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Biosimilars could be a casualty of Supreme Court Health Care Decision

The decision expected this Thursday by the Supreme Court of the United States on the constitutionality of the Patient Protection and Affordable Care Act (PPACA) may impact the development and approval of biosimilars.

Part of the PPACA signed into law by President Obama on March 23, 2010 was the Biologics Price Competition & Innovation Act (BPCI).

This amended the Public Health Service Act (PHS) to create a pathway under section 351(k) for the licensing of biological products that are “interchangeable” or “biosimilar” to an FDA-licensed product.

In addition, to a licensing pathway, the regulatory framework introduced “exclusivity” periods that prevented approval of a 351(k) application until 12 years after the first license of the reference product. I doubt very much that Congress will want to have to negotiate exclusivity provisions again.

I am not a regulatory expert, but my understanding is that if the Court declares the PPACA unconstitutional in its entirety, the BPCI would be lost too.

At the risk of venturing an opinion, I don’t think the Court will want to cause collateral damage to uncontroversial parts of the PPACA such as the BPCI, but it is something to watch out for this Thursday.

Many commentators think it likely the Court will uphold certain parts of the PPACA and invalidate other provisions. This was the approach the Court followed in a decision earlier this week on Arizona Immigration Law (Arizona v. United States).

However, until a decision is published by the Court, nobody knows.  Thursday is set to be a landmark day whatever the Court decides.

Update June 28, 2012

In a 5:4 opinion, the Supreme Court has upheld several provisions of the Patient Protection and Affordable Care Act (PPACA). The Court did not rule the PPACA unconstitutional in its entirety which was the only way the biosimilars provisions would have been lost. Therefore, from a biosimilar regulatory perspective, nothing has changed as a result of today’s decision – the exclusivity and approval pathway are maintained. This is good news for the biotechnology industry.

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BAY 86-9766 shows early promise at AACR Pancreatic Cancer Conference

A diagnosis of stage IV pancreatic cancer is pretty much a death sentence.

People are often diagnosed in the advanced stage of the disease – 49.5% are diagnosed in stage IV – and the prognosis is generally not good.  Sadly most don’t live long, even with the latest treatments.

According to the National Cancer Institute (NCI) SEER survival monograph, the relative survival rates are extremely poor. Across all types of pancreatic cancer, only 5% of people live for 5 years, and only 23% survive 1 year.  Three to five months is the median survival time for those with untreated metastatic pancreatic cancer.

In the United States, there were 33,730 new cases of pancreatic cancer in 2006 and 32,300 deaths!  There is, therefore, an unmet need for effective new pancreatic cancer treatments.

Preclinical data presented by Nicole Teichmann and colleagues at the recent American Association for Cancer Research (AACR) special conference on Pancreatic Cancer in Lake Tahoe, NV suggests that BAY 86-9766 may be an interesting compound to watch as it moves forward in clinical development.

“We showed in our endogenous mouse model that our novel chemotherapeutic agent leads to dramatic tumor shrinkage after only one week of treatment,” said Nicole Teichmann, Ph.D., of the Klinikum rechts der Isar at the Technische Universität München in Munich, Germany in an AACR press release.

Although impressive tumor shrinkage was seen in the preclinical trial of BAY 86-9766, a novel MEK1/2 inhibitor, “in most animals the tumors relapsed typically after 3 weeks of treatment,” according to Teichmann’s abstract.  This suggests that there is an escape pathway that may also need to be targeted for the drug to be more effective.

One of the signaling pathways involved in pancreatic cancer is the Raf-MEK-ERK pathway (75-90% of pancreatic cancers have a K-ras mutation), which is why a MEK inhibitor such as BAY 86-9766 that targets this pathway may be effective.

However, pancreatic cancer represents a challenge for drug development and many drugs have failed in clinical development.

Sorafenib despite being an inhibitor of Raf-1 kinase and EGFR2, failed to show any effect in pancreatic cancer.  Adding sorafenib to gemcitabine did not improve survival significantly.

Recently, Infinity Pharmaceuticals terminated a pancreatic cancer phase 2 trial with their Hedgehog inhibitor, saridegib (IPI-926).

Despite scientific evidence suggesting that hedgehog signaling plays an important role in pancreatic cancer, patients receiving saridegib with gemcitabine did worse (i.e. lived for a shorter period) than they would if they had just received gemcitabine alone.

