Why do Promising Cardiovascular Drugs Fail?

In the world of drug development, the journey from promising molecule to approved medication is fraught with challenges. Nowhere is this more evident than in the field of cardiovascular medicine, where, despite significant unmet medical needs, the number of new drugs entering late-stage clinical trials has been declining. This blog explores the critical issue of why even promising drug candidates often fail to progress to pivotal Phase 3 trials, highlighting the importance of collaboration, partnerships, and efficient trial management in overcoming these hurdles.

The Declining Landscape of Cardiovascular Drug Development

The cardiovascular therapeutic area has seen a troubling trend in recent years. Between 1990 and the present day, the percentage of initial drug targets that go on to any Phase 3 trials for cardiovascular disease has reduced from 21% to 7% (from available evidence of publicly known commercial drug targets), yet CV drugs still represent one-third of R&D spending.

This decline somewhat reflects the improvement in CV deaths over this same period, which may raise the bar of effectiveness to be commercially viable to progress to phase three. Yet, given that cardiovascular disease is still the largest killer globally, this decline reflects more the scientific challenges plus also significant financial and operational hurdles that pharmaceutical companies face in bringing new treatments to market.

A Critical Breaking Point

The transition from Phase 2 to Phase 3 represents a critical juncture in drug development, particularly for cardiovascular therapies. Studies indicate that around a third of drugs entering Phase 2 studies fail to progress to Phase 3, and among those that do advance, over half fail primary efficacy endpoints in Phase 3. This high attrition rate reflects not only scientific challenges but also significant financial hurdles.

Cardiovascular outcome trials (CVOTs) are particularly resource-intensive and time-consuming. They can take nearly a decade to complete, requiring thousands of patients and hundreds of millions of dollars in funding. For small and mid-sized biotechnology companies with promising Phase 2 data, this enormous financial burden often proves insurmountable without external support or partnerships.

Case Studies

Istaroxime by Windtree Therapeutics

Istaroxime represents a clear example of a promising cardiovascular therapy hampered by funding constraints despite positive clinical data. This first-in-class dual-mechanism therapy demonstrated improved systolic blood pressure, cardiac function, and renal function without increased risk of cardiac arrhythmias in multiple Phase 2 trials.

Despite these promising results, Windtree Therapeutics has been actively seeking partnership opportunities and, in a last-ditch effort, had to switch to seeking non-dilutive funding to advance the drug into Phase 3 development. This highlights how even drugs with strong efficacy data can struggle to progress without the right collaborations and financial support.

Omecamtiv Mecarbil by Cytokinetics

Another example is omecamtiv mecarbil, a cardiac myosin activator developed by Cytokinetics for heart failure treatment. Despite years of development and promising early clinical data, the drug faced a significant setback when the FDA rejected it in February 2023.

Rather than abandoning the program, Cytokinetics needed external funding to pursue additional Phase 3 testing. In May 2024, the company announced an expanded strategic funding collaboration with Royalty Pharma that included a hefty sum of $100 million in upfront capital specifically earmarked to fund a new Phase 3 study called COMET-HF.

This case demonstrates how even established biotech companies with promising cardiovascular candidates can struggle to independently fund the extensive Phase 3 trials required for regulatory approval, despite strong initial results. In this case a flawed trial design risked failure and more than doubled the cost to obtain approval (Study still ongoing)

The Cost of Delays and Failed Partnerships

The impact of delays in finding the right collaborators and partnerships cannot be overstated. Studies show that clinical trial delays can result in losses of $40,000 per day or $8 million per day across the sum of all clinical trials globally. These delays not only increase the cost of trials, which are already intensive endeavors, but also extend the time it takes for potentially life-saving treatments to reach patients.

Strategies for Success

To address these challenges and increase the likelihood of promising cardiovascular drugs reaching Phase 3 trials and beyond, several strategies should be considered:

Early Partnership Development: Companies should begin seeking potential collaborators and funding partners early in the development process, ideally before completing Phase 2 trials.

Diversifying Clinical Trial Sites: Expanding and diversifying the clinical trial site network can accelerate enrollment, potentially reducing both trial duration and costs.

Streamlining Trial Design: Developing innovative trial designs that can generate convincing evidence with smaller sample sizes may help reduce the financial burden of Phase 3 trials.

Fostering Open Communication: Creating channels for open dialogue between sponsors, CROs, and healthcare professionals can lead to more efficient trials and better outcomes for all stakeholders.

Aligning Incentives: Ensuring that the goals of the trial team align with the professional interests and needs of the healthcare professionals involved can improve trial execution and data quality.

Conclusion: A Call for Collaboration

The path from promising Phase 2 results to successful Phase 3 trials in cardiovascular drug development is fraught with challenges. However, by recognizing the importance of early collaboration, efficient trial management, and strategic partnerships, we can work to bridge the funding gap that prevents many potential breakthrough treatments from reaching patients.

As we move forward, it’s crucial for the pharmaceutical industry, regulatory bodies, and healthcare professionals to work together to create a more supportive ecosystem for cardiovascular drug development. By doing so, we can ensure that promising therapies have the best chance of making it through the critical Phase 2 to Phase 3 transition and ultimately reaching the patients who need them most.

Sources

Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company - https://pmc.ncbi.nlm.nih.gov/articles/PMC4031952/

Phase II Trials in Drug Development and Adaptive Trial Design https://pmc.ncbi.nlm.nih.gov/articles/PMC6609997/

Strengthening Clinical Trial Performance through Sponsor https://www.cloudbyz.com/resources/digital-transformation/strengthening-clinical-trial-performance-through-sponsor-and-clinical-site-collaboration

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