Acusphere, Inc. (ACUS.PK) today issued the following letter to shareholders:

Dear Fellow Shareholders:

As I have done in the past, I want to provide you with an update on the Company’s progress since my last letter of October 2009, and our plans moving forward in the coming months. We have made substantive progress on our stated goals, and we are now working diligently on the next phase of our strategy. Moving the development of our lead product candidate, Imagify™ (Perflubutane Polymer Microspheres) for Injectable Suspension, forward remains our critical mission, because it remains the leader in myocardial perfusion assessment with ultrasound, an important investigational area. It continues to show promise in addressing a potential $2 billion market that is growing, and it offers compelling competitive advantages over the standard of care, nuclear stress testing. We continue to believe strongly in Imagify’s potential for the condition proposed, and we are committed to realizing that opportunity.

As you know, in early 2009, we received feedback from the U.S. Food & Drug Administration (FDA) in the complete response letter to our New Drug Application (NDA) stating that another clinical trial would be required for U.S. approval, this one demonstrating that Imagify with ultrasound is superior to ultrasound without Imagify. With that feedback, we quickly took steps to reduce our burn rate dramatically, and we restructured our partnership agreements to regain worldwide rights to our Imagify intellectual property. Since then, we have completed several pivotal tasks that are critical to our ability to close a partnership with a larger pharmaceutical company – achieving greater clarity about the U.S. trial design, cost and timing, as well as the likely requirements for approval of Imagify in Europe. I am pleased with our progress on each of these.

Imagify Is the Leader in Myocardial Perfusion Assessment with Ultrasound

First a word on Imagify’s current market position. Ultrasound is one of the least expensive, most widely available and most convenient ways to image the body, but ultrasound alone is not capable of assessing myocardial perfusion (e.g. blood flow in the heart muscle). The ability to evaluate perfusion in the heart muscle allows for early detection of coronary artery disease (CAD) – the leading cause of death in the U.S. and many other parts of the world. We believe that Imagify, if approved, has the potential to improve the ability of heart stress ultrasound tests (stress ultrasound) to compete with the nuclear stress test, an inconvenient and expensive standard for assessing perfusion today. More than 10 million nuclear stress tests and stress ultrasounds are performed each year in the U.S., providing Imagify with a market potential of more than $2 billion per year in the U.S. alone. In Europe, approximately 3 million CAD imaging procedures are performed each year, representing an additional $600 million market, with substantial opportunity for growth since the prevalence of heart disease is about the same as in the U.S. and the population sizes are similar. We believe our Imagify Phase 3 clinical program demonstrates that the efficacy of Imagify with ultrasound is non-inferior, or equivalent, to nuclear stress. Imagify was evaluated in more than 1,000 patients and as a result, we believe that it is well tolerated, with a safety profile similar to other drugs used in this patient population.

Regulatory Requirements for Approval of Imagify in the U.S. and Europe

According to the FDA’s complete response letter, another clinical trial demonstrating the benefits of stress ultrasound with Imagify compared to stress ultrasound without Imagify would be required for approval. (Our clinical trials compared ultrasound with Imagify to nuclear stress imaging.) Following many months of intense work, in late January 2010, we met with FDA and reached agreement on the overall design of the proposed new U.S. trial. While additional work remains to achieve final agreement on the specifics of the clinical protocol and statistical analysis plan, we believe we now have sufficient information to provide a scope for the trial. We forecast that this trial will cost approximately $15 million and will require about 2 years to complete, based upon enrollment of 850 patients. We are confident that this trial has a high probability of success, based upon what is known in the literature about the superior performance of nuclear stress to stress ultrasound and based upon our Phase 3 trial results demonstrating that Imagify with ultrasound has equivalent efficacy to nuclear stress. Reaching agreement on a trial design with FDA is a significant accomplishment, and one that helps position us better for our next phase of implementing our strategy.

In Europe, we believe the prospects for approval of Imagify without another trial are good, based upon a recently completed full review of our European regulatory status by two independent European regulatory consultants. Therefore, our focus over the next several months will be on preparing the Marketing Authorization Application (MAA) for filing in Q4 2010, building upon the work that our previous partner, Nycomed, had done, in concert with our NDA.

We have no plans for additional regulatory work in the U.S. until we raise additional capital. Since approximately 14 months and $3 million will be required to produce clinical trial material (CTM) at a contract manufacturing firm we have identified, our timeline calls for finalizing the clinical protocol and statistical analysis plan with FDA once the CTM production is underway.

Operational Plans

Also in October 2009, we announced that we sold equipment in our commercial manufacturing facility in Tewksbury, Mass., to Hovione Farmaciencia SA, for a total of $2.5 million. $1.9 million was received at the closing in October and the remaining $0.6 million was received in February 2010. Hovione has moved all the equipment out of the Tewksbury facility, and we have relocated to smaller, more cost-effective space in Cambridge, Massachusetts.

At the end of February, 2010, we had an unaudited cash balance of approximately $1.9 million. Our existing cash should fund operations into the third quarter of 2010 without considering any additional capital we might raise, providing us additional time to explore financing options for Imagify’s continued development. But understandably, given the time constraints associated with our cash balance, we are exploring all financing options right now.

