Study supports aggressive use of atorvastatin (Lipitor)

The antidyslipidemics market is driven by the statins, which account for 87% of this segment. However, as many statins are expected to face patent expiry in the coming decade manufacturers are looking to novel products to protect their franchise. Such products include combination such as Pfizer's atorvastatin/torcetrapib. For further information on the future of antidyslipidemics see our recent features:

• Antidyslipidemics markets
• Dyslipidemia - Statins Dominate Treatment Pathway
• Pipeline Insight: Antidyslipidemics

Another trend in the antidyslipidemics market is the move towards more aggressive therapy (ie multiple agents; higher doses; prolonged treatment; broader use etc). Atorvastatin (Lipitor), which has been approved at 10, 20, 40 and 80mg, has been shown to reduce coronary events and revascularization procedures in patients with multiple risk factors for coronary heart disease. Recent studies with atorvastatin 80 mg support the overall safety of this dose during long-term treatment. However, physicians appear reluctant to use high doses of statins.

Today's edition of LeadDiscovery's DailyUpdates service (29th March, 2006) features a journal article that presents the results of a retrospective analysis of pooled data from 49 clinical trials of atorvastatin in 14,236 patients.

The study found that similar numbers of patients experienced at least 1 adverse event whether they were treated with placebo, atorvastatin 10 mg or atorvastatin 80 mg. Withdrawals due to treatment-related adverse events were also similar. Treatment-associated myalgia was not different between the two doses while no cases of rhabdomyolysis were reported in any group. Persistent elevations in hepatic transaminases was observed in 0.1%, 0.6%, and 0.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. The study authors conclude that atorvastatin 80 mg has a positive safety profile.

According to Datamonitor, responsible for the publication of the features mentioned above, sales of Lipitor across the seven major markets are expected to reach $12.4 billion in 2006.

Moreover, Dr Duncan Emerton, senior cardiovascular analyst at Datamonitor, predicts that greater uptake of atorvastatin 80mg would increase Lipitor revenues for Pfizer due to its higher price. "Recent positive clinical trial data from the ASTEROID trial for AstraZeneca's rosuvastatin (Crestor) has had a huge impact on uptake of Crestor in the US in a very short space of time. As such, this data has the potential to positively impact sales of Lipitor due to migration of current lower-dose Lipitor users to the higher, more expensive dose. As to whether or not this data is sufficiently robust to cause physicians who currently prescribe other statins to migrate to high-dose Lipitor, my gut-feel is that Pfizer will see negligible migration from the competition due to physician and patient familiarity with other statins and no real compelling reason to switch."

Diagnosing acute congestive heart failure

Heart failure affects more than 5 million people in the U.S. , and 550,000 new cases are diagnosed each year. It is the most common cause of hospitalization in people older than 65 years of age. Approximately 20% of hospitalizations are due to acute congestive heart failure translating into a health-care system cost of $15 billion.

The condition, which can develop as a complication of acute myocardial infarction or as an acute exacerbation in patients with previously compensated chronic heart failure, requires effective diagnostics and improved therapeutics options. As discussed in our recent feature “Chronic and Acute Heart Failure” the late-stage heart failure pipeline is weak in terms of quantity and quality, with almost all candidates being in Phase I and II of development, and the majority of these are being developed for acute heart failure. Thus it is likely that patients will continue to receive current standards of care, primarily anti-diuretics, for the foreseeable future, although ADHERE, the largest registry of acute chronic heart failure patients has made a number of important advances such as underlining the benefits of rapid initiation of vasoactive therapies.

Given the paucity of the pipeline for acute congestive heart failure, the best hope of clinical improvement will involve improved utilization of existing therapies. For example, early initiation of vasoactive therapies can half mortality rates and reduce the need for transfer to ICU/CCU by 80%. This together with a reduction in hospital stay time means that better and earlier uptake of vasoactive therapies will dramatically lower the health-care burden. However early intervention requires rapid and accurate diagnosis. Molecular markers are particularly important for the diagnosis of cardiovascular disease driving a large market in this area (see Cardiac Marker Diagnostic Tests Markets). The measurement of natriuretic peptide levels has driven a significant component of the cardiac molecular diagnostics market.

