New Options for Patients: New Preliminary Clinical Data on SPR720 and Our Stepwise Plan to Explore the Broad Potential of SPR720 in NTM

We recently announced positive preliminary, blinded data on SPR720 that we believe supports the further development of SPR720 as an oral agent for the treatment of NTM pulmonary disease.  The data released:

• Identify a dose range for SPR720 to explore in human trials that is supported by animal and hollow fiber models across a range of NTM pathogens
• Suggest that SPR720 is safe and well-tolerated in a SAD/MAD clinical trial of healthy volunteers at the predicted therapeutic dose range
• Support progression of SPR720 into our planned Phase 2 dose-ranging clinical trial in non-refractory NTM-lung disease patients, pending acceptance of an investigational new drug application by the FDA. We believe that the proposed Phase 2 clinical trial will establish an efficient paradigm for the progression of new anti-NTM agents.

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What do current data points in NTM tell us and how might SPR720 play a role in treatment?

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Preliminary data support SPR720’s potential to treat patients with in NTM infections

As an oral, broad spectrum agent that preliminary data suggest is well-tolerated, SPR720 could afford us the opportunity to treat patients across their disease journey. Currently, approved treatments only exist for approximately 25% of NTM patients that are treatment refractory meaning they have failed all available treatment options and still suffer from the disease⁽¹⁾.A major unmet need exists for the majority of NTM patients that are not treatment refractory.Recent FDA panels and industry correspondence as well as our discussion with KOLs highlight the need in NTM to improve a patient’s function and quality of life: early treatment mattersas it gives patients a chance to retain lung function and maintain quality of life.Patients that have suffered from refractory disease often have sustained progressive, permanent inflammatory lung damage that makes recovery and improvements in quality of life more challenging.

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Figure 1: NTM Patient Journey

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The therapeutic potential of SPR720 in the treatment of NTM lung disease is supported by multiple layers of evidence  

1. The active derivative of orally administered SPR720 demonstrates in vitro (laboratory) activity versus avium, M. abscessus, M. kansasii and other relevant NTM species.
2. SPR720 demonstrates robust activity in animal (murine) and hollow fiber infection models of NTM lung disease. These models support a prediction of the plasma exposure required to treat these infections (pharmacodynamic target).
3. Clinical toxicology studies have demonstrated that the required exposure is well-tolerated in animal models—we term this the “therapeutic index”.
4. Data in primates shows that SPR720 penetrates into lung fluid at concentrations sufficient for antimicrobial activity.
5. The active portion of SPR720 penetrates at high concentration into human macrophages that are infected with NTM, as shown in in vitro This is important because intracellular infection is important in the biology of NTM lung disease.
6. Based on these supporting data, we have now completed a single- and multiple-ascending dose trial in healthy human volunteers. The preliminary data from the trial show that at doses of 500 mg or higher, the mean plasma drug exposures of SPR719, the active metabolite of SPR720, are consistent with those suggested by in vitroand in vivomodels of SPR720 to be necessary for clinical efficacy against target NTM pathogens.

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Data support a more efficient and informative development pathway for SPR720

The properties of SPR720 and a review of data supporting prior advances in the field frame our opportunity for a more efficient development pathway. This pathway employs more efficient measures of patient benefit and more precise measurements of disease burden, ultimately assisting us in discovering the potential of our product candidates faster. We plan to take a stepwise approach to developing new treatments for NTM patients, as is the case with HIV, TB, oncologic agents and other diseases treated with therapeutic combinations. The next step is to show that these data translate to a positive biological effect in patients. Specifically, following our submission of an IND with the FDA and acceptance of that IND, we intend to assess in a Phase 2a clinical trial how SPR720 works on its own versus a placebo in patients. This is a standard first step in the development of new combination therapies, such as for TB and HIV. We plan to adapt this study design to allow early and efficient assessment of candidate drugs for the treatment of NTM lung disease. Should it be successful in Phase 2, SPR720 could potentially be the only novel agent that will have demonstrated microbiological activity as monotherapy, independent of ineffective and poorly tolerated background therapy.Why do we have conviction that the Phase 2 design is appropriate and that positive results would be a meaningful advance for patients? Because clinical studies evaluating the therapeutic benefit of standard of care combination therapy, clarithromycin as a single agent, and inhaled amikacin all have demonstrated an early, measurable decrease in sputum bacterial burden ^{(2, 3, 4, 5)}. Furthermore, these data support the long-term predictive power of early treatment response. Thus, among patients who demonstrated a decrease in sputum bacterial burden in response to the initiation of anti-NTM treatment, an early response was predictive of longer-term benefit. ⁽¹⁾

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Figure 2: Initial Rate of Bacterial Response After Predicts Long-term Response to Pulmonary MAC Treatment with Clarithromycin

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‍A successful result could follow the paradigm set by TB and HIV medicines and targeted oncologic therapy – response rate relative to placebo coupled with PK/tolerability/macrophage penetration would be evidence of SPR720’s therapeutic benefit relative to other agents in development and provide strong support for future development.SPR720 is the only novel oral agent in clinical development for NTM and we look forward to advancing it into patients. We are inspired by the opportunity to help thousands of patients with NTM that still don’t have any new options, and we look forward to working with the patient community, clinicians, and our colleagues at the FDA as we build a Phase 2 clinical plan around these goals.

David Melnick, M.D.

Chief Medical Officer of Spero Therapeutics