On June 29, 2020 Aileron Therapeutics (NASDAQ:ALRN), a biotechnology company advancing a novel chemoprotective therapy for cancer patients, reported that it has enrolled the first patient in the open-label Phase 1b schedule optimization part of its ongoing Phase 1b/2 clinical trial, evaluating ALRN-6924’s potential to protect patients against chemotherapy-induced toxicities (Press release, Aileron Therapeutics, JUN 29, 2020, View Source [SID1234565066]). Patients in this open-label trial have p53-mutated extensive disease small cell lung cancer (SCLC) and are being treated with second-line topotecan following administration of ALRN-6924. The schedule optimization part of the trial is intended to determine whether ALRN-6924 given six hours before topotecan further enhances the protective effect of ALRN-6924 against severe hematological adverse events observed when ALRN-6924 was given 24 hours before topotecan in the dose optimization part of the trial, as reported by Aileron earlier this month.

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"Following our recent announcement of positive interim data from the Phase 1b dose optimization part of this ongoing Phase 1b/2 study, we are pleased to reach another key milestone in our advancement of ALRN-6924 to potentially transform the treatment paradigm for cancer patients undergoing chemotherapy," said Manuel Aivado, M.D., Ph.D., President & CEO of Aileron Therapeutics.

Dr. Aivado explained, "Chemotherapy remains a critical cornerstone treatment for millions of cancer patients. Unfortunately, in the process of killing cancer cells, chemotherapy inadvertently harms healthy cells, too. This leads to a multitude of common, damaging, severe toxicities. We treat healthy cells ahead of chemotherapy to prevent those toxicities, importantly, without interrupting chemotherapy’s potent onslaught against cancer cells. ALRN-6924 could dramatically improve patients’ quality of life by improving their tolerance to chemotherapy."

ALRN-6924’s novel mechanism of action leverages the innate ability of intracellular p53 protein to induce cell cycle arrest in healthy cells to prevent toxicities driven by chemotherapy’s off-target effects in bone marrow and potentially other tissues and organs. In patients with p53-mutant cancers, which represent approximately 50% of all cancer patients, ALRN-6924 is designed to shield healthy cells from chemotherapy while preserving the susceptibility of cancer cells to chemotherapy.

About the Phase 1b/2 Study

The ongoing Phase 1b/2 study is designed to identify an optimal dose and schedule of ALRN-6924 administration to reduce chemotherapy toxicities such as severe anemia, thrombocytopenia, and neutropenia caused by topotecan in patients with small cell lung cancer. There are two parts to the Phase 1b study: (i) dose optimization and (ii) schedule optimization.

In the dose optimization part, which enrolled 18 patients, ALRN-6924 was administered at three dose levels (0.3, 0.6, and 1.2 mg/kg) 24 hours before each dose of topotecan on days 1 through 5 of every 21-day treatment cycle. An expansion cohort of the dose optimization part of the trial at the 0.3 mg/kg dose level is ongoing.

Aileron announced positive interim findings from this part of the trial in June 2020. ALRN-6924 demonstrated a protective effect against severe chemotherapy-induced anemia and thrombocytopenia across all dose levels as compared to historical controls. In addition, patients treated with 0.3 mg/kg ALRN-6924 met the protocol-defined criteria for reduction of NCI CTC Grade 3/4 neutropenia to ≤50% in the first treatment cycle triggering the expansion cohort in up to eight patients.

In the schedule optimization part, ALRN-6924 is being administered at two dose levels (0.3 and 0.6 mg/kg) 6 hours before each dose of topotecan on days 1 through 5 of every 21-day treatment cycle. Aileron expects to enroll approximately 20 patients in this part of the study.
"We were highly encouraged by the strong chemoprotective effect of ALRN-6924 seen in the dose optimization part of this study as previously reported, as it reinforces our belief that ALRN-6924 can selectively induce cell cycle arrest to protect cancer patients from the toxic side effects of chemotherapy," said Vojo Vukovic, M.D., Ph.D., Chief Medical Officer of Aileron. "The schedule optimization part of the trial is intended to inform whether ALRN-6924 given six hours before topotecan can further enhance the protective effects we have observed when giving our drug 24 hours before topotecan."