The Infinity news release noted that “the median survival for patients receiving saridegib plus gemcitabine was less than the historical median survival for single-agent gemcitabine of approximately six months.” Not surprisingly, the trial was terminated.

Other Hedgehog compounds being evaluated in pancreatic cancer include Roche’s vismodegib (Erivedge), which was initially approved in advanced, refractory basal cell carcinoma last year.  The drug is also being tested in trials for pancreatic cancer, including one with gemcitabine and another with gemcitabine plus nab-paclitaxel (Abraxane).

Interestingly, Celgene are waiting for the final data to mature on their phase III trial in pancreatic cancer with nab-paclitaxel and gemcitabine.  The interim results were encouraging, but it is too early to tell if the outcomes will be significantly improved by the combination. You can read more about the scientific rationale for nab-paclitaxel in pancreatic cancer on Pharma Strategy Blog.

The efficacy and safety of BAY 86-977 in combination with gemcitabine is currently being evaluated in a phase 2 trial of patients with non-resectable, locally advanced or metastatic pancreatic cancer.

Caution must, therefore, be expressed as to whether BAY 86-9766 will be effective given that so many promising pancreatic cancer drugs have failed in drug development.

It remains to be seen whether BAY 86-9766 will live up to the promise of the preclinical data presented at the AACR pancreatic meeting in Lake Tahoe.

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Problems with Alpharadin ASCO SRE data?

At the 2012 American Society of Clinical Oncology (ASCO) annual meeting, data was presented by Dr Oliver Sartor (ASCO 2012 Abstract 4551) that showed radium-223 (Alpharadin) significantly delayed time to first skeletal-related event (SRE) in patients with castratation-resistant prostate cancer (CRPC) and bone metastases.

The SRE data for radium-223 from the ALSYMPCA phase III trial was first presented at ASCO GU earlier this year.

ASCO 2012 radium-223 data discrepancies

Algeta in a communication I received today, however, have advised that the data contained in the ASCO 2012 abstracts has “discrepancies.”  In the absence of more precise information, the discrepancies may or may not be significant.

As with good practice, the sponsors have conducted further verification of the ALSYMPCA SRE data in preparation for the US FDA NDA regulatory submission. This has resulted in changes in the numbers previously reported for SRE data in the ASCO 2012 abstracts (Abstract #4551, LBA #4512). Though discrepancies were noted, the overall interpretation of the results has not changed. The SRE data will be disclosed once all additional data verification and analyses activities are completed.

Mike Booth, Algeta Communications & Corporate Affairs, June 15, 2012 email communication.

While the message that radium-223 significantly delays time to first SRE may not have changed, data accuracy is important and should not be taken lightly.

In his ASCO 2012 prostate cancer poster discussion, Evan Yu, Associate Professor at the University of Washington, made no mention of any “discrepancy.” Instead he used the data in Sartor’s poster that showed the time to first SRE with radium-223 to be 13.6 months versus 8.4 months with placebo, a delay of 5.1 months.

Dr Parker presented updated ALSYMPCA trial data at ASCO 2012 that showed a 5.5 month delay in time to first SRE with radium-223 (12.2 versus 6.7 months). Dr Sartor’s poster was based on 541 patients on radium-223, while Dr Parker’s data was for 614 patients. This suggests that the two presentations represent data at different time points.

Were Bayer and Algeta aware of the issues at the time of ASCO and chose not to say anything?  Obviously, if the discrepancies are small or insignificant then it would not make much difference, but a large difference would be more of a concern.

What is the accurate SRE data for radium-223 from the ALSYMPCA trial?

I look forward to a future press release from Algeta/Bayer clarifying this, and hope that they will advise ASCO if corrections need to be made to the data previously presented and published.

ASCO 2012 What is the Optimal Sequencing of Advanced Prostate Cancer Drugs?

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

There is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

ASCO 2012: Zytiga fails to show overall survival pre-chemo

Men with advanced prostate cancer want to know “if I take this drug, will I live longer?” Unfortunately, for abiraterone acetate (Zytiga®) in the pre-chemotherapy setting i.e for asymptomatic or mildly symptomatic men, doctors will only be able to say, “maybe” and tell the patient there is a strong trend towards an overall survival (OS) advantage.

You can read my Xconomy article published yesterday, on why I think it was a mistake for the abiraterone acetate COU-AA-302 trial (302 trial) in chemotherapy-naïve (pre-chemo) men to be stopped early.  The results were presented on Saturday at the American Society of Clinical Oncology (ASCO) meeting in Chicago.

