Hope for an Alzheimer’s breakthrough remains despite Dimebon's failure

On March 3rd we highlighted a press release issued by Medivation/Pfizer announcing that a Phase 3 study of Dimebon in Alzheimer's disease had failed to meet any of its clinical endpoints, despite high hopes of the drug after promising Phase 2 results. This is a significant setback for Dimebon's developers, particularly Medivation, however as recently discussed in our recent feature, Pipeline Insight: Alzheimer's Disease, there remains significant hope for the millions of Alzheimer's sufferers and their caregivers in the pipeline.

On March 3, Medivation and Pfizer announced that its big hope for Alzheimer's disease, Dimebon (latrepirdine; Medivation/Pfizer), failed to achieve clinical benefit over placebo in one of its pivotal Phase 3 trials. In the trial, dubbed the CONNECTION study by the company, investigators were unable to demonstrate that Dimebon significantly slowed the progression of the disease based on any of the five commonly used endpoints. Speaking in a press conference, Medivation's CEO David Hung stated: "The outcome of the trial was unexpected, and is obviously a major disappointment, especially for Alzheimer's patients and their caregivers."

The result certainly comes as a surprise to those tracking the progress of the drug. The CONNECTION data stand in stark contrast with positive Phase 2 results released in 2006, which served to greatly raise expectations of what was purported to be a future blockbuster for Alzheimer's disease. Indeed, on the strength of these data, Dimebonhad previously been forecast to achieve annual sales of around $5 billion in the seven major markets by 2018, placing it as one of the biggest-selling drugs at this time.

Early analysis of the CONNECTION data suggests that the placebo response was greater than that previously seen and that Dimebon showed 'a materially weaker response'. The study results, drawn from 598 participants across the US, Europe and Latin America, contradict those from the preceding Phase 2 trial, which involved 183 patients in Russia. These Phase 2 data were so encouraging that they were published in the July 2008 issue of the Lancet (Doody et al).

However, even before the CONNECTION data were revealed, some experts were skeptical of the outcome of the Russian trial. In its press announcement for the Phase 3 trial, Medivation conceded that the Russian results may have been limited by the small sample size, the involvement of just one geographical location and the use of only one language to communicate disease severity.

In June of 2009 we featured a report Emerging Clinical Trial Locations Eastern Europe which focussed on decision by the the biopharmaceutical industry to reduce costs by conducting clinical trials in what are referred to as the emerging markets. This report analyzed implications and factors which need to be taken into consideration when conducting clinical trials in Eastern Europe. The discord between Phase 2 study data and CONNECTION highlights one negative aspect of off-shoring trials. According to another recent report Global Clinical Trial Business Report & Analysis 2008-2018 the global clinical trials business was worth $50bn in 2008, with a growth of rate of 10%. Broadly we ask what affect CONNECTION will have on this market.

For the moment however it is time to focus on Dimebon. Despite the reservations of Medivation many remained highly encouraged by the Phase 2 data and regarded Dimebon as one of the most promising candidates in late-stage development for Alzheimer's disease. Indeed, Pfizer's decision to in-license the drug at such a high cost is testimony to these high hopes.

Medivation will face a rough patch, though it is not yet over for Dimebon

Medivation has suffered as a result of Dimebon's failure, with its share price plummeting by 68% to $13.04 from an all-time high of $40.49 only the day before the announcement. With future milestone payments and royalties hanging in the balance and no products currently on the market, Medivation has undoubtedly suffered a major blow. However, although the CONNECTION results are certainly a setback, they do not necessarily spell the end for Dimebon. The company is expected to now pin its hopes on additional Alzheimer's trials already underway such as CONCERT and CONTACT as well as Dimebon's secondary indication in Huntington's disease, for which it is currently in Phase 3 development in the HORIZON trial.

