Michael Becker's  Instablog

In our August 2009 article titled “Treating Parkinson’s Disease: Investment Opportunities and Challenges,” we reviewed some of the historical challenges associated with developing treatments for Parkinson’s disease [PD] and cited reasons for optimism going forward in addition to highlighting several promising companies making progress. Since that time, many of the companies we featured have reported clinical progress, presented promising new data, and produced significant returns for investors – with several stocks reaching 52-week highs. In view of renewed investor enthusiasm for companies working in the area of PD, the purpose of this article is to provide an update on previously mentioned companies and introduce some new players that are making headlines in the PD space.

Improvements on Existing Therapies

Levodopa [L-dopa] is one of the most commonly prescribed medicines for PD. L-dopa initially reduces the symptoms of slowness, stiffness and tremor associated with PD; over time the dose of L-dopa needs to be increased often resulting in drug related complications. Several biopharmaceutical companies are developing new drug formulations of currently approved medicines:

Impax Laboratories, Inc.

Shares of Impax Laboratories, Inc. (IPXL), which were trading around $7.50 at the time our initial PD article published, recently reached a new 52-week high of $10.86, representing a 45% increase in a matter of months. The company recently initiated a multinational Phase III trial of its late-stage drug candidate IPX066 in advanced PD patients. IPX066 is an investigational extended release carbidopa-levodopa product intended to rapidly achieve and then sustain effective blood concentrations of levodopa, potentially improving PD clinical symptom management. This is the second of two Phase III studies designed to support marketing approval of IPX066 in Parkinson’s disease. In June 2009, Impax reported the initiation of the first Phase III study of IPX066 in treatment naïve PD patients.

Nupathe Inc. and SurModics, Inc.

Privately-held Nupthe Inc., a neuroscience-focused specialty pharmaceutical company, recently announced a partnership with SurModics, Inc. (SRDX), a leading provider of drug delivery and surface modifications to the healthcare industry, for development of NP201. NP201 is a biodegradable sustained release formulation of an approved dopamine agonist and the first long-acting treatment available in broadly acceptable dose form that maintains the potential to provide sustained relief from Parkinson’s disease without motor response complications. NP201 leverages NuPathe’s long-acting delivery [LAD™] technology and SurModics’ proprietary biodegradable polymer matrix implant technology to achieve optimal drug release over an extended period of time. NP201 consists of a dopamine agonist formulated to provide effective relief of the signs and symptoms of Parkinson’s disease [e.g., tremor, rigidity, postural instability] for 1-3 months with a single administration. By providing stable, continuous drug delivery over an extended period, NP201 may significantly decrease the dose complications associated with current treatments. Furthermore, many researchers believe that continuous, stable stimulation of the dopamine receptors may slow the progression of the disease.

Neurotrophic Factors and Gene Therapy

Neurotrophic factors are a family of proteins responsible for the growth and survival of developing neurons and the maintenance of mature neurons. Neurotrophic factors represent an attractive drug class because of their anti-apoptotic properties*. Several classes of neurotrophic factors exist, each with unique pharmacodynamic properties. Investigators are still in the process of understanding the different receptor targets of these proteins and the downstream cellular responses; therefore, the best individual or combination of neurotrophic factors is not yet known. Despite these challenges, several companies are proceeding with development of this promising class of drugs.

Local administration of neurotrophic growth factors is required to achieve therapeutic concentrations in the target tissue, although the site of administration and method of delivery have represented significant historical barriers. We believe gene therapy is among the more promising delivery alternatives for companies seeking to restore abnormal cellular signaling, especially in diseases with difficult to reach targets such as PD, and several companies have demonstrated considerable progress.

Ceregene, Inc.

Just a few days after our original PD article published in August, privately-held Ceregene, Inc. announced that the Michael J. Fox Foundation for Parkinson’s Research [MJFF] will provide funds for long-term follow-up testing of patients enrolled in the company’s Phase II trial of CERE-120. CERE-120 is an adeno-associated virus [AAV] carrying the gene for neurturin [NRTN], a naturally occurring neurotrophic factor that repairs damaged and dying dopamine-secreting neurons. The funding will enable Ceregene to collect and analyze more extensive data for up to 48 months from patients with advanced PD who were enrolled in the double-blind, controlled trial which ended in November 2008. The Phase II trial involved 52 patients and failed to demonstrate a difference in the primary endpoint in treated versus the control group. However, the study suggested improvements in secondary endpoints at 12 months. Based on those findings, and insight gained from analyses of post-mortem brain tissue from two CERE-120 treated patients, the company has revised the dosing regimen and expects to initiate a new trial of CERE-120 in the near future.

