expression.
In December 2012, Celldex had its end of Phase 2b meeting with the FDA for the CDX-011 program. Based on this meeting, Celldex intends to initiate a randomized study of CDX-011 for accelerated approval in patients with triple negative breast cancer that also over-express GPNMB in the second half of 2013.
Since triple negative breast cancers do not express estrogen, progesterone, and HER2 receptors, these cancers are resistant to conventional targeted treatments, including hormonal and HER2-targeted therapies. According to the National Breast Cancer Foundation, triple negative breast cancer occurs in about 10% to 20% of diagnosed breast cancers.
Celldex plans to initiate a pivotal, randomized, accelerated approval study of CDX-011 in patients with triple negative breast cancers that over-express GPNMB in the second half of 2013. Last year, the FDA drafted new guidelines for clinical trials researching early stage triple negative breast cancer in an effort to expedite the development of drugs to treat these cancers.
CDX-1401, developed from Celldex's APC Targeting Technology, is a fusion protein consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor, DEC-205, linked to the NY-ESO-1 tumor antigen.
Researchers have detected NY-ESO-1 in 20% to 30% of all melanoma, lung, esophageal, liver, gastric, prostate, ovarian and bladder cancers. CDX-1401 is intended to selectively deliver the NY-ESO-1 antigen to dendritic cells to generate strong immune responses against cancer cells expressing NY-ESO-1.
Celldex is developing CDX-1401 for the treatment of malignant melanoma and a variety of solid tumors which express the proprietary cancer antigen NY-ESO-1, which the company licensed from the Ludwig Institute for Cancer Research in 2006. Preclinical studies have shown that CDX-1401 is effective for activation of human T cell responses against NY-ESO-1.
On October 29, 2012, Celldex announced that The Phase 1 study of CDX-1401 was the first clinical study to demonstrate that an off-the-shelf vaccine targeting dendritic cells in vivo through DEC-205 could safely lead to robust immunity when combined with TLR agonists in cancer patients. Significant anti-NY-ESO-1 titers occurred in 79% of evaluable patients.
In 2013, Celldex plans to initiate a Phase 2 study of CDX-1401 in combination with CDX-301 sponsored by the Cancer Immunotherapy Trials Network of the National Cancer Institute.
CDX-1127 is a human monoclonal antibody that targets CD27, a potentially important target for immunotherapy of various cancers. Celldex entered into license agreements with the University of Southampton in the United Kingdom for intellectual property related to uses of anti-CD27 antibodies and with Medarex, a Bristol-Myers Squibb (BMY) subsidiary, for access to the UltiMab technology to develop and commercialize human antibodies to CD27.
CDX-1127 has been shown to activate immune cells that can target and eliminate cancerous cells in tumor-bearing mice and to directly kill or inhibit the growth of CD27 expressing lymphomas and leukemias. Both mechanisms have been seen even at low doses in appropriate preclinical models.
In November 2011, Celldex initiated an open label, dose-escalating Phase 1 study of CDX-1127 in patients with selected malignant solid tumors or hematologic cancers at multiple clinical sites in the United States. The Phase 1 study is designed to test five escalating doses of CDX-1127 to determine a Phase 2 dose for further development based on safety, tolerability, potential activity and immunogenicity.
On April 8, 2013, Celldex reported the results of an in vitro study analyzing the activation of human T cells with CDX-1127 at the American Association of Cancer Research (AACR) annual meeting.
"The results of this study confirm that CDX-1127 elicits potent activation of T cells by inducing their proliferation and release of important immune modulating cytokines," Tibor Keler, PhD, Celldex's Senior Vice President and Chief Scientific Officer stated. "Most importantly, we have shown that the activation is highly regulated, which limits any safety concerns related to non-specific stimulation of the immune system that similar candidates in this class have faced. This finding is supported by the good safety profile seen to date in our ongoing multi-dose Phase 1 human clinical trial. We believe CDX-1127 is an exciting entrant to the field of immunotherapy and look forward to presenting clinical data from planned solid tumor and hematologic expansion cohorts from our Phase 1 study by year-end."
The company anticipates reporting data from the CDX-1127 program in the second half of 2013.
