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“The Pink Sheet”
Prescription Pharmaceuticals & Biotechnology
Parkinson’s Disease At A Crossroad: Deals And Emerging Therapeutics
The last five years have seen an explosion in novel approaches to Parkinson’s disease. The PD field is advancing on all therapeutic fronts, including drugs, devices, and – risen from the ashes – gene therapy. The most striking progress is being made, however, in pharmaceuticals, with large and small players pursuing new targets and pathways, discovery tools and platforms, delivery technologies, and much-needed indications. None of the new generation of agents has made it to market yet, but several compounds targeting symptom control are in late-stage testing, and may launch in 2012. Some of the most intriguing candidates, which show evidence of upstream disease modification, are still in preclinical testing and unpartnered. While most of the deal action is focused on drugs targeting alleviation of PD motor symptoms or reduction of levodopa “off” periods and of levodopa-induced dyskinesias (LID), significant dollar amounts, albeit via fewer deals, are flowing into early-stage disease-modifying approaches (“Building the New Generation of Drugs in Neurodegeneration” “IN VIVO” February 2010). PD is a late-onset neurodegenerative disease (NDD) characterized by the destruction of dopamine-producing nerve cells in the substantia nigra, a midbrain structure that plays a role in reward, addiction and movement. Dopamine controls muscle movement and the death of dopaminergic cells results in the characteristic motor deficits known as Parkinsonism. These range from mild to severe and include difficulty swallowing and walking, loss of fine hand movements, rigidity and stiffness. No cure exists for the disease. Approximately 800,000 patients in the U.S. are diagnosed with PD, a number which is predicted to increase to 1,000,000 over the next seven years. Worldwide prevalence of the disease stands at approximately 6.3 million. The current PD therapy market is thoroughly genericized, beginning with the mainstays of treatment, the catecholamine precursor levodopa and carbidopa, which is co-administered with levodopa to prevent its breakdown. These, along with the main dopamine agonists pramipexole, ropinirole and rotigotine, and the MAO B inhibitors selegiline and rasagiline dominate the treatment landscape. Generic utilization is likely to grow over the next decade driven by public and commercial plans, consumer thrift and growing comfort with generics, and the absence of a significant new compound on the horizon that is nondopaminergic, safe and tolerable, and clinically meaningful. The development of agents that improve on the generic standards of care by better controlling PD motor problems, or, more significantly, by regulating upstream events in the PD pathophysiological cascade, have been hindered by obstacles, some technical, some the consequence of a gun-shy investment climate. On the R&D side, the lack of robust animal models or of validated biomarkers of disease detection or progression is a problem. Regarding early detection of PD, Michael Ross, a managing partner with San-Francisco based SV Life Sciences, notes that imaging agents and better diagnostic tools are being Reprinted with permission from “The Pink Sheet.” Unauthorized photocopying prohibited.
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developed, but nothing in the PD world matches recent advances in the early detection of Alzheimer’s using a combination of imaging and cerebrospinal fluid biomarkers (“Alzheimer’s Hearing Explores Role Of Early Diagnostic Tools In Drug Trials” “The Gray Sheet” December 2010). Adding to the R&D challenges, the last six years has been a graveyard of failed candidates. The result is that big pharma has an apparently conflicted stance toward PD: intrigued, mindful of aging population dynamics and advances in molecular tools and understanding of the disease; but also chastened by failures in NDD R&D, and attentive to the allure of less risky, better trodden routes to market. Indeed, R&D activity in PD has picked up sharply in recent years, but most of the deal-making activity, with a few noteworthy exceptions, has been focused on agents addressing symptom control and also on secondary aspects of PD such as dementia, depression and pain. To some extent, biotechs working on disease modification are simply not courting big deals as of yet. As
Ross, who sits on the board of PD startup Link Medicine, puts it – “Disease-modification companies are
not ready for prime time yet. We’ll do a deal when we have the data … The deals being done now in the PD
space are the ones that can be done.” Ross was also SVLS’s man on the board of Rinat Neuroscience when
Pfizer Inc. acquired it for $500 million in 2006 largely for its expertise in large-molecule therapeutics for
neurological disease; he is an experienced hand in early-stage NDD plays.
