Company: MIRA
Filing Date: 2025-07-29
Form Type: PRER14A
Source: 0001641172-25-021434
Chunk: 209

Company: MIRA PHARMACEUTICALS, INC.
Filing Date: 2025-07-29
Form: PRER14A
Chunk 209
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armacologic Milestones in Diabetic Peripheral Neuropathy (DPN) Treatment

Duloxetine (Cymbalta, Eli Lilly)

In September 2004, duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), became the first medication to receive U.S. FDA approval specifically for the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN). As a dual reuptake inhibitor, duloxetine exerts its therapeutic effect through the enhancement of both serotonergic and noradrenergic neurotransmission in the central nervous system (CNS). While the exact mechanism underlying its central pain-modulating activity remains incompletely understood, the inhibition of norepinephrine reuptake is widely believed to play a critical role in attenuating neuropathic pain pathways.

Pregabalin and the Evolution of Anticonvulsant Therapies

Historically, traditional anticonvulsants have been utilized off-label for neuropathic pain management since the 1960s. However, the treatment paradigm shifted in 2004 when pregabalin(Lyrica) received FDA approval specifically for the management of DPN-related pain. As a next-generation GABA analog, Pregabalin works by attaching specific parts of nerve cells—known as calcium channels—to help calm overactive nerve signals that cause pain, thereby reducing excitatory neurotransmitter release and alleviating pain.

The American Academy of Neurology (AAN) and other leading clinical guidelines currently endorse pregabalin as a first-line therapeutic option for DPN, citing robust evidence for its efficacy in pain reduction and its positive impact on sleep quality—an important aspect of overall disease burden.

Market Significance

The approvals of duloxetine and pregabalin marked pivotal moments in the formalization of treatment protocols for DPN, reflecting growing recognition of neuropathic pain as a distinct and manageable clinical entity. Both agents have maintained strong market positions due to their efficacy profiles, though ongoing unmet needs around tolerability, partial response, and disease modification continue to drive demand for next-generation therapeutics.

| Moore Financial Consulting |

| MIRA Pharmaceuticals, Inc. | April 2025    |
| Valuation                  | Page 10 of 28 |

Emerging Therapies in Diabetic Neuropathic Pain (DNP)

As the prevalence of diabetic peripheral neuropathy continues to rise, significant unmet needs persist in the management of chronic neuropathic pain. Several novel agents are currently in development, targeting alternative mechanisms of action