Phase 1b/2 Trial – Next Steps

While enrollment in the 6-hour dosing schedule is underway, Aileron is continuing to enroll patients in the expansion cohort of its 0.3mg/kg dose level using the 24-hour schedule.

As previously reported, the company plans to report topline data from the schedule optimization and final data from the dose optimization parts of the trial in the fourth quarter of 2020. Aileron expects that these results will enable the company to determine a recommended ALRN-6924 dose and schedule for subsequent trials.

Aileron is carefully monitoring the effect of the coronavirus pandemic on its clinical trial sites and the healthcare system, which may impact the future timing of the trial and the company’s planned data announcements.

About ALRN-6924
ALRN-6924 is a first-in-class dual MDM2/MDMX inhibitor that is currently being evaluated in a Phase 1b/2 clinical trial as a chemoprotective agent to protect against chemotherapy-related toxicities.

On June 29, 2020 Starpharma (ASX: SPL, OTCQX: SPHRY) reported its SN-38 nanoparticle, DEP irinotecan in combination with an immuno-oncology (IO) agent (anti PD-1 antibody) showed superior anti-tumour activity and significant survival benefit in two colorectal cancer (CRC) models when compared to the anti PD-1 antibody alone (Press release, Starpharma, JUN 29, 2020, View Source [SID1234561510]). These results included improvement in both survival and efficacy in the particularly aggressive CT-26 CRC model.

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The median survival for the combination of DEP irinotecan + IO agent (anti PD-1 antibody) was 40 days compared with 13 days for the IO agent alone (refer to the study results below). The enhanced combination benefit seen with DEP irinotecan was not seen with conventional irinotecan + the same IO agent. These preclinical results provide a strong rationale for clinical evaluation of DEP irinotecan in combination with IO agents, potentially opening up significant additional commercial opportunities.

IO agents including Keytruda (an anti PD-1 antibody) have been approved and have been highly successful in a range of cancers including lung cancers and melanoma. However clinical trial results thus far with IO agents alone have been disappointing in some cancers, including CRC. Anti PD-1 antibodies have been a major breakthrough in cancer treatment, but substantial unmet need remains and non-responders make up more than 75% of all incident cancers, highlighting the need for more effective agents and combinations[2].

DEP irinotecan is a novel, patented dendrimer nanoparticle of SN-38, the active metabolite of irinotecan. DEP irinotecan recently progressed to phase 2. In a phase 1 trial conducted in major cancer centres in the UK, DEP irinotecan was well-tolerated and patients generally experienced less severe side effects than with conventional irinotecan, including no cases of severe diarrhoea, for which conventional irinotecan has a FDA black box warning. Encouraging efficacy signals with DEP irinotecan were also observed in 50% of evaluable patients – not only in patients with CRC but also in patients with breast and pancreatic cancer.

Dr Jackie Fairley, Starpharma CEO, commented: "We are delighted to see the dual benefits of combining DEP irinotecan with an immuno-oncology (IO) agent. These results indicate that DEP irinotecan in combination with an anti PD-1 antibody could boost the efficacy over anti PD-1 antibody alone, or IO combinations with standard chemotherapeutic agents. IO agents including anti PD-1 antibodies have yielded excellent efficacy results in some patient groups. However, between 30-60% of patients do not respond to IO treatments alone[3], therefore there is significant commercial interest in combination approaches, including with chemotherapeutics, to overcome this limitation[4]".

"In addition, there have been no observations of immune-mediated toxicities in patients treated with DEP irinotecan. Given immune-mediated toxicities can be problematic with IO agents, the lack of overlapping side-effects further strengthens the rationale for combining IO agents with DEP irinotecan", added Dr Fairley.

DEP irinotecan is one of three DEP products in clinical development by Starpharma, and is currently in a phase 2 clinical trial at leading UK hospitals, The Christie, The Royal Marsden and Newcastle Freeman Hospital. Two further sites, the Beatson (Scotland) and Kinghorn Cancer Centre (Sydney) will be opened shortly.

The market for IO agents is expected to exceed US$55 billion by 2025[5]. Market leading products include the PD-1 antibody Keytruda (Merck; 2019 sales: US$ 11.08B)[6] and Opdivo (BMS; 2019 sales: US$ 7.20B), the CTLA-4 inhibitor Yervoy (BMS; 2019 sales: US$ 1.49B)[7] and the PD-L1 inhibitor Imfinzi (AZ; 2019 sales: US$ 1.47B)[8].