Thus, for the next decade, the PD market will likely continue to be dominated by generics (dopamine precursors and agonists) and incremental advances in adjunctive symptom control. Several drugs that work through non-dopamine pathways to reduce levodopa “off time” (with use of levodopa over time, patients experience sudden and erratic ‘off’ periods characterized by severe Parkinsonism before their next dose of medication) are in late-stage trials and will probably enter the market in the near term, but they are not expected to have a significant commercial impact. In so far as these drugs come into use, they will paradoxically result in increased utility of generic dopaminergic drugs (see chart below). A Few Late-Stage Advances In Symptom Control Pave the Way
Products targeting the alleviation of symptoms fall into two broad groups: small molecules, primarily targeting G-protein coupled receptors (GPCRs); and conventional mainstays of PD therapy reformulated for improved pharmacokinetics, a cleaner side effect profile, and/or more convenient administration. In May 2011, Heptares Therapeutics Ltd., the U.K. biotech focused on GPCR research, announced the
latest in a series of licensing agreements with major pharmaceutical companies, this time with Shire
, a subsidiary of Shire Plc (“Shire To Strengthen CNS Focus With Option On Heptares’
Novel Parkinson’s Therapy” “The Pink Sheet” DAILY, May 9, 2011). Heptares, hot off a recently
concluded CNS deal with Takeda ($2.7 million upfront, $4.5 million in equity investment, $96 million in
downstream milestones and royalties), is a rock star in the world of well-funded, roundly courted specialists
in the optimization of previously intractable GPCR targets, and the generation of optimized chemistries.
The Shire deal focuses on Heptares’s Adenosine A2A antagonist program, a nondopaminergic approach that can reduce levodopa ‘off time’ and may potentially have a neuroprotective effect. As part of the deal, Shire gets an exclusive option, including worldwide development and commercialization rights, to license optimized chemical structures against the A2A receptor post completion of preclinical studies. In exchange, Heptares gets an undisclosed upfront and, upon exercise of the option by Shire, an option-triggered payment, plus future milestones and royalties based on sales. Trouble is, when the products from the Shire/Heptares alliance enter the market eight to 10 years from now,
they will likely find a PD landscape adequately served by a host of improved next-generation agents for
symptom amelioration. Those with A2As in early stage development, such as Shire/Heptares, will have to
contend with data from two A2As now in late-stage development (Merck & Co.’s preladenant in PIII, and
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Parkinson’s Disease: Representative Recent Deals and Financings
Transaction Category
Therapeutic Approach
Deal Terms
Symptom Control
Merck licensed rights to a preclinical mGluR4 program for PD, and is currently advancing leads toward the clinic. Addex has received $4.8 million up front, is eligible for up to $167 million in milestones and royalties. UCB Group licensed exclusive global rights to Biotie’s SYN115, and an option to SYN118. Both drugs are in PII for PD. The deal includes $725 million in commercial milestones and Impax licensed GSK exclusive worldwide rights to its Phase III PD drug IPX066, excluding US and Taiwan. GSK pays $11.5 million up front, $175 million in milestones, and royalties. Disease Modification
Terms not disclosed other than that it is a 50- 50 split in costs and revenues, and spans Roche takes a global license to two preclinical Roche may pay > €500 million ($644 million) in milestones plus staff costs and double-digit sales royalties. Recent Series C round raised $45 million. In Clarus Ventures, SV Life two earlier rounds, Link Medicine raised and aggregation of toxins Sciences, (leading Source: Elsevier Strategic Transactions Database

Kyowa Hakko’s istradefylline just out of PIII). Other companies working on the next wave of highly
selective A2A modulators further back in development include Domain and Biotie/UCB.
Other GPCRs that may be entering the market in the same timeframe include modulators of nicotinic
receptors (Neuraltus, Targacept) and of mGluR4 and 5 (Addex/Merck; Domain/Merck Serono, and
Novartis, which has an internally developed molecule). Todd Sherer, CEO of the Michael J. Fox
Foundation (MJFF), notes that until Phase III data exists on the late stage A2A products and they gain some
utility in the field, their clinical value as adjunctive therapy is unknown.
Sherer says that the metabotropic glutamate receptor comes just behind A2A blockers as the target du jour. Novartis’s mGluR5 antagonist against LID recently completed a pair of Phase II trials in Germany; the company expects to file for approval in Europe in 2012. Reprinted with permission from “The Pink Sheet.” Unauthorized photocopying prohibited.
