FDA Grants SM-88 Orphan Drug Status for Pancreatic Cancer

The FDA granted an orphan drug designation to the oral investigational modified proprietary tyrosine derivative SM-88 (racemetyrosine) as a treatment for patients with pancreatic cancer, according to an announcement from Tyme Technologies, Inc, the drug developer.¹

“Receiving orphan drug designation for SM-88 is another important milestone to emerge from our innovative pipeline of cancer metabolism-based compounds,” Steve Hoffman, chairman and chief executive officer of Tyme, stated in a press release. “We are pleased with the progress we are making in the clinic and believe that SM-88, which is now in multiple late-stage clinical trials offers the potential to play a significant role in establishing a new treatment paradigm for more than 57,000 patients who are diagnosed with pancreatic cancer annually within the United States.”

SM-88 is comprised of a tyrosine derivative (D,L-alpha-metyrosine), an mTOR inhibitor (sirolimus), a CYP3a4 inducer (phenytoin), and an oxidative stress catalyst (methoxsalen). The investigational agent is thought to have potential as an agnostic anticancer agent through its ability to disrupt the metabolism of the cancer cell, boost signaling activity, and activate cell apoptosis.

Updated results from the phase 2 TYME-88-Panc study (NCT03512756) were presented during the 2019 World Congress on Gastrointestinal Cancer and showed that treatment with SM-88 led to a median overall survival (OS) of 6.4 months in patients with advanced pancreatic cancer.²

Furthermore, the RECIST clinical benefit rate (CBR) of stable disease (SD) or better was 44% with available imaging. A 92% reduction in the risk of death was observed in patients who at least reached SD (HR, 0.08; P = .02). Moreover, the CBR proved to be durable, with the majority of patients who received SM-88 continuing to have SD or better at 7 months or more.

In the multicenter, open-label, 2-part trial, SM-88 was examined in patients with pancreatic ductal adenocarcinoma who had radiographic progressive disease, received 1 or more prior lines of treatment, and had an ECOG performance status of 0-2. In the trial, patients were randomized to receive either 460 mg daily or 920 mg daily of SM-88. All participants were given daily methoxsalen at 10 mg, daily phenytoin at 50 mg, and sirolimus at 0.5 mg daily.

In part 1 of the trial, investigators set out to determine the optimal dosing of SM-88 and understand whether early clinical benefit could be observed to support additional development of the agent. To this end, previous data showed that the majority of 28 evaluable patients, or 67.8%, were alive as of December 31, 2018, which was a median 4.3 months of follow-up posttreatment initiation.³

Updated data included 49 heavily pretreated patients with radiographically progressive metastatic disease who had significant disease-related morbidity. Baseline characteristics were noted to be comparable between the intent-to-treat (ITT) population (n = 49) and the efficacy-evaluable population (n = 38). The median age of study participants was 66.5 years and over 80% of patients had previously received 2 or more lines of treatment.

The 6.4-month median OS was reported in the efficacy-evaluable population, while the preliminary median Kaplan-Meier–derived OS in the ITT population was 3.6 months.

Data from subgroup analyses were also released during the meeting. Results revealed that screening criteria linked with rapidly declining prognostic factors included those who received more than 2 lines of previous treatment, those older than 75 years of age, and those with albumin of less than 3.5 g/dl. Notably, patients without these poor prognostic factors experienced a stronger survival trend (HR, 0.36; 95% CI, 0.1-1.3; P = .12).

Subgroups observed to have experienced improved survival outcomes with the investigational agent included females (HR, 0.21; 95% CI, 0.06-0.73; P = .01), as well as patients who received 1 or 2 prior therapies versus those who had 3 or more prior lines of treatment (HR, 0.56; 95% CI, 0.21-1.5; P = .26). Patients who had baseline circulating tumor cells (CTCs) of 50 or less cells/4 mL also showed a trend toward improved OS (HR, 0.26; 95% CI, 0.06-1.2; P = .08).

Additional results showed a median decrease of CTCs of 63%, with 56.3% of patients with CRC decreases having an OS of greater than 180 days compared with 37.5% of those with CTC increases. The 24 patients with 80% or greater CTC reduction trended toward improved OS (HR, 0.4; 95% CI, 0.11-1.5; P = 1.8), while patients with 50 or less cells/4 mL at nadir also showed favorable OS outcomes (HR, 0.64; 95% CI, 0.2-2.1; P = .45). Moreover, patients with the longest survival at 261+, 262+, or 343+ days experienced both a greater than 80% reduction in CTCs and less than 50 cells/4 mL.

With regard to safety, serious adverse effects (SAEs) considered to potentially be related to SM-88 were observed in 4% of the ITT group; these toxicities included abdominal pain, arthralgia, and hypotension. One participant who experienced an SAE continued on treatment. Ninety-four percent of patients in the ITT group experienced all-grade AEs; 17% of these were those to potentially be related to the study drug and 12% of the events were grade 3/4.

During the 2020 AACR Virtual Annual Meeting II, SM-88 also demonstrated antitumor activity in 2 xenograft studies. The agent appeared to broadly effect the immune dynamics of the tumor microenvironment of several cancers.⁴

The agent is also under investigation in the Precision Promise adaptive randomized phase 2/3 registration-intent trial (NCT04229004) as a second-line monotherapy for patients with pancreatic cancer, and in the phase 2 HopES Sarcoma trial (NCT03778996) as a maintenance monotherapy in patients with previously treated metastatic Ewing sarcoma and as salvage monotherapy in patients with clinically advanced sarcomas.

References

1. TYME announces orphan drug designation for SM-88 as potential treatment for patiwnts with pancreatic cancer. News release. TYME Technologies, Inc. August 3, 2020. Accessed August 3, 2020. https://bwnews.pr/31dn0RP.
2. TYME provides business update and reports fourth quarter and fiscal year 2019 financial and operating results. News release. TYME Technologies. May 29, 2019. Accessed August 3, 2020. https://bit.ly/2ENCnsD.
3. Noel MS, Wang-Gillam A, Ocean AJ, et al. SM-88 therapy in high-risk poor prognosis pancreatic cancer (PDAC). Ann Oncol. 2019;30(suppl 4):iv16. doi:10.1093/annonc/mdz155.058.
4. Vandell A, Eckard J, Hoffman S, et al. In vitro and in vivo anticancer effects of D/L-alpha-metyrosine (SM-88), a novel metabolism-based therapy. Presented at: AACR Virtual Annual Meeting II. June 22-24, 2020. Abstract 5998. bit.ly/3fUGGjg.