B-type Natriuretic Peptide (or BNP), also referred to as brain natriuretic peptide, was first identified in 1988. The heart is a major source of circulating BNP which is activated by ventricular distension due to increased intracardiac pressure and is an excellent hormonal marker of ventricular systolic and diastolic dysfunction. BNP levels are related to the severity of signs and symptoms of heart failure and are able to differentiate heart failure from other conditions manifested by dyspnea, one of the primary presenting symptoms of acute heart failure, such as COPD. This is of importance since it can be difficult to distinguish between the two conditions and the use of therapeutics typically used to treat COPD can exacerbate heart failure.

Given its diagnostic potential, the measurement of plasma BNP as an aid in heart-failure diagnosis was approved by the FDA in 2000 and at the time it was suggested that measurement of BNP levels should be part of the diagnostic approach to patients with suspected heart failure. Several BNP assays are now commercialized, including Abbott’s AxSYM; Bayer’s ADVIA; and Biosite’s TRIAGE platforms.

At the time of release from the cardiomyocyte, BNP is co-secreted along with a biologically inert amino-terminal fragment (NT-proBNP) and in 2002, the FDA cleared a NT-proBNP laboratory test for diagnosing congestive heart failure. Sales of assays based on NT-proBNP have overtaken those based on BNP. The leading NT-proBNP diagnostic is Roche Diagnostics’ Elecsys proBNP which has propelled Roche to pole position amongst suppliers of cardiac biomarker assays. In 2005 global sales of Elecsys proBNP reached $760 million. In addition, based on the same antibodies as the Roche proBNP assay, there are now two other NT-proBNP assays either on the market (Dade-Behring) or soon to arrive to market (Ortho Clinical Diagnostics).

Earlier this year James Januzzi and colleagues published the results of a major study including data from four sites in three continents confirming the utility of NT-proBNP as an indicator of acute congestive heart failure (Eur Heart J. 2006 Feb;27(3):330-7). Data recently presented at the AHA suggested that NT-proBNP and BNP have similar accuracy for predicting heart failure in patients; however, NT-proBNP is a better predictor of mortality. This latter point is important since it may allow better identification of high risk patients and thus selection for more intensive monitoring.

Despite the utility of NT-proBNP as a marker of heart failure, the influence of medical illnesses that raise concentrations of NT-proBNP other than heart failure should be considered. In particular, chronic renal disease is associated with increased NT-proBNP levels. It is possible therefore that a patient with chronic renal disease who presents with dyspnea could be falsely diagnosed as having chronic heart failure on the basis of high NT-proBNP levels due to reduced clearance. On the other hand it is possible that already elevated levels due to renal failure are not increased further by co-morbid heart failure. These potential problems are not trivial since a large number of heart failure patients also suffer renal failure. A second study conducted by Januzzi and colleagues and highlighted in the March 28th edition of DailyUpdates thus analyzed data from the PRIDE study, specifically with the aim of evaluating whether NT-proBNP can accurately identify acute congestive heart failure in dyspneic patients across a range of glomerular filtration rates.

As expected, the study demonstrated a significant inverse relationship between renal function and NT-proBNP values in dyspneic patients with and without acute congestive heart failure. However, this relationship was suggested to reflect the presence of underlying structural heart disease and increased plasma volume in patients with chronic kidney disease rather than simply reduced clearance. Furthermore, the study concluded that NT-proBNP was useful for both diagnosing and excluding acute congestive heart failure across a wide spectrum of renal function (with results comparable with those reported for BNP). In addition, regardless of renal function, NT-proBNP maintained its exceptional value for estimation of short-term mortality in congestive heart failure.