Status of Partnership Discussions

Once we regained worldwide rights to Imagify in June 2009, we immediately began discussions with larger pharmaceutical companies about a potential acquisition or partnership as a means to fund and complete the clinical trial for Imagify that FDA requires for approval. We are confident that we have a compelling story for potential partners - Imagify is the leading ultrasound contrast agent for perfusion imaging, it addresses a potential U.S. market of $2 billion, substantial data already exists on more than 1,000 patients and the new trial required by FDA should have a high probability of success.

We were pleased by the interest expressed in Imagify, and based upon feedback from these discussions, in October we turned our focus to addressing the most pressing issue: clarifying the regulatory requirements for approval in the U.S. and Europe so that the cost, timing and risk profile for the next trial would be easier to predict. Having reached agreement on the overall trial design with FDA and completed a European regulatory assessment, we are recommencing these partnering discussions with renewed energy, and broadening our discussions to include companies with a strong presence in Europe where the path to commercialization may be quicker. In order to complete a transaction on reasonable terms, we still must address many other issues, and I would note in particular that our limited cash position obviously puts us in a more vulnerable negotiating position. That said, however, we are approaching this effort with what we believe to be a strong product candidate, with strong science and a large market potential, so we are optimistic about our opportunities.

Recent Accomplishments

Since October 2009, we have accomplished many important goals, all designed to further the development of Imagify:

• Retained a clinical research organization (CRO) to design the next clinical trial
• Prepared a synopsis of our proposed trial design for FDA
• Met with FDA for feedback on this synopsis
• Obtained FDA feedback that makes the cost, timing and risk profile of that trial more predictable
• Completed a European regulatory assessment concluding that the prospects for Imagify’s approval in Europe without another trial are likely.

Goals for 2010

Given the positive outcome of the European regulatory assessment, we will be allocating our regulatory resources this year toward Europe, where approval may be much faster than in the U.S. Our plans include the following steps:

• Conduct a pre-MAA filing meeting with the European rapporteur at the European Medicines Authority (EMA) (Q3 2010)
• Reach agreement on the Paediatric Investigational Plan required before submitting the MAA (Q4 2010)
• Submit the MAA (Q4 2010)

At the same time, we will also be focused on re-commencing discussions with potential strategic partners, especially with companies in Europe, and closing additional financing that enables us to begin work on establishing a contract manufacturer to prepare for the manufacturing site inspection by the European Medicines Authority (EMA) as well as to produce CTM for the U.S. clinical trial. We will also be finalizing the trial protocol and statistical analysis plan.

I would like to thank you for remaining supportive as we move forward, and for playing an important role in the continued development of our exciting drug candidate, Imagify.

Sincerely,
Sherri C. Oberg
President and Executive Chairman

About Acusphere, Inc.

Acusphere (ACUS.PK) is a specialty pharmaceutical company that develops new drugs and improved formulations of existing drugs using its proprietary microsphere technology. We are focused on developing proprietary drugs that can offer significant benefits such as improved safety and efficacy, increased patient compliance, greater ease of use, expanded indications or reduced cost. Our lead product candidate, ImagifyTM (Perflubutane Polymer Microspheres) for Injectable Suspension, is a cardiovascular drug for the detection of coronary artery disease, the leading cause of death in the United States, for which a New Drug Application (NDA) was submitted to the U.S. Food & Drug Administration (FDA) in April 2008 and filed in June 2008. Imagify and the Company's other product candidates were created using proprietary technology that enables Acusphere to control the porosity and size of nanoparticles and microspheres in a versatile manner that allows them to be customized to address the delivery needs of a variety of drugs. For more information about Acusphere visit the Company's web site (www.acusphere.com).

Forward-looking Statements

The above press release contains forward-looking statements, including statements regarding, the NDA submission for Imagify and likelihood of regulatory approval and the commercial opportunity for Imagify. There can be no assurance that Imagify will be approved for the indication the Company is seeking, or at all. The Company's actual results may differ materially from those anticipated in these forward-looking statements based upon a number of factors, including anticipated operating losses and existing capital obligations, uncertainties associated with research, development, testing and related regulatory approvals, including uncertainties regarding regulatory evaluation of the Company's statistical analysis plan and clinical trial results and uncertainties regarding the potential effects of not achieving clinical endpoints, limited time to date for the Company to review the details of the clinical trial results, capital needs and uncertainty of additional financing, uncertainties regarding the cost, timing and ultimate success of the qualification of the Company's commercial manufacturing facility in accordance with applicable regulatory requirements, complex manufacturing, high quality requirements, lack of commercial manufacturing experience, dependence on third-party manufacturers, suppliers and collaborators, uncertainties associated with intellectual property, competition, loss of key personnel, uncertainties associated with market acceptance and adequacy of reimbursement, technological change and government regulation. The Company notes that effective as of March 3, 2009, pursuant to a Form 15 filing made with the SEC, it is not currently required to file periodic reports with the SEC, including annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K. Readers are cautioned not to place undue reliance on any forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly release the results of any revisions to these forward-looking statements that may be made to reflect events or circumstances that occur after the date of this press release or to reflect the occurrence of unanticipated events.