This is rather straightforward – the team has reported their success in the creation, delivery, and in vivo control of expression of single and multiple genes that may be used to trigger an immune response against a malignancy.
EXOSOME/STEM CELL MODULATION OF THE IMMUNE SYSTEM
This approach is based partly on the expertise that Intrexon secured via the acquisition of Medistem recently. Exosomes from immune-privileged stem cells are an ideal allogeneic delivery vehicle for a variety of therapeutic molecules (e.g., proteins, mRNAs, and miRNAs), much as tumors use exosomes to evade the immune system, stimulate blood vessel formation, and facilitate metastases.1 Like stem cells, they have intrinsic homing capabilities, based on adhesion molecules on their surface, but membrane modifications can yield more specific tissue targeting.2
These 30 – 100 nm vesicles also have basic traits that render them attractive for commercial applications – notably they can be isolated easily via ultrafiltration and are stable when stored frozen.3,4
While development of exosomal therapeutics is still in its infancy, there is evidence that this approach to treating disease has tremendous potential. We note, for instance, that exosomes from mesenchymal stem cells suppressed angiogenesis at least partially through the transfer of miR-16. The micro-RNA downregulated expression of vascular endothelial growth factor in breast cancer cells in vitro, and treatment with the mesenchymal stem cell exosomes blocked growth of breast cancer in vivo.5 (miR-16 is deleted or significantly downregulated in various cancers, including chronic lymphocytic leukemia, prostate cancer, and lung cancer, while upregulation of this miRNA is associated with survival in triple negative breast cancer.6,7,8,9) It is interesting to note that the effectiveness of exosomes as delivery vehicles for such biological therapies is enhanced by radiation via increased cellular uptake of the exosomes, suggesting that exosome-based immunotherapy will one day be combined with radiation to treat certain diseases.10
Exosomes offer yet another approach to treating cancer and that is through the presentation of tumor-specific antigens to the immune system. For instance, exosomes from genetically modified dendritic cells of the immune system have been used as a cell-free vaccine, successfully stimulating T and B cell-mediated anticancer immunity.11
Considerable work has been done in this area, and it may constitute yet another approach for the Ziopharm-Intrexon team to pursue.
CHIMERIC ANTIGEN RECEPTOR-MODIFIED T CELLS
Chimeric antigen receptors (CARs) are synthetic transmembrane proteins that have both antigen binding and cell activating capabilities for directing the specificity and function of T lymphocytes and other immune cells. The two functions are associated with separate components (see Figure 1): (i) an extracellular antigen recognition site that may be derived from antibodies or a natural ligand with specific binding properties and (ii) an internal signal generating component derived from the endogenous T cell receptor (ζ) or an antibody-binding receptor of cytotoxic cells (FcRγ).12 This structure imparts T cells with the ability to target a wider variety of cell surface antigens than possible with inherent T cell receptors and to do so in a manner that is independent of the Major Histocompatibility Complex. A sampling of antigens that have been targeted by CARs is presented in Table 1on the next two pages.13
Improvements to the basic structure since the first CAR was created in 1989 has led to the insertion of one and then two signal enhancing regions (e.g., the T cell stimulatory domain CD28 and two of the TNF superfamily, OX-40 and 4-1BB) to the antigen binding portion. These modifications enabled the second-generation CARs not only to activate the T cell, but also to improve T cell expansion and persistence. Improvements associated with the third generation CAR provide for two costimulatory domains that are combined with the activation domain. This structure has exhibited greater potency in preclinical research.
Safety of CAR T cell immunotherapy: Results from clinical trials have identified three types of safety issues with this type of therapy. One involves the tumor-associated antigen being targeted. Since there are few tumor associated antigens that are cancer specific, the potential exists for “on-target, off-organ” activity when the T cell properly identifies the antigen, but in both malignant and normal tissues. The seriousness of this off-organ targeting depends on the nature of the normal tissue and the extent of the immune attack. Another safety issue, called cytokine release syndrome (aka cytokine storm), is caused by excessive cytokine levels caused by positive feedback loops within the immune system that can result in organ failure and death. This has occurred in a few cases, possibly associated with
patients who had a greater cancer burden when the immunotherapy was initiated. Tumor lysis syndrome is another safety concern associated with an overwhelming level of tumor destruction that releases large quantities of cellular components from the destroyed cells in a short period of time.
