Stifel -Intrexon Update – Second Cohort Enrollment Completed for Ziopharm’s Ad-RTS-IL-12 Study in GBM
June 28, 2016
XON – NYSE
Target Price — $57.00
Intrexon Update – Second Cohort Enrollment Completed for Ziopharm’s Ad-RTS-IL-12 Study in GBM
Yesterday afternoon, Ziopharm announced updated enrollment in its ongoing Phase I trial of Ad-RTS-IL-12 + veledimex in glioblastoma – enrollment in the second cohort was completed and the third cohort is now open to patients. This news follows last month’s preliminary data, which showed the company’s gene therapy candidate was safe and showed signs of activity. Given historical controls, the interim results showing 10 of 11 patients are still alive at median of 6.2 months is interesting, and, pending final data, potentially compelling. In addition, in light of Amgen’s recently approved T-VEC and the expectation that many GBM patients undergo surgery, we believe Ziopharm’s Ad-RTS-IL-12 approach could be medically tractable, if efficacy is eventually compelling.
Ad-RTS-IL-12 is another powerful IO approach. Much of oncology is currently
focused on enticing the patient’s immune system to help destroy tumors. This goal
is probably much less far fetched than it once seemed as it’s now clear that most
tumors contain the remains of immune responses. It is thought that these
anti-tumor immune responses arose to fight these semi-foreign growths (tumors),
but were shut off by what is called the tumor micro-environment (thus allowing the
tumor to grow). These ineffective immune cells that recognized the tumor but could
not destroy it are called tumor infiltrating lymphocytes (TILs). Attempts to get TILs
to finish their job have focused on checkpoint immunotherapies such as Ipilimumab
(anti-CTLA-4) and Nivolumab (anti-PD-1) that block the activity of the
immunosuppressive tumor microenvironment and thereby enhance the activity of
the anti-tumor TILs.
Ad-RTS-IL-12 + Veledimex. Ziopharm has taken an alternate approach to this
problem and is attempting to activate TILs through expression of IL-12, a
pro-inflammatory cytokine that activates the TIL’s and probably other T-cells
resulting in stronger anti-tumor responses. However, a major problem with
stimulatory cytokines, such as IL-12, is their significant tendency to cause side
effects – so administering them systemically is problematic (the NCI has attempted
this administration in humans and has not adopted a mode of administration using
Intrexon’s technology, we believe). Ziopharm is approaching this problem using
one of Intrexon’s most well-known tools – called the RheoSwitch. The RheoSwitch
itself is a two part gene regulatory element controlled by the orally available drug
veledimex. When veledimex is administered orally, tumors that have been injected
with Ad-RTS-IL-12 start to express IL-12. The data here are not fully disclosed, but
Ziopharm management has indicated that IL-12 can be measured systemically and
that IL-12 side effects are reversibly observed after induction. Most importantly,
when veledimex is withdrawn, the expression of IL-12 slows and then stops over
the course of several hours. (continued...)
It's probably still early days, but the goal of getting just enough IL-12 expression
and concomitant TIL activation to fight the tumor, but not be too toxic for the
patient seems reasonable.
Ad-RTS-IL-12 in comparison Amgen’s Imlygic. Imlygic (T-VEC) seems an
analogous therapeutic and takes a dual approach blocking the cellular protein
ICP47 (allowing antigen to be presented) in addition to stimulating immune cells to
attack tumor cells. In Imlygic, Amgen has altered the cold sore virus, made
several genetic modifications, including increasing its selectivity for cancer cells,
to generate a therapeutic that is directly injected into the tumor. Subsequently,
macrophages are stimulated to secrete the GM-CSF cytokine and an anti-tumor
response is invoked. When injected into melanoma, the drug has shown a 16.3%
durable response rate in patients. Given that Imlygic is delivered via injection,
Ziopharm’s approach of directly injecting the drug into tumors seems more
medically acceptable. In addition, given the clear activity of Imlygic and possibility
that Imlygic expresses the less powerful GM-CSF cytokine than IL-12 (used in
Ad-RTS-IL-12), we find the Ziopharm program increasingly interesting.
Interim Ad-RTS-hIL-12 Phase I results. In May, Ziopharm announced interim
data from its ongoing single-arm, dose escalation, recurrent GBM study. In cohort
one, 86% of patients remain alive with a median follow up time of 6.8 months
(n=7). Additionally, in the May press release, the company noted that 91% of all
11 patients were still alive with a median follow up time of 6.2 months (cohort two
was not fully enrolled yet). We note all patients enrolled had high-grade, recurrent
glioma and nine of these 11 patients had previously failed salvage therapy.
Furthermore, Ziopharm notes that mOS for patients these settings is
approximately 6-7 months and 3-5 months, respectively. Given these historical
controls, we find the preliminary data interesting and potentially compelling.
Ziopharm expects to present updated data later this year.
Glioblastoma treatment paradigm. Treatment for GBM upon initial diagnosis
typically involves surgery, radiation, and chemotherapy. Maximum tumor resection
is considered the best option for those where surgery is possible/appropriate. We
note carmustine wafers are approved as an adjunct to surgery/insert into the
resection. In newly diagnosed GBM patients, the drug’s label lists a 12.9 month
mOS for those on carmustine + radiation arm versus an 11.6 month mOS for
patients on the placebo + radiation arm. In recurrent GBM patients, the drug’s
label lists a 6.5 month mOS for those on carmustine + radiation arm compared to
a 4.6 month mOS for patients on placebo + radiation arm.
Temodar, an alkylating agent, is also approved for newly diagnosed glioblastoma
patients and to be administered with radiation and subsequently as maintenance
treatment. Temodar’s label lists a median OS for radiation therapy + Temodar of
14.6 months versus 12.1 months on radiation therapy alone. Lomustine is another
alkylating agent that is approved for patients with brain tumors. However this
chemotherapy is approved only in those who have already undergone surgery
and/or radiation therapy. Finally, we note Avastin is approved in glioblastoma as a
single agent for adult patients with progressive disease following prior therapy.
The drug’s label lists a 19.6% ORR and a 3.9 month median duration of response.
Target Price Methodology/Risks
We value the company via a sum-of-the-parts approach where some of the pieces
of the company are valued via formal methods (principally DCF) and other, earlier
stage parts of the company are valued principally based on competitor valuations.
Overall, this approach results in a calculated market capitalization of $6.685 billion.
Based on a current share count of 116.861 million, we arrive at a 12-month price
target of $57.
Thanks for posting - better than guys blaming others for their failures. I agree with this - this deal makes partnerships or more likely a buyout near term almost certain. Its obvious what is going on here.
RBC after the bell- Flagging it: We're basically near/at "zero pipeline" value for biotech now - Group trading at 12–14x on 2017E, well below the S&P500
Flagging it: We're basically near/at "zero pipeline" value for biotech now
Group trading at 12–14x on 2017E, well below the S&P500 – see updated chart
June 27, 2016
RBC Capital Markets, LLC
Michael J. Yee
Keeping one eye on fundamentals and compelling valuation (the other on short-term uncertainty)
Realizing it's pretty tough out there as global equity markets continue to correct from Brexit, we'd be remiss to not keep our "fundamental" hat on for longer-term investors who understand biotech should likely continue on, and while there will be some relative "risk off" period and investment uncertainties in the short term (currency impact, EU regulatory/pricing questions, if any), we think these shouldn't be too bad and on the whole biotech should be OK and fundamentals should be intact. We have seen global crises and economic uncertainties of a wide degree of seriousness over the last decade (2008 financial crisis, Greek debt crisis, US debt downgrade, Obamacare uncertainty, etc.) and generally those were longer-term opportunities for investors after the dust settled. We didn't say this was the bottom—and we are at key technical support levels on the IBB this week—but we are at least flagging what's happening on a valuation basis and that historically this is an important point to mark.
In this pullback, we've received more and more calls from investors looking at these opportunities right now and we've said in the past that buying biotech when 1) it's trading below the S&P500 multiple and 2) it's trading near a "zero pipeline" value has generally been a winning solution over 12–18 months. The longest periods when these criteria existed were about Jan 2010–June 2011 post financial crisis and when Obamacare was being implemented and it wasn't clear how HC would be impacted and investors didn't want to ow
Med Tech letter has a great track record. 2 yrs ago Huberts stock letter rankings ranked them #1 of 267
They will be right about ZIOP soon imo
The clinical data is quite encouraging particularly when factoring in that the first cohort included patients with a poor prognosis (life expectancies in the range of 3-5 months for three patients and 6-7 months for the others). Given the very short life expectancy for these very sick patients, we should get even stronger signs of survival as early as this year. In our view, the results to date suggest a likely survival benefit. The second cohort has not been followed long enough to yield meaningful survival data, but importantly one patient was successfully maintained on veledimex by reducing the dose from 40 to 20 mg/m2, thus demonstrating both the flexibility and safety of the IL-12 dosing regimen.
The existing IL-12 trial data will mature quickly given the very short life expectancy for this very sick group of patients. In our view, a survival benefit would allow ZIOP to proceed directly to a pivotal registration trial by early 2017 and also qualify the gene therapy candidate for accelerated approval. Important follow up data that could show a significant survival benefit versus historical controls may be presented as soon as the annual meeting of the Society for Neuro-Oncology, November 17-20 (http://www.soc-neuro-onc.org). This would also represent a huge de-risking event for the IL-12 gene therapy candidate that could have potential in a broad range of tumor types. We also expect the company to start an IL-12 combination trial with a checkpoint inhibitor in glioblastoma patients with a major I/O player sometime soon. This could also be accompanied by a partnership as the PD-1 space is hyper competitive and the Big Boys are looking to differentiate their specific PD-1s.
ZIOP is a BUY under 12 with a TARGET PRICE of 18
Stunning this guy has lived four times the 3 months expected and is skiing a yr later wow
Silly MTSL is one of the best stock newsletters two yrs ago Hubert ranked them #1 of over 240 stock newsletters. ZIOP is down with the sector since the Hillary tweet, the Shrekel disaster, cascading to Valeant etc, the blowing up of the PFE-AGN deal by treasury. MTSL is one of the best newsletters all time. a dip of small bio picks in a sector massacre does not change that
MTSL-ZIOP – Passes BBB, SAE's/Severe Tox rapidly reversed on discontinuation. Expect partner with PD-1 with Big players looking to differentiate in hyper competitive space. Buy under $12 for $18 target.
ZIOP – Presents Encouraging IL-12 Glioma Data at ASCO
ZIOP reported encouraging IL-12 data at ASCO showing both good survival duration (10.7 months) and safety in very sick brain cancer patients who have exhausted all available treatment options. Two cohorts of patients have been treated thus far. Seven patients (ages 32 – 58 years) with advanced brain cancer (10 with glioblastoma and 1 with Grade III glioma) received 2 x 1011 virus particles injected intra-tumorally and veledimex (20 mg/m2) orally for 14 days. The second cohort’s four patients (ages 37 –55 years) received a 40 mg/m2 of activator ligand. All patients in the first cohort and three of the four in the second suffered multiple recurrences prior to enrollment. The seven patients in the first group had 2.7 prior lines of therapy (three with temozolomide and bevacizumab) and six are still alive with a median survival of 6.8 months (range: 5.2 – 10.7 months). Patients in the latest group had 2 prior lines of therapy and all are alive (range: 0.8 – 3 months). Both the efficacy and safety highlighted in the abstracts were confirmed at ASCO. In our view, ZIOP’s IL-12 gene therapy candidate has the potential to be the first gene therapy approved for a solid tumor.
Important safety data demonstrated that veledimex passes the blood brain barrier and that serious and severe toxicities are rapidly reversed upon its discontinuation. The most common adverse events (mostly Grade 1 & 2) were headache, fever, nausea/vomiting, decreased white blood cell and platelet counts, and elevated liver enzymes. Two subjects in the first cohort had these adverse events, but with greater severity, and two experienced other toxicities, notably aseptic meningitis and mild cytokine release syndrome.
The clinical data is quite encour
Griffin knows the company better than anyone. Kirk access through former Griffin covering analyst CB
I do think a deal is coming - there is no reason to cut this percentage now if you are not doing a deal also the change of control twenty day weighted avg makes a big pop very good for XON and Kirk on conversion. And the 1% per month is meant to give Big Pharma some urgency to get the deal done. My take is ZIOP has a buyout offer by the end of July. Good luck to the longs - there really has been nothing but good fundamental news and positive data and publications - ZIOP is stuck in the XON short attack and lies and the sector meltdown. Other small caps are down 85% or so - ZIOP is still up from the beginning of 2015 - not many other bios are. Adding
It is better - also lots of analyst reports and Med Tech letter ZIOP comments with original bold and slides and links posted that cannot be posted on Yahoo.