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Friday, 24 February 2017

Cancer vaccines: déjà vu all over again

News of two cancer vaccine clinical trial failures brought to mind the famous Yogi Berra quote “déjà vu all over again”.
"For the Win"

Argos Therapeutics was forced to halt a Phase III study of rocapuldencel-T in renal cancer patients when an interim data analysis indicated that continuing the study was futile. Agenus, somewhat shyly, announced the halting of a Phase II study of its Prophage G-200 vaccine in newly-diagnosed glioma patients for the same reason.

Both rocapuldencel-T and Prophage® are “personalized” vaccines which present cancer antigens derived from the patient’s own tumour.  In theory, these so –called “neoantigens” should be able to get around the problem of tumour-induced host tolerance and elicit cancer-fighting T cell responses.

Despite their sophistication, the Argos and Agenus candidates were unable to induce effective immune responses. A variety of other personalized cancer vaccines are in development but the complexity of neoantigen design is well-recognized and fine-tuning of epitope-predicting algorithms will require accumulation of a large body of clinical data. 

Although still a long way from validation, the prospect that the bespoke neoantigen approach might achieve the stunning outcomes observed in the minority of checkpoint inhibitor-treated individuals in a far larger percentage of treated patients has prompted several high-ticket licensing deals in the past year.

Cancer vaccine success has proved largely elusive over the past three decades, with only Dendreon’s ill-fated prostate cancer vaccine, Provenge®, managing to secure regulatory approval (call me a purist, but I don’t consider Amgen’s Imlygic® a vaccine. We can agree on “immunotherapeutic”). 

As someone whose professional interest in cancer vaccines goes back to the 90s, I’m hopeful that the broader renaissance in cancer immunotherapy will, directly or indirectly lead to useful cancer vaccines, either through combination with tolerance breaking biologics or small molecules or through a better understanding of the subtle interplay between tumours and the host immune system.

To quote Mr Berra once again, “It ain't over 'til it's over”. 

Image By Bowman Gum (Heritage Auctions), via Wikimedia Commons

Monday, 20 February 2017

Faced with financial burden, younger cancer survivors are more likely to skimp on Rx drugs

A passing line in my recent post on cancer drug pricing made reference to the financial burden faced by American cancer patients: an American Cancer Society publication posted online today indicates that the burden among “non-elderly” cancer survivors (those under 65 years old) is sufficient to make this group more likely to delay, skip or even forgo medication than those without a history of cancer.

Zeng and colleagues examined National Health Interview Survey data from 9,000 individuals with, and 93,000 individuals without, a history of cancer. They found 31.6% of respondents recently diagnosed with cancer and 27.9% of those with a past  cancer diagnosis had made some change in prescription drug use for  financial reasons, compared with 21.4% of respondents  without a cancer history. Cancer survivors in health plans with lower premiums but with a higher threshold before costs are met (“high deductible” plans) were more likely to request lower cost medications than those without a cancer history (32% vs. 22.5%, respectively).

A shift away from hospital or community-administered infused cancer drugs towards self-administered oral medications, along with changes in health plan structure have increased the out-of-pocket burden, with those under 65 (and not enrolled in Medicare) being hardest hit.
The authors did look at the impact of cost-imposed changes in medication on quality of life but conclude by proposing that prescribers should consider the consequences of  financial burden and shape their treatment decisions accordingly.

People with Cancer History More Likely to Change Prescriptions to Save Money. American Cancer Society press release online February 20th 2017. http://tinyurl.com/hkk7xcb

Do cancer survivors change their prescription drug use for financial reasons? Findings from a nationally representative sample in the United States.Zeng Z et al. Cancer. doi:10.1002/cncr.30560. Published online February 20th 2017. http://tinyurl.com/jjtabyu (Subscription required for full text).

Saturday, 18 February 2017

This week- CRISPR patent decision, Merck abandons Alzheimer’s study

Items of note that I hope to revisit in future blogs: 

PTAB, the USPTO Patent Trial and Appeal Board, found in favour of the Broad Institute with respect to claims of interference brought by UC Berkeley. CRISPR-Cas9 genome editing is touted as a revolutionary enabling technology and a potentially viable means of treating genetic disorders. With future revenues and academic pride at stake, the PTAB decision is unlikely to be accepted as the final word. 
Read Sharon Begley’s excellent commentary here: http://tinyurl.com/jx95ces (“The CRISPR patent decision: Your six takeaways”. STAT online February 16th 2017) and Kevin Noonan’s explanation of the PTAB decision here: http://tinyurl.com/hvegf3n (“PTAB Decides CRISPR Interference in Favor of Broad Institute -- Their Reasoning”. PatentDocs online February 16th 2017). 

Merck called a halt to a pivotal study of verubecestat in mild-to-moderate Alzheimer’s disease. Failure in AD studies is, unfortunately, the norm, and again calls into question the rationale of targeting amyloid beta protein. Verubecestat will continue to evaluated in a separate study being conducted in patients with prodromal symptoms , although study read out is two years away. 

