Targacept success could reignite interest in nicotinic drugs

Targacept continued on its recent strong form that has seen shares in the North Carolina-based group rise by 20% in the last month, by reporting strong top-line phase IIb results for its major depressive disorder (MDD) drug, TC-5214. News that TC-5214 as a supplemental therapy was highly effective in reducing depression, irritability and severity of illness, this time round caused the shares to more than double to $7.25.

The success of TC-5214, coming soon after Targacept’s partner AstraZeneca decided to take ADHD drug, AZD3480, into phase IIb trials triggering a $10m milestone payment (AstraZeneca's partnering decisions boosts Targacept while MAP heads for the door, July 9, 2009), provides more validation of Targacept's one pharmacological class strategy. If TC-5214 had failed to show benefits the market might have started to doubt the group’s ability to produce marketable drugs, as its core pipeline is based on neuronal nicotinic receptor (NNR) products.

Targacept is planning on initiating phase III trials of TC-5214 in the first half of 2010, but partnering discussions are expected to start almost immediately. The drug is one of Targacept’s few unpartnered assets.

Strong showing

TC-5214 itself is a broad spectrum NNR antagonist that works by stopping the overstimulation of NNRs and other receptors that cause depression. There had already been high hopes for the drug following the results of the phase II Tridmac trial, with patients receiving the drug in combination with Celexa showing significant improvements in their symptoms of depression.

The trial was designed in two phases, with patients diagnosed with MDD first receiving Celexa, a selective serotonin reuptake inhibitor (SSRI), for eight weeks to determine the level of response to the drug. Those who did not respond well were randomised into the second double blind phase of the trial, and either given Celexa, with TC-5214 or a placebo for a further eight weeks.

As measured by the Hamilton Depression (HAM-D) rating scale the patients in the active arm showed striking improvements in symptoms of depression. What also impressed investors, other than the magnitude of the response, was the onset of improvement after only two weeks and the drug’s ability to address irritability, a core and hard to treat symptom of MDD.

Difficult therapy area

While they both still have a long way to go in development, the success of both TC-5124 and AZD3480 could start to inspire confidence that NNRs are finally coming of age. At present there are only two marketed products, including Pfizer‘s anti-smoking treatment Chantix, which was recently slapped with a black box warning following concerns about heightened risk of suicide and behavioural changes that have been associated with the product.

The other product is Targacept’s own Inversine, a treatment for high blood pressure, but this only generates annual revenues of around $1m.

But investors should be reminded that there have been numerous failures of nicotinic drugs (see table below), particularly nicotinic agonists, with a significant proportion being Targacept's products (Targacept in need of technology validation, December 9, 2008).

Depressingly for the many companies working on drugs in this field only one product is currently in phase III, and 12 candidates have been abandoned or suspended in phase II and III trials.

Abandoned / Suspended Nicotinic Agonists
Phase Product Count
Phase III 1
Phase II 11
Phase I 4
Pre-clinical 4
Total 20

Of the companies other than Targacept hoping that they could get buck the trend and get the next NNR-based treatment on the market, the most advanced is NutraPharma with RPI-78M, its treatment for the rare genetic disorder adrenomyeloneuropathy that causes degeneration of nerve fibres and the adrenal gland (see table). However, the market has yet to assign any value to the drug, which has orphan drug status and is already being supplied on a compassionate basis.

Neuronal Nicotinic Receptor drugs
Annual Sales WW - ($m)
Phase Pharmacological Class Product Generic Name Therapeutic Subcategory Company 2008 2009 2010 2011 2012 2013 2014
Marketed Nicotinic partial agonist Chantix/Champix varenicline Other CNS drugs Pfizer 846 734 772 833 913 975 1,026
Alpha 4 & beta 2 nicotinic agonist Inversine mecamylamine Other anti-hypertensives Targacept 1 1 1 1 1 1 1
Phase III Nicotinic acetylcholine antagonist RPI-78M - Other CNS drugs Nutra Pharma - - - - - - -
Phase II Nicotinic acetylcholine agonist ABT-089 pozanicline Other CNS drugs Abbott Laboratories - - - 14 40 66 92
Alpha-7 nicotinic agonist R3487/MEM 3454 - Nootropics Roche - - - - - - 50
Alpha 4 & beta 2 nicotinic agonist TC-5214 mecamylamine Anti-depressants Targacept - - - - - - -
Nicotinic acetylcholine agonist ABT-894 sofinicline Non-narcotic analgesics Abbott Laboratories/NeuroSearch - - - - - - -
Alpha-7 nicotinic agonist EVP-6124 - Anti-psychotics Bayer AG/Mitsubishi Tanabe Pharma/EnVivo Pharmaceuticals - - - - - - -
Alpha 4 & beta 2 nicotinic agonist AZD3480 (TC-1734) ispronicline Nootropics AstraZeneca/Targacept - - - - - - -
Alpha 4 & beta 2 nicotinic agonist Mecamylamine CR mecamylamine Anti-diarrhoeals AGI Therapeutics - - - - - -
Alpha 4 & beta 2 nicotinic agonist ATG-3 mecamylamine Eye preparations CoMentis - - - - - - -
Nicotinic acetylcholine agonist GTS-21 - Other CNS drugs CoMentis - - - - - - -

Abbott Laboratories' ABT-089, which is forecast to have sales of $92m by 2014, has completed phase II trials in adult and child ADHD and is expected to report phase II data in Alzheimer’s soon, but given the patchy data in ADHD and the fact the phase II Alzheimer's data was expect in March, the 2011 launch date looks slightly ambitious.

The US group also has two other NNR products in development including phase I ADHD drug ABT-560 and phase II treatment, ABT-894, which is also being studied in ADHD, but a phase II programme in diabetic neuropathic pain was abandoned in June after failing to show sufficient efficacy.

Like the majority of NNRs in development, Roche’s R3487 is classed as a CNS drug. The product was acquired as part of Roche’s acquisition of Memory Pharmaceuticals and is currently in phase II trials for cognitive impairment associated with schizophrenia. Results are expected by the end of September and analysts have already penciled in sales of $50m by 2014.

With its current strong showing of data, Targacept may become the dominant force in the NNR market, a fact that larger companies have not failed to notice given the number or partnerships it already has. This supremacy can be perhaps put down to the group’s persistence and sheer number of NNR products, which look as if they might have started to come good.

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