Sound Pharmaceuticals Hires Two New Executives to Speed Development of Meniere’s Drug

By Brian Taylor

SEATTLE, WASHINGTON — announced this week that it has hired two senior executives. Paul Hoskins, appointed to the position of Senior Director of Clinical Operations and G. Michael Wall, appointed to the position of Senior Director of Pharmaceutical Development. The new executives join the company with substantial backgrounds in the pharmaceutical industry. Sound Pharmaceuticals hopes that the new additions will help them accelerate a drug development program to treat Ménière’s disease. 
Ménière’s disease affects an estimated 600,000 people in the US, and approximately 5 million worldwide. The debilitating condition — with symptoms of vertigo, hearing loss and tinnitus — is typically managed, with varying degrees of success, through dietary changes, diuretics and steroids.
Currently, there are no FDA-approved drugs to treat Ménière’s disease.
 

Accelerating Ménière’s Drug Development

Paul Hoskins joins Sound Pharmaceuticals with more than two decades in the biotech and pharmaceutical industry, most recently as an Executive Director of Research at Merck. He brings a significant level of experience in clinical trials, and has provided operational expertise to in-man trials conducted in Europe, Asia, Latin America and the US.
G. Michael Wall joins the company with over 25 year in the biotech and pharmaceutical industry. Mr. Wall was a Senior Director of Alcon, now Novartis, for two decades. In his previous role with Alcon, he led the development and approval of Ciprodex, an antibiotic/steroid otic drop for ear infections, and Patinas, an antihistamine nasal spray for allergic rhinitis.
 
“We are pleased to have two experienced biotech executives join our team and advance our clinical trials in this important area of neurotology” —Jonathan Kil, MD, Co-Founder and CEO, Sound Pharmaceuticals
 
Source: Sound Pharmaceuticals, PSBJ

Meniere’s Update #1

By Alan Desmond

In my last post, I made the statement, “Meniere’s is poorly understood and not very responsive to treatment intended to regulate fluid pressure within the labyrinth. There are several theories regarding the cause of Meniere’s symptoms, but no one knows for sure.” I say this based on literature review, my years of experience, and I reflect back on a ten part series I did on this blog in 2012 titled “Treatments for Meniere’s disease: Fact, Fiction, or Biological Plausibility.”

Things can change so quickly that I thought it wise to review that series, and update where necessary. I don’t think I will need ten parts for the update, but let’s begin.

I began the series discussing the use of betahistine, which is used frequently in the United Kingdom, but is not approved by the FDA in the United States. As of August, 2016, it is still not approved by the FDA and there is little additional research. There is one important additional study performed in Germany that was published in 2016. It seems to confirm the FDA opinion that Betahistine is safe, but probably ineffective in treating Meniere’s disease. Like many treatments for Meniere’s disease, they found no differences between the patients taking Betahistine and taking a placebo. Excerpts of the article and a link to the full article are pasted below.

There is one excerpt from the article that caught my eye, so I share it here:
“How betahistine might have an effect in the prophylactic treatment of Meniere’s disease is so far unknown. It could lead to an improvement of labyrinthine microcirculation, thereby rebalancing the production and resorption of endolymph. The drug was first registered in Europe in the 1970s and has been administered to more than 100 million patients so far.”

Think about that, no one is sure of the mechanism of action, there is no evidence that it makes a difference, yet over 100 million patients have been prescribed Betahistine.  Here’s an excerpt from the abstract:

Efficacy And Safety Of Betahistine Treatment in Patients with Meniere’s Disease: Primary Results of a Long Term, Multicentre, Double Blind, Randomised, Placebo Controlled, Dose Defining Trial (BEMED trial).

Adrion C¹, Fischer CS², Wagner J³, Gürkov R⁴, Mansmann U⁵, Strupp M⁶; BEMED Study Group
Participants received placebo (n=74), low dose betahistine (2 × 24 mg daily, (n=73)), or high dose betahistine (3 × 48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients’ diaries during a three month assessment period at months seven to nine. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several observer-reported parameters to assess changes in audiological and vestibular function.

STUDY ANSWER AND LIMITATIONS:

Incidence of attacks related to Meniere’s disease did not differ between the three treatment groups.
 
I found a second study that is equally interesting. In 2014, JJ Nauta published a meta-analysis of 12 studies measuring efficacy of Betahistine for treating vertigo and Meniere’s disease. His conclusion was that Betahistine almost doubled the chances of reducing symptoms of vertigo compared to placebo. Journal reviewers (Database of Abstracts of Reviews of Effects (DARE) did not take kindly to what they apparently perceived to be biased and unsupported conclusions. The reviewers conclude:
“There were substantial limitations to the review, and there was little evidence, which was varied. Given these limitations, the treatment effect may have been overestimated. The author’s conclusions cannot, therefore, be considered to be reliable.

Conflict of Interests: The author was an employee of Abbott, a manufacturer of betahistine.”
It appears that betahistine, while widely used in Europe, is a harmless, but probably ineffective treatment for Meniere’s disease.