The Bispecific CAR T cell: An important modification to the basic CAR structure involves the insertion of two different antigen binding sites. (See Figure 2.) This bispecific immunotherapy requires two interactions to enable the T cell to identify a malignant cell, thus reducing the risk of “on-target, off-organ” activity. The structure permits more precise control over T cell cytotoxicity by separating the primary activation signal from the costimulation and persistence signals that are combined in the second- and third-generation CARs.
Figure 2. Bispecific CAR T Cell Design13
Additional Genetic Modifications to T Cells: Besides adding CARs to T cells, genetic modifications have enabled the expression of such cytokines as IL-2, IL-7, IL-15, and IL-21 that promote cell growth, differentiation/functionality, and survival. This is important because by increasing the persistence of the CAR T
cells, these cytokines greatly enhance T cell performance. Note that many patients have undergone lymphodepletion in preparation for CAR T cell therapy to provide a more favorable environment for the therapeutic cells to survive and eradicate a tumor. This may be attributed in part to an elevation in IL-15 levels. However, the conditioning procedure, which involves high doses of chemotherapies such as cyclophosphamide and fludarabine or radiotherapy, is particularly difficult for the young and elderly given its debilitating effects and the potential for serious infections.
Another genetic modification to CAR T cells results in expression of IL-12. That is the very cytokine Ziopharm has been studying clinically via its Ad-RTS-hIL-12 for melanoma and breast tumors. Inclusion of this DNA vector can greatly improve the performance of CAR T cells. Indeed, one study found that expression of the cytokine by CAR T cells enhances tumor eradication, even without prior lymphodepletion, suggesting it expands the suitability of the cell therapy to a broader range of cancer patients.14 IL-12 can also render the CAR T cells resistant to regulatory T cell inhibition and/or reprogram immune-suppressive cells, stimulate the release of other immunomodulators including the inflammatory agent interferon-γ, and attract other immune cells, such as macrophage, into the vicinity
of a tumor.15,16,17 What’s more, the benefits of IL-12 released by genetically modified cells were not replicated by systemic administration of the cytokine.18
Optimization with Intrexon’s Expertise: Synthetic biology offers the means to create the most advanced CAR T cells, whether it involves a 3rd generation structure or a bispecific/multi-specific design. Intrexon has already demonstrated an ability to create a key component of CARs, the single-chain, variable fragment (scFv) antibody-like binding site,19 and its RheoSwitch provides a mechanism for controlling expression of such genes as IL-12 in vivo. The RheoSwitch is a mechanism for controlling delivery of a cytokine, thus adding a proprietary measure of safety to the living therapeutic agent. (We note two clinical trials of IL-12 immunotherapeutics lacking such capability were halted.20) A “kill switch” may also be included to terminate the genetically modified T cells if necessary.
We believe the company’s LEAP technology will greatly aid in the preparation of CAR T cells at two key points, in the selection of a starting cell population and subsequently in the identification of T cells that are appropriately cytotoxic based on the expression of the chimeric antigen receptor + a DNA-based medicine (e.g., IL-12). Both selection points contribute to the characteristics of the final population of genetically modified cells. Intrexon is also able to optimize cell culture conditions, which can influence the quality of cells. (One example of this capability is its success in optimizing culture conditions for Fibrocell Science’s therapeutic fibroblasts last year.) The importance of T cell quality has been substantiated by independent scientists who showed that a low number of highly
proliferative T cells mediated a more dramatic effect against large tumor burdens than larger quantities with a lower propagative capacity.21
A Newly Defined Regulatory Environment: Obviously, all of the aforementioned factors will come into play in the clinic, but they will also play a role in satisfying the FDA and other regulatory agencies. We note that the FDA’s
latest guidance on cell and gene therapies treats CAR T cells as a true investigational product.22 As such, the agency wants sponsoring companies to define the “active ingredient” in their product. And since CAR T cells are a living
therapeutic agent, the manufacturing process must be well controlled to yield cells with specified ranges of viability and potency. Accordingly, we believe the recent guidance from the FDA has defined the regulatory path to approval for new immunotherapies, thus setting the stage for Ziopharm and Intrexon to develop new cancer treatments, including CAR T cells and exosomes. Another, related issue is defining the cells for patent purposes.
