The regulatory uncertainty surrounding Shire’s hypotension drug midodrine (ProAmatine and generics) leaves Chelsea Therapeutics International Ltd. in a good position for its newly submitted Northera (droxidopa).

FDA Commissioner Margaret Hamburg is currently weighing whether to grant a hearing on the Center for Drug Evaluation and Research’s proposal to withdraw midodrine’s accelerated approval because of failure to confirm efficacy. If FDA decides to approve droxidopa, the alternative treatment could affect the decision on midodrine.

The timing will be close. Chelsea’s pending NDA for the norepinephrine prodrug for treatment of neurogenic orthostatic hypotension could see regulatory action by the end of March 2012. That is approximately two months after the deadline Shire and several generic companies have been given to make their case for why Hamburg should grant a hearing.

Northera’s user fee date could fall around the time that Commissioner Hamburg decides whether to hold a hearing on ProAmatine.

Chelsea could stand to inherit a ready-made patient population if Hamburg concludes, either with or without a hearing, that midodrine – the only drug approved for treating orthostatic hypotension – should come off the market for failure to verify clinical benefit.

But even if the commissioner decides to keep midodrine available, droxidopa could stake its claim to the orthostatic hypotension market, particularly if it is approved with labeling that is strong on efficacy and clean on safety.

It remains to be seen, however, whether CDER agrees that Chelsea has succeeded in doing what it says Shire has not: demonstrating that a treatment for orthostatic hypotension has a symptomatic benefit.

Subset Of Orthostatic Hypotension Patients

In an NDA submission announced Sept. 28, Chelsea seeks approval for treatment of symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency and non-diabetic autonomic neuropathy.

The company requested a priority review from FDA’s Division of Cardiovascular and Renal Products. If granted, a six-month review would put the user fee date in late March. As a new molecular entity, however, droxidopa is likely to go before an advisory committee – a process that could extend the review timeline beyond the six-month target.

NOH involves a sudden drop in blood pressure when a patient stands up from a sitting or lying position. It is caused by diminished synthesis or release of norepinephrine used by autonomic nerves to regulate vasoconstriction. The condition can lead to dizziness, lightheadedness and fainting; in some cases, patients have difficulty standing unaided for more than a few minutes a day, Chelsea said.

Droxidopa has been marketed in Japan since 1989. It is an orally active synthetic precursor of norepinephrine that replenishes diminished levels of norepinephrine within the autonomic nervous system, thereby treating the root cause of NOH.

In an interview with “The Pink Sheet,” Chelsea executives said NOH accounts for about 85% of the broader symptomatic orthostatic hypotension population. For the remaining 15% of patients, their conditions are the result of cardiovascular problems or diabetes.

Two Therapeutic Options

Approximately 180,000 patients in the U.S suffer from NOH, Chelsea Vice President of Marketing and Sales Keith Schmidt said. About 80,000 of them take midodrine, while another 80,000-90,000 take fludrocortisone – a synthetic adrenocortical steroid that works by increasing sodium retention, enhancing plasma volume and raising blood pressure. It is not FDA approved for orthostatic hypotension.

Midodrine is the only FDA-approved treatment for symptomatic orthostatic hypotension. It works through activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing increases in vascular tone and blood pressure.

The drug’s label carries a boxed warning about the risk of marked elevation in supine blood pressure and advises that therapy should be reserved only for those patients whose lives are considerably impaired despite standard clinical care.

Midodrine received accelerated approval in 1996 based on its effect on an increase in one-minute standing systolic blood pressure, a surrogate marker considered likely to correspond to clinical benefit.

Shire acquired the ProAmatine NDA in 2000 and completed two confirmatory trials, but CDER concluded the studies failed to verify and describe the drug’s clinical benefit. In August 2010, CDER formally proposed to withdraw the ProAmatine NDA and the midodrine ANDA approvals. Shire’s request for a public hearing on the proposed withdrawal has been pending for more than a year (Also see "Amid Avastin Noise, Shire Quietly Awaits Word On ProAmatine Public Hearing" - Pink Sheet, 8 August, 2011.).