Study Results

Significant enhancement of anti PD-1 antibody (anti PD-1 Ab) activity by DEP irinotecan in both CT-26 and MC-38 colon cancer models (Figure 1 and 2)

Anti PD-1 antibody alone had minimal impact on this CT-26 model, but efficacy was greatly enhanced when combined with DEP irinotecan in both the CT-26 (Figure 1) and MC-38 (Figure 2) models. The CT-26 model is recognised as being a highly aggressive CRC model, therefore this result is particularly impressive.

Figure 1: Mean tumour volumes over time as measured in the mouse allograft study using CT-26 murine colorectal cancer cells (n=5). DEP irinotecan + anti PD-1 Ab in combination had a statistically significant greater anti-tumour effect than anti PD-1 Ab alone (p=0.0002) and DEP irinotecan alone (p=0.0146).

Figure 2: Mean tumour volumes over time as measured in the mouse allograft study using MC-38 murine CRC cells (n=5). DEP irinotecan + anti PD-1 Ab combination had a statistically significant greater anti-tumour effect compared with anti PD-1 Ab alone (p=0.0001).

Significant survival benefit seen with DEP irinotecan + anti PD-1 Ab combination (Figure 3)

Enhanced survival, which was statistically significant, was seen in both the DEP irinotecan treated group and the DEP irinotecan + anti PD-1 Ab combination group (Figure 3a CT-26 (p=0.0014) and Figure 3b MC-38 (p<0.0001)). Median survival was extended more than 3‑fold, from 13 days (anti PD-1 Ab alone) to 40 days (DEP irinotecan + anti PD-1 Ab) in the CT-26 allograft study and 22 days (anti PD-1 Ab alone) to >64 days (DEP irinotecan + anti PD-1 Ab) in the MC-38 allograft study.

Kaplan-Meier survival curve in the mouse allograft study using a) CT-26 and b) MC-38 murine CRC cells. Dotted line shows the median survival (days).

Superior combination benefit of anti PD-1 Ab provided by DEP irinotecan compared to conventional irinotecan

The combination of DEP irinotecan + anti PD-1 Ab had a significantly greater anti-cancer effect than anti PD-1 Ab alone (p=0.0016) or conventional irinotecan + anti PD-1 Ab (p=0.0156) and the DEP irinotecan + anti PD-1 Ab combination also showed improved survival (p<0.0001). Median survival was extended from 14 days (anti PD-1 Ab alone) to 27 days (DEP irinotecan + anti PD-1 Ab) in the CT-26 model.

a) Mean Tumour volumes over time as measured in the mouse allograft study using CT-26 murine colorectal cancer cells (n=12);b) Kaplan-Meier survival curve in the mouse allograft study using CT-26 murine colorectal cancer cells. Dotted line shows the median survival (days).

Study Methods

These studies were conducted for Starpharma by an internationally recognised translational cancer group using mouse allograft models which are the standard means of assessing efficacy of IO agents, including anti PD-1 antibodies. Testing of IO agents requires a functioning immune system, so anti-cancer efficacy cannot be assessed in human cancer xenograft models.

Study 1:

Balb/c mice were inoculated subcutaneously with the murine colorectal (CT-26) cell line (5 mice/group). Dosing groups were as follows:

Vehicle Control: – antibody isotype control, twice weekly ip, for 4 doses – on day 1 (200 µg per mouse) then on days 5, 8 and 12 (100 µg per mouse)
Anti PD-1 Ab: anti PD-1 Ab, twice weekly ip, for 4 doses – on day 1 (200 µg per mouse) then on days 5, 8 and 12 (100 µg per mouse)
DEP irinotecan: DEP irinotecan (18mg/kg) once weekly iv, for 3 weeks and antibody isotype control twice weekly ip, for 4 doses
DEP irinotecan + anti PD-1 Ab: DEP irinotecan once weekly iv, for 3 weeks and anti PD-1 antibody twice weekly ip, for 4 doses
Study 2:

C57BL/6 mice were inoculated subcutaneously with murine colorectal (MC-38) cells (5 mice/group). Dosing groups were as follows:

