Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘drug development strategy’

One of the most interesting sessions I attended at this year’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago was the Clinical Science Symposium (CSS) on the next generation of EGFR inhibitors.

We’ve previously written on the blog about the data for AZD9291 and CO-1686 presented at ASCO, but the CSS also featured an informative discussion by Larry Schwartz, MD, Professor of Radiology at Columbia University Medical Center which raised questions about how we should evaluate new lung cancer drugs.

In a presentation entitled, “Getting the Right Drug to the Right Patient Faster,” Schwartz who is a diagnostic radiologist, discussed and critiqued abstract 8012 by Gideon Michael Blumenthal and colleagues at the U.S. Food and Drug Administration (FDA).

Larry Schwartz ASCO 2014

A meta-analysis of fifteen trials involving 12,534 patients (median N = 698) from nine experimental agents (tyrosine kinase inhibitor = 5, chemotherapy = 2, monoclonal antibody = 2) submitted to the FDA for treatment of metastatic non-small cell lung cancer (NSCLC) cancer in initial or supplemental New Drug or Biologics License Applications since 2003 was performed by Blumenthal and colleagues.

Their analysis showed a strong correlation (R² of 0.89) between overall response rate (ORR) and progression-free-survival (PFS) but only a weak or no correlation between ORR and overall survival (OS) (R² of 0.07) or between PFS and OS (R² of 0.09).

Dr Blumenthal noted in his conclusion that further work is ongoing to corroborate these findings given the lack of correlation between OS and ORR could have been due to high cross-over, under-power and long post-progression survival.

He went on to note that what the findings do show is that “a drug with a large effect on ORR is likely to have a large effect on PFS, conversely a drug with a small ORR may have a small effect on PFS.

The debate around objective response and outcomes is a very interesting one, as is the drive to find better biomarkers of response to improve chances of clinical trial success.

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The FDA approval earlier this week of ibrutinib (Imbruvica) for the treatment of mantle cell lymphoma (MCL), and the recent approval of GA101 / obinutuzumab (Gazyva), for previously untreated chronic lymphocytic leukemia (CLL) is good news for patients.

The forthcoming annual meeting of the American Society of Hematology (ASH) in New Orleans (Dec 7 – 10, 2013) is set to be an exciting event with the launch of new products to treat blood cancers.

Both ibrutinib in MCL and obinutuzumab were granted “breakthrough therapy” designation (BTD) from the FDA. Over the past several months I have been researching what a BTD may mean for cancer drug development.

The catchy “breakthrough” title has given companies and the FDA a noticeable bonanza of good PR, but there’s been a paucity of critical analysis by the media. I have yet to see a convincing argument that that there was a compelling need for a new approval pathway for cancer drugs, or that innovative and breakthrough cancer drugs such as imatinib (Glivec/Gleevec) and crizotinib (Xalkori) could have got to market any faster.

One of the key FDA decision makers is John K. Jenkins, MD, Director, Office of New Drugs in the Center for Drug Evaluation and Research (CDER); he’s Richard Pazdur’s boss. I had the privilege to conduct a phone interview with him over the summer.

In my first post from this interview, subscribers to Premium Content will obtain Dr Jenkins’ perspective on what constitutes a breakthrough? If you are an investor you want to try and predict what may be a “breakthrough” before it becomes one…

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.

Drug Development Pipeline

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.

Cost of Sequencing Human Genome

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.

NIH Drug Repurposing Table

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.

The video below is well worth watching:

San Francisco – “Translational research is the key to successful drug development” according to William N. Hait MD, PhD, global therapeutic area head of oncology, Johnson & Johnson.

Hait presented a plenary session on “overcoming barriers to new drug development” at the recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference in San Francisco.

How do we define translational research?

The definition Hait most likes is from Duke Ellington: “if it sounds good, it is good

The challenge of drug development is that with rare exceptions the process is slow, inefficient and expensive.

Hait outlined several challenges to translational research, including:

  • Complexity – imagine blocking the traffic in mid-town manhattan. If you blocked one cross-town route, traffic would slow and then find another route.

This in my opinion is a good visual metaphor for the cross-talk that occurs in cancer. Block one target, and the cancer finds another route.  This highlights the need for combination therapy.

rational combinations of targeted agents may require studying two or more unapproved agents” said Hait.

Novel-novel combinations are something that many companies are nervous about, but if there is a solid scientific rationale then this is something I think we will see more companies doing.

For further insight into how academia is facilitating this type of combination trials, I recommend Sally Church’s interview on Pharma Strategy Blog with Gordon Mills at ECCO/ESMO in Stockholm.