Clinical trials involving CAR T cells: Table 2 provides a list of ongoing clinical studies on the ClinicalTrials.gov website.23 Numerous studies are investigating immunotherapies targeting CD19, which is a glycoprotein found on the surface of B cells. Though CARs against CD19 do not discriminate between normal and malignant B cells, the temporary depletion of B cells does not preclude treatment, since immunoglobulin administration provides protection against infection until the population is restored. Other cell surface antigens being targeted include: (i)HER2 (see also ErbB, EGFR, and EGFRvIII), which refers to a human epidermal growth factor receptor that is overexpressed on breast cancer and other malignancies; (ii) GD2, which is found on neuroblastoma and melanoma cells and to a lesser extent on normal cells of the cerebellum and peripheral nerves; and (iii) several proteins involved in cell proliferation, migration, adhesion and/or activation (i.e., CD30, CD33, CD138, CEA, integrin 4αβ receptor, and fibroblast activation protein).
Best report ever written on ZIOP - Griffin on ZIIOP: Emergence of an Elite Immunotherapy Specialist- Partner talks heat up-portion of 8 INDs will involve partners. Raise target to $12 - The clinical program continues to advance
See Investorvillage ZIOP board for entire report and link..won't fit here - here is a little...
Expansion of the immunotherapy platform paves the way to multiple cancer treatments. We believe Ziopharm and its collaborator Intrexon have been in a “stealth” mode, while preparing new cancer therapies for clinical trials. Besides the DNA-medicine IL-12 that is already in human studies, new opportunities are being pursued via exosomes, T cells with chimeric antigen receptors, and stem cells. The expanded platform is suitable for treating both hematological cancers and solid malignancies.
Partnering talks have heated up. Clinical data on the Company’s lead candidate, a RheoSwitch controlled gene for interleukin-12 (IL-12), has apparently generated interest in other DNA-based medicines that could be created, delivered, and controlled via synthetic biology. As a result, we believe a portion of the eight INDs that Ziopharm plans to file in 2014 and 2015 will involve collaborations covering much of the immunotherapy platform.
The clinical program continues to advance. Ziopharm’s IL-12 medicine will enter three clinical trials this quarter. One, involving patients with the deadly brain cancer glioblastoma, is designed as a Phase 1/2 study. Initially, the trial will evaluate the safety of the DNA-based therapy for a later, more advanced examination of its effectiveness. Preliminary results should be available in the December quarter. Meanwhile, Ziopharm will initiate Phase 2b trials of the IL-12 medicine for breast cancer and melanoma. We believe the objective will be to optimize the dosing regimens in preparation for pivotal trials. Preliminary results will likely become available in 2015.
Ziopharm has sufficient capital to finance operations into mid-2015. The Company closed last year with $68 million of cash on hand and an annual burn rate of $40 million to $45 million budgeted for 2014 and 2015. Although this suggests that external financing will be sought around the New Year, the aforementioned collaborations may provide non-dilutive financing.
Investors should see significant progress in the months ahead. Ziopharm will provide updates on the status of the patients treated in its early clinical trials of IL-12 for melanoma and breast cancer in the second half of the year. Perhaps even more exciting will be news of collaborations with major pharmaceutical companies. We continue to rate ZIOP shares a BUY and have raised our price target to $12 per share.
