Cancer Vaccines: Doomed to Fail?

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Some ideas sound good in theory but just never manage to work out in real-world experience, and cancer vaccines are on their way to that destination. Following the failures of Vical and Merck KGaA with their respective cancer vaccines, GlaxoSmithKline (NYSE: GSK  ) has announced the second pivotal trial failure for its MAGE-A3 cancer vaccine. Glaxo will continue to try to identify patient sub-populations in both melanoma and lung cancer that could/do respond to a clinically significant degree, but the odds are good that this high-risk/high-reward program is on its last legs.

Another miss for MAGE-A3
Glaxo announced on Thursday that a Phase III study (MAGRIT) of its MAGE-A3 cancer vaccine failed to meet its co-primary endpoints in a study in non-small cell lung cancer. This follows the failure of MAGE-A3 to show sufficient efficacy in patients with melanoma last year and is broadly consistent with expectations that there was only a slim chance that this compound was going to prove effective (most sell-side analysts seemed to be factoring in only a 10% to 20% chance of success).

Glaxo is not entirely finished with MAGE-A3 just yet. The company's scientists are going over the data from both melanoma and lung cancer in the hope of finding identifiable patient subgroups that show a stronger, clinically relevant response to the vaccine. Glaxo is not generally a company that refuses to accept failure and looking for subgroups is a valid notion, as tailoring cancer treatments to particular genotypes (personalized medicine) is a validated approach.

This news was a minor negative for Glaxo, in no small part because the odds of success were seen as low and the resulting risk-adjusted expected contribution to Glaxo's future sales was quite modest. For Agenus, the small biotech that developed the adjuvant for MAGE-A3, the consequences were more serious and the shares fell nearly 12% on the news.

Vaccines on their heels...
Cancer vaccines sound great in theory, but they have yet to really make a mark in real-world oncology. Dendreon's (NASDAQOTH: DNDNQ  ) Provenge is approved and actively marketed, but the drug has failed to catch on as a prostate cancer treatment. Provenge adds about four months to median survival time for metastatic prostate cancer, but the procedures involved (blood is taken from the patient and sent to Dendreon, who manufactures a customized vaccine) and the high cost of treatment led to disappointing adoption and less than $300 million in annual revenue.

On a relative basis, though, Dendreon's Provenge has been a rousing success. Merck KgaA's Stimuvax / tecemotide (partnered from Oncothyreon) also failed in a lung cancer study, but like Glaxo Merck is hoping to find an identifiable patient subgroup that responds better. Vical announced the failure of its Allovectin melanoma vaccine in 2013 and abandoned the program.

... but not done yet
The mechanism of action of oncology vaccines make too much sense to abandon the approach entirely. Cancer vaccines can be broadly divided between those that stimulate/prompt the patient's own immune system to destroy cancer cells and those that directly target and attack cancer cells, and there are still products in pipelines worth watching.

Glaxo has its early stage PRAME ASCI vaccine for lung cancer and the WT1 vaccine for breast cancer. Aduro has had some encouraging early stage success with its GVAX/CRS-207 approach, and Celldex (NASDAQ: CLDX  ) is approaching an interim analysis in the pivotal study of its rindopepimut vaccine for EGFRvIII-positive glioblastoma. Rindopepimut showed a nine-month improvement in overall survival in a Phase II study, which is quite encouraging for this difficult-to-treat cancer. Celldex also has the early stage vaccine CDX-1401 in trials in various solid tumors.

Last and not least is Amgen's (NASDAQ: AMGN  ) T-Vec (talimogene laherparepvec). T-Vec works as both an oncolytic vaccine (directly destroying cancer cells) and a stimulant to the immune system and clinical results have been encouraging. Phase III overall survival data in melanoma should be available soon, and although PD-1/PDL-1 therapies may ultimately prove more successful in melanoma, success in this indication would provide some much-needed validation to the approach.

The bottom line
The good news for Glaxo is that although it seems unlikely that the company will recoup the money spent on developing MAGE-A3, the failure of this vaccine only reduces the long-term fair value by about 1% or 2%. Looking at the wider field, it remains to be seen whether cancer vaccines have a permanent seat at the table as a viable oncology approach, with Celldex and Amgen likely the best bets for near-term success.