CDX-301 is a FMS-like tyrosine kinase 3 ligand, or Flt3L, stem cell mobilizer and dendritic cell growth factor. CDX-301 has demonstrated a unique capacity to increase the number of circulating dendritic cells in both laboratory and clinical studies. In addition, CDX-301 has shown impressive results in models of cancer, infectious diseases and inflammatory/autoimmune diseases.
Celldex licensed CDX-301 from Amgen Inc. (AMGN) in March 2009.
In February 2013, Celldex presented final results from a Phase 1 multi-dose study of CDX-301 in 30 healthy subjects. The Phase 1 study evaluated seven different dosing regimens of CDX-301 to determine the appropriate dose for further development based on safety, tolerability, and biological activity. The data from the study were consistent with previous clinical experience and demonstrated that CDX-301 was well-tolerated and could effectively mobilize hematopoietic stem cell populations in healthy volunteers. Based on the safety profile and the increases observed for CD34+ stem cells and dendritic cells, Celldex plans to initiate a pilot study in hematopoietic stem cell transplant by the end of 2013.
CDX-1307 utilizes monoclonal antibodies to deliver vaccine directly to the patient's immune system and focuses the immune system against hCG beta (hCG-β), a cancer-associated target believed to play a role in more aggressive forms of the disease. hCG-β is an established tumor-associated antigen that is over-expressed in a variety of common cancers including those of the colon, lung, pancreas, esophagus, breast, bladder, cervix, stomach, and prostate, but not expressed in most normal tissues.
CDX-1307 has been evaluated for the treatment of advanced colorectal, pancreatic, bladder, ovarian and breast cancers in two Phase 1 trials.
In October 2009, Celldex announced positive results from Phase 1 studies of CDX-1307 in patients with advanced epithelial cancers, including breast, colon, bladder and pancreatic cancer.
The studies enrolled more than 80 patients with heavily pretreated, advanced-stage breast, colon, bladder and pancreatic cancer, with an average of 4.6 prior therapies across the treatment population. All patient cohorts demonstrated a favorable safety profile with no dose limiting toxicity to date.
Researchers found that the combination of CDX-1307 with TLR agonists significantly enhanced immune responses against hCG-β, providing strong humoral responses in 88% of patients and cellular immune responses in 57% of patients analyzed to date. Immune responses occurred even in the presence of high circulating levels of hCG-β, suggesting that the CDX-1307 can overcome antigen tolerance in advanced and heavily pretreated cancers. Nine patients in the studies experienced disease stabilization from 2.3 months to 11.4 months following the initiation of CDX-1307 vaccination. Two of these patients have received multiple courses of CDX-1307 and continue treatment with stable disease at 6.4 and 11.4 months.
Celldex believe these data provide the basis for advancing CDX-1307 into a front-line patient population selected for hCG-β expressing cancers.
CDX-1135 is a molecule that inhibits a part of the human immune system called the complement system. The complement system is comprised of proteins that are initiators of the body's inflammatory response against disease, infection and injury. Excessive complement activation also plays a role in some persistent inflammatory conditions.
CDX-1135 is being assessed for certain rare renal diseases involving dysregulated complement and therapeutic intervention in Antibody-Mediated Rejection (AMR) and other inflammatory conditions where the complement system is thought to have a critical role in the disease pathogenesis.
Celldex is conducting a Phase 1 study of CDX-1135 as a therapy for dense deposit disease (DDD), a rare genetic condition affecting 2 to 3 people per million worldwide. DDD is a devastating disease that is caused by uncontrolled activation of the alternative pathway of complement and leads to progressive kidney damage in children. There is currently no treatment for patients with DDD and about one-half of those with DDD progress to end-stage renal disease within 10 years. Because DDD recurs in virtually all patients who receive a kidney transplant, transplantation is not a viable option for these patients. In animal models of DDD, CDX-1135 treatment showed evidence of reversal of kidney damage.
Celldex is planning to initiate a pilot study of CDX-1135 in a small number of DDD patients to determine the appropriate dose and regimen for further clinical development based on safety, tolerability and biological activity with data expected by the end of 2013.