We believe the Ziopharm-Intrexon team has been working in a “stealth mode” on an array of novel immunotherapies to treat cancer. Intrexon’s recent acquisition of Medistem has opened the door to the use of exosomes and stem cells as delivery vehicles for DNA-based medicines. Another area of collaboration is in the field
of chimeric antigen receptor (CAR) modified T cells and possibly other immune cells. These synthetic receptors offer a means of activating cytotoxic T cells against cancer without the involvement of the Major Histocompatibility Complex that is essential for endogenous T cell receptor function. Research suggests that certain CAR T cell designs avoid the specificity limitations of monoclonal antibodies, yet create a more robust and safer immune attack. Hence, it is not surprising that CAR T cells are probably the hottest area of immunology research today. But the Ziopharm-Intrexon team offer even more – based on Intrexon’s technologies, Ziopharm is positioned to develop combination immunotherapies that might, for instance, include CAR T cells with exosomes expressing a CTLA-4 decoy to thwart immunosuppression by tumors or stem cells secreting the immune stimulant IL-12 in the vicinity of a tumor. The regulatory path to commercialization has also become better defined through an FDA draft guidance that was issued last summer. We think the time is ripe for Ziopharm to emerge as the leader in immunotherapies and to enter into partnerships with pharmaceutical companies that want to commercialize cancer immunotherapies.
Meanwhile, the Company is scheduled to initiate a Phase 1/2 study to assess its DNA-based medicine expressing IL- 12 as a therapy for glioblastoma. Two Phase 2b trials of the therapy will probably commence as well for breast cancer and melanoma and follow-up data from the Phase IIa trials should be available by year end. In all, the Company’s goal is to initiate eight clinical studies of immunotherapeutics in 2014 and 2105. Some will probably be sponsored by corporate partners.
We continue to rate Ziopharm Oncology shares a BUY and have raised our price target to $12.00 per share in recognition of the promise of the expanded immunotherapy platform. Then, too, the recent weakness exhibited by
the biotech sector has rendered this stock all the more attractive.
READING THE R&D TEA LEAVES
Limited information has emerged on Ziopharm’s immunotherapy program probably to avoid giving potential competitors information about the research focus and the status of specific programs. But based on the nature of Intrexon’s expertise in synthetic biology and the data that has been made public, we believe there are three general areas in which the collaborators are working:
Carl Quintanilla tweet -:
The last three yrs - 2nd halves of April have been positive for the S&P by an avg of 2.2.%
Art Cashin thinks the selloff of the high flyers is over
Cramers AAP charitable trust adds more CELG today..stand by its conviction in $CELG. Still a consensus BUY, this AAP holding should be great for the long term ...
T Rowe Price Portfolio Mgr Josh Spencer on FM Halftime "Time to Buy Growth Stocks - many of these stocks are oversold..now is the time to be brave - earnings growth..selling legacy slow growers here and adding growth"
"We think when you look out 2 yrs you will be very happy you bought these oversold stocks"
I had posted the first few rallies often fail - then one day the big take down reverses (this happened 2 days in a row with yesterday imo the bottom and final capitulation)....but now you will need to survive intraday pullbacks and pass the test - today I think we can do that....what we need is an up open like this am - followed by 2 or 3 intraday pullbacks but then a strong close...its pretty simple - the rips are sold until all those puking stock in fear are satiated - then the shorts cover and longs waiting to buy the bargains feel stability ("I would rather buy 10 points higher into strength than catch a falling knife is their mantra) today I think we could pass the test.
If you were short and made money in this devastation - at least for the large caps trading so cheaply - would you really stay short over the long weekend into all the earnings preview analysts reports and company conference calls where after a month quiet period management can finally address the overblown fears....As I said I thought yesterday was the capitulation bottom and reversal....today is the day I think we withstand the intraday sells after up open but then add to that up open..Fingers crossed.