A number of specific points are worth highlighting from this PRIDE analysis. Firstly, although NT-proBNP was increased with severity of renal dysfunction, levels were commonly below the cut points for ruling in congestive heart failure as defined in PRIDE. Secondly NT-proBNP levels were significantly higher in patients with congestive heart failure compared to those without across a broad range of glomerular filtration rates. Thirdly, ROC curves (a standard measure of accuracy in diagnostic tests) were not significantly different in patients with high and low glomerular filtration rates although the authors suggest that the cut point at which congestive heart failure can be diagnosed should be increased very slightly from 900 to 1200pg/ml. Notably, at optimal cut-points, the data for NT-proBNP compare rather favorably to those for BNP.This is of particular relevance, as the vendors of the various assays for BNP have been focusing on this topic as an area of possible advantage for BNP over NT-proBNP. The results from PRIDE not only show absolute parity for NT-proBNP with the diagnostic data for BNP from prior studies of patients with impaired renal function, but also extend the understanding of the role of natriuretic peptides in prognostication in those with impaired renal function as well, data that are not available for BNP.

Thus, in conclusion, NT-proBNP measurement is a valuable tool for the diagnostic and prognostic evaluation of dyspneic patients even in the presence of impaired renal function.

Cdk5 inhibitors as novel candidate analgesics

According to our recent feature Pain Therapeutics 2005 the value of the pharmaceutical market for pain relief approached $23 billion in 2004. The dynamics of the pain market have however altered greatly over the past few years, in particular as a result of the troubles surrounding the multi-billion dollar Cox-II class.

The pain market can be divided into acute pain which is well served by OTC medications (see The US Market for OTC Pain Medication), post-operative pain and chronic pain. One of the most complicated areas of analgesia is the treatment of chronic neuropathic pain. Combining treatment resistance and a poorly defined market, clinicians and pharmaceutical companies alike have found it difficult to approach the field of neuropathic pain. This is perhaps best highlighted by the success of Pfizer's gabapentin (Neurontin) which was largely used off-label as an analgesic. Gabapentin was originally approved by the FDA as an anti-convulsant for use in the treatment of epilepsy, and in 2003 it led the global anti-convulsant market with global sales across all indications of over $2.7 billion. It is however estimated that a significant proportion of gabapentin's sales are for neuropathic pain indications despite never receiving official approval for this indication in the US apart from postherpetic neuralgia.

Gabapentin remains the gold standard treatment to beat in the EU and US neuropathic pain markets, which were estimated at a combined total of $2.5 billion in 2005, reaching $4 billion in 2007. A number of recent events have altered the gabapentin market however. Firstly, in 2004 generic versions of the drug hit the market reducing sales of Neurontin by 77%. Secondly, in July, 2004, Pfizer won EU approval to market the follow-up to gabapentin, pregabalin (Lyrica) for the treatment of neuropathic pain and as an adjunctive therapy for partial seizures in patients with epilepsy. The FDA then approved pregabalin for the management of neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia in December 2004 (this was in addition to its approval as a treatment of epilepsy). Lyrica is expected to generate $0.9 billion in 2006.

Like gabapentin, pregabalin, a 3-substituted analogue of gamma-amino butyric acid (GABA) binds to calcium channels and modulates calcium influx as well as influencing GABergic neurotransmission. This mode of action translates into anti-epileptic, analgesic and anxiolytic effects. Because it is more potent than gabapentin, pregabalin achieves efficacy at lower doses. This increases its therapeutic index with respect to gabapentin and should lead to fewer dose-related side effects.

Currently, Pfizer’s main competition comes in the form of generic gabapentin and Lilly's duloxetine (Cymbalta), which entered the market as an antidepressant in August, 2004, and was also approved in September of that year as a treatment for diabetic peripheral neuropathic pain. The drug's sales during the first nine months of 2005 totaled $451 million and are projected to hit $1 billion by 2007.

While current opportunities for the treatment of neuropathic pain are largely limited to gabapentin, pregabalin and duloxetine, a large number of molecular targets are currently being evaluated in the lab and in early stage clinical trials (see our feature Pipeline Insight: Neuropathic Pain - Pipeline Drugs Fail to Nail Neuropathic Pain). Today’s edition of DailyUpdates (March 22^nd, 2006) highlights a PNAS study that advances Cdk5 inhibitors as novel candidates for the treatment of neuropathic pain.