If the currently ongoing Phase 3 trials also fail, Pfizer, which signed a collaboration deal with Medivation in September 2008 and has since co-developed the drug, stands to lose most or all of the return on its large investment. The company's initial upfront payment to Medivation was $225m, one of the largest of its type in recent years. Still, the CONNECTION setback is limited somewhat by Pfizer's existing presence in the Alzheimer's marketplace, through its market-leading compound Aricept (donepezil) and the extensive portfolio of pipeline candidates which it inherited following the acquisition of Wyeth.

One positive to come out of the failure is that there will not be significant ramifications for other drugs in development for Alzheimer's disease. We have featured the Alzheimer's pipeline in recent months (see Pipeline Insight: Alzheimer's Disease). The area is characterized by high risk and high reward. At the time of publication Dimebon and Johnson & Johnson/Wyeth's bapineuzumab were forcasted to reach blockbuster status. As discussed in the report, within the current pipeline, Dimebon is unique in its mode of action. The drug is a small molecule mitochondrial permeability transition pore (MPTP) blocker, as well as an NMDA receptor antagonist and cholinesterase inhibitor. Unlike Dimebon, the majority of the other pipeline candidates are targeted towards the hypothesized Alzheimer's disease etiology. Drug developers' focus has shifted from neurotransmitter replacements to biological agents that affect beta-amyloid and tau protein, both hallmarks of the disease. The next eagerly awaited compound for which Phase III results will be announced is likely to be bapineuzumab (Johnson & Johnson/Pfizer), a humanized monoclonal antibody for beta-amyloid. However, given the high attrition rate in the pipeline, expectations will be tempered.

As other markets stall, the high risk/high reward of Alzheimer's is tempting

There remains an enormous unmet need in the treatment of Alzheimer's disease. For the millions of elderly people worldwide, there are just four drugs available to them that can only offer a modest symptomatic effect. Even so, these treatments cannot slow or modify the course of this neurodegenerative disease, which is the ultimate goal in Alzheimer's therapy. However, despite this need, drug developers have struggled to get new agents to market and the pipeline over the past 10 years is littered with late-stage failures. Indeed, excluding reformulations, no new drugs have launched for Alzheimer's disease since Namenda (memantine; Forest/Merz/Lundbeck) arrived in 2002. Since then, around 20 products have failed Phase III trials.

With this in mind, then, the news about Dimebon may not be such a surprise after all. It is, of course, a big disappointment to those in the Alzheimer's community, but the future looks bright. As other core therapy markets become less profitable, both major pharmaceutical and biotech firms are increasingly looking to the huge potential of the untapped Alzheimer's disease market. Investment into Alzheimer's drug R&D continues to grow exponentially and, ultimately, this is the best news for sufferers: it is only a matter of time before an effective therapy arrives.

Related research

• Pipeline Insight: Alzheimer's Disease - The ultimate high-risk, high-reward therapy market priced ($11,400 August 2009)
• New Approaches to Pharma R&D: Evolving strategies to rejuvenate R&D efficiency priced ($5,700 May, 2009)
  
• Pipeline Insight: Mild Cognitive Impairment - Unlocking the potential of prodromal Alzheimer's disease and beyond ($11,400 April 2009)
  
• Updates-Plus-Nicotinic Receptors (Monthly intelligence service)
  

Avandia's MammaScreen - Answering the question of how to treat small tumours in breast cancer patients

As reported in our recent feature "Breast Cancer - Targeted Therapies, New Cytotoxics and Vaccines" the incidence of breast cancer in the seven major markets is close to 0.5 million, while over 100,000 women will die from the disease. Despite advances in treatment over the past decade, significant unmet needs remain. This level of demand and the large patient potential makes breast cancer a relatively attractive indication for drug developers. Collectively, late-phase pipeline candidates are forecast to achieve $2,230m in sales in 2017 in the seven major pharmaceutical markets.

