Phase 2 Discovery, Inc.

Amgen (NASDAQ: AMGN) today announced that LUMAKRAS® (sotorasib) has been approved in Japan for the treatment of KRAS G12C-mutated positive, unresectable, advanced and/or recurrent non-small cell lung cancer (NSCLC) that has progressed after systemic anticancer therapy. "Today's approval of LUMAKRAS as the first and only KRASG12C inhibitor marks a paradigm shift in the treatment of patients with non-small cell lung cancer in Japan," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "In just over three years since the first patient was dosed in the pivotal CodeBreaK 100 trial, LUMAKRAS is now approved in nearly 40 countries, illustrating our commitment to accelerating transformative medicines for patients living with cancers that have yet to be fully addressed." The approval by the Japan Ministry of Health, Labour and Welfare (MHLW) is based on positive results from the Phase 2 CodeBreaK 100 clinical trial in NSCLC, the largest trial conducted to date for patients with the KRAS G12C mutation. Based on the approved label in Japan, LUMAKRAS 960 mg, orally administered once-daily, demonstrated an objective response rate (ORR) of 37% (95% CI: 28.8-46.6) in 123 evaluable patients (including 10 Japanese patients* with a data cutoff date: Sept. 1, 2020). Adverse reactions were observed in 128 (67%) of 190 patients† (including 13 Japanese patients). The most common adverse reactions (incidence ≥ 5%) were diarrhea (28%), nausea, increased alanine aminotransferase (ALT) and increased aspartate aminotransferase (AST) (16% each), fatigue (11%), increased blood alkaline phosphatase (8%), vomiting (7%) and abdominal pain (5%). Results from the Phase 2 CodeBreaK clinical trial in NSCLC were published in The New England Journal of Medicine. "KRAS gene mutations are one of the oldest known cancer driver gene mutations," said Steve Sugino, president and representative director, Amgen K.K. "However, it has proven to be very difficult to develop drugs for the treatment of KRAS gene mutations. For nearly 40 years, researchers have said that the mutation was 'undruggable.' I am very pleased that LUMAKRAS is now approved as a new treatment option for patients in Japan." "The prognosis for patients with non-small cell lung cancer who have distant metastases or whose disease has relapsed after surgery, is generally poor," said Tetsuya Mitsudomi, M.D., professor, Department of Surgery, Division of Thoracic Surgery at Kindai University School of Medicine, past-president of the International Association for the Study of Lung Cancer (IASLC) and past-president of the Japan Lung Cancer Society (JLCS). "Recent developments in molecular-targeted drugs and immunotherapy have dramatically improved the prognosis for these patients. However, despite the relatively high frequency of the KRAS G12C mutation, no drugs specifically targeting this mutation have been available until recently. Therefore, the approval of LUMAKRAS in Japan is a major milestone in the treatment of non-small cell lung cancer patients with KRAS G12C mutations." On March 11, 2021, the MHLW designated sotorasib as an orphan drug. *3 subjects (including 1 Japanese subject) without measurable lesions at baseline as determined by the central review were excluded. †Patients with non-small cell lung cancer who received at least 1 dose of this drug 960 mg in the phase I and II parts. About LUMAKRAS®/LUMYKRAS® (sotorasib) Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.1 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk pro rapid, deep and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.2 Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, over 4,000 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use. In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS® is also approved in the United Arab Emirates, the European Union and Switzerland, and in Canada and Great Britain under the FDA's Project Orbis. Through Project Orbis, Amgen also has Marketing Authorization Applications (MAAs) for sotorasib in review in Australia, Brazil, Singapore and Israel. Additionally, Amgen has submitted MAAs in South Korea, Turkey, Taiwan, Colombia, Thailand, Mexico, Hong Kong, Saudi Arabia, Argentina, Kuwait and Qatar. LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors. About Non-Small Cell Lung Cancer and the KRAS G12C Mutation Lung cancer is the second most prevalent cancer in the world, and the total number of patients in Japan is estimated to be about 169,000.4Lung cancer is also the leading cause of cancer site-specific mortality worldwide and in Japan, with an estimated 82,300 deaths annually.5 About 85-90% of lung cancer patients are classified as having NSCLC (such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma).NSCLC is a life-threatening, serious disease, and the 5-year survival rate of patients with stage IV NSCLC in Japan is 10.8% for adenocarcinoma and 2.7% for squamous cell carcinoma, indicating that the prognosis of this disease is still poor. KRAS G12C is the most common KRAS mutation in NSCLC.8 KRAS G12C mutation is reported to be found in approximately 13% of lung adenocarcinoma in the U.S. and 4.5% of non-squamous cell carcinoma in Japan.There is a significant unmet need as there are limited treatment options for patients with NSCLC harboring KRAS G12C mutations who have failed or lost response to first-line treatment. Outcomes with available therapies have been suboptimal, with median progression-free survival after second-line therapy reported to be approximately 4 months in patients with NSCLC harboring KRAS G12C mutations. About CodeBreaK The CodeBreaK clinical development program for Amgen's drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.2,3 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.2 The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been published. CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally-advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes. Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment. A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201).