Cyclin-dependent kinase 5 (Cdk5) is a unique member of the serine-threonine kinase family of cyclin-dependent kinases. This family is well known for its involvement in the cell cycle and Cdk inhibitors, particularly inhibitors of Cdk2 and Cdk4 are being developed for the treatment of cancer. Cdk5 differs from other members of the Cdk family being modulated by its activator, p35. Furthermore, cell cycle regulation has not yet been established as function of Cdk5 and for the moment its appears to be more important as a modulator of neural activity. Cdk5 is mainly active in postmitotic neurons because of the selective neuronal expression of its activators, p35 and p39.

Cdk5 is involved in various physiological roles within the CNS as well as a number of pathological processes such as addiction and neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Cdk5/p35 has also been indirectly linked to nociceptive pathways. For example Cdk5 regulates the activation of mitogen activated protein kinase (MAPK) in nociceptive neurons potentially modifying the hyperalgesia that results increased MAPK activity. Cdk5 has also been implicated in other pathways known to modulate pain such as calcium calmodulin kinase II, delta FosB, the NMDA receptor and the P/Q type voltage-dependent calcium channel. More directly, roscovitine, a non-selective Cdk5 inhibitor, attenuates formalin-induced nociceptive responses

In the PNAS study highlighted here Tej Pareek and colleagues from the NIH report on the expression of Cdk5/p35 in the CNS. The study demonstrates a co-localization of Cdk5 and p35 in TRPV1 positive primary afferents within the spinal cord, dorsal root ganglia and trigeminal ganglia. The expression and activity of Cdk5 increased following the induction of inflammatory pain. Perhaps most importantly, deletion of p35, which leads to reduced Cdk5 activity, resulted in analgesia in animals exposed to noxious heat. Conversely, overexpression of p35 was hyperalgesic in this model.

The present study clearly demonstrates the involvement of Cdk5/p35 in the processing of pain and demonstrates that blocking these proteins reduce the responsiveness of normal pain pathways. These data suggest that at a minimum Cdk5 inhibitors may be of benefit in acute pain.

In a recent Cell Cycle paper [full text], Tej Pareek and Ashok Kulkarni, co-authors on the PNAS paper reported that the analgesic activity of morphine wore off with time in a tail withdrawal model. This resistance to morphine is a well known feature that limits the utility of morphine. Deleting p35 not only enhanced the maximal analgesia attributed to morphine, it also blunted the resistance. The use of Cdk5 inhibitors may therefore not only be useful when used alone, this strategy may also improve the utility of morphine. Ideally this would allow morphine dose-reduction which would have the added benefit of minimizing systemic side effects. In our recent feature on post-operative pain, Orthopedic Postoperative Pain, a major conclusion based on a survey of 180 surgeons and anesthetists is that prescription of opioids in mild to moderate postoperative pain may be restricted by the physician's perception of opioids as being less well tolerated. Agents such as Cdk5 inhibitors that could improve tolerance would thus be of considerable use. Opioids also represent a cornerstone for the treatment of cancer pain and indications for Cdk5 could potentially be extended to cover this subtype of pain. Of interest Cyclacel are currently developing Seliciclib (CYC202; R-Roscovitine) as a phase II(a) candidate for the treatment of non-small cell lung in combination with leading cytotoxic drugs, and as a monotherapy for B-cell malignancies. This is of interest because in addition to inhibiting Cdk subtypes associated with cell cycle progression, and hence anti-cancer activity, roscovitine is also a reference Cdk5 inhibitor within the same potency range. It will be interesting to see therefore whether roscovitine offers pain relief in the trials currently underway.

A role for Cdk5 in the treatment of chronic neuropathic pain would however be the ultimate goal considerable the limited opportunities currently available for this pain type. Further studies investigating the efficacy of Cdk5/p35 blockade in models of neuropathic pain are therefore eagerly awaited.

Rituxan approval to mark a new era of B-cell targeted therapies of autoimmune disease?

