Ridinilazole

Ridinilazole (INN,[1] previously known as SMT19969) is a non-absorbable[2] small molecule antibiotic for oral administration to treat Clostridium difficile infection (CDI).[3] The Centers for Disease Control and Prevention (CDC) estimates 500,000 cases of CDI per year and on average 29,000 deaths per year attributed to CDI in the United States (USA). The CDC estimates a similar number of cases in the European Union (EU) each year.[4]

Ridinilazole
Clinical data
Other namesSMT19969
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC24H16N6
Molar mass388.42 g/mol
3D model (JSmol)

As of October 2015 its mechanism of action "remains to be fully determined."[2] However, Summit Therapeutics believes that ridinilazole may be able to selectively target C. difficile without causing collateral damage to natural gut flora and thus is able to reduce CDI recurrence rate.[4] In preclinical studies, ridinilazole showed a potent bactericidal effect against all strains of C. difficile tested.[3]

Ridinilazole was designated as a Qualified Infectious Disease Product (‘QIDP’) and was granted Fast Track status by the U.S. FDA.[3] This status is reserved for drugs designed to treat diseases where there is currently a gap in the treatment, or a complete lack thereof. This Fast Track status adds five more years of exclusivity for ridinazole.

Commercialization

Ridinilazole is manufactured by Summit Therapeutics. Summit Therapeutics plans to partner with another pharmaceutical company to begin Phase 3 trials. They predict for both the US and EU launch to occur in 2021 with peak sales of £930 million. Summit will receive a flat 20% royalty rate. Models predict that royalties will rise from £25.6 million in FY2022 to £75.2 in FY2027. Ridinilazole has been de-risked with positive Phase 2 data.[4]

Summit Therapeutics estimates that the price will be $1,200 for one course of therapy in the US and approximately 20% less in the EU. This is in contrast to Merck's Dificid (fidaxomicin) which was priced at $2,800 per course of therapy. Dificid did not sell well because it cost nearly four times as much as the generic vancomycin alternatives.[4]

According to H.C. Wainwright, ridinilazole is currently undervalued since ridinilazole allows the patients gut microflora to be preserved which helps prevents deadly recurrent infections and allows for the use of ridinilazole as a first line therapy, in contrast with antibiotics already on the market.[4]

Intellectual Property

Patents

Ridinilazole is not available for composition of matter patent protection worldwide. However, ridinilazole still has several other patents in several key domestic and international markets, including the three biggest markets:[4]

  • European Union: In Summit Therapeutics’ native EU market the methods of use for CDI patent expires in 2029 and the patent for second generation agents is good until 2031.[5]
  • United States: The methods of use for CDI patent and the hydrates of ridinilazole patent expire in 2029. The patents for second generation agents expires in 2031.[6] Summit has applied for several other patents that are still pending.
  • Japan: The patent expires in 2029.[5]

Although ridinilazole has been patented, Summit Therapeutics has not yet signed a partnership to continue with Phase III clinical trials. Therefore, the patent life may need to be extended.

Competitors

There are several other competitors with new drug candidates targeting C. difficile. The most promising of these other drugs is Merck's Zinplava (bezlotoxumab) which was recently approved. Market analysts don't know how the approval of bezlotoxumab will affect the valuation of ridinilazole. Bezlotoxumab is not an antibiotic, but it is used to in conjunction with antibiotics to increase their effectiveness in treating CDI.[7] Other pharmaceutical companies working on drugs to treat CDI include Synthetic Biologics, Sanofi, and Shire.[4]

Regulatory Information

Phase I & II Clinical Trials

Ridinilazole was approved for Phase III clinical trials after a successful Phase II ('CoDIFY') study showed that ridinilazole was tolerated at all doses and has a highly selective profile. Ridinilazole showed a sustained clinical response (SCR). The study was a double-blind, randomized, active-controlled, multi-center trial with 100 patients comparing ridinilazole to vancomycin. Adults in the trial had a clinical diagnosis of CDI with no more than 24 hours of antimicrobial treatment and no more than 3 cases of CDI in the previous 12 months. One-half of the study participants received a 200 mg of ridinilazole twice a day; the other half received 125 mg of vancomycin four times a day.[4]

In a Phase II proof-of-concept trial in CDI patients (‘CoDIFy’), ridinilazole showed statistical superiority in SCR rates compared to the standard of care, vancomycin. In this trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy.[3] SCR rates were 66.7% for ridinilazole compared to 42.4% for vancomycin.[8][9] Rates of clinical cure at the end of treatment was 77.8% (compared to 69.7% for vancomycin).[4] There was also a reduction in recurrent CDI: 34.8% with ridinilazole (compared to 14.3% for vancomycin). Ridinilazole might be more useful for at-risk groups. This includes patients aged 75 or greater, patients with severe cases of CDI, and patients with prior episodes.

There was no increase in adverse effects associated with ridinilazole. Ridinilazole decreased gastrointestinal (GI) adverse effects. Only 40% of patients reported adverse GI effects, compared to 56% of cases with vancomycin.[4] These results show that ridinilazole might be useful in the aforementioned at-risk groups and as a first line treatment. Lowering the rate of recurrent CDI via use of ridinilazole could save the U.S. healthcare system $30,000 per patient due to a decreased number of hospitalizations.

As of August 2016, there is currently an ongoing Phase II clinical trial underway in the US comparing ridinilazole with fidaxomicin in the treatment of CDI.[10]

Phase III Clinical Trials

The partner with Summit Therapeutics must conduct 2 randomized, double-blind trials comparing ridinilazole to vancomycin or fidaxomicin. These trials will take two to three years, thereby predicting a 2021 commercial launch.[4]

References
  1. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74" (PDF). World Health Organization. p. 418. Retrieved 3 October 2016.
  2. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. 2015
  3. Summit Therapeutics Announces Publication of Preclinical Data Showing Ridinilazole Outperformed Standard of Care in Reducing C. Difficile Toxins That Drive Disease Symptoms. Feb 2016
  4. Werther, Carol Ann (September 15, 2016). "Ezutromid Has the Potential to Treat All Duchenne Patients; Initiating Coverage With a Buy". H.C. Wainwright & Co. H.C. Wainwright & Co. Retrieved November 7, 2016.
  5. PLC, Summit Therapeutics. "Summit Therapeutics Granted Key European Patent for Novel Antibiotic Ridinilazole for Treatment of C. Difficile Infection". GlobeNewswire News Room. Retrieved 2016-11-21.
  6. "ridinilazole U.S. patent | C Diff Foundation". cdifffoundation.org. Retrieved 2016-11-21.
  7. "Two approvals in two days for Merck". BioPharma Dive. Retrieved 2016-11-21.
  8. PLC, Summit Therapeutics. "Summit Therapeutics Announces Novel Antibiotic Ridinilazole (SMT19969) Achieves Statistical Superiority Over Vancomycin in CoDIFy Phase 2 Clinical Trial for C. difficile Infection". GlobeNewswire News Room. Retrieved 2016-11-21.
  9. New Drugs Online Report for ridinilazole
  10. "A Study of Ridinilazole (SMT19969) Compared With Fidaxomicin for the Treatment of Clostridium Difficile Infection (CDI) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-21.
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