Celldex is developing therapeutic human antibodies to a signaling molecule known as CD89 or Fcα receptor type I (FcαRI). CD89 is expressed by some white blood cells and leukemic cell lines, and has been shown to be important in controlling inflammation and tumor growth in animal models.
Celldex has proprietary, fully human antibodies to CD89 in preclinical development. Depending upon the specific antibody used, anti-CD89 antibodies can either be activating and thus stimulate immune responses, or down-regulating and anti-inflammatory.
Celldex also has a preclinical program, CDX-014, a fully-human monoclonal antibody-drug conjugate that targets TIM-1, a molecule that is highly expressed on renal and ovarian cancers with minimal expression in normal tissues. CDX-014 has shown potent activity in preclinical models of ovarian and renal cancer.
Celldex and Rockefeller University investigators are collaborating on an effort to develop a vaccine against the human immunodeficiency virus (HIV), the virus known to cause Acquired Immune Deficiency Syndrome (AIDS). The vaccine, called DCVax-001, is an APC-targeted vaccine consisting of a fusion protein of a human monoclonal antibody with specificity for the dendritic cell receptor, DEC-205 linked to an HIV antigen. This program has been funded through a grant from the Bill & Melinda Gates Foundation. The vaccine is currently being tested in a Phase 1 trial in healthy volunteers at Rockefeller University.
Celldex plans to enroll approximately 300 patients with triple-negative breast cancer with tumors that also over-express the protein GPNMB. [The antibody portion of CDX-011 hones in on GPNMB-expressing tumors.] The patients will be randomized 2:1 to receive treatment with CDX-0-11 or Roche's Xeloda (capecitabine.) The primary endpoints are overall response rate or progression-free survival. Celldex says it will be able to submit for FDA approval (accelerated approval) as long as one of the two endpoints are met.
Celldex chose not to pursue a Special Protocol Assessment (SPA) agreement with FDA for the trial because regulators were copacetic with either overall response (with durability) or PFS as clinically meaningful endpoints given the lack of current treatment options for triple-negative breast cancer, Celldex chief medical officer Tom Davis told me in an interview. Pfizer (PFE_) employed "either/or" primary endpoints for its pivotal trial of the lung cancer drug Xalkori, so there's precedent for this design, added Davis.
The study will begin enrolling patients in the second half of the year, with accrual taking approximately 18 months. Top-line data will likely be approximately nine months later.
In addition to having triple-negative breast cancer that over-expresses GPNMB, the patients in the study will also be resistant to prior treatment with anthracyclines and taxanes. In other words, the patients in the accelerated approval trial will enter with less advanced disease than the patients who participated in the previous phase II study of CDX-011. [I wrote about the results from the CDX-011phase II study when they were presented last December.]
Celldex powered the new study with the assumption that Xeloda-treated patients (the control arm) will have a 15% response rate and PFS of 4 months. The company believes CDX-011 can double response rate to 30% and improve PFS by 2.25 months.
As I write this column on Thursday morning, Celldex shares are down about 5%. Hard to attribute the selling to anything specific, but I know the timelines for the '011 trial are a bit longer than what management told investors during the roadshow leading up to last month's stock offering.
The trial is certainly not without risk, which could also be weighing on the stock. Earlier-stage patients should, theoretically, respond better to CDX-011 but then it's more difficult to use results from the completed CDX-011 trial as an accurate comparator. [And don't forget, the old trial was quite small.]
Cancer drug expert, consultant and blogger Sally Church (@maverickNY) pointed to this study (via Twitter) of Avastin in second-line triple negative breast cancer patients. Median PFS was 6 months for Avastin plus chemotherapy versus 2.7 months for chemotherapy alone.
"If Avastin can achieve 6 mon after taxanes in TNBC, then comparing 011 to capecitabine 2nd line will need to match that."
Lots to think about in terms of handicapping the results from the CDX-011 trial. There's also plenty of time.
Celldex is more than just CDX-011. On its call Thursday morning, the company said to expect patient enrollment in the phase III study of rindopepimut in brain tumor patients to wrap at the end of the year. The first interim look at data from the study will take place in mid-2014.
An earlier-stage drug candidate, the complement inhibitor CDX-0135, has also generated some investor interest. A small pilot study in Dense Deposit Disease should have data by year's end.
