Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord. MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord. This may cause inflammation and areas of scarring on nerves resulting in loss or decrease in function. An estimated 400,000 Americans have MS with about 2.5 million cases worldwide. 

Current therapy for MS is focussed on prevention of relapses and/or slowing of disease progression using immunomodulatory drugs.  FDA approved therapies include Avonex (interferon beta-1a IM ), Betaseron  and Extavia, (interferon beta-1b SC ),  Copaxone (glatiramer acetate SC),  Rebif (interferon beta-1a SC), Novantrone (mitoxantrone IV) and Tysabri (natalizumab IV).   Some analysts place worldwide expenditures on these drugs at greater than 8 billion dollars annually.  Unlike fingolimod and cladribine which are pills taken by mouth, all of the above therapies are delivered by the intramuscular (IM) route, the subcutaneous (SC) route or the intravenous (IV) route. 

Fingolimod is a sphingosine-1-phosphate-receptor modulator that is thought to work by preventing movement of lymphocytes from lymph nodes and in doing so decreases the damage that these lyphocytes can exact on the central nervous system.  Cladribine’s mechanism of action is different – 2-chlorodeoxyadenosine triphosphate – an active metabolite of cladribine accumulates in cells, disrupts their metabolism and leads to cell death.   Cladribine preferentially impacts lymphocytes and in doing so decreases the number of so called ‘autoagressive’ cells available to attack the nervous system. 

The two recently published clinical trials in the New England Journal of Medicine showed efficacy for cladribine (CLARITY trial) and fingolimod (FREEDOMS trial) when compared to placebo over a 2-year period.  Statistical significance was achieved for the primary endpoint – which was the annualized relapse/recurrence rate in both trials.  In fact, the relative risk reduction was reported as an impressive 50%+ reduction in both trials.  In  a third trial comparing fingolimod to interferon beta 1a, fingolimod was superior. 

Those familiar with the Tysabri story are well aware of the importance of safety when considering immune response modifiers in the treatment of multiple sclerosis and  the safety profile of cladribine and fingolimod will surely be closely scrutinized going forward.  A detailed discussion of the safety of these oral therapies is not possible here however adverse events of note described in these three trials included herpetic infections,  solid tissue cancers, macular edema, basal cell carcinoma, melanoma, breast cancer, transient bradycardia, first- and second-degree heart block,   and lymphocytopenia.  Should approval of either of these agents occur, physicians and patients will need to do the requisite risk/benefit analysis before initiating treatment and FDA mandated post marketing surveillance will likely be critical in addressing any long term safety concerns.

This brings us to the next question – will physicians and patients get the chance?  Well, as mentioned in the first paragraph Merck KGaA was issued a ‘refuse to file’ letter for cladribine suggesting anything but imminent approval while Novartis  filed its NDA for fingolimod in late January 2010.    Interested readers are directed to www.nejm.org to access the three clinical trials referred to above in their entirety as well as an excellent accompanying editorial.  Thanks for reading.

Antegren is a humanized monoclonal antibody designed to inhibit the migration of immune cells into tissues where they may play a role in causing or propogating an inflammatory response. The company states that it is the first alpha-4 antagonist in the new selective adhesion molecule (SAM) inhibitor class. Approximately 2,800 patients have received natalizumab in clinical trials for both Crohn’s disease and MS; headache, fatigue, and nasopharyngitis were the most commonly reported side effects. BioHorizon has currently assigned Antegren a first in class 75/100 innovation status variable score.

Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord. MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord. This may cause inflammation and areas of scarring on nerves resulting in loss or decrease in function. An estimated 400,000 Americans have MS. BioHorizon utilizes an incident case number of 10, 400 new cases of MS in the U.S. per annum and assigns an 11/100 value to the burden of illness variable.

BioHorizon is currently monitoring 23 emerging technologies for the treatment of Multiple Sclerosis. Of these 23 drugs, Avonex®, Betaseron®, Rebif®, and Copaxone® are already approved for this indication while Antegren is the only Phase III technology currently in the BioHorizon database. Although currently designated as Moderate Impact technology, we feel that the high degree of innovation exhibited by this treatment and the large unmet medical need surrounding MS will result in significant technology impact. Health Services clients should commence preliminary assessment activities within the next quarter and watch for news regarding approval.

Technology Details
Target Disease / Indication: Multiple Sclerosis
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine/Neurology
Regulatory Status: Phase III
BioHorizon Impact Score: 53/100 – Moderate Impact

It is estimated that in excess of 300, 000 patients are diagnosed with Alzheimer’s disease annually in the United States. Biohorizon assigns Alzheimer’s disease a value of 33/100 for the Burden of Illness variable.