DailyUpdates March 1^st, 2006: Genentech and Biogen Idec announced yesterday (press release) that the FDA has approved Rituxan (Rituximab) in combination with methotrexate to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Approved by the FDA in November 1997, Rituxan was the first therapeutic antibody approved for treating cancer in the US. A supplemental Biological License Application (sBLA) was approved for Rituxan in April 2001, adding several new uses related to B-cell non-Hodgkin's lymphoma. To date, more than 250,000 patients worldwide have been treated with Rituxan. Sales of Rituxan have grown impressively over the past seven years. The growth rate is now slowing and future growth is expected to come from new indications.

REFLEX, a Phase III clinical study of Rituxan in rheumatoid arthritis, met its primary endpoint and underpins the FDA’s approval. Analysts believe that additional approval for the treatment of rheumatoid arthritis will add a further $375 million to the global sales for this product. Rituxan is also being evaluated in Phase II/III clinical trials for primary progressive and relapsed remitting multiple sclerosis, ANCA-associated vasculitis, systemic lupus erythematosus.

REFLEX showed that a significantly greater proportion of patients who received a single treatment course of two infusions of Rituxan with a stable dose of methotrexate achieved American College of Rheumatology (ACR) 20, 50 and 70 response rates compared to patients who received placebo and methotrexate. The study included patients with active rheumatoid arthritis who had an inadequate response or were intolerant to prior treatment with one or more TNF antagonist therapies and current methotrexate therapy.

At 24 weeks, patients receiving Rituxan displayed clinically and statistically significant improvements in rheumatoid arthritis signs and symptoms, including pain and disability. In patients receiving Rituxan ACR 20, ACR 50 and ACR 70 was achieved by 51%, 27% and 12% of patients (compared to 18%, 5% and 1% of placebo treated patients).

In REFLEX, the most frequently reported adverse events that occurred with Rituxan were primarily infusion-associated. Serious adverse events occurred in 7% of patients receiving Rituxan and methotrexate compared to 10% in patients receiving placebo and methotrexate. Less than 1% of acute infusion reactions were serious. The incidence of serious infections was 2% in Rituxan-treated patients and 1% in placebo-treated patients.

Rituxan is the first treatment for rheumatoid arthritis that selectively targets CD20-positive B-cells. Through this unique mechanism of action, Rituxan may affect multiple pathways by which B-cells are believed to contribute to the initiation and development of rheumatoid arthritis.

Yesterday’s news is good for Rituxan and rheumatoid arthritis patients alike; it also establishes a clear proof of concept for the development of other B cell-targeted therapies for the treatment of rheumatoid arthritis, other autoimmune disorders.

Another B-cell target that has considerable promise is BAFF (also known as BLyS). This target is fully evaluated in our recent report BAFF & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics - Proof of concept, indications and development activity

BAFF plays a key part in the control of B-cell biology in secondary lymphatic organs. In particular BAFF stimulates the maturation and survival of B-cells within germinal centers of the spleen, other lymphatic organs and lymph nodes.

There is particularly good evidence to support a role of BAFF in the etiology of rheumatoid arthritis, and especially in a subset of patients with synovial germinal centers. BAFF is able to promote the production of rheumatoid factor while its blockade is able to prevent the progression of an animal model of disease. Blockade is also able to reduce IgG release by human synovial tissue suggestive of clinical efficacy. In patients, articular BAFF levels are increased, and convincingly, Human Genome Science’s phase II study of the neutralizing anti-BAFF monoclonal antibody LymphoStat-B revealed an ACR 20 response in 35% of patients as compared to 16% in controls. ZymoGenetics is also targeting BAFF for the treatment of rheumatoid arthritis.

One particular advantage of blocking BAFF and/or APRIL for the treatment of rheumatoid arthritis is that this approach may improve both the efficacy and safety of TNF blocking drugs. One risk associated with TNF therapies is the development of lymphoma but since targeting the BAFF family appears to be an approach to this cancer, a therapeutic such that blocks BAFF is appealing in a combination therapy.

Hopefully yesterday’s news on Rituxan will mark the start of a new era in the treatment of autoimmune disease.