Understanding the Lan-DeMets alpha spending function with O’Brien-Fleming boundary based on number of death events observed is challenging for non-experts.

However, the bottom line is that the 302 trial failed to meet the pre-specified hazard ratio for stopping early, and by so doing it failed to meet one of its co-primary endpoints. This is disappointing because the trial most likely only needed another 92 deaths to occur before it would have reached significance, and this would have occurred in a matter of months.

The co-primary endpoint of radiographic progression free survival (rPFS) was, however, met in the 302 trial. Whether rPFS reflects tangible clinical benefit is unknown.  The FDA have (to my knowledge) not approved a prostate cancer drug on the basis of rPFS , overall survival remains the regulatory standard.

I also learnt for the first time at ASCO about the problem of bone flare in patients receiving abiraterone. Charles Ryan, MD who presented the 302 data, discussed this is an ASCO educational session on prostate cancer imaging.

Bone scan flare is a spurious, “worsening” bone scan in the context of clinical response that reflects increased intensity of lesions, not new lesions.  In other words a brighter image on a bone scan may not represent disease progression.

In a previously published study, Dr Ryan showed a 43% incidence (10/23) of bone flare with abiraterone.  He advised attendees at the ASCO 2012 educational session to “look for, and CONFIRM new lesions before calling progression based solely on bone scans.”

Although the rPFS data for the COU-AA-302 trial was read centrally, and is therefore presumed to be more reliable as a result, I would have welcomed more discussion on the extent rPFS correlates with survival following the COU-AA-302 data presentation at ASCO.  I expect the Oncologic Drugs Advisory Committee (ODAC) will vigorously discuss this in more detail when Johnson & Johnson seek a pre-chemotherapy indication for abiraterone based on the COU-AA-302 data.

Bearing in mind overall survival has been the de facto standard in advanced prostate cancer, it will be interesting to see how the FDA and ODAC will view what is essentially a failed trial with a non-significant OS.  Will precedent be broken, opening the floodgates for future sponsor submissions based on PFS?

Update January 24 2013: FDA & EMA approve Zytiga Pre-Chemo in CRPC

With little fanfare and no ODAC, the FDA issued a press release on December 10, 2012 announcing that abiraterone acetate (Zytiga) had received approval “to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.”

The press release states: “The FDA reviewed Zytiga’s application for this new indication under the agency’s priority review program. The program provides for an expedited six-month review for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists.”

The fact that there was an unmet need for prostate cancer treatments prior to chemotherapy was clearly key to their decision making. The press release notes that “patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo.”

However, the FDA in their carefully worded press release make no mention of the fact that the difference of 5.2 months in median overall survival failed to reach the pre-specified value for statistical significance.

In other words, although JNJ have expanded the label for abiraterone to include the pre-chemo indication, they cannot make the claim that taking abiraterone prior to chemotherapy definitely results in men living longer (overall survival). All we can say is that the data was trending towards a statistically significant overall survival advantage. To many this may seem academic, but overall survival remains the benchmark that drives cancer drug development and by which treatment effectiveness is judged.

As I noted in my post from ASCO 2012 for Xconomy, most likely statistical significance for overall survival would have been reached in a few months, which is why I and others thought the trial had been stopped too early. I would be surprised if other companies follow JNJ’s strategy, and expect Medivation will seek to show a significant overall survival advantage for enzalatumide (Xtandi) in their pre-chemotherapy PREVAIL trial.

Johnson & Johnson announced on January 11, 2013 that abiraterone has also received approval in the European Union for the pre-chemotherapy prostate cancer indication following a positive recommendation from the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA).

It will be interesting to see if there is any new data in the updated interim analysis for the COU-AA-302 trial (abiraterone pre-chemo) that will be presented at the 2013 ASCO Genitourinary Cancers (ASCO GU) symposium in Orlando next month.

 

Repetitive brain injury from high impact sports generates similar pathophysiology to traumatic brain injury in soldiers blown up by IEDs

Several retired American Football stars have ended up with chronic traumatic encephalophy (CTE), previously known as dementia pugilistica. It’s similar to Alzheimer’s disease in that the brain ends up with neurofibrillary tangles.

CTE has also been seen in soldiers who have experienced blast induced traumatic brain injury (bTBI) from improvised explosive devices (IEDs). I previously wrote on this blog about how nanotechnology may revolutionize the detection of TBI using a nanomaterial that changes color.

Research published in the May 16, 2012 issue of Science Translational Magazine by Lee Goldstein and colleagues from the Molecular Aging and Development Laboratory at Boston University & other institutions, compared CTE neuropathology in blast-exposed military veterans and athletes with repetitive concussion injury.

For the first time they have shown similarities in what happens to the brains of soldiers when they are blown up and to athletes in sports that have repeated head impacts.

The reseachers looked at 8 post-mortem brains, 4 military veterans aged 22 to 45 with a history of blast exposure were compared to 4 athletes aged 17 to 27 who were either American Football players or, in one case, a wrestler. Despite the small sample size, the results showed similar brain trauma in the two groups:

“the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.”

It is worth noting that the brain neuropathysiology seen was different from that seen with Alzheimer’s disease (AD).

The researchers went on to develop a mouse model that could be used to investigate the link between blast exposure, brain neuropathology and behavior.  I encourage you to read the STM paper for full details on this.

Some of the key findings of their mouse experiments were:

  • Blast exposure induces traumatic head acceleration in a blast neurotrauma mouse model
  • Single-blast exposure persistently impairs axonal conduction and long-term potentiation of activity-dependent synaptic transmission in the hippocampus
  • Single-blast exposure induces long-term behavioural deficits that are prevented by head immobilization during blast exposure.

The authors conclude that their results “provide compelling evidence linking blast exposure to long-lasting brain injury.”

What this research suggests to me is:

  • An ongoing need to design safer head protection for athletes and soldiers
  • The need to monitor and detect traumatic brain injury (I wrote last year about how nanomaterials were being developed to monitor blast exposure)
  • Need to identify those genetic factors (e.g. carrying the APOE e4 allele leads to a high risk of developing Alzheimer’s disease) that may lead to a heightened risk of developing dementia or CTE.

The paper by Goldstein and colleagues in STM is well worth reading if you have an interest in this area and the debate about the safety of young people in high-contact sports.

Reference

ResearchBlogging.orgGoldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

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TEDMED 2012: Francis Collins on how to brings drugs to market faster

If like me, you didn’t attend TEDMED in Washington DC, then you can now watch videos from the TEDMED 2012 conference.

With my interest in innovation and how to bring drugs to market faster, one video that caught my attention was by Francis Collins MD, PhD, Director of the National Institutes of Health (NIH) who talked about the challenges of going from basic science (fundamental knowledge) to its application.

In his presentation, Dr Collins talks about how it can take 14 years of research and the screening of 10,000 compounds to bring 1 new drug to market.

How can we do better was the theme of his presentation, how to make drug development go faster and be more successful?

One way to go faster is to take advantage of technology such as the ability to read the human genome, the cost of which has dramatically decreased.

Using progeria as an example, Dr Collins discussed how older drugs may be effective in new indications.  Drug repurposing will be a partnership between academia, government, private sector and patient organizations, he said.

He also discussed how human cells can be used to test whether drugs are going to be safe and effective before any animal or human experiments are done.

The opportunities for drug development are exciting if the right partnerships, talent and funding are put in place. It will be interesting to see how Dr Collins vision plays out over the next few years.

I expect that as we learn more about the human genome, and better understand molecular targets, we will see more new drugs come to market that make a difference in the lives of patients.

Innovation in Neurotechnology: how a paralyzed person uses thoughts to control a robotic arm

Research published online first today, and in the May 17 2012 issue of Nature describes promising results of a clinical trial with tetraplegics (all four limbs paralyzed) that allowed the control of an external robotic arm (DEKA arm) using an embedded microarray in the brain, the BrainGate neural interface system.

One of the two study participants who had the array implanted 5 years ago, was able to use her mind to control a robotic arm and serve herself coffee from a bottle, 15 years after she became completely paralyzed & unable to speak.

The results from a team of researchers from the Department of Veterans Affairs, Brown University, MGH, Harvard Medical School (BrainGate Research Team) and the German Aerospace Center, Institute of Robotics and Mechatronics are promising.

The BrainGate system is the size of a small pill, and consists of a grid of 96 electrodes that are implanted in the motor cortex of the brain. By placing the grid next to the part of the brain that controls movement, neuronal activity associated with a movement can be translated into a computer command that drives an external robotic device.

The results reported by Leigh Hochberg MD, PhD & colleagues in Nature, offers hope to those paralyzed or who have limbs amputed, that in the future, innovations in neurotechnology may allow thoughts to control prosthetics or external robots.

How does it work, according to clinical trial subject T2:

I just imagined moving my own arm and the [DEKA] arm moved where I wanted it to go.

Subject S3 commented:

I think about moving my hand and wrist. I’m right handed so, it’s very comfortable and feels natural to imagine my right hand moving in the direction I want the robotic arm to move.

The challenge with this type of medical news is the danger of hype over hope, so to better put the results in perspective, I am delighted to have some expert commentary in the form of a guest blog post from D. Kacy Cullen, Ph.D, Assistant Professor at the University of Pennsylvania, Department of Neurosurgery Center for Brain Injury and Repair.

The Cullen laboratory at Penn applies Neural Engineering principles and technologies to the area of Neurotrauma, and is actively researching how to use neural tissue engineering-treatments to promote regeneration and restore function.

Commentary by D. Kacy Cullen, PhD 

This work is a natural extension/combination of the group’s previous work (1) involving human patients and computer cursor movements, and (2) non-human primates and robotic arm control.  So, this “next step” was anticipated, and in fact larger trials (involving various groups) are being initiated to investigate brain-based neural interface systems to drive the DEKA arm in subjects with limb loss (i.e. absent CNS damage/deficits).

The most compelling features to me were the decoding/training algorithm and the fact that one of the patients had her micro-electrode array implanted 5 years earlier.

Decoding/training: The use of signal filtering/thresholding in combination with open-loop (imagining and watching movement) and closed-loop (controlling the arm with visual feedback) recording/training was innovative and relatively efficient (31 min). However, in each case, the subjects had worked controlling arms previously (over years for S3 and 3 trials for T2).

A major challenge with recording ensemble neuronal activity in the motor cortex (or anywhere in the cortex) is signal attenuation and drift over time; so, each day/session typically requires re-training and re-calibration.

I would be curious to see how the subjects did in other independent trials – perhaps visual feedback can allow the user to “correct” the cortical inputs and hence reduce movement errors more rapidly in subsequent trials.  Nonetheless, it is remarkable that the subjects were able to manipulate the arm and drive it in a controlled and useful manner in a relatively short amount of time.

5 years: using an electrode array implanted 5 years earlier to control the robotic limb is very impressive.  The finding bodes well for the potential of this brain-based approach to yield useful cortical data chronically.

A major challenge is that over time the brain gradually rejects these non-organic electrodes, causing a build up of micro-scar tissue around the electrodes and a decreased neuronal density in the vicinity of the electrodes.

This process is partly due to mechanical mismatch between the electrode the brain causing inflammatory “micro-motion”.  This is likely exacerbated by subject motion/walking, which would not be an issue with the patients in this study but will be for the amputee study.

Nonetheless, this study noted “lower spike amplitudes and fewer contributing (active) channels” compared to earlier years, which is consistent with micro-scar tissue and fewer neurons close to electrodes.

Although this work is a natural next step, I do not want to trivialize the supreme competence, technical savvy, and attention to detail necessary to pull this off.  This group is highly competent and has the experience and skill to execute this very complex and multi-faceted neural engineering project to assist chronically disabled patients.

Reference

ResearchBlogging.orgHochberg, L., Bacher, D., Jarosiewicz, B., Masse, N., Simeral, J., Vogel, J., Haddadin, S., Liu, J., Cash, S., van der Smagt, P., & Donoghue, J. (2012). Reach and grasp by people with tetraplegia using a neurally controlled robotic arm Nature, 485 (7398), 372-375 DOI: 10.1038/nature11076

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AACR 2012: Promising CML & PI3K compounds from Indian company Piramal Healthcare

India to me conjures up thoughts of curry, cricket and call centers.  When I think about the Indian pharmaceutical industry, global manufacturers of generics such as Ranbaxy, Natco and Dr Reddy’s Laboratories come to mind.

What I don’t associate India with, is pharmaceutical drug discovery and the development of new drugs.

Pharmaceutical R&D is not only expensive, but requires a high-degree of expertise and comes with a high risk of failure.

Companies in the United States, Europe and Japan still develop most new drugs.

However, that may change in the future as the emerging economies in Brazil, Russia, India and China (BRIC) start to fund innovation and invest in drug discovery.

If we expect the economies of the BRIC group of countries to overtake the economies of the G-6 countries in the next 40 years, then it’s likely they will start developing their own pharmaceutical drugs.

Early signs of this were on show at the recent annual meeting of the American Association for Cancer Research (AACR) in Chicago.

Piramal Healthcare, part of an Indian conglomerate with $900 million of turnover in FY2011, presented four posters at the meeting on promising early-stage drug development compounds, including:

  • P7170, a Phosphoinositide 3-Kinase (PI3K)-mammalian Target of Rapamycin (mTOR) and Activin Receptor-Like Kinase 1 (ALK1) inhibitor.
  • P2745, an orally bioavailable molecule effective in imatinib resistant chronic myeloid leukemia cell lines including those with the T315i mutation.

P2745 is currently in Phase 1 drug development in India, and could be a potential competitor to Ariad’s Ponatinib in relapsed/refractory CML, given that it also inhibits the T315i mutation.

A few days after the AACR annual meeting, Piramal announced that they had acquired the molecular imaging portfolio of Bayer Pharma AG, including the rights to Florbetaben, a PET tracer for the detection of beta-amyloid plaque, a hallmark of Alzheimer’s disease.

The first presentation of the phase III trial results for florbetaben will take place tomorrow in the emerging science session at the annual meeting of the American Academy of Neurology (AAN) in New Orleans.

Piramal estimates the global market potential for PET imaging agents for Alzheimer’s disease to be $1.5 billion.

“We plan to build a promising portfolio in the pharma space, including our newly acquired Molecular Imaging assets, which will help us create a global branded pharma business”

said Ajay Piramal, Chairman of the Piramal Group in a press release.  The rise of the Indian pharmaceutical industry looks set to continue.

AACR 2012: Future is combinations of novel cancer agents

A standing room only audience at the recent annual meeting of the American Association for Cancer Research (AACR) heard from several distinguished speakers on what the future of cancer drug therapy is likely to look like: combinations of novel cancer agents.

This AACR session was one of the highlights of the meeting and would have merited from being part of the plenary program.

Jeffrey Engelman from MGH persuasively presented on why we need combination therapies to overcome resistance. He noted that:

  • Most cancers are not sensitive to currently available single-agent therapies
  • Even when sensitive to single-agent therapies, cancers develop resistance, often necessitating combinations

One of the challenges of this approach will be “identifying effective combinations,” he said.

Roy Herbst from Yale, presented on some of the practical challenges involved with the early phase testing of two drugs, and challenged the audience with a critical question:

“Do we possess the necessary translational tools that will help us identify the right drug combinations, ratios and schedules with the right patient?”

Stuart Lutzker from Genentech described their experiences of clinical trials with rational drug combination of trastuzumab and pertuzumab for HER2+ breast cancer.  He concluded that:

“Rational drug combinations have begun to yield exciting Phase III results and should be preferred over empiric drug combinations.”

The Pharma Strategy Blog video interview with Gordon Mills from ECCO/ESMO 2011 in Stockholm offers some interesting insights into how MD Anderson are helping to facilitate academia-industry combination trials with novel compounds from different companies in order to achieve more rational drug design and improve outcomes for people with cancer.

http://youtu.be/FXkcSry6EtQ

If two or more novel cancer drugs are required to interrupt key pathways or to avoid adaptive resistance, what does this mean for the regulatory strategy?

Janet Woodcock addressed some of these challenges in her AACR presentation, and discussed how the:

“FDA would not want to approve a combination regimen with two new agents unless each contributed to the effect.”

Draft guidance on “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination” was published by the Agency in December 2010. Click here for a PDF copy.

The document gives examples of a number of different phase II trial designs that can be used to demonstrate the contribution each drug makes to the combination, and the additive effect seen.

As an example, if each drug in a combination has activity and can be administered individually then the guidance document suggests a multi-arm phase II trial may be needed that compares the impact of either drug alone versus the combination and standard of care.  An adaptive trial may also be used if appropriate.

Dr Woodcock noted that future cancer drug development is likely to include increasing use of combinations, adaptive trials to evaluate various drug and diagnostic combinations and increasing attention to the use of novel biomarkers.

The message I took home from the AACR annual meeting is that the future of cancer therapy is in combinations, and we can expect more clinical trials with two unapproved agents (novel-novel combinations) in the future.

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