In October, the commissioner’s office announced a timeline for additional submissions by CDER, Shire and the ANDA holders. Based on this schedule, a decision on whether a hearing will be convened is not expected until the first quarter of 2012 at the earliest (Also see "Shire’s Request For ProAmatine Hearing Will Go Unanswered Until 2012" - Pink Sheet, 24 October, 2011.).

Current midodrine sales are about $35 million to $37 million a year, according to Chelsea. The drug is marketed by five generic companies. Although Shire no longer sells the branded product, it has been fighting to keep midodrine on the market.

Shire asserts that re-analyses of the two completed post-approval studies, coupled with extensive clinical experience and the unmet need for viable treatment options, supports maintaining approval.

In a Sept. 22 press release, Shire reiterated that it is “committed to ensuring midodrine remains available for patients who critically need this medicine and who would be left without alternative treatments should it be withdrawn from the market.”

However, this argument could sound a hollow note if droxidopa gains FDA’s blessing. If approved on the basis of clinical studies demonstrating symptomatic benefit, droxidopa would provide an on-label treatment option for those NOH patients currently taking midodrine.

One Trial Wins, Another Misses

Chelsea’s NDA includes data from two placebo-controlled Phase III trials.

In Study 301, conducted under a special protocol assessment, more than 160 patients were evaluated for symptomatic and functional improvements using the Orthostatic Hypotension Questionnaire composite. This instrument assesses the symptoms of low-blood pressure and the degree to which they interfere with activities of daily living. Droxidopa treatment was associated with a clinically and statistically significant improvement in the OHQ composite, Chelsea said.

In Study 302, which preceded Study 301, the primary efficacy endpoint was change in the dizziness component of the Orthostatic Hypotension Symptom Assessment. The 101-patient study failed to demonstrate statistically significant improvement on this endpoint.

Chelsea executives point out that Study 302 had fewer participants, and therefore less power, to demonstrate a significant effect on the primary endpoint than did Study 301. Additional analyses of Study 302 confirmed statistically significant symptomatic benefit across multiple clinically relevant components, as well as a significant improvement in the OHQ composite, the company said.

Labeling based on improvements in a composite symptomatic endpoint “will be much richer than it would have been if we were just talking about dizziness,” Chelsea’s Schmidt said.

Chelsea’s Schmidt said the success of Study 301 on the composite endpoint should make for an attractive label. “The label will be much richer than it would have been if we were just talking about dizziness,” he said.

Simon Pedder, Chelsea’s president and CEO, said FDA agreed with the company’s plan to file an NDA with Study 301 serving as the pivotal trial and Study 302 providing supportive efficacy data. Nevertheless, it remains to be seen how FDA’s cardio-renal division will view the data, particularly given that one of the studies missed its primary endpoint.

Improved Compliance Vs. Higher Cost

It is unclear what effect, if any, droxidopa’s regulatory status will have on the current tussle over the future availability of midodrine.

CDER’s proposal to withdraw midodrine due to the failure to confirm clinical benefit was without regard to currently available or future alternative treatments. However, the agency does consider the availability of other therapeutic options when evaluating the risk/benefit equation for a drug.

Even if midodrine remains available, Chelsea executives believe droxidopa will have several advantages over the older product, including labeling with clinical data showing a benefit on clinically important symptoms and activities of daily living, and a milder side effect profile that should aid compliance.

In addition to supine hypertension, midodrine is associated with adverse effects commonly seen with alpha agonists, including tingling, numbness and goosebumps. Compliance with the drug regimen is poor, with approximately 50% of patients taking fewer pills than prescribed or going off therapy, Schmidt said.

Fludrocortisone also presents its own safety issues, according to Schmidt. Water-weight gain associated with the drug can be problematic for frail and elderly patients, along with those who are overweight or have cardiovascular disease.

While Chelsea believes it has a marketing advantage on both efficacy and safety over midodrine and fludrocortisone, it faces an uphill battle when it comes to price. The average daily costs for midodrine and fludrocortisone treatment are $6.19 and $0.26, respectively, it noted.

The company has been using a droxidopa price of $30 per day in its modeling assumptions. At this price, the company believes the drug could generate $300-$375 million in U.S. sales within three to five years of launch, assuming 70% patient compliance.

By Sue Sutter

Chelsea’s Hypotension Drug Droxidopa Could Fill Void If FDA Pulls ProAmatine

More from Archive

More from Pink Sheet