In addition - this means they have NO financing risk, they already have no FDA risk imo - the minute they cancelled the need for the second Ph 3 that was gone - and you have a company with almost $400 million in cash with a multi-billion dollar platform drug with possible near term catalysts of positive FDA news on stability testing, possible acceptance by EU of the one Ph 3 to approve - which would lead to a quick EU partnership imo even before approval - and of course with Big Pharma holding up and biotech pounded - there will be muitiple M&A of biotechs and ACAD has to be on the top of the list by Big Pharma with CNS drugs - and although CEO is fine going it alone - it does not mean an offer won't come. Added 12,000 ACAD Friday - looking for 8000 more this week
CELG, ACAD, CRMD, EPZM, XLRN, ZIOP my top picks here - bios will be bought in my IRA heavy Monday morning. No sector will have more deals, good data and earnings beats than this sector over the next 3, 6, 12, 24, 26 and 48 months. None. Its time to BUY THE FEAR
Brilliant $28.50 secondary (+$197 million) when ACAD already enough cash to get to commericalization ($186 million @ Dec 31) gives them $383 mill in cash to work with in 2014/2015. 1 of many ACAD is a screaming buy again in 18s/19s here....
added 12,000 last wk - looking for another 8,000 this week.
One of the lowest risk / highest reward biotechs with secondary done at $28.50 ensuring sufficient cash through commercialization, Stellar Phase 3 safety / efficacy data already in the bank, so good FDA said no 2nd Ph 3 needed, FDA on its side in DESPERATE need of something to replace the off-label anti--psychotics being prescribed despite specific black box warning against giving to demetia patients - literally killing those patients and EU talks going well per update last week.
They will prevail - after the Markman briefs - and additional "UNCLEAN HANDS" brief (it appears NAtco paid a CELG employee in Canada to steal revlimid illegally obtained for their tests and then tried to block access to that employee for the Markman hearing/patent trial) -its rather clear per RBC, Leerink and Baird...there is a chance the Unclean hands case could throw the entire case out - and that is already being reviewed without an oral argument - could result in decision before markman...the 3 new patents Natco didn't contemplate makes 2023-24 a lock - if settled their this stock goes up 50 bucks - if they settle and give natco one yr 2026 - which is likely in my opinion - this stock goes up $100 in 3 months - Then CELG focus turns to EU 1st line, Abrax/Pom surge, Otezla launch/PsO approval& AS data(Apr)& 200 Ph 2 & 30 Ph 3s + partner trials
CELG / Large Cap biotech 2 yr PE's are now trading at a 22% discount to big phama despite having 4x's the growth. It has the highest gross margin in the entire S&P 500 - better than GOOG, Apple, GILD - the other 499 co's....they just got Otezla approved in PsA, Psoriasis approval coming, AS Ph 3 data (2.5 mill patients) soon possible on earnings call. CEO on CNBC said near term positive/excited about this yrs guidance so Q1 WILL BE GREAT. Working on 5 separate billion dollar a yr drugs soon plus 200 Ph 2 and 30+ phase 3 trials and they own drugs and equity of the most innovative early stage bios in the world including XLRN, EPZM, BLUE, MPSYY, AGIO and MANY others (CEO said they own 14% of the biotech IPO's). Best CFO in all of healthcare who is buying back billions in stock that will be accretive forever (buying growth at 70% discount with 2017 PEG ratio of 0.3). Markman briefs out this week derisk the patent case significantly per Leerink, Baird, RBC (80%+ chance of settlement per RBC)...CELG is one of the most compelling cheap growth stocks in the industry now trading at Value PE's less than the S&P 500 and Big Pharma despite the 4x's EPS growth vs those.
Celgene Patents Seen Holding Up; Summer Street Says Buy Shrs
Celgene Patents Seen Holding Up; Summer Street Says Buy Shrs
2014-04-11 14:08:37.600 GMT
By Sasha Damouni
April 11 (Bloomberg) -- Celgene Revlimid patents seen holding up, Summer Street analyst Carol Werther said in note;would be buyers of shares.