- The pivotal ACT IV study continues to actively accruing patients at more than 142 centers around the world. Enrollment is going well with a targeted accrual date at the end of 2013 and a potential for BLA filing in 2015.
- Based on our discussion with the FDA and with breast cancer experts and specialists, we believe we have a well-defined approval path ahead of us for CDX-011 in breast cancer. As Anthony mentioned, the next step is the initiation of a clinical trial suitable to support accelerated approvals in patients with triple negative breast cancer that also overexpress GPNMB. Specifically, as outlined on slide seven, we expect this trial to be a 2:1 randomized study accruing approximately 300 patients.
We’ve designed a direct comparison study at CDX-011 versus capecitabine, also known by the trade name Xeloda.
As you’ve heard before, GPNMB overexpression is defined as 25% of tumor cells testing positive.
With the trial size of 300 patients, we should be able to confirm with confidence our response rates to CDX-011 of 30% or PFS benefit of 2.25 months
And there is a high level of enthusiasm for the return of CDX-011 to the clinic, which will support strong enrollments. We intend to include approximately 75 to 100 academic and community centers across North America into the study and anticipate accrual to take about 18 months. Final readout could occur within nine months of accrual completion. With positive results, this would position us for a BLA filing in the late 2015-2016 timeframe.
While we will follow patients for an overall survival in the study targeting accelerated approvals, we also plan to sequentially initiate a Phase 3 study in all patients with metastatic breast cancer that overexpress GPNMB. This study could both confirm full approval and expand the treatment indications. The details of this study will depend on initial results from the accelerated approval study that we would anticipate that it would begin prior to results reading out from that accelerated approval study.
- So for rindo we’re are looking at some of the newer therapeutics that have come out over the past few years plus what’s already being paid for in GBM such as Avastin. So our models would look at anywhere between $80,000 and $100,000 for rindo, and for 011 we’re looking at least the last two drugs that have been approved as ADCs which are in the range of between $90,000 and $100,000.
- And remember Boris, it’s an neither/or; either we hit the ORR benefit or the PFS benefit. So, it’s an neither/or.
- Well, our data for EMERGE would suggest that within the triple negative population about 40% will test as high expressers.
- Cantor Fitzgerald
Okay and on the larger GPNMB expression study with the full complement of all comers in that, would that also be study based on similar end points, or would you go for NOS endpoint at that point?
Well, the confirmatory study would need to be OS, again the FDA standard for full approval is survival and they would want that trial to provide OS data. It would be sized for overall survival. That said, there could also be early looks that might accelerate the process, but that’s the tradition and that’s basically what the FDA recommended in our meeting.
- ROTH Capital Partners
And taking the question. Not to belabor a particular point, I just wanted to make sure, and maybe it’s a rhetorical question at this point, with regard to the either/or, ORR or PFS for the 011 study, I just want to make sure that this is linking up with your FDA discussions and this was something that the FDA was okay with?
Yeah, hi, Joe. We certainly discussed co-primaries with the FDA and they agreed. This is something that they have seen many times and are comfortable with and drugs have been approved with the either/or approach. It’s basically a concept of sharing the alpha, you assign different parts of your alpha error to the specific endpoints and then they can be free-standing approvable endpoints.
- Anthony Marucci
Thank you, Operator. And thanks everyone for joining us today. I want to close the call by directing you to the final slide number 11, our 2013 milestones.
To recap, 2013 will be a very busy year for Celldex. We intend to continue our focus on maximizing the accruals for the ACT IV rindo third registration study with the goal of completing accrual by the end of the year. We complete the ReACT window Phase 2 program and the data from both arms also by the end of the year. Initiate a pivotal accelerated approval study for CDX-011 in metastatic triple negative breast cancer in the second half of the year. Initiate a pilot study of CDX-1135 in Dense Deposit Disease with data expected by yearend, enroll the expansion cohorts for 1127 with data expected in the second half of the year, and finally, we’ll initiate a study of 301 in transplant settings once we complete our discussions with the FDA on next steps. And we hope to collaborate with the NCI funded CITN Group on a Phase 2 combination study of 1401 and 301.