Meniere’s Update #2 Diet and Diuretics

By Alan Desmond

Diet and Diuretics

Meniere’s disease is believed to be the result of too much inner ear fluid in the affected ear. Some practitioners believe that overall fluid retention in the body is connected to fluid retention in the inner ear. Diet and diuretics are intended to reduce overall fluid retention with the goal of reducing volume of inner ear fluid (endolymph). The 1985 Committee on Equilibrium made an expert panel recommendation to prescribe a low salt diet and/or diuretics for Meniere’s patients. The effectiveness of this recommendation has been studied with less than impressive results. If you want to review my original posts on this subject, click here and here.

Salt Restriction

There has been one notable study regarding salt consumption and Meniere’s disease since my initial 2012 post. Miyashita and colleagues published a study this year (2016) where they monitored sodium levels in Meniere’s patients over two years. They reported that those with the lowest sodium levels had modest improvement in hearing and vertigo complaints compared to patients with higher sodium levels. This study was quite small (only 13 patients total). The authors proposed the theory that reduced sodium levels leads to increases in plasma aldesterone levels, which they believe may lead to increased endolymph absorption. Per WebMD “Aldosterone helps regulate sodium and potassium levels in the body. This helps control blood pressure and the balance of fluids and electrolytes in the blood.“

Diuretics

Earlier this year (2016) researchers from Duke University performed an extensive literature review of articles evaluating the efficacy of diuretics in treating Meniere’s symptoms. In the introduction, they state “Despite the widespread use of diuretics for this condition, limited evidence for its efficacy has been demonstrated.” In the discussion section, they state, “If clinicians observe strict adherence to the strength of the evidence as the basis for which clinical decisions are made, the efficacy of diuretics in the treatment of MD is speculative at best. However, in situations where a large body of low level evidence exists with a lack of affirmative high level evidence, we should not preclude the use of such therapies.” Finally, they conclude, “Multiple low evidence level studies report that oral diuretic therapy may be beneficial in the medical management of MD…. “These conclusions are mitigated by multiple limitations, including the natural history of MD, study design, and the possibility of publication bias.”

Is There Any Potential Harm?

At least one study by Pirodda and colleagues (2011) suggests that lowering salt intake can result in “abrupt lowering of blood pressure: a subsequent exaggerated vasomotor response including local ischemia could be responsible for more or less permanent damage.” I am not aware of any clinical studies to support this theory.
To wrap up this post, I include a paragraph from a recent  2015 review by Syed and colleagues titled “Ménière’s Syndrome or Disease: Time Trends in Management and Quality of Evidence Over the Last Two Decades". Please click on the link for the full article with references.

Medical Treatment

For MS/D (Meniere’s syndrome/disease), medical treatment typically encompasses conservative treatment (low-salt diet and lifestyle modification) and or diuretics and betahistine (outside the United States). It has been suggested that a high-salt diet can influence the osmotic gradients in the inner ear, resulting in endolymphatic hydrops; however, investigators have challenged the simple notion that salt restriction affects the fluid dynamics of the ear in ways that would significantly influence the degree of hydrops. We found one study (type III evidence) to support the role of salt restriction and diet modification in reducing the frequency or severity of symptoms from MS/D in the last 20 years. The Luxford et al. study investigated patients’ willingness and ability to modify their diets, including ease of use of the low-salt and caffeine-free diets, and Nutrition education by referral to a registered dietician suggests improved outcomes in the medical treatment of MS/D. They concluded that nutrition education by referral to a registered dietician may improve outcomes in the medical treatment of Ménière’s disease. However, they did not investigate the pathophysiologic effects of the dietary changes.

Diuretics have been in use in the treatment for Ménière’s for several decades and are thought to reduce the degree of endolymphatic hydrops by reducing the extracellular fluids in the body. A recent Cochrane review found “there is no good evidence for or against the use of diuretics in MS/D.” We found no studies reporting the specific use of diuretics in the treatment of MS/D in the last two decades.

Summary

Although diet and diuretics continue to be the mainstay of treatment for early or suspected Meniere’s disease, it appears the general sentiment is that it might help and it will do no harm. It also allows some time to pass, so both the patient and clinician get a better picture of the disease before more aggressive treatments are considered. Nothing really dramatic has changed on this topic since my original post in 2012.

Meniere’s Update #3 – Meniett Device

By Alan Desmond

In 2012, I reported here that meta-analysis demonstrated no benefit in reducing the frequency or severity of Meniere’s episodes when compared to placebo. Since that time, one particularly high quality clinical trial and one updated meta-analysis have been published.

First, the updated meta-analysis: A group out of China reviewed multiple studies and did not state that there was no benefit, but certainly did not give the Meniett a ringing endorsement. Here are the last few lines from their publication, “This study has some limitations. First, the included studies may suggest that Meniett therapy might be effective but the conclusion was significantly restricted by the overall lack of control groups and the apparently shortened follow-up period. Second, most of the included studies were retrospective and had small sample sizes. Third, few of the included reports provided detailed information about severity of the disease, and we were unable to identify the impact of disease severity on the prognosis. Fourth, previous endolymphatic sac surgery or intratympanic gentamycin perfusion and bilaterality of the disease may confound the evaluation.

Finally, our meta-analysis showed that: 1) Meniett therapy may prevent vertigo attacks and substantially reduce its frequency in MD patients; 2) the impact of Meniett therapy on hearing remains uncertain; 3) Meniett therapy may alleviate the functional deficit and improve the quality of life; and 4) the optimal effect of Meniett therapy might last for approximately 18 months. In conclusion, it seems that Meniett therapy is, to some extent, effective for the treatment of MD, and may serve as a second-line treatment.”  

Next, a new, independent study:
Researchers from Europe (France and Italy) performed a randomized, double blind, placebo controlled study with the goal of determining whether the Meniett device reduced the number of episodes of vertigo associated with intractable Meniere’s disease, and whether there was any noted impact on daily life.

Patients meeting the study criteria were randomly placed into two groups. One group received recommended Meniett treatment, while the second group received a placebo treatment. Patients in both groups showed improvement, which may have been the result of other medical treatment, or possibly a result of the natural course of the disease. No differences were noted between the two groups at the completion of the treatment regimen.

While it is hard to make definitive statements about the effectiveness of treatments for a fluctuating and mysterious disease like Meniere’s disease, the evidence keeps building that the Meniett device is a plausible idea, with little evidence of clinical effectiveness.

Meniere’s Update #4

By Alan Desmond

Endolymphatic Sac Surgery

This week, I had intended to provide the fourth post in the Meniere’s update series with some clarity on the role of surgical procedures intended to reduce endolymphatic pressure in patients with Meniere’s disease. My initial 2012 post on this topic discussed the lack of definitive information surrounding the benefit of these procedures. My hope was to review articles published since 2012 and gain some clarity or offer some conclusions. That did not happen. I think my reading made me even more confused.

Unlike some of the treatments discussed earlier in this series, there are quite a few new contributions to the literature regarding endolymph sac decompression and shunting procedures. I will discuss a few and conclude with at least one unifying theme.

In 2014, researchers at the University of Michigan did a comparative study of what they describe as “second echelon treatments for Meniere’s disease.” I think this is an accurate descriptor, as the procedures compared are usually attempted after diet and diuretic, and before ablative procedures such as labyrinthectomy are considered. The “second echelon treatments” studied were: 1. the Meniett device (reviewed here last time), 2. endolymphatic sac decompression, and 3: intra-tympanic gentamicin.

There was no significant difference in symptom relief, residual auditory perception, or number of patients going on for labyrinthectomy when comparing the three treatment options.

Researchers from the University of South Carolina performed an extensive “Systematic Review and Meta-Analysis” of various Endolymphatic Sac Surgeries. The article is extremely detailed and worth reading. The link above will bring you to the abstract, but you may need to purchase the article to get the full text. Here is their conclusion:

“In conclusion, ESS (sac decompression or sac shunting) controls vertigo in the short term (>1 yr of follow-up) in at least 3 of 4 patients with MD who have failed medical therapy, without prior trial of intratympanic steroids or gentamicin. In the long term, vertigo control with the pooled patient data demonstrates a similar 75% Category A/B result. It should be noted, however, that the long-term results are less favorable when the same cohort of patients is followed up over time (73% control at 16 mo follow-up versus 63% at approximately 6.5 yr of follow-up).

There is no statistical difference between sac decompression and mastoid shunting procedures in controlling vertiginous symptoms or preserving hearing in the short-term or long-term follow-up periods. There is also no difference in vertigo control between shunt procedures with and without silastic. There is, however, a statistical difference in hearing preservation, both in the short and long term, between shunting with and without silastic, in favor of no silastic.

This analysis raises the issue of using silastic in ESS. Although vertigo control is similar in the short and long term, silastic sheeting seems to have a small but statistically significant adverse effect on hearing. In our opinion, a fair assessment would be that once the sac is opened, placing silastic does not add benefit and may be deleterious.”

The third study compared the benefits of endolymphatic sac surgery compared to tenotomy of the middle ear muscles. SAY WHAT? Tenotomy is defined as “a surgical act which involves division of a tendon.” These authors out of Italy report that severing the stapedius and tensor tympani tendons had similar vertigo control to endolymphatic sac surgery, but tenotomy resulted in better outcomes for functional level measured by DHI, need for additional surgery and residual hearing preservation. WHAT?

I admit that I was unfamiliar with tenotomy of the middle ear muscles as a treatment for Meniere’s disease. Let me do a little homework and get back to you on that.

If you have been able to wade through this, you will note one unifying theme. All of the procedures discussed have similar impact on control of vertigo symptoms, and that effect is not terribly different than the natural course of Meniere’s disease in patients that do not undergo any of the mentioned procedures.