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  • Report this Comment On March 24, 2014, at 1:30 PM, markwhite179 wrote:

    ONCE - Has the solution.

    OncoSec s lead candidate is ImmunoPulse, which locally delivers plasmid DNA encoding interleukin

    12 (IL-12) into tumor cells. ImmunoPulse is under three Phase II clinical trials targeting melanoma,

    Merkel cell carcinoma (MCC), and cutaneous T-cell lymphoma (CTLC) respectively.

  • Report this Comment On March 25, 2014, at 1:31 AM, DocLogic7 wrote:


    You stated "Looking at the wider field, it remains to be seen whether cancer vaccines have a permanent seat at the table as a viable oncology approach, with Celldex and Amgen likely the best bets for near-term success." I understand that no treatment may end up being permanent but why would you say this and not mention anythng about the recent success of engineered T-cell vaccines or the precedent setting approvals given to NWBO and their DCVax-L treatment by the German PEI which is the equivalent of our FDA? Or why would you not mention that there is a currently pending phase lll DSMB interim look for efficacy decision being waited on for that same treatment after an initial continuation recommendation based on safety was given? Does income generated from patients treated in Germany as early as this summer or a potential DSMB early stop for efficacy not count as near term?

    The German approvals are unique in many ways and allow NWBO to be reimbursed by the German federal insurance program there and also allows for the treatment to be given to foreigners who are willing to pay full price for it which means medical tourism will soon be increasing in Germany. These decisions also expanded the parameters for partcipation beyond those of their approved phase lll trial there to include all forms of glioma and GBM in both newly diagnosed as well as recurrent patients and not just newly diagnosed GBM patients. This is essentially a conditional approval that is renewable after 5 years, not just 1 year, which is what they could have recommended if they were less certain. All of these patients will essentially be either directly in or indirectly partcipating in the full approval process that will culminate at a later date and will allow NWBO to advertise their product commercially. This is because all of the patient data will be used for making ongoing decisions regarding continued reimbursement for treatment and patient participation parameters that are steps that run parallel to the phase lll trial results. Since the German decision was made concerning DCVax-L, there has been some indication that other European countries might be willing to have their national insurance cover treatment for their citizens choosing to go there to be treated as well. If this turns out to be the case then the German hospitals applying for and receiving reimbursement will have their hands full.

    By the way, why is it that the insiders at Amgen seem to be selling their shares as fast as they are gettng them and haven't bought any with their own money any time recently? Maybe you could also help me understand why NWBO has 4,000 sq. ft. of space rented at the ASCO conference center, which is in line with what the big biotechs and pharmas have. DR. Subiah at M.D. Anderson has submitted an abstract last minute for consideration at ASCO in relationship to DCVax-Direct which is NWBO's next generation, first in man, dendritic cell vaccine for ALL solid tumors. Is the end of May to the beginning of June considered near term?

    Disruptive technologies can cause major damage to the status quo. Those who know that it is coming and have the wherewithall to influence the markets by the moves they make, and make money whether the market moves up or down, often make trend setting moves that prepare the table for their success. Recent news concerning drug pricing over at GILD has given those who have wanted a good reason to justify some "asset reallocation" to their clients the ability to do so. While doing this they can create some subsequent pricing pressure in specfic areas where they have an interest in a sector they are leaving which helps them build their positions there. Diverting attention from and discouraging attention paid to specific targets is a strategy that works. Who wants the best fishing spots over fished? I expect this selective biotech and pharma selling and buying to continue into a trend as reports from various immunotherapies in clinical trials, including vaccines, begin to make more headlines and separation between those companies that will enjoy great success and those who will be left behind becomes more clear to those who have not yet been made aware of the potential ramifications of the various treatments. I expect we will be hearing much more about CLDX, ONCS, NLNK, NWBO and others in the near future, much more. Best wishes.

  • Report this Comment On March 31, 2014, at 5:39 AM, Ballchinnian wrote:

    T-vec has no side effects and a unique mechanism of action. There is no reason to think that it won't be used in combination rather than in competition with other therapies, such at PD-1 and PD-L1 blockers. Indeed, it could well be synergistic with other immunotherapies, teaming up to draw the immune system into the fight.

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Stephen D.

I'm an ex-Wall Street sell-side and buy-side analyst who has spent most of the last 10 years writing on a wide range of industries and investment ideas.

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