Vedanta Biosciences, a clinical-stage company that is developing a potential new category of oral therapies based on defined bacterial consortia, today announced that its Phase 2 clinical trial of VE303, an orally administered investigational live biotherapeutic product in development for the prevention of recurrent C. difficile infection (CDI) in high-risk patients, met its primary endpoint of preventing disease recurrence through Week 8. VE303 achieved a 31.7 percent absolute risk reduction in rate of recurrence when compared with placebo, representing a greater than 80 percent reduction in the odds of a recurrence. This is the most advanced clinical trial of an investigational drug based on a rationally defined bacterial consortium, a microbiome-based therapeutic approach that delivers orally administered candidates of precisely known composition that can be manufactured with pharmaceutical-grade consistency. The positive results of the Phase 2 study triggered a $23.8 million contract option from the Biomedical Advanced Research and Development Authority (BARDA), part of the HHS Office of the Assistant Secretary for Preparedness and Response, to support a Phase 3 clinical trial of VE303, which Vedanta plans to initiate in 2022. “We believe these results are an important step forward for the prevention of C. difficile infection and the microbiome field at large. These data substantially add to the evidence in support of a therapeutic approach that bypasses the use of fecal donations or their spore fractions. Those first-generation approaches have shown variability in outcomes across studies, potential for transmission of infectious agents, and have significant challenges in scalability for serving large populations,” said Bernat Olle, Ph.D., Chief Executive Officer of Vedanta Biosciences. “From our inception, Vedanta has focused on delivering advances that will enable us to rationally design and manufacture – at scale – therapeutics based on defined bacterial consortia, which we believe can address the limitations of earlier approaches and potentially be broadly applicable across a range of diseases.” Recurrent CDI causes approximately half a million infections each year in the United States, including up to 165,000 recurring infections and up to 45,000 deaths. Existing treatments include antibiotics, which can further damage the gut microbiome. This can leave patients vulnerable to both CDI recurrence and infection by a variety of other bacterial species, which could encourage the spread of antibiotic resistance. VE303 is a potential new tool against CDI that is designed to reconstitute a patient’s gut microbiome while supporting better antibiotic stewardship in the healthcare system. Summary and topline data from the Phase 2 CONSORTIUM trial The Phase 2 CONSORTIUM trial was a randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of VE303 to treat patients at high risk of recurrent CDI. The trial enrolled 79 patients who had completed a successful course of treatment with standard-of-care antibiotics for recurrent CDI or for a primary CDI episode with one or more characteristics that placed those patients at high risk of recurrence. The trial evaluated low-dose VE303, high-dose VE303 (the active treatment groups), and placebo. Following completion of their standard-of-care antibiotic treatment for CDI, trial participants were randomized to one of the 3 groups and dosed once daily for two weeks. Trial participants were followed for a total of 24 weeks, to monitor for long-term safety, colonization dynamics, and additional recurrent CDI episodes. The primary objective of the trial was to establish a dose regimen for a potential Phase 3 clinical trial, based on the safety and efficacy of the VE303 regimens compared with placebo. The primary efficacy endpoint of the trial was the CDI recurrence rate in each of the 3 groups within 8 weeks after the start of dosing. At 8 weeks, efficacy outcomes were assessed for 78 patients: 29 from the high-dose group, 27 from the low-dose group, and 22 from the placebo group. The topline efficacy results are based on a prespecified analysis conducted after all patients had reached the Week 8 visit, using the intent-to-treat population. The high dose of VE303 met the primary endpoint of a lower recurrence rate within 8 weeks versus placebo (13.8 percent versus 45.5 percent) using a prespecified analysis that incorporated the results of toxin and PCR testing, or a clinician’s diagnosis and treatment of a CDI recurrence when no stool sample was available for testing. This 31.7 percent reduction in absolute risk of recurrence reflects a greater than 80 percent reduction in the odds of a recurrence in the high-dose group compared with the placebo group (odds ratio 0.192; 90 percent confidence interval 0.048, 0.712; p=0.0077). Through the Week 8 