  • Inaccuracy of preclinical models – our models don’t always predict preclinically what activity a drug will have in the clinic.
  • Efficacy of Clinical Trial Recruitment  – need to have alignment of incentives. 20% of US patients are eligible for clinical trials, but only 3% participate.
  • Developing Biomarkers.  Difficult to obtain serial biopsies for oncology biomarker analysis.  Circulating tumor cells may be future, but current instruments can only capture and enumerate and offer limited characterization. According to Hait, the next–generation platform will be exciting.  It will allow third parties to offer additional functionality that can be integrated with the platform.
  • Drug resistance – a nemesis that just doesn’t want to go away.
  • Overcoming the Regulatory Environment – challenges include: scientific complexity, endpoint consistency, global harmonization, companion diagnostic tests, proper comparators, equipoise.

In spite of this complexity, Hait noted the FDA approved 34 new drugs in 2011. Several cancer drugs had a short time from submission to approval and met their PDUFA target date.  “These are incredible accomplishments,” he said.

  • Market Access – Hait asked the audience: “Would you buy a Porsche 911 that only works for 20% of the people, but we don’t know if you are one of the 20%?” Healthcare authorities need to decide cost/benefit of drugs, and regulatory approval does not automatically mean a new product will be reimbursed. There may be need for future trials with health comparators, or innovative agreements where the healthcare authority only pays for those patients who respond.
  • Workforce – academic physicians may end up being segmented into three groups: master clinicians, clinical investigators, physician-scientists. This may provide better career development than the current system.

Hait offered a few suggestions for improvement:

  • Move to phenotypic screening rather than target-based screening. In vivo shRNA screening was discussed.
  • Disease based drug discovery teams – the hope is that in-depth focused teams will predict better results.
  • More intense academic-industry collaboration with a focus on complementary expertise.

The limitation of this plenary presentation was that it only offered the perspective of one senior industry professional. I would have welcomed a balance of views on the barriers to new cancer drug development, and more focused take-home solutions.

If you want to hear more on this topic, AACR have a free podcast that you can download of an interview they did with Dr Hait at the Molecular Targets meeting.

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San Francisco – the AACR-NCI-EORTC international conference on Molecular Targets and Cancer Therapeutics kicked off last Saturday with two educational sessions, including one that I attended on “Clinical Trial Paradigms in the Era of Novel Therapies.

The session had an impressive line-up of speakers:

  • New paradigms for early-phase trials (James Doroshaw)
  • Phasing out phase III trials: How much evidence do we need if the target is clearly hit? (Jaap Verweij)
  • Development of clinical trials incorporating genomic signatures: Lessons learned? (Lisa McShane)
  • Clinical trial designs for targeted therapies (John Crowley)

James H. Doroshow, deputy director for clinical and translational research at the National Cancer Institute, started his presentation by reviewing the causes of phase II trial failure:

  • 19% Safety
  • 51% Efficacy
  • 29% Strategic

He stated that the overall success rate of recent phase II trials was 18%.

As the debate continues about whether more cancer clinical trials should be done in Phase 2, the key issue according to Doroshow remains lack of a demonstrable proof of mechanism (POM) in many drug trials. That goes hand-in-hand with a lack of molecular markers which can be used to select trial subjects.

“Lack of molecular markers with proven clinical utility follows lack of clinically-demonstrable proof of mechanism”

He provocatively asked:

Should we perform early phase trials without generating evidence supporting POM patient by patient?

His view was that to obtain POM, you need to demonstrate drug action on intended tumor target early in development, prior to expectation of efficacy.

Jaap Verweij in his presentation used the examples of crizotinib, vismodegib, vemurafenib and imatinib in GIST as examples of drugs that had:

  • functionality for a target
  • aimed at a specific population
  • availability of a selection marker.

They are the poster children of targeted therapy, and he convincingly showed that the phase 1 trials of those compounds were largely predictive of the phase 3 results.

His conclusion was that phase I trial can be considered predictive of a phase III study so long as there is a large enough sample size.

We may need to look for bigger increments which should allow us to perform smaller trials,” he said. This would allow trials that are quicker and cheaper. However, he acknowledged that it was not likely we can completely eliminate phase 3 trials particularly for combination therapies or chemotherapies.