Read Merck’s announcement here: http://tinyurl.com/gvay5qu (“Merck Announces EPOCH Study of Verubecestat for the Treatment of People with Mild to Moderate Alzheimer’s Disease to Stop for Lack of Efficacy. Company press release online February 14th 2017.)

Friday, 17 February 2017

For most cancer drugs, the price isn’t right

Drug pricing is now a regular headline feature. The past year saw Valeant, Mylan, Pfizer and United Health receive unwanted attention around seemingly unjustifiable increases in the prices of patent-expired medicines and a promise from the Trump presidency that the soaring cost of medicines would be brought under control.  

Spiralling prices impact on all medical conditions, but  the fair pricing of cancer drugs is particularly emotive. The six-figure cost of newer therapies is straining public and private healthcare systems. Stiff co-payments impose an often intolerable burden on US cancer patients and their families and high pricing restricts access to cancer drugs in less-developed economies.

Cancer drug development is expensive. Newer treatments target particular mutations or other aberrations specific to certain tumour types, with the consequence that the accessible patient population is reduced to a subset of cancer sufferers.

Developers argue, reasonably enough, that pricing must cover the expanding cost of development and still generate sufficient profit for reinvestment in R&D. The costliest of cancer drugs can still represent good value if treatment outcomes, such as increased survival or measurable improvement in quality of life over best standard of care can be expected for the majority of treated patients, but a large and growing body of evidence points to a serious disconnect between cancer drug pricing, clinical efficacy and true value.
An analysis published this month by Vivot and colleagues compared the clinical efficacy of cancer treatments approved by the FDA between 2000 and 2015 using measures of clinical benefit developed by American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO).

Evaluation was possible for 37 of the 51 drugs approved by the FDA. ESMO criteria indicated that just over one-third of drugs (13 or 35%) showed “meaningful clinical benefit”. The scale of benefit obtained by applying ASCO criteria was in the range 3.4 to 67, with a median value of 37. No relationship was indicated between benefit and price.

A similar study by Salas-Vega and colleagues at the London School of Economics found that cancer drugs approved in the decade to 2013 resulted in no discernible increase in overall survival for certain cancers (breast cancer being a notable exception), with all new drugs contributing an average gain in overall survival benefit of just under three and a half months.

Blaming the situation on drug company rapaciousness is naive, although it’s clearly in the industry’s interest to be viewed by both governments and the public as part of the solution. Alignment of pricing and outcome needs a major shift in the basis for drug approval (one that may not be compatible with President Trump’s vision of a truncated FDA approval process), along with a better understanding on the part of prescribers, payers and patients of cancer drug benefit in the context of toxicity, quality of life and individual and societal cost.

Future cancer treatments may perhaps be truly transforming, with functional cure becoming a realistic expectation. Science aside, the challenge will be in developing equitable payment mechanisms that reward innovation without placing cancer treatments out of reach of the majority.

Clinical Benefit, Price and Approval Characteristics of FDA-approved New Drugs for Treating Advanced Solid Cancer, 2000-2015. A Vivot et al. Ann Oncol mdx053. https://doi.org/10.1093/annonc/mdx053. http://tinyurl.com/j4uhv3f

Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines. Sebastian Salas-Vega, Othon Iliopoulos and Elias Mossialos. JAMA Oncol. Published online December 29, 2016. doi:10.1001/jamaoncol.2016.4166. http://tinyurl.com/glo9gvz

Friday, 10 February 2017

ASCO 2017 Annual Report again picks immunotherapy as “Advance of the Year “

ASCO, the American Society of Clinical Oncology, is probably best known to followers of the pharma and biotech industries for its high profile annual conference, always the subject of intense sector analyst scrutiny.  ASCO also publishes a highly-readable annual report highlighting clinical advances in cancer therapy and the shape of future research.

Once again, immunotherapy (dubbed “Immunotherapy 2.0” by ASCO) takes the honours as “Advance of the Year”, underscoring the breakthrough nature of this approach to cancer treatment and its expanding role across a growing number of cancer indications.

Put very simply, immunotherapy utilises the patient’s own immune system to combat cancer. Tumours thrive by deploying a variety of countermeasures which are highly effective in subverting the immune response.  A mechanism common to several tumour types is surface expression of proteins that lock onto receptors (“immune checkpoints”) present on T cells,  resulting in their deactivation. By deliberately blocking this interaction, T-cell “seek and destroy” functions can be restored.

Immune checkpoint inhibitors were first approved on the basis of their efficacy in metastatic melanoma, with the first being Yervoy® (ipilimumab: Bristol Myers Squibb) in 2011, followed by Keytruda® (pembrolizumab: Merck) and Opdivo® (nivolumab: Bristol Myers Squibb) in 2014 and,  most recently, Tecentriq® (atezolizumab: Roche) for the treatment of some forms of lung cancer. A number of other biologic immune checkpoint inhibitors are in late stage clinical evaluation.