In October 2009, BioSante Pharmaceuticals, Inc. (BPAX) completed its merger with Cell Genesys, Inc. and now owns a sixteen [16] percent equity ownership position in Ceregene, a former subsidiary of Cell Genesys.

Phytopharm plc

Phytopharm plc (LSE: PYM) is developing Cogane™, a novel non-peptide, orally bioavailable neurotrophic factor inducer that readily crosses the blood brain barrier. In preclinical models, Cogane reverses the changes in the area of the brain involved in Parkinson’s disease by inducing the body’s own production of neurotrophic factors including glial cell line-derived neurotrophic factor [GDNF].

Phytopharm recently announced two positive results from studies for Cogane. In the first study, funded by a grant from MJFF, Cogane demonstrated efficacy in a preclinical study using a non-clinical, non-human primate model of PD resulting in a 43% reduction in parkinsonian disability. In the second study, the company reported Phase 1b, 28-day safety data demonstrating that Cogane was well tolerated, with blood levels of Cogane reaching efficacy levels seen in the non-human primate model. The promising results, although still early in clinical development, demonstrate the scientific and financial interest in this biologic pathway and a Phase II, proof-of-concept study for Cogane is planned to commence in the second quarter of 2010.

Shares of Phytopharm soared more than 300% to a new 52-week high of 26.95 pence on the news.

Oxford BioMedica

Oxford BioMedica (LSE: OXB) recently presented data that positions the company at the forefront of gene therapy for PD. Oxford BioMedica recently announced new data from the ongoing Phase I/II trial of ProSavin®, its novel gene therapy for the treatment of PD. All patients treated at the second dose level have completed their six-month assessments and have shown further improvement in motor function. The maximum improvement was 53% and the average was 34% relative to patients’ pre-treatment motor function. The Principal Investigator, Professor Stéphane Palfi of the Henri Mondor Hospital in Paris, is expected to present interim results from the trial at the European Society of Gene & Cell Therapy Annual Congress, being held November 21-25, 2009, in Hannover, Germany.

In addition, Oxford BioMedica recently released preclinical studies demonstrating increased dopamine production without the addition of L-DOPA resulting in decreased disease severity without the dyskinesias associated with L-DOPA [1]. Movement and posture were significantly improved after two weeks [p < 0.05], reaching 77% and 85% of respective normal levels. Overall, these preclinical data suggest that ProSavin may offer significant benefit in the clinical setting, treating the primary symptoms of Parkinson’s disease as well as reducing the severe side-effects of long-term L-DOPA therapy. These conclusions are supported by initial data from human clinical trials.

Oxford BioMedica has clearly taken the lead in the race for novel PD therapies. In addition to the excellent safety profile, ProSavin delivers three genes, AADC [aromatic amino acid decarboxylase], TH [tyrosine hydroxylase] and CH1 [GTP-cyclohydrolase 1], addressing multiple protein targets associated with PD pathophysiology. As Oxford BioMedica continues clinical development, including dosing optimization, this therapy could potentially offer long-term improvements in patients afflicted with PD.

Shares of Oxford BioMedica, which were trading around 10.00 pence at the time our original PD article published, more than doubled and reached a new 52-week high of 21.75 pence on the news, resulting in upgrades from research analysts.

Neurologix, Inc.

Neurologix, Inc. (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]. In its third quarter of 2009 financial results press release, Neurologix reported that its Data Monitoring Committee held its second meeting to review the progress of the ongoing Phase II study of NLX-P101 and recommended that the trial continue unmodified. Despite having one of the most clinically advanced gene therapy solutions for PD, Neurologix also disclosed that the company must secure additional funding by December 31, 2009, or shortly thereafter, otherwise its ability to continue as a “going concern” may be in doubt. While the company remains on track to complete all surgeries for the Phase II study before year-end, the first efficacy results from this trial won’t be available until around mid-year 2010.

Link Between Gaucher’s Disease and PD Published

Recent clinical data has demonstrated that a mutation in the gene encoding glucocerebrosidase [GBA] in patients with PD is the most common genetic risk factor for Parkinson’s disease identified to date. The lysosomal enzyme GBA is deficient in patients with Gaucher’s disease; lack of a functional copy of GBA results in accumulation of glucocerebroside in many tissues including the liver, lungs, brain, and spleen. In a recent New England Journal of Medicine [NEJM] article, 20% of Ashkenazi Jewish Patients and 7% of Non–Ashkenazi Jewish Patients were found to be carriers of a GBA mutation [2]. Patients with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.

Amicus Therapeutics, Inc.

Amicus Therapeutics, Inc. (FOLD) recently presented data demonstrating a correlation between GBA and alpha-synuclein, an upregulated PD protein that can form aggregated insoluble amyloid fibrils and neuronal toxicity. Alpha-synuclein up-regulation and aggregation has previously been shown to be critical in the development of PD. Amicus’ in vivo data shows that increasing GBA activity re-established alpha-synuclein homeostasis. In a mouse model overexpressing alpha-synuclein, Amicus was able to restore normal synuclein levels by increasing the GBA activity with Plicera™ [afegostat tartrate], the company’s experimental, oral therapy for the treatment of Gaucher disease that belongs to a class of molecules known as pharmacological chaperones.

This is important for two reasons: 1) by restoring GBA activity to normal levels, this could potentially decrease the risk of PD for patients with a GBA genetic mutation and 2) in patients that are not carriers [i.e. normal GBA but elevated synucleins], the preclinical data has shown that increasing GBA activity above normal levels restores alpha-synuclein levels, possibly slowing disease progression. Amicus, which has also received funding support from MJFF, plans to continue its preclinical chaperone molecule optimization, including Plicera, in an in vivo PD motor deficit model.

Success in this area could reignite investor interest in Amicus, which recently announced negative results from a Phase II trial with Plicera in Gaucher’s disease. The genetic link between GBA and PD is clear and although the direct molecular relationship between these two proteins in not completely understood, GBA is a new and attractive therapeutic target for PD. Importantly, in the Phase II trial for Gaucher’s disease, Amicus demonstrated an increase in GBA activity in those patients receiving Plicera and the company recently reacquired global development and commercialization rights to the product candidate from Shire plc (SHPGY).

Amicus has a clear lead in developing small molecules that increase GBA activity and despite the Gaucher’s disease trial setback, complete GBA restoration may not be needed to restore normal synuclein levels. Amicus will continue with lead optimization for GBA in the brain, including Plicera, for the treatment of PD along with other GBA chaperone molecules. Clearly, Plicera is an attractive lead compound because much of the preclinical and phase I safety studies have been completed and it has been shown to cross the blood brain barrier.

Conclusion

While treatment of PD is complex due to the disease location, difficulty in clinical trials, and multiple causes of pathophysiology, investor enthusiasm for companies working in this area is warranted in view of recent progress.

Several companies, such as Impax Laboratories and Nupathe, are developing new drug formulations of currently approved medicines. If approved, these drugs could improve the side effect profiles of the FDA approved medicines. From an investors perspective, these companies are attractive since the FDA approval process will be much more straightforward and physician acceptance will be high because these drugs are an improvement on a known drug class.

Other companies, although generally earlier in development, are using neurotrophic factors and gene therapy approaches to directly address the disease mechanism. While much riskier, these new technologies could drastically change the disease outcomes of those patients afflicted with this debilitating disease. Speed to market combined with superior efficacy will be critical for high market penetration.

* Neurotrophic factors were discovered in 1948 in the brain. Originally thought to be exclusive to the brain, these peptides are now found to have broader applications in other cell types and locations. Due to their pharmacodynamic properties such as reducing ER stress, neurotrophic factors possess anti-apoptotic properties and could serve as therapies for many diseases such as myocardial infarctions/ischemia and stroke.

References:

1. Sci Transl Med. 14 October 2009 1:2ps2
2. N Engl J Med. 22 October 2009;361(17):1651-61

Disclosure: No positions

By Michael D. Becker, Janet L. Dally, and Jeffrey Martini, Ph.D.

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