There are over 100 drugs in clinical development for breast cancer. These are primarily targeted therapies and cytotoxics. Unlike cervical cancer (see our earlier editorial Advaxis lights up the future for cervical cancer ) therapeutic vaccines account for just a small part of clinical development . Importantly, the majority of clinical trials of drugs in late-phase development for breast cancer are in the metastatic setting. This reflects the higher level of unmet need, lower bar to market entry and shorter trial completion time as compared with the adjuvant or neoadjuvant treatment setting.

In addition to developing improved treatments, better diagnostic and prognostic tools are equally required. For example, primary tumor size, in addition to axillary lymph node status, is considered to be one of the most important prognostic factors in breast cancer, with small tumor size being an indicator of good prognosis. However, even small tumors can metastasize. Predicting which patients with small tumors will metastasize represents an unmet need that will likely be addressed by advances in the field of molecular diagnostics.

Another of our featured reports "Molecular Diagnostics in Cancer Testing" describes this rapidly-advancing area. New technologies and applications are being continually added. The technologies that come under the umbrella of molecular diagnostics include first-generation amplification, DNA probes, fluorescent in-situ hybridization (FISH), second-generation biochips and microfluidics, next-generation signal detection, biosensors and molecular labels, and gene expression profiling using microarrays.

Together the global in vitro diagnostics market generated sales of over $40bn in 2008. The market will generate nearly $60bn in 2014. One diagnostic tool described in"Molecular Diagnostics in Cancer Testing" is Agendia's MammaPrint. This prognostic tool was cleared by the FDA in 2007 to predict breast cancer recurrence.

Specifically MammaPrint provides a unique 70-gene signature to identify which early-stage breast cancer patients are at risk of distant recurrence following surgery, independent of Estrogen Receptor status and any prior treatment. Unlike previous generation genomic tests, MammaPrint interrogates all of the critical molecular pathways involved in the breast cancer metastatic cascade. It analyzes 70 critical genes that comprise a definitive gene expression signature and stratifies patients into two distinct groups — low risk or high risk of distant recurrence.

Breast cancers are staged according to the absence (N0) or presence (N1-3) of nodal involvement and the size of tumor. MammaPrint has previously demonstrated prognostic power according to nodal involvement. Today's featured journal article from the Annals of Surgical Oncology report on the prognostic ability of the MammaPrint signature specifically in patients with small invasive tumours. This is particularly important given that the number of patients presenting with such tumors is expanding in parallel with breast cancer screening programs and increased awareness

The study reported by Mook et al took a retrospective look at 964 breast cancer patients, 14% of whom had a pT1ab tumor (primary; 0-1cm), 86% had a pT1c tumor (1-2cm). The majority of patients were node negative. During follow-up 154 patients developed distant metastases. The probability of metastasis-free survival at 10 years was 90% and 86% for pT1ab and pTc patients classified as low risk compared to 76% and 72% classified as high risk. Simply put, the chance of metastasis-free survival at 10 years was increase 2.5-3.5-fold in the low risk group.

Among the 964 patients 57% received no adjuvant systemic therapy while almost all of the others received endocrine- and/or chemotherapy. The prognostic ability of MammaPrint was similar irrespective of therapy.

So what do these data mean? Mammograms have come under significant criticism over the past few years for a number of reasons. Firstly, false-positive results from mammograms expose women to unnecessary biopsies. Secondly, there is the issue of how to medically manage women who have been diagnosed with breast cancer following screening. The issue is particularly troublesome in those individuals with small tumours as treatment guidelines are vague for T1 stage disease. The present study demonstrates the significant benefit of MammaPrint; specifically it can identify those women who are at high risk and may require more aggressive adjuvant chemotherapy and likewise those at lower risk who may gain protection from endocrine therapy without suffering the adverse events of chemotherapy. Mammograms are undeniably useful; we hope that MammaPrint will address some of the criticism screening has attracted and contribute to the overall advance of breast cancer management.

See also:

• In Vitro Diagnostics Market Analysis 2009-2024
• The Worldwide Market for Cancer Diagnostics
• Cancer Diagnostic Testing World Markets
• Molecular Diagnostics in Cancer Testing