So we look forward to progressing development across our broad pipeline which turns out to be a very busy year. We’ll continue to have multiple opportunities to update you on our progress, but as always we welcome your questions at any time. So thank you for your time today and have a great day.
Alles hübsch, würde ich meinen.
Naja... das ganze ist ja noch sehr unsicher. Aber prinzipiell ist der GPNMB+ Anteil wohl etwa so wie HER+, d.h. grundsätzlich könnte es schon in Richtung Herceptin gehen. Zusätzlich könnte CDX-011 noch in anderen Krebsarten angewendet werden.
ja, ist schon eine schwierige Abwägung, wie viele potentielle Patienten ich von vornherein ausschließen will. Um so enger ich die Kriterien mache, um so mehr kommerzielles Potential verliere ich.
Für eine Minibude wie Celldex würde ich aber sagen, dass sie erst mal die Wahrscheinlichkeit der Zulassung in einer Nische optimieren sollten - die Kür kann später kommen.
Wie auch immer, der Markt hat heute freundlich auf die Daten reagiert.
Ein paar Einschätzungen von Feuerstein:
Celldex plans to meet soon with the U.S. Food and Drug Administration to get sign-off on a plan for a confirmatory study of CDX-011, which if positive, could lead to an accelerated approval, said CEO Anthony Marucci.
Based on these data, Celldex would like to run a confirmatory trial for CDX-011 in patients with triple-negative breast cancer that also contains high levels of GPNMB, pending FDA agreement. Approximately 5,000 to 9,000 breast cancer patients in the U.S. fit this category, according to various estimates.
Ich spinne jetzt mal ein bissel rum und "schätze" das Umsatzpotential für den US-Markt:
Preis CDX-011: 5.000 Dollar / Monat (das würde irgendwo zwischen Herceptin und Perjeta liegen)
Behandlungszeit 10 Monate
Umsatzpotential (konservativ) ca. 250 Mio. Dollar
Wenn man höhere Patientenzahlen und einen höheren Preis unterstellt, kann man auch auf 500 Mio. Dollar kommen.
Und das wäre erst der Anfang, den man wird ggf. versuchen, CDX-011 schon in früheren Krankheitsstadien einzusetzen und möglicherweise sind noch andere Indikationen als Brustkrebs machbar.
Wenn die für 2013 anstehende Studie ein Erfolg wird, dann beginnt die Geschichte ja erst und ein enormes klinisches Entwicklungsprogramm sollte dann angestoßen werden.
Das schreit eigentlich nach einer Verpartnerung mit einen großen Pharma - die US-Rechte sollte Celldex aber in jedem Fall behalten!
Soweit ich es verstehe, war bei Beginn der Studie noch unklar, wo die GPNMB-Schwelle anzusetzen ist. Als Aufnahme-Kriterium hat man >5% bei Tumor- oder Stroma-Zellen (Stroma-Zellen sind die den Tumor umgebenen Zellen, die mit dem Tumor interagieren) gewählt, wobei offensichtlich fast alle Patienten mehr als 5% GPNMB in den Stoma-Zellen aufweisen, in den Tumorzellen aber nur 30%. Am Ende wurde aber nur der Tumoranteil betrachtet. Anscheinend gibt es auch Patientinnen in der Studie, die unter 5% GPNMB im Tumor aufweisen. Ich hätte es auch interessant gefunden, die Stroma-Zellen mit einzubeziehen. Im Poster ist die Patientin mit dem am längsten anhaltenden PR triple negative und GPNMB negativ... Tumor-GPNMB liegt unter 10% wahrscheinlich unter 5%. Trotzdem hat hier CDX-011 eine deutliche Wirkung.
Da CDX-011 auf GPNMB wirkt, ist es eigentlich trivial, dass ein höherer Anteil auch zu einer höheren Wirkung führt. Vielleicht ist es aber auch nicht sinnvoll, den Anteil zu hoch zu wählen. Sollte man nicht auch den Stroma-Anteil miteinbeziehen?
Falls es dich interessiert, so twittert u.a. Sally Church live von ASH... z.B. gerade über Genmab's Darutumumab. Dabei finden sich immer die einen oder anderen interessanten Infos: