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What value Retinostat if good?
Updata on Avalanche Biotechnologies (NASDAQ: AAVL)
2015-02-08yixiLeave a comment
In the past one month, the highly hyped gene and cell therapy companies such as Avalanche Biotechnologies (NASDAQ: AAVL), Juno Therapeutics (NASDAQ: JUNO), and Kite Pharma (KITE) have slid significantly. But I still have a bullish view on these stocks and see the sharp pullback as an attractive buying opportunity. Here is my own due diligence on Avalanche.
Overview
Avalanche is a biotechnology company focused on developing gene therapies for the treatment of eye diseases. Avalanche shares closed at $33.27 or market capitalization of $747 million on February 6, 2015. The company has no marketable product, and so it completely bakes in future success.
Pipeline
Avalanche’s lead product candidate is AVA-101 for the treatment of wet age-related macular degeneration (AMD). AVA-101 is a subretinal injection of AAV2 vector transmitting the sFlt-1 gene, which encodes a soluble isoform of the VEGF receptor, an endogenous anti-VEGF protein.
AVA-101 is currently in Phase IIa testing and top-line results from the trial are expected in mid-2015. The upcoming Phase IIa data could be a major catalyst. Following the ongoing Phase IIa trial, the company plan to conduct a Phase IIb trial in the U.S. in the second half of 2015.
Avalanche’s next generation anti-VEGF gene therapy, AVA-201, delivers the same sFLT-1 gene but uses next-generation AAV vector. It is an intravitreal injection for the prevention of wet AMD. The company intends to initiate IND-enabling studies for AVA-201 in 2015.
Avalanche’s third candidate is AVA-311 for the treatment of X-linked Retinoschisis (XLRS), a rare disease caused by mutations in the RS1 gene (approximately 10,000 patients). Avalanche has completed a preclinical study with AVA-311 in a mouse model.
Clinical data
In animal models, AVA-101 expression has been shown to last up to 17 months. Thus, Avalanche completed a twelve-month Phase I trial in Australia.
Eight patients were randomized into three groups: control, low AVA-101 dose (10^10 vg) and high AVA-101 dose (10^11 vg). All patients received two initial doses of Lucentis at Day 0 and Week 4 and the patients in the active arms received AVA-101 on Day 7. Beginning with the Week 8 visit, Lucentis was given as frequently as needed.
No significant drug-related safety concerns were observed. The AAV vector was not detected outside of the treated eye. From Week 8 to Week 52, the control patients and the patients receiving AVA-101 needed 3.0 and 0.33 Lucentis injections, respectively.
Visual acuity improved in the high and low dose AVA-101 treated groups by an average of 8.7 and 10.3 letters from baseline, respectively. By contrast, the control patients lost 3.5 letters of visual acuity. The visual acuity data appear comparable to standard Lucentis treatment.
Potential
AMD is the leading cause of vision loss in the elderly. While wet AMD represents only 10% of the number of cases of AMD overall, it is responsible for 90% of the AMD-related severe vision loss. The incidence of new cases of wet AMD in the U.S. is approximately 150,000 to 200,000 a year.
Current standard-of-care therapies include Avastin (bevacizumab), Lucentis (ranibizumab), and Eylea (aflibercept). Lucentis costs $2000 per dose, in other words, $48,000 for the recommended two years of treatment. In 2013, Lucentis and Eylea achieved worldwide sales of $4.3 billion and $1.9 billion, respectively.
Current standard-of-care therapies require frequent injections into eyes. Gene therapy offers a potential long-term solution to treat wet AMD with one injection. Assuming AVA-101 was priced at $20,000 per treatment, it would be realistic to expect peak sales at $2 billion. Moreover, Avalanche may pursue other indications, such as diabetic macular edema (DME) and retinal vein occlusion (RVO).
Collaboration
In May 2014, Regeneron Pharmaceuticals (NASDAQ: REGN) inked a $640 million deal with Avalanche. Regeneron has a time-limited right of first negotiation for a potential license to develop and commercialize AVA-101. Avalanche has the option to share up to 35% of the development costs and profits. Regeneron has successfully developed Eylea for the treatment of wet AMD and DME. The collaboration would reduce risks and increase chances of success.
Competition
There are multiple companies developing gene therapies for ophthalmic diseases. Genzyme, a fully owned subsidiary of Sanofi (NYSE: SNY), is testing AAV-sFLT in a Phase I trial. Genzyme’s AAV-sFLT is an intravitreal injection, which are commonly performed, and represent a relatively convenient and low-risk procedure. Applied Genetic Technologies (NASDAQ: AGTC) intends to develop gene therapy for wet AMD as well. Both Genzyme and Applied Genetic fall behind Avalanche.
It’s hard to say Genzyme or Avalanche gene therapy approach is superior over the other at such an early stage of development. Interestingly, the tight financial relationship between Sanofi and Regeneron might have influence on the competition between Genzyme and Avalanche.
Management
CEO and co-founder Thomas Chalberg is a former Genentech executive who helped launch and commercialize Lucentis. CMO Samuel Barone served as a Medical Officer in the Office of Cellular, Tissue and Gene Therapies at the FDA before he joined in the company in June 2014.
Finances
Avalanche has a healthy balance sheet with $165 million in cash and no debt. With a burn rate of about $20 million/year, Avalanche should have enough cash to fund the remaining Phase II studies for AVA-101.
5% and Greater Stockholders include Zygtech (10.3%), Venrock (9.6%), Fidelity Management & Research (13.7%), Regeneron Pharmaceuticals (7.4%), Deerfield Management Company (6.6%), and Thomas Chalberg (7.3%).
Given $1.5 billion annual sales, 35% profits share, 50% odds of approval and 5× sales multiple, I set my price target at $58 (or market capitalization of $1.3 billion). If Avalanche’s Phse IIa results are negative, game over.
Thanks George, i`ll pass that on. Fingers crossed for Retinostat!
the immunotherapy had worked and she remains clear
http://www.bbc.co.uk/news/health-31365272
Fortunately, by then the immunotherapy had worked and she remains clear of cancer after more than a year.
Vicky said: "I can really get on with my life and put this in the back of my mind."
Her consultant at the Royal Marsden, Dr James Larkin, is hopeful that immunotherapy may even be able to deal with the problem of resistance.
He told me: "With immunotherapy, you've reprogrammed the system so inside the patient you have an immune system that can recognise tumour cells.
"If a bit of the tumour does become resistant, the experience to date certainly seems to be that the immune system can still deal with that."
Several immunotherapy drugs are undergoing trials for other cancers, such as lung and kidney, and early results look promising.
Like all new cancer treatments, they are expensive - just one of the drugs Vicky was given costs £75,000 per patient, although the NHS has negotiated a confidential discounted price.
So while these new weapons offer the hope of keeping cancer at bay for longer, they present hard choices for health spending.
Panorama reports on the cancer patients who are pioneering a new generation of drug treatments. Patients given just months to live are keeping the disease at bay for years; for some there is even talk of a cure. More than one in three of us will develop cancer, but huge advances in genetics are transforming our understanding of the disease and how to combat it. Panorama was given unprecedented access to trials at the Royal Marsden and Institute of Cancer Research and talked to patients old and young as well as their families and medical teams.
Cancer cure?
Little British girl on Breakfast this morning in total remission with gene therapy.
PREVIEW: Panorama - Can you Cure my Cancer? On BBC 1 9pm tonight
A Panorama special tonight that is sure to be provocative and ask some very interesting questions around a subject that affects many lives.
This reports on the cancer patients that are pioneering a new generation of drug treatments.
The program shows that there may be a light at the end of the tunnel for patients with suggestion that there might be a cure to the condition.
There is also help for patients who have been given months to live and are now keeping the disease at bay for years.
They are pushing these through very quickly ! Bodes well for OXB
HTTP://www.fiercebiotech.com/story/bristol-myers-races-fda-immuno-oncology-star-nivolumab/2014-07-10
HTTP://www.ascopost.com/issues/january-25,-2015/fda-approves-nivolumab-for-advanced-melanoma.aspx
Hamill explained more technical details about the collaboration between the two companies:
Oxford will manufacture several batches of a lentiviral vector used to deliver Novartis' CTL019 technology. This is an experimentat immunotherapy program Novartis recently licensed from the University of Pennsylvania. It is currently in Phase 1/2 trials to treat various B cell cancers (eg relapsed leukemia in children) and the approach uses patients' own T cells, which are removed and engineered using the Lentivector approach to recognise cancerous B cells more effectively. The cells are then re-infused into patients, where they now attack the cancer (an autologous treatment approach).
It appears to us that the University of Pennsylvania likely used Oxford's intellectual property in its early stage trials and that now it is progressing as a commercial program with Novartis, Oxford's intellectual property is locked in. Oxford will manufacture the engineered viruses for next Phase 2 trials of the program. Novartis purchased one of Dendreon's Provenge facilities in late 2012, which we assume is handling the next step, to treat patients autologous T calls with the engineered virus and grow them up. In the final step these are then put back into patients and are now engineered to recognise and remove cancerous B cells.
Some very promising early results have been seen with the program, including two complete responses published a fortnight ago in the New England Journal of Medicine.
HTTP://www.pharmaphorum.com/news/novartis-expects-10-nme-filings-by-end-2016
HTTP://blogs.shu.edu/cancer/2014/10/26/immunotherapy-of-cancer-roche-newlink-1-billion-deal-for-ido-inhibition/#more-1045
HTTP://blogs.shu.edu/cancer/2014/10/22/lentiviral-vectors-for-gene-transfection-in-car-t-cell-therapy/
HTTP://news.investors.com/012615-736198-cancer-car-t-therapy-drives-hot-biotech-ipos.htm?ven=seekingalphacp&src=aurlbpw&__source=seekingalpha
Can CAR-T Work On Tumors?
Still, there are a great many unknowns given the early stages of testing going on — Novartis is farthest along with phase two studies, while others range from phase one to preclinical. This is especially important because what really matters in cancer is the duration of the response — especially if the companies go beyond blood and into solid tumors, which make up the majority of cancers.
"In solid tumors, metastases often reside in different tissues and at different sites," wrote Leerink analyst Howard Liang in his Jan. 13 initiation report on Juno. "CAR-T cells will have to engage the initial tumor, expand, and circulate throughout the body to find these metastases. Without adequate persistence, these cells may not live long enough to accomplish this."
Another great unknown hanging over the industry is price. This is basically what sank the only cell therapy so far to hit the market: Dendreon's Provenge. These personalized therapies are expensive to produce, and Provenge's degree of superiority to other treatments was deemed by many to be too low to justify its $93,000 price tag.
Normally drug companies don't talk about price this early in the game, so many were surprised when Kite CFO Cynthia Butitta said at the JPMorgan Healthcare Conference this month that she expects the treatment to cost $150,000. She said the company plans to start talking with insurers about reimbursement this year.
However, if and when Kite's product comes to market, it might well not be Kite anymore. Quenneville says another factor driving these stocks is that CAR-T may well provide the next hunting ground for big acquirers.
"I think that's the way people are thinking about it to some extent," he said. "People think it's a viable platform."
HTTP://www.onclive.com/web-exclusives/17-cancer-drugs-on-breakthrough-therapy-list/1
Read More At Investor's Business Daily: hxxp://news.investors.com/technology/012615-736198-cancer-car-t-therapy-drives-hot-biotech-ipos.htm#ixzz3Qmj7mwv9
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thanks , i`ll spread the word george
worth a listen from 5mins
Yes, I believe results should arrive in March.
I have been fighting with a few Neanderthals for ages. I will re-post that George. I was derided for saying many months ago that royalties on ctl-019 and expanded indications could be 1% of $10billion (Maybe a higher %). Tim Watts confirmed that we were due royalties to me but they still didn`t understand what Dawson describes as potentially spectacular income. Time will tell.
i`ll copy that to the other board George. Thanks
And we have take-off
Re time-scales, if OXB`s car t shows results like above and gets FDA Breakthrough Therapy designation then again someone who knows better than most says "Rapid time to US approval. The newly empowered FDA is clearly indicating its intent to approve novel immunotherapies on the back of significant differences in overall response rate compared with standard of care coupled with interim analysis of PFS.
The EMA currently continues to request demonstrated improvements in overall
survival compared with the standard of care. However, we believe that, ultimately, the EMA will adopt the FDA’s somewhat more realistic regulatory hurdle, although it may slow EU approval in the interim.
Consequently, we anticipate that the development time for a novel immunotherapy
from late pre-clinical to approval for a first-line metastatic setting could be 5 years and as little as 3 years in the end stage setting (such as autologous T cell transfers) in the US.
Adoptive immunotherapy was one of the hottest topics at the December, 2014 ASH Meeting. Adoptive immunotherapy uses immune cells that are engineered with CARs (Chimeric Antigen Receptors) to search for and destroy tumor cells while ignoring other tissues in a cancer patient's body. In the race to get CAR-T cells to clinic, Cellectis (OTCPK:CMVLF), a French biotech under the radar of investors in the US and undervalued, is behind six other companies. But I predict Cellectis's could eventually win because of its gene editing capabilities.
Novartis (NYSE:NVS) is arguably in 1st place: the FDA gave CTL019 Breakthrough Therapy status on July 7, 2014. Novartis-funded the successful phase I/IIA trial of CTL019 which is the name given to CAR-T cells that targeted lymphocytic leukemia cell marker CD19 in this trial. The positive results were published in the October 16, 2014 issue of NEJM. The research on CTL019 in acute lymphocytic leukemia was conducted by physician-scientists from the University of Pennsylvania. David Porter, a leading U Penn researcher on CAR-T, was co-author on 16 presentations at ASH, 7 of which were focused on CAR-T. The U Penn team was first to publish successful use of CD19 CAR-T in a patient with chronic lymphocytic leukemia in New England Journal of Medicine in 2011.
Kite Pharma (NASDAQ:KITE) can arguably claim 2nd place because of its rights to the CAR-T intellectual property of researchers at NCI and NIH. Positive phase 1 results for KTE-C19, which also targets the leukemia-associated CD19 antigen, were published in the October 13, 2014 issue of The Lancet. KTE-C19 has just progressed to phase 2 for B-lymphocyte malignancies (NCT00924326). On December 22, 2014, Kite announced its NDA for FDA approval of KTE-C19. KITE-affiliated researchers also genetically engineer T-Lymphocytes to express T cell receptor (TCR), trials of which are in phase 2 (NCT01967823) and earlier for solid tumors. EGFRvIII-CAR is in phase 2 for glioblastoma (NCT01454596).
GlaxoSmithKline (NYSE:GSK) in collaboration with Adaptimmune is (I will not keep repeating the word "arguably") tied for 3rd in the race to get T-cell-based cancer therapy to clinic. Adaptimmune announced almost simultaneously with the 2014 NEJM and Lancet publications cited above, favorable results in a pilot trial of NY-ESOc259T in 8 patients with sarcoma. Adaptimmune's T-cell therapy uses TCR (T-Cell Receptors) instead of CARs. The advantage of TCR over CAR T-cells is vastly greater number of potential targets: instead of targeting only CD19 or CD20 which are pretty specific to B-lymphocytes, TCR T-cells can be directed against other tumor-specific antigens. Adaptimmune has two phase 1/2 trial for myeloma (NCT01352286 and NCT01892293), two for NY-ESOc259T (NCT01343043 and NCT01567891) in solid tumors (sarcoma and ovarian cancer), and another for NY-ESO1 in melanoma (NCT01350401). GSK/Adaptimmune have not yet published trial results, did not present any CAR-T or TCR therapy results at 2014 ASH, and have not announced an NDA submission.
P.S. if we clear 10p and more importantly get drugs to market, I`ii fly over to the states and buy you lunch!
They have been asking about you and saying george was correct. I occasionally post a few facts but do not get involved due to that A...-ho.. shatter. He accused me of being you at one stage! I concentrate on ADVFN oxb bulls thread. Please join and contribute. Some good posters on there. Wave was a dealer.. quote, " Inst seller (not buerkbye) at 7.3 is done/not reloading, little supply now, woo-hoo, let's test 8p+"
In most cancers, tumour-specific antigens are not well defined, but in B cell cancers (such as CLL
and ALL) the CD19 antigen is an attractive target that has been validated by a number of
approaches. Expression of CD19 is highly restricted to B cells and not detected on other normal
tissues, including hematopoietic stem cells, thus making it a safe tumor antigen. The approach is to
modify T cells with a CAR that mimics the signaling of the natural T cell receptor (TCR) when
encountering tumor antigen. This creates a universal tumor-specific TCR that can be used across
patients with a common tumor antigen.
With CAR immunotherapy, the T cells are drawn from a patient's blood then transduced ex vivo so
they are able to identify and bind to cells that express the CD19 antigen present on a patient's
cancerous cells. When the modified T cells are re-introduced into the patient's blood, they seek out
and destroy the targeted cancer cells.
The activation and re-targeting of the patient’s T cells is achieved by genetically modifying them
using a lentiviral vector, which expresses an antibody-like protein that is the basis of the CAR. It is
at this stage that Oxford BioMedica’s expertise with lentivirus vector in general and production in
particular is expected to come into play. Oxford BioMedica will initially be responsible for
manufacturing several batches of a lentiviral vector encoding CTL019 technology. This is the vector
that will be used to transduce patients’ immune cells (T-cells) in an ex vivo process before they are
re-infused back into the patients.
The University of Pennsylvania says these re-engineered T-cells currently cost about $20,000 per
patient, much less than a bone-marrow transplant, and believes the higher volumes of production
scale-up will be likely to reduce the price tag. Such pricing assumptions are, in our view, realistic
and fall in a similar range to those we envisage for Oxford BioMedica’s own proprietary lentivirus
vector based gene therapy products (RetinoStat, StarGen and UshStat).
Jimenez is a star, a brilliant guy who gets the job done.
“I’ve told the team that resources are not an issue. Speed is the issue,” says Novartis Chief Executive Joseph Jimenez, 54. “I want to hear what it takes to run this phase III trial and to get this to market. You’re talking about patients who are about to die. The pain of having to turn patients away is such that we are going as fast as we can and not letting resources get in the way. ”
http://www.forbes.com/sites/matthewherper/2014/05/07/is-this-how-well-cure-cancer/
BRIEF-Novartis plans 2015 registration trial of leukemia drug
Mon Jan 12, 2015 12:30pm EST
Healthcare »
Jan 12 (Reuters) - Novartis AG : * Says plans 2015 registration trial of ctl019 in acute lymphoblastic leukemia
with eye on filing for approval in 2016 * Says expects approvals of heart failure drug lcz696 in 2h 2015
Thanks KarinCA and George. I wish OXB was listed in the states. Market cap would be a lot higher!
HTTP://drupal.ffbwebtest.syssrc.com/research-call-today%E2%80%99s-science-tomorrow%E2%80%99s-breakthroughs
HTTP://www.blindness.org/content/gene-therapy-restores-vision-patient (not oxb)
The first link talks about Stargen and Ushstat. They are excited about the trials.
Estimated sales $590m/year if successful.I presume OXB will get a standard cut i.e. 15-20%
For the benefit of anyone else George;
Listen from 3mins 80 and make your own mind up. OXB`s IP is worth a fortune. Look at the other company valuations. We get a % of CTL-019 and other Car-T, add that to everything else and put a PE on it. I am confident the value will rise significantly.
Thanks George
HTTP://www.bioleaders-forum.com/Content/Cell-and-Gene-Therapy-Forum-Agenda/3_17/
Commercialisation of gene therapy products - a fully integrated lentiviral vector strategy
12:15 - 12:35
Ability to translate pre-clinical animal models
Selection of appropriate endpoints
...
Peter Nolan
Peter Nolan
Thanks for that George. You are a font of knowledge. Tim Watts has sent a few nice email replies to me recently. I see he is doing a presentation in New York this month. I reckon a few interesting months lie ahead. Best wishes for now.
Yes I read that before, thanks George. Exciting times. Novartis may snap up OXB. What do you think?
Basel, January 1, 2015 - Novartis announced today that it has completed effective January 1, 2015 the divestment of its Animal Health Division to Eli Lilly and Company (Lilly) for approximately USD 5.4 billion. The completion of this transaction is part of a comprehensive set of transactions announced last April, that will focus Novartis on its three leading businesses of global scale: innovative pharmaceuticals, eye care, and generics.
HTTPS://www.wsj.com/articles/novartis-completes-sale-of-animal-health-division-to-eli-lilly-1420098815
You are correct George. I should have said if the treatment is expanded beyond Leukaemia.
The early-stage trial of CTL019 engineered cells conducted by researchers at the University of Pennsylvania indicates the potential of the complicated treatment, which analysts have estimated may generate $10 billion a year if its uses expand beyond leukemia. The therapy can provoke serious side affects, however, and eight of the 30 patients required intensive care for severe cytokine-release syndrome.
“We are excited by these results, which indicated how effective CTL019 may be in fighting ALL, a leading cause of childhood cancer deaths,” said lead investigator Stephan Grupp, a professor at the university.
Yes George, OXB are in line for a small % royalty from sales of ctl019. Analysts are guessing at $10 billion sales per year! I would not be surprised if OXB merge with Novartis or something similar happens.
Hi George, good to see that you are well. I post on advfn re OXB now as shatter was an idiot. Looking very good for OXB now. Best wishes, Marcus (aka wblack)