By Michael D. Becker, Jeffrey Martini, Ph.D., and Janet L. Dally
Parkinson’s disease [PD] is the most common of the neurogenerative diseases affecting 1 in 100 people over the age of 60. Approximately 1.5 million Americans currently suffer from the disease and it is estimated that 60,000 Americans are newly diagnosed each year. PD is both a chronic and progressive disease.
While the precise cause of PD is not fully understood, it is associated with the loss or impairment of the dopaminergic neurons [nerve cells] in the middle region of the brain called the substantia nigra [SN] that leads to an alteration in the activity of the brain networks that control movement. These neurons produce a chemical called dopamine, which allows smooth, coordinated function of the body’s muscles and movement. When approximately 80% of a patient’s dopamine-producing cells are damaged, the symptoms of PD appear. These include impaired motor skills and speech, muscle rigidity, tremor, slowing of physical movement [bradykinesia], loss of balance, and a loss of physical movement [akinesia] in extreme cases.
There are a number of effective medicines that help to ease the symptoms of PD rather than slowing disease progression or curing the disease. While global sales of PD therapeutics exceed $3 billion, most of these approved medications do not work over long periods of time due to the progressive nature of the disease. For this reason, biotechnology companies continue to develop new therapies to potentially slow the progression of the disease and death of nerve cells.
One of the most commonly prescribed medications is levodopa [L-dopa]. L-dopa is converted into dopamine by enzymes in the brain. The drug reduces the symptoms of slowness, stiffness and tremor and most patients initially benefit from the treatment. Over time, the dose of L-dopa may need to be increased in patients with advanced PD, which can lead to drug-related complications such as involuntary, repetitive movements [dyskinesia] and motor fluctuations.
Impax Pharmaceuticals, Inc. (IPXL) commenced a Phase 3 trial of IPXO66 for the treatment of PD patients with mild symptoms in April 2009. IPX066 is an extended release carbidopa-levodopa product which is intended to produce a fast and sustained concentration of L-dopa. In June 2009, Impax announced positive interim results based on data from the first 13 patients of a Phase 2 active–controlled, multi-center crossover study in advanced PD patients. The interim results demonstrated that IPX066 provided more than two additional hours of reduction in motor off time during waking hours as well as increased duration of finger tapping speeds and prolonged improvements in walking speeds in comparison with generic Sinemet [cardiodopa-levodopa]. IPX066 extended release formulation is designed to enhance patient compliance as a result of less frequent dosing. By early 2010, Impax anticipates initiating a second Phase 3 trial of IPX066 in patients with advanced PD.
Another class of drugs called dopamine agonists may be used instead of L-dopa or in combination with it. Other medications that do not stimulate dopamine receptors and improve movement in PD include amantidine, anticholinergic medications and selegiline, an inhibitor of the enzyme monoamine oxidase B [MAO-B].
As PD progresses and medications no longer improve the patient’s mobility or cause significant side effects, surgical treatment may be considered. In advanced PD, deep brain stimulation [DBS] surgery is an alternative that may be utilized. DBS surgery involves placing a thin metal electrode into a brain target site and attaching it to a computerized pulse generator, which is implanted under the skin in the chest. This surgery improves the patient’s movement in the “off-medication” state to be more like movement in the “on-medication” state. The most serious potential risk of DBS is bleeding in the brain that can lead to stroke, with infection representing another serious potential risk of DBS.
Efforts by biotechnology companies to find a cure or treatment that slows the progression of PD have been challenging and complicated due to a variety of issues, including:
- Late diagnosis of PD after substantial nerve cell death has occurred
- Long history of dramatic placebo effects in PD
- Difficulties with drug delivery
- Challenges in assessing clinical outcomes resulting in expensive clinical trials
Neurotrophic factors, such as neurturin [NRTN], glial cell line-derived neurotrophic factor [GDNF], and brain-derived neurotrophic factor [BDNF], were incorporated into the first biotechnology therapies for PD and other neurodegenerative diseases. While none of these products have been commercialized to date and several clinical studies have disappointed, there is reason for optimism going forward.
To date, the major difficulties encountered in the use of neurotrophic factors for the treatment of PD may relate to drug delivery issues. For example, neurotrophic factors do not cross the blood-brain barrier and cannot be taken orally. In addition, there are side-effects associated with systemic administration resulting from binding to extra-target receptors. Local administration of neurotrophic growth factors is therefore required to achieve therapeutic concentrations in the tissue, although the site of administration and method of delivery have represented significant barriers to date.