John Crowley reviewed the different phase III trial designs, including my least favorite, the “all comer” design.  The ridaforolimus sarcoma phase 3 trial presented at ASCO this year is a good example of how an “all comer” design yielded less than stellar results, and failed to identify the subset of sarcoma patients that optimally respond.  This is the type of phase 3 trial that runs the risk of failure if there are too many non-responders in the heterogeneous patient population.  This problem can often be avoided by more rigour in phase 2 trials to identify the optimal treatment period, relevant biomarkers and subsets of patients most likely to respond.

There is a lot of interest in how to design cancer clinical trials better, bring drugs to market more quickly and more efficiently.  While I enjoyed the content of this session, I did wonder whether it would have been better presented as a roundtable with more audience interaction and engagement rather than the perspective of a few.

A webcast of this session will be available on December 8 from the American Association for Cancer Research (AACR).

Academic institutions are now bringing pharma/biotech companies together and facilitating rational combination trials that make solid scientific sense.

Combining at least two targeted drugs looks to be increasingly necessary in order to develop innovative new cancer treatments, where turning off one target may stimulate another, thus both need to be targeted for there to be an overall effect.

However, one company may not have all the pathways and drug targets covered by their portfolio.  The result is that companies may have to work together in combination trials with each providing one drug from their portfolio.

That was one of the key messages I took from Gordan Mills (UT MD Anderson Cancer Center) in his recent video interview with Sally Church from Pharma Strategy Blog:

Sally Church’s video interview with Professor Mills is well worth watching if you have not already done so.

Not only are universities and research institutions well placed to judge the scientific merits, but as Mills points out they can facilitate things as an independent third party and actively help bring partnerships together.  Given that combination therapies may be needed in order to turn off different parts of signaling pathways and cross-talk, I think we are likely to see more of this approach.

It’s going to be new territory for many companies – how to enter into a potential joint venture or alliance? However, if it results in a therapy that works, it is going to be win-win for all parties. It may also improve efficiency in drug development and lead to better use of patients in early stage development.

Some examples of where this is happening already in oncology include AstraZeneca and Merck with their MEK-AKT approach and GSK (MEK) with Novartis (PI3K), to name a couple.  This is a new trend we are likely to see more of in the future.

I can see universities hiring alliance managers who have industry experience to ensure these collaborations run smoothly.

The topic of the industry/academia interface in rational cancer drug development will also be discussed in a plenary session at the forthcoming American Association for Cancer Research (AACR) meeting on Molecular Targets and Cancer Therapeutics (November 12-16, 2011) in San Francisco.

How academia can better help the pharma/biotech industry bring innovative, rational drug combinations to market is a topic that I think we will be reading more about in coming months.

In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease.  They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

  1. It is still early-stage preliminary research on a small group of subjects.
  2. The exact function of ubiquilin 2 is not well understood.
  3. Not all ALS patients have the UBQLN2 mutation
  4. If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
  5. UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

ResearchBlogging.orgDeng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source:  LA Times & Fierce Biotech

Nanotechnology is set to have a major impact on drug development and new products for the diagnosis and treatment of cancer.  Research from UCSF and Northwestern University published earlier this year in “Science Translational Medicine” shows this potential.

Edward Chow and colleagues describe how binding the cancer chemotherapy doxorubicin (DOX) to carbon nanoparticles 2-8nm in diameter in the form of a diamond, “nanodiamond” (ND), improved drug efficacy and overcame drug resistance.  Although this pre-clinical animal research has not yet been confirmed in humans, it raises the possibility of more efficient chemotherapies and the hope of increased survival rates as a result.

The conclusion from this research is that nanodiamonds may be a viable drug delivery platform for small molecules, proteins and nucleic acids. This technology could have an application in wide range of diseases.

Why is nanoparticle-mediated drug delivery more effective? The paper suggests one reason is that the nanodiamond-doxorubicin complex (NDX) allows for a more gradual release of DOX, allowing for increased tumor retention and increased circulation time.

It’s important to note that the NDX complex does not specifically target the drug efflux pumps, such as MDR1 and ABCG2 transporter proteins, responsible for chemoresistance. Instead the NDX complex appears to overcome drug resistance passively by the way DOX is released from the nanodiamond.

This research shows that taking old drugs and combining them with new drug delivery technology may offer therapeutic benefits.  The authors conclude that this research, “serves as a promising foundation for continued NDX development and potential clinical application.”

If successful in humans, it will translate into new product development and market opportunities for emerging biotechnology and biopharmaceutical companies.

 

ResearchBlogging.orgChow, E., Zhang, X., Chen, M., Lam, R., Robinson, E., Huang, H., Schaffer, D., Osawa, E., Goga, A., & Ho, D. (2011). Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001713

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