Vehicle Control: – antibody isotype control, twice weekly ip, for 4 doses – on days 1, 5, 8 and 12 (200 µg per mouse)
Anti PD-1 Ab: anti PD-1 antibody, twice weekly ip, for 4 doses – on days 1, 5, 8 and 12 (200 µg per mouse)
DEP irinotecan: DEP irinotecan (30mg/kg) once weekly iv, for 3 weeks and antibody isotype control twice weekly ip, for 4 doses
DEP irinotecan + anti PD-1 Ab: DEP irinotecan (30mg/kg) once weekly iv, for 3 weeks and anti PD-1 antibody twice weekly ip, for 4 doses
Study 3:

Balb/c mice were inoculated subcutaneously with murine colorectal (CT-26) cells (12 mice/group). Dosing groups were as follows:

Vehicle Control: – antibody isotype control, twice weekly ip, for 4 doses – on day 1 (200 µg per mouse) then on days 5, 8 and 12 (100 µg per mouse)
Anti PD-1 Ab: anti PD-1 Ab, twice weekly ip, for 4 doses – on day 1 (200 µg per mouse) then on days 5, 8 and 12 (100 µg per mouse)
Irinotecan + anti PD-1 Ab: Irinotecan (75mg/kg) once weekly iv, for 3 weeks and anti PD-1 antibody twice weekly ip, for 4 doses
DEP irinotecan + anti PD-1 Ab: DEP irinotecan (20mg/kg) once weekly iv, for 3 weeks and anti PD-1 Ab twice weekly ip, for 4 doses
In all studies, tumours were measured twice weekly using electronic callipers. The tumour volume (mm3) data represent the mean ± standard error of the mean (SEM). Tumour volume data was analysed using a two-way ANOVA – mixed effects analysis. Survival curves were analysed using ANOVA with a Log-rank (Mantel-Cox) test. Note: If error bars do not display on the graphs, they are not visible because they are shorter than the height of the symbol.

On June 29, 2020 Lantern Pharma (NASDAQ: LTRN), a clinical stage biotechnology company focused on leveraging artificial intelligence ("A.I."), machine learning and genomic data to streamline the drug development process and to identify the patients that will benefit from its targeted oncology therapies, reported that it surpassed the milestone of 450 million curated data points being utilized in its proprietary A.I. and machine learning-powered platform, RADR (Response Algorithm for Drug Positioning and Rescue) (Press release, Lantern Pharma, JUN 29, 2020, View Source [SID1234561531]).

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RADR leverages genomic, transcriptomic, clinical and drug sensitivity data points across more than 145 drugtumor interactions to predict the potential response cancer patients will have to potential drugs, therefore enabling a more personalized approach to therapy that is aimed at better outcomes. Lantern is establishing collaborations and partnerships to expand the functionality of RADR, including algorithms that can operate 200 to 300 percent faster than its existing algorithms, enabling the company to develop robust, gene signatures that can be used to guide patient enrollment in trials and as a companion diagnostic (CDx). During the most recent data enrichment campaign, Lantern focused on significantly increasing the depth and amount of data for: nonsmall cell lung cancer, ovarian cancer, glioblastoma, and gliomas. Reaching this milestone of over 450 million curated data points for oncology drug development will bring greater precision and speed in helping Lantern with its objective of personalizing oncology therapy with reduced risk and cost.

"Our approach in leveraging machine learning to develop biologically relevant, multi-gene signatures in days or weeks allows our team to more efficiently review and test novel insights about the complex mechanisms that can drive patient response to a drug," said Panna Sharma, CEO of Lantern Pharma.

As a pioneer in the application of machine learning to oncology-focused drug development and clinical trial design, Lantern has published gene signatures derived from RADR as posters and presentations at both ASCO (Free ASCO Whitepaper) and AACR (Free AACR Whitepaper). Lantern’s pipeline of compounds includes one candidate in an active Phase 2 clinical trial for metastatic, hormone-refractory prostate cancer using a genomic signature for patient selection; another candidate in preparation for a Phase 2 clinical trial in non-small cell lung cancer in a targeted patient population; and a third candidate in two pre-clinical programs for biomarker-defined solid tumors and glioblastoma.