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The next decade will see a raft of traditional and novel drugs reformulated for superior efficacy and/or convenience in PD symptom control. Darren Eskow of Easton Associates notes that, in so far as PD is a high-unmet need condition that is not under much scrutiny from payers, so reformulated versions of old-line PD treatments will likely be reimbursed.”It’s an elderly patient population. The commercial plans don’t see these patients,” he points out. Instead, the challenge for reformulated generics will be to achieve premium pricing. For instance, Toronto-based Cynapsus Therapeutics is betting the farm on APL-130277, a reformulation
of apomorphine, an approved injectable for PD ‘off’ periods, using a rapidly dissolving sublingual thin film
strip technology. The company is pursuing a low-cost (estimated $20 million), accelerated 505(b)(2) path to
approval. CEO Anthony Giovinazzo says that APL-130277 has a similar PK profile to injectable
apomorphine. “25%-40% of levodopa treated PD patients experience ’off’ periods. We have demonstrated a
nearly identical absorption profile to the injected version, but without the inconvenience and injection site
issues.” Neurologists would welcome a more benign administration alternative, particularly in PD patients
with cognitive impairment or severe tremors who are unable to self-inject.
Disease Modification – The Grand Wager
Six strategies stand out among R&D efforts aimed at modifying the disease process in PD: protein misfolding approaches, proteostasis, gene-targeting drugs, neurotrophic factors, stem cell therapies and zinc-finger technologies. Although there are interesting developments in cellular and gene therapy (“Neurologix Gene Therapy Shows Ability To Improve “On Time” In Parkinson’s” “The Pink Sheet” DAILY” June 9 2011), biopharma approaches are the main subject of deals. Protein misfolding, wherein aggregated deposits of misfolded proteins are found in the brains of patients
suffering from NDDs such as Alzheimer’s and PD, is a particularly attractive therapeutic strategy.
Examples include Pfizer’s 2010 purchase of FoldRx for an undisclosed sum; a half-dozen companies
pursuing upstream interventions against alpha-synuclein toxicities (an abnormal protein accumulation in the
brains of PD patients) including Belgian-based reMYND which struck a R&D collaboration with Roche, or
Link Medicine, a Boston-based startup with strong venture backing; and Biogen Idec’s big bet ($32 million
upfront, $395 million in milestones) on three preclinical antibody programs against NDDs, one of them
targeting alpha-synuclein, which it acquired from Swiss-based Neurimmune.
Todd Sherer at MJFF says that programs focused on the LRRK2 gene mutation, thought to account for 5%
of familial PD patients, are of particular research interest and mentioned early stage programs at Pfizer,
Lundbeck, and GSK. The LRRK2 gene is now believed to be the most common genetic contributor to the
disease, and some recent evidence suggests that genetic variation in LRRK2 may be involved in the more
common, sporadic form of PD. Much of the research in LRRK2 is taking place at small biopharmas like
Zenobia Therapeutics, which is seeking small molecule protein kinase inhibitors against LRRK2. MJFF
provides funding to Zenobia.
Proteostasis Therapeutics, another Cambridge-based startup, takes what is perhaps the boldest approach to
PD disease modification. The company is developing small molecules, or proteostasis regulators, to control
the body’s natural protein balance. Its approach envisions a complex web of interacting biological processes
required to maintain that balance. When healthy, the network ensures that every protein will properly
dispatch its functions – folding, degradation and transport of proteins to appropriate locations in the cell –
to prevent damage.
In 2008, the company raised a series A round of $45 million, led by HealthCare Ventures, Fidelity
Biosciences, New Enterprise Associates, Novartis Option Fund and Genzyme Ventures. And on May 25th,
2011, Proteostasis announced a deal with Elan Corp., its first industry collaboration, in which Elan will pay
the startup $20 million upfront and $30 million to fund R&D over the next five years. In return Elan gets a
24% stake in the company, a seat on its board and first rights to any drugs that come out of the alliance.
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Chris Mirabelli – a co-founder of Isis, and founding investor in FoldRx – who represents HealthCare
Ventures on Proteostasis’ board – notes that the biotech’s remit goes beyond NDD to encompass metabolic
diseases, LSD conditions like Gaucher and Fabry, emphysema and more. He sees the company’s role as
melding systems biology with systems pharmacology. “How do the molecules we find change the
network?” He is also adamant that “polypharmacy is key … the science is taking us here.”
Mirabelli is confident that single-pathway approaches will not change PD and restore neural health, and that the companies pursuing single-pathway approaches to symptom control in the belief that they are taking a less risky path to market may ultimately be mistaken. The real risk, big picture, may lie in neglecting the longer-term route to disease modification – a point that big pharma should take note of. Risk-Free Trial Offer
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