timepoint, the proportion of these high-risk patients remaining recurrence-free in the high-dose cohort was 86.2 percent, compared with 54.5 percent of the placebo recipients remaining recurrence-free at that timepoint. Using C. difficile toxin testing alone to define recurrence, which has been historically reported to miss 20 to 50 percent of CDI cases, was not a robust enough analysis to demonstrate a statistically significant difference between either of the active treatment groups and the placebo group. “Although a number of antibiotics are approved to treat C. difficile infection, recurrence occurs frequently—often repeatedly—and is a major cause of morbidity and mortality. The CONSORTIUM trial is the first randomized, controlled trial to show that a defined bacterial consortium has the potential to prevent recurrent C. difficile infection, using an analysis that follows standard clinical practice in relying upon physician assessment, along with results of toxin and PCR testing, to establish a C. difficile diagnosis,” said Mark H. Wilcox, M.D., Professor of Medical Microbiology at the University of Leeds and a prominent CDI expert. “As defined bacterial consortia can provide consistent composition and quality and do not rely on feces obtained from human donors for manufacture or delivery, VE303 may address some of the potential issues with lack of product consistency, scalability, and risk of infection associated with existing approaches.” Overall, VE303 was observed to be generally well-tolerated in the trial. Most participants reported one or more adverse events, but in similar proportions across groups. Few serious adverse events were reported in the trial, and none were determined to be treatment-related by either the trial investigators or Vedanta. The final results and statistical analysis will be available following completion of long-term safety follow-up and locking of the complete trial database. Vedanta intends to present the final data analysis at a future medical conference. Based on the Phase 2 data, BARDA has exercised its first contract option for additional funding of $23.8 million pursuant to its existing 2020 contract with Vedanta. Total committed funding under the BARDA award to date is $31.2 million, inclusive of this first contract option. The contract provides for reimbursement of up to $76.9 million, subject to additional prespecified milestones being achieved and the availability of funding. About VE303 VE303 is an orally administered, investigational live biotherapeutic product (LBP) in development for the prevention of recurrent C. difficile infection in patients at high risk for recurrence. VE303 is produced from pure, clonal bacterial cell banks, which yield a standardized drug product in powdered form and bypasses the need to rely on direct sourcing from donor fecal material of inconsistent composition. VE303 consists of a defined consortium of eight well-characterized strains of live bacteria designed to restore colonization resistance against gut pathogens. Vedanta Biosciences received a $5.4 million research grant from the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) in 2017 and a contract of up to $76.9 million from BARDA in 2020 to support clinical studies of VE303. VE303 was granted Orphan Drug Designation in 2017 by the U.S. FDA for the prevention of recurrent CDI. About Vedanta Biosciences Vedanta Biosciences is leading the development of a potential new category of oral therapies based on defined consortia of bacteria isolated from the human microbiome and grown from pure clonal cell banks. The company’s clinical-stage pipeline includes product candidates being evaluated for the treatment of high-risk C. difficile infection, inflammatory bowel diseases, advanced or metastatic cancers, and food allergy. These investigational therapies are grounded in pioneering research – published in leading journals including Science, Nature, and Cell – to identify beneficial bacteria that live symbiotically within the healthy human gut, fight pathogens and induce a range of potent immune responses. Vedanta Biosciences controls a foundational portfolio of more than 40 patents and has built what it believes to be the world’s biggest library of bacteria derived from the human microbiome. Proprietary capabilities include deep expertise in consortium design, vast datasets from human interventional studies and cGMP-compliant manufacturing of oral LBP candidates containing pure, clonally derived bacterial consortia in powdered form. Vedanta Biosciences was founded by PureTech Health (LSE: PRTC, Nasdaq: PRTC) and a global team of scientific co-founders who pioneered Vedanta’s modern understanding of the cross-talk between the microbiome and the immune system. This project has been supported in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. 75A50120C00177.