Current approved therapies for Alzheimer’s include Aricept® and Namenda®. Biohorizon is following 43 emerging drug therapies for Alzheimer’s disease. Seven of these therapies are in Phase III or beyond in their development. Neurochem contends that Alzhemed is a novel small molecule part of a new class of therapies that it calls ‘GAG (glycosaminoglycan) mimetics’. Glycosaminonglycans are thought to play a role in the formation of amyloid plaques. In theory, interrupting the assembly of these plaques could alter the clinical course of disease. This unique approach earns Alzhemed an Innovation score of 75/100.

If approved, Alzhemed would represent a first in class therapy for a common, chronic disease. We see potentially significant demand and diffusion pressures, but at this time have assigned a 10/100 score to the Predicted Demand/Diffusion variable. Overall, Alzhemed is placed in Biohorizon’s Moderate Impact Technology category with an Impact Score of 51/100. We do not recommend any preliminary assessment activities for our health services clients at this time; however, favorable Phase III results could dramatically alter this position.

Technology Details
Target Disease / Indication: Alzheimer’s Disease
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine/Neurology
Regulatory Status: Phase III
BioHorizon Impact Score: 51/100 – Moderate

Nicotine by itself does not induce an antibody or immune response. However, when conjugated with an immunogenic protein such as recombinant cholera protein, an immune response is generated. These anti-nicotine antibodies may bind to the nicotine in a smoker’s blood and decrease or reduce the positive effects that nicotine creates in the smoker. In the Phase I trial, TA-NIC was delivered by 5 vaccinations over 8-20 weeks with a booster given 9 months after the first injection.

According to the 2001 National Health Interview Survey, approximately 22.8% of American adults (46.2 million) are currently smokers. Smoking rates in the United States have been declining since 1965.

The Biohorizon Emerging Health Technology Database contains two other emerging technologies for the treatment of Nicotine Addiction/Smoking Cessation, NicVax and Acomplia™. Notably, Nabi Pharmaceutical’s NicVax is another Phase I therapeutic vaccine, while Sanofi’s Acomplia™ is a Phase III drug therapy under development for both obesity and smoking cessation.

TA-NIC is an early stage therapeutic vaccine for smoking cessation with interesting Phase I trial results and substantial obstacles in the form of pivotal Phase 3 trials to overcome. We currently recommend no assessment activities for health services clients at this time.

Technology Details
Target Disease / Indication: Smoking Cessation/Nicotine Addiction
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine/Addictions
Regulatory Status: Phase I
BioHorizon Impact Score: 53/100 – Moderate

The purpose of the double-blind, placebo-controlled study is to evaluate the efficacy and safety of dexanabinol as a neuroprotectant agent in severe TBI patients. Enrolled patients were given a single dose of 150mg dexanabinol or placebo within six hours after injury and received the standard care normally provided to TBI patients in intensive care units. The primary endpoint for the study will be patient outcome as measured on the Glasgow Outcome Scale – Extended (GOSE) six months after injury.

Physical trauma to the brain triggers a complex network of cascades that produce neuronal damage and death far beyond that caused by the initial insult. Dexanabinol, a tricyclic dextrocannabinoid, is thought to exert its neuroprotective effect through three mechanisms of action that suppress these toxic and inflammatory cascades induced by TBI: the inhibition of NMDA stimulated calcium influx, the inhibition of TNF alpha and other inflammatory cytokines, and free radical scavenging.

Annually in the United States, there are about two million emergency room visits for head injury, about 300,000 admissions for head trauma, and approximately 52,000 deaths. According to Pharmos Corporation, the annual market potential for a drug treating new TBI victims in the U.S. is over $500 million. Currently, there is no FDA approved product for the treatment of severe head injury.

Dexanabinol remains a Moderate Impact Technology in the Biohorizon Emerging Health Technology Database, with no assessment activities recommended at the present time for clients operating trauma programs. However, Dexanabinol has the potential to transform the management of patients with severe TBI and as such should be monitored closely over the coming months.

Technology Details
Target Disease / Indication
Traumatic Brain Injury

Technology Classification
Drug

Body System
Nervous System

Program Area
Medicine/Neurology

Regulatory Status
Phase III

BioHorizon Impact Score
51/100 – Moderate

Indiplon is a unique non-benzodiazapine agent that acts on a specific site of the GABA-A receptor. Indiplon has been shown to bind selectively to the specific subtype of GABA-A receptors within the brain believed to be responsible for promoting sleep. There are two formulations of indiplon: immediate release and modified release. Both formulations are being studied in clinical trials to address different types of sleep problems. Insomnia is a prevalent condition in the United States, with nearly one-half of the adult population reporting trouble sleeping a few nights per week or more, according to the National Sleep Foundation's (NSF) Sleep in America Poll 2002. Approximately 35% of the adult population reports that they have experienced insomnia every night or almost every night within the past year. According to some analysts, the $2 billion market for sleep disorder drugs could eventually rise to $3 billion. However, we feel that existing approved therapies like Sanofi’s AmbienR, and King’s SonataR, combined with the promise of imminent new treatments like Sepracor’s Estorra™, make the insomnia marketplace a competitive one.

If approved, we feel indiplon will represent a Moderate Impact Technology, and recommend no early assessment activities at this time.

Technology Details
Target Disease / Indication: Insomnia
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine/Psychiatry
Regulatory Status: Phase III
BioHorizon Impact Score: 54/100 – Moderate

Wet AMD is a disease that causes a loss of central vision. It is caused by choroidal neovascularization (CNV), a growth of abnormal blood vessels under the central part of the retina, or the macula. These vessels leak fluid and cause scar tissue that attacks central vision, resulting in a deterioration of sight over a period that can range from a few months to three years. About 500,000 people are diagnosed with the eye disease each year, with 400,000 of those in the United States and Europe. Of those, 125,000 are classic, 175,000 are minimally classic and 200,000 have the occult form of the disease.

Visudyne therapy is a two-step procedure. Following intravenous administration, Visudyne is activated by a non-thermal laser light directed at the eye. This process is known as photodynamic therapy. Visudyne selectively targets abnormal blood vessels under the retina, resulting in a reduction in their growth, without affecting normal/healthy retina tissue. This in turn stops the leakage associated with wet AMD. Together with its partner Novartis, QLT reported Visudyne sales of $357 million dollars for the year ended Dec 31, 2003. Wall Street analysts have projected earnings in the $500 million dollar range for 2004. There are currently no competing, approved, photodynamic therapies for the treatment of wet AMD. In November 2003, a competing treatment showed “no improvement” over QLT’s treatment. According to a QLT statement, data from phase III trials for Macugen, a drug being developed by Pfizer and Eyetech Pharmaceuticals “do not appear to offer any treatment benefit over (Visudyne) “.

We feel Visudyne represents true innovation, and based upon our assessment of disease prevalence, treatment efficacy, and demand/diffusion characteristics have designated it a High Impact health technology. We are advising clients to initiate preliminary assessment activities.

Technology Details
Target Disease / Indication: Age Related Macular Degeneration
Technology Classification: Drug-Photodynamic Therapy
Body System: Nervous System
Program Area: Surgery/Ophthalmology
Regulatory Status: Approved
BioHorizon Impact Score: 73/100 – High

A 28-week study published in the New England Journal of Medicine compared memantine with placebo in persons with moderate-to-severe Alzheimer’s disease. Among the patients who completed the study, memantine appeared to confer benefit in terms of activities of daily living and other measures. A second study published in the Journal of the American Medical Association concluded that: “In patients with moderate to severe AD receiving stable doses of donepezil (Aricept), memantine resulted in significantly better outcomes than placebo”. These results together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD. Currently advertised Internet prices place the cost of treatment at approximately $6.00/day or $2190/year for 112 tabs (from www.memantine-supple.com, accessed Jan 30, 2004). This is comparable to the cost of Aricept. The study in JAMA raises the possibility of Namenda being used in addition to Aricept in the control of Alzheimer’s and would represent an approximate doubling of direct drug costs per patient. Wall Street analysts have estimated sales for Namenda in the $800, 000, 000/year range. Forest Laboratories have announced recent substantial increase in sales force to support anticipated sales requirements.

We think that Forest Laboratories’ Namenda has the potential to become a High Impact health technology and therefore recommend pharmacy and therapeutic programs begin some early assessment activities. Particular attention should be paid to therapeutic regimens using Namenda in addition to Aricept as this represents a significant direct cost increase.

Technology Details
Target Disease / Indication: Alzheimer’s Disease (moderate to severe)
Technology Classification: Drug
Body System: Nervous System
Program Area: Medicine
Regulatory Status: Approved
BioHorizon Impact Score: 75/100 – High