Wednesday, March 22, 2006

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 22nd, 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.


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