* CELG has been under pressure due to Markman hearing, concerns on Revlimid
* CELG down 18% YTD vs S5HLTH up 0.9%
* Also says recent Summer Street conversations w/ consultants suggest that if Otezla is priced at significant discount it
will be used prior to biologics
* Separately, CELG announced recently it will present interimdata from ongoing Phase 2a study of sotatercept in patients with end-stage renal disease on hemodialysis at NationalKidney Foundation 2014 Spring Clinical Meeting
Don't listen to Ortigia he missed a triple telling you to short from the 50s - he's bitter because of that - add today this was the bottom - triple bottom held nicely - green close for sure.
Bounced off triple bottom 135.50 nicely - gonna go green - that was the bottom - ETF shorts will cover - added at open - see investorvillage CELG board for more info
Not gonna listen to a guy that said short CELG all the way from 50s to $170....this is nothing but a sector rotation but CELG will be in the 200s once the Natco BS case is settled later this yr...you missed the triple from 50 and you will miss the coming double from here
ISI - Biotech is at a 22% discount to pharma on 2 year forward PE basis -
Biotech is at a 22% discount to pharma on TWO year forward PE basis
Earlier today I sent out our comps sheet and noted that 1 year forward PEs for biotech and pharma are at parity.
Many of you requested that we run 2 year forward PEs.
Turns out that biotech is trading at a 22% discount to pharma on this metric.
Biotech's two year forward PE is 14.7x while Pharma's is 17.9.
RBC - CELG close to value stock now -key catalyst-80% chance of settling after Markman brief read-should go up & unlock big value on settlement...
April 11, 2014
Biotech update: Are we at "value" levels? GILD 10–12% FCF yield...CELG close...
As the "growth-to-value" rotation continues and investors debate why it's happening (everything is pointed to, including Yellen macro comments, rising rates, various funds simply taking down risk/beta in a big way, selling the biggest winners because they also have the longest way down, then shorts piling
in...), we think it has created a dislocation in the biotech market where the "baby is thrown out with the bathwater". While we acknowledge that biotech stocks can always get cheaper as the overall market conditions are challenging, our point is that as investors sell growth we think "not all growth is created equal", especially when we look at not only PE and earnings but also cash flow generation. Maybe itwill be Q1 earnings when investors begin to see this a bit, but it's probably when we roll into mid or
H2-14 as investors start valuing on 2015 and seeing that they trade as cheap as pharma.
For the "value" investors, GILD and CELG are most attractive given much higher growth rates than AMGN (CELG has key catalyst of 80%+ chance of settling after we read Markman documents but AMGN is outperforming with more defensive nature), and BIIB is less the valuation call but it's getting cheap
and we think it's a buy because it has the best late-stage pipeline and that simply matters a lot if Tysabri for SPMS is positive because it can be 30% accretive in one day.
So look at the FCF yield now...(see p.2). Analyzing various "value" metrics, we think investors should look at the significant cash generation over the next few years: FCF yield and EV/EBITDA (i.e., back out the cash). The large cap biotech group has pulled back so much that the four now trade at: 1) PE of 15x on 2015E and 12x on 2016E, which is cheaper than US pharm
OT - J&J Unit Janssen Says 17 Died in Japan After Xeplion Treatment for Schizophrenia ACAD - Pimavanserin safe and effective for Schizophrenia - another potential HUGE market imo...
From: FIRST WORD (BLOOMBERG/ 731 LEX A)
At: 4/08 22:43:36
J&J Unit Janssen Says 17 Died in Japan After Xeplion Treatment
April 9 (Bloomberg) -- Johnson & Johnson unit Janssen
Pharmaceuticals says 17 died since schizophrenia treatment
Xeplion went on sale in Japan in Nov.
* Cause of death, risk factor not yet identified, Janssen says
in statement posted on website
* About 10,700 patients have taken the treatment: statement
* Link to statement (Japanese language):
This was the most upbeat about the POSSIBLITY of EU accepting this one trial for filing than ever before in my opinion. This would be huge and not in current price. EU is larger mkt than US and NOT IN MODELS
Sentiment: Strong Buy