From the outset, checkpoint inhibitor treatment has been notable for impressive increases in patient survival, although not across the board. Reliable identification of those patients most likely to benefit from checkpoint inhibitor therapy remains a frustration. Optimum duration of therapy also remains to be established. Given the cost of checkpoint inhibitor treatment (around £30,000 before an undisclosed discount in the UK and around $150,000 in the US), patient selection and length of treatment are of key importance to healthcare systems already struggling with soaring cancer therapy expenditure.

Recent checkpoint inhibitor approvals include treatment of head and neck, bladder and renal cancers and Hodgkin’s lymphoma, and evaluation is progressing in liver, breast, gastric and other cancers. The need to attain market dominance is a major driver of clinical trial activity: at the end of 2016, Merck’s Keytruda® was being trialled against 30 tumour type in more than 350 registered studies, of which around 100 studies will evaluate treatment combinations.

Hundreds of micro and mid-cap companies are looking to stake a claim in the immunotherapy (aka “immuno-oncology) space. Some are hopeful that repurposed drugs can modify the tumour microenvironment to favour the immune system, while others believe that combination with checkpoint inhibitors and other agents can boost the so far disappointing efficacy of cancer vaccines.

Tumour immunology remains poorly understood. Potential big winners in next generation immunotherapy are those companies engaged in the unravelling of tumour defence mechanisms to find exploitable vulnerabilities.

Who knows, but given the rate of progress, the 2027 ASCO “Advance of the Year” could well be “Immunotherapy 12.0”.

ASCO 12th Annual Report on Progress Against Cancer. 2017 Clinical Advances. Online 1st February 2017    http://tinyurl.com/zwzv5vg

Sunday, 5 February 2017

Biosimilars: good for patients, good for payers and very good for lawyers

I should add “and yours truly” to the title of this post, having been lucky enough to work with several companies, either active in biosimilar development or having a biologics franchise at risk from biosimilar competition (both in some cases). 

Biosimilars, functionally identical versions of complex biologic medicines such as human growth hormone, colony stimulating factor and erythropoietin were first launched in ex-US markets almost a decade ago, largely with modest impact on originator product sales. Regulatory approval of biosimilar versions of high earning biologics indicated in autoimmune disease treatment has dramatically changed the landscape by threatening key multi-billion dollar earners: Humira® (adalimumab: AbbVie); Enbrel® (etanercept: Amgen/Pfizer) and Remicade® (infliximab: J&J/MSD).

Remicade® lost patent protection in the larger European markets in February 2015 and faced immediate competition from an infliximab biosimilar developed by Celltrion, a South Korean company, (confusingly marketed as two brands, Inflectra® and Remsima®) and which had gained traction in “early adopter” countries such as Norway and Denmark due to its unexpectedly high discount to Remicade®. J&J posted a 20% decrease in Remicade® revenue for 2015.

A biosimilar version of Enbrel® (Benepali®: Biogen) approved in Europe just over a year ago is set to to at least match the uptake of biosimilar infliximab. Humira®, with global sales of close to $16 billion, is under threat from a slew of heavyweight pharma and biopharma companies developing adalimumab biosimilars. 

Given the potential for cost-saving, it’s no surprise that healthcare systems are keen to take advantage of biosimilars. In Europe, national authorities have taken a pragmatic view of biosimilar interchangeabilty, with gradual lessening of prescriber issues over extrapolation of use into indications not included in registration studies. US biosimilar guidelines are under development but four FDA approvals in 2016 have signalled that there are no inherent barriers to regulatory success. Lower acquisition cost should (eventually) translate into more patients receiving biologics therapy with neutral impact on expenditure by public and private payers. 

It’s also hardly surprising that, faced with a significant hit to hard-to-replace established franchises, J&J, Amgen and AbbVie are fighting an intense rearguard action in the US and UK courts to delay biosimilar entry. J&J have, so far, lucked out to Pfizer in the US, with the latter launching Celltrion’s infliximab biosimilar in November 2016 after overturning a patent challenge. Amgen’s lawyers have successfully delayed the entry of Novartis’s biosimilar version of Enbrel® until at least late 2018. 

AbbVie is fighting multiple challenges from Amgen, Boehringer Ingelheim and others in the US with the expectation that biosimilar market entry can be delayed until at least 2023 (the core Humira® patent expired in the US in December 2016). Biogen/Samsung Bioepsis and Fujifilm Kyowa Kirin Biologics have challenged AbbVie in the UK courts to ensure a clear runway after European patent expiry in October 2018. 

AbbVie’s broad portfolio of granted and pending Humira® patent applications makes for a tough nut to crack, but it’s an indicator of just how far biosimilars have matured in that lawyers and judges, and not regulatory authorities, will now dictate the path to successful biosimilar commercialisation. Patent lawyers are likely to do equally well in the near future as biosimilar versions of the best selling biologic cancer treatments, Herceptin®, Avastin® and Rituximab/MabThera® win regulatory approval.