For example, Amgen, Inc. (NASDAQ:AMGN) discontinued its randomized, double blind placebo controlled Phase 2 study of recombinant GDNF for the treatment of advanced PD in 2004. By way of background, Amgen acquired GDNF and several other product candidates through the 1994 acquisition of Synergen, Inc. for approximately $240 million [although Synergen had about $125 million in cash at the time – resulting in an enterprise value closer to $115 million]. The clinical trial of GDNF did not meet its primary endpoint of symptom improvement after six months of treatment as defined by the Unified Parkinson’s Disease Rating Scale [UPDRS]. The company also later identified potential safety issues, as high doses of the drug damaged some monkey brains and a few patients developed antibodies against the drug.
The failure of Amgen’s Phase 2 GDNF trial may have been related to the site and method of delivery, which included monthly injections of GDNF into the lateral ventricle. In other words, sufficient concentrations of GDNF may not have diffused through the ventricular wall and brain parenchyma to the putamen. This is supported by the success of chronically infusing a low dose of GDNF into the dorsal putamen using an implantable pump [SynchroMed™ by Medtronic, Inc. (NYSE:MDT)]. Although primarily a safety study in only five patients, chronic GDNF infusion resulted in improved motor function in all patients, reduction in off-time duration and severity, reduction in dyskinesia duration and severity, and a corresponding increase in on-time duration. After 12-months, there was a 39% improvement in the off-medication motor sub-score of the UPDRS and 61% improvement in the activities of daily living sub-score.
In addition to implantable pump delivery technology, gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. In this regard, Amsterdam Molecular Therapeutics [Euronext: AMT] obtained a license from Amgen to use their GDNF gene for the development of a treatment for PD in September 2008. Amsterdam Molecular Therapeutics intends to combine the GDNF gene with their proprietary adeno-associated virus [AAV] gene therapy platform, which the company believes may provide a solution for delivering GDNF to the brain to protect and enhance the function of nerve cells that produce dopamine.
While gene therapy offers hope, a Phase 2 trial of CERE-120 in advanced PD patients conducted by privately-held Ceregene, Inc. still underscores the importance of drug delivery to the appropriate portion of the brain. CERE-120 is an AAV vector carrying the gene for NRTN, a naturally occurring protein which repairs damaged and dying dopamine-secreting neurons. In November 2008, the company announced that the Phase 2 clinical trial did not meet the primary endpoint of improvement in the UPDRS motor off score at 12-months of follow-up, although several secondary endpoints suggested a modest clinical benefit. In May 2009, Ceregene announced that at the 18-month additional protocol described analyses of the Phase 2 clinical trial; CERE-120 demonstrated a clinically modest improvement and statistically significant treatment effect in the primary efficacy endpoint.
Ceregene, which expects to conduct a follow-on Phase 2 trial later this year, suggests that the deficient axonal transport of the degenerating nigrostriatal neurons in advanced PD impaired transport of CERE-120 from the putaminal terminals in the putamen region of the brain where the therapy was delivered to the nigral cell bodies. The company believes that it can overcome the transport problems associated with degenerating neurons by modifying the dosing paradigm of CERE-120 to also directly target the cell bodies in the SN. Genzyme Corporation (GENZ) has licensed ex-North American rights for the development and commercialization of CERE-120 from Ceregene.
Several additional gene therapy programs are currently in clinical development for the treatment of PD:
Neurologix, Inc. (OTC:NRGX) is developing NLX-P101, an AAV vector delivering an inhibitory therapeutic gene [glutamic acid decarboxylase, or “GAD”] which is inserted in the subthalmic nucleus [STN]. Among the most clinically advanced gene therapy solutions for PD, NLX-P101 is currently in Phase 2 trials. GAD catalyses synthesis of gamma-aminobutyric acid [GABA], the major inhibitory transmitter in the brain. Neurologix’s non-dopaminergic approach aims to restore function to GAD to increase the production of GABA to turn off hyperactivity in the STN. NLX-P101 may avoid some of the off-target side effects typical of dopamine stimulating agents. The open label Phase 1 clinical trial in 12 patients with advanced PD demonstrated statistically significant improvements in both clinical symptoms and improved brain network activity and NLX-P101 was safe and well tolerated. Researchers reported the clinical outcomes were encouraging, with the treated patients showing significant improvements in both the “on” and “off” states of their illness. Neurologix anticipates completing patient enrollment in the Phase 2 clinical trial by the end of 2009.
In July 2009, Oxford BioMedica [LSE: OXB] announced an update on its Phase I/II clinical trial of ProSavin in patients with mid-stage PD. ProSavin is a novel gene therapy which uses the company’s LentiVector® system that delivers three enzymes required for the synthesis of dopamine. The product is administered locally to the striatum and requires several hours of surgery. Interim trial results demonstrated that three patients in the first cohort [lowest dose level] have maintained their improvement in motor function after one year, with an average improvement of 29%. The investigator assessments of the three patients in the second cohort [2X dose level] demonstrated the patients have achieved a similar benefit at three-months. One patient in the second cohort to reach the six-month assessment has shown further improvement. The motor function is assessed according to the UPDRS in the “off state”. ProSavin has been safe and well tolerated in all patients treated to date. Based on PDQ-39 score, a standard measure of clinical benefit that is recorded by the patient answering a questionnaire, Oxford BioMedica plans to proceed to the third patient cohort [5X dose level] utilizing its new delivery technology for the administration of ProSavin. The new, less invasive technique reduces the surgical time and facilitates delivery of higher doses. Oxford BioMedica intends to complete the ongoing study in the second half of 2010.
Separate from its deal with Ceregene, Genzyme Corporation is conducting a Phase 1 open label safety study of an AAV encoding human Aromatic L-Amino Acid Decarboxylase [AADC] in patients with PD. Genzyme acquired the rights to AAV-hAADC-2 from Avigen, Inc. (AVGN) in December 2005. The enzyme AADC converts L-dopa into dopamine. Over time in patients with PD, the brain loses its ability to convert the L- dopa to dopamine and thus the treatment with L-dopa becomes less effective. The investigational drug, AAV-hAADC-2, is injected into the striatum and is intended to provide, directly to the brain, the missing enzyme AADC. It is designed such that advanced PD patients will respond to a lower dose of L-dopa without experiencing the debilitating side effects. Primate studies demonstrated the investigational drug to be effective, long-lasting and safe. A single administration of AAV-hAADC-2 in the striatum of primates with Parkinsonian symptoms demonstrated stable expression of AADC and significant behavioral responses to low levels of L-dopa without developing dyskinesias or other debilitating side effects.
In addition to drug delivery and gene therapy advances, other promising neurotrophic factors have recently been discovered and are in preclinical development. For example, a 2003 issue of the Journal of Molecular Neuroscience described the discovery of mesencephalic astrocyte-derived neurotrophic factor [MANF] that selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. MANF, which is being developed by privately-held CNS Protein Therapeutics, Inc., is also more selective in the protection of dopaminergic neurons at lower and middle concentrations, although GDNF is more selective at higher concentrations. The discovery of MANF and other novel neurotrophic factors may renew investor interest in this class of drugs.
Beyond solving scientific and clinical issues, another challenge facing biotechnology companies developing promising PD therapies is obtaining the funding necessary to continue the preclinical studies and clinical trials. In the current economic environment, some companies will not have the capital to move these product candidates forward and will discontinue development unless they have access to capital through financing or collaborations.
For example, Neurogen Corporation (NRGN) announced that it suspended the enrollment of additional patients in its ongoing Phase 2 clinical trials for PD and restless leg syndrome in order to conserve capital in May 2009. The company has eliminated approximately fifty percent of its staff positions and plans to further decrease staff consistent with its planned reduction in operations and efforts to conserve capital. Neurogen announced it is pursuing strategic options including a sale of the company or sale of its assets.
While a comprehensive review of PD development is beyond the scope of this article, additional public biotechnology firms in early [eg, preclinical or Phase 1] development for the treatment of PD include Addex Pharmaceuticals Limited [SIX: ADXN], Amicus Therapeutics, Inc. (NASDAQ:FOLD), Depomed, Inc. (DEPO), and Prana Biotechnology Limited (NASDAQ:PRAN).
Treatment of PD represents a critical unmet medical need that may be addressed by the aforementioned technologies. Current medications only address the symptoms of this debilitating disease and do not halt the progression of PD. As demonstrated by the significant increase in Impax Pharmaceuticals’ stock price since the initiation of its Phase 3 trial, recent advances in drug delivery, the promise of gene therapy, and the discovery of novel neurotrophic factors may encourage investment in biotechnology companies developing novel therapies that ease the symptoms of PD, slow disease progression, or offer hope to cure the disease.
Disclaimer: This article contains the author’s own opinions, and none of the information contained therein constitutes a recommendation that any particular security, portfolio of securities, transaction, or investment strategy is suitable for any specific person. To the extent any of the information contained in the article may be deemed to be investment advice, such information is impersonal and not tailored to the investment needs of any specific person.
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