Mr. Sharma continued, "Because of the increasing availability of large-scale biomarker, genomic and patient data, and rapidly maturing technologies like artificial intelligence and machine learning, oncology is undergoing a monumental shift in the way cancer drugs are discovered, developed, studied, targeted, and commercialized. Lantern is at the forefront of this transformation. For Lantern, exceeding 450 million data points is a significant milestone in our work, and demonstrates our commitment to leveraging paradigm changing technologies that transform oncology drug development with the ultimate objective of cost-effectively personalizing treatment for patients."

Lantern Pharma is ahead of the initial platform development schedule, reaching 400 million data points by the end of 2020, which puts Lantern on track to reach over 1 billion data points earlier than expected. The developmental focus on increasing the number of data points, and improving the performance of the algorithms is expected to yield additional targeted indications for Lantern’s current pipeline of drugs, and also help to uncover additional compounds and therapies that can be in-licensed or acquired and subsequently developed in a more efficient manner that leverages the insights from Lantern’s data-driven, A.I.-enabled approach.

The market opportunity for RADR as a platform for the development of targeted oncology therapies is significant. The highly scalable RADR platform can be leveraged in multiple real-world applications, in addition to drug development, including: identifying potential drug combinations, predicting synergies with immune-oncology agents, developing companion diagnostics (CDx) and evaluating compounds for therapeutic efficacy and optimal positioning. Lantern is a pioneer in the adoption and implementation of data-driven and machine-learning enabled processes for drug development. The intersection of A.I., machine learning and genomics is considered a rapidly growing trend as researchers and investors turn to big data approaches to transform the cost, risk and timeline of oncology drug development.

"Lantern Pharma is using genomics, machine-learning and big data in an effort to develop potentially life-saving cancer drugs, and our ability to fulfill this mission with greater efficiency and speed will be enhanced by focusing on the overall strength and scale of our platform," concluded Mr. Sharma.

On June 29, 2020 VITRAC Therapeutics, LLC (VITRAC) reported that initiated the global clinical development of VIC-1911, an oncology candidate formally known as TAS-119, which was licensed from Taiho Pharmaceutical Co., Ltd. (Taiho), a Japan-based oncology company (Press release, VITRAC Therapeutics, JUN 29, 2020, View Source [SID1234561547]). Two Phase-1 clinical studies have been conducted in the US and Europe by Taiho. VITRAC obtained an exclusive and global development and commercialization rights for TAS-119, and its IND has been successfully transferred to VITRAC in the US with a new code name, VIC-1911.

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"It is our honor to succeed the development of this drug that has been diligently developed by Taiho, and to be able to develop a potent Aurora A specific inhibitor, VIC-1911. This drug will give more treatment options to cancer patients since Aurora Kinase plays key oncogenic roles related to their mitotic activity, promote cancer cell survival, and proliferation," said Keizo Koya, Ph.D., President of VITRAC Therapeutics.

VITRAC also made an alliance with JS InnoMed Holdings (JSI) by sublicensing the China rights of VIC-1911 to accelerate the global development. "JSI is an amazing biopharmaceutical company filled with creative and distinguished scientists managed by a notable leader, Dr. Jintao Zhang. It is exciting to collaborate on a global scale towards the development of this drug with potential to ameliorate the lives of patients," said Dr. Koya.

On June 29, 2020 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported that the U.S. Food and Drug Administration (FDA) has approved Roche’s Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection, a fixed-dose combination (FDC) of Perjeta and Herceptin with Halozyme’s ENHANZE technology, administered subcutaneously in combination with intravenous (IV) chemotherapy, for the treatment of eligible patients with early and metastatic HER2-positive breast cancer (Press release, Halozyme, JUN 29, 2020, View Source [SID1234561532]). This is the first time a product has been approved combining two monoclonal antibodies that can be administered by a single subcutaneous injection utilizing Halozyme’s ENHANZE technology.

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"We are excited that HER2-positive breast cancer patients in the U.S. will now have the option to receive this important therapy in a meaningfully shorter period of time," said Dr. Helen Torley, president and chief executive officer. "This subcutaneous delivery was shown to be preferred to IV administration by 85% of patients in the PHranceSCa study due to less time in the clinic and more comfortable treatment administration. Phesgo is the second product to receive FDA approval this year, and the first demonstrating the ability to combine two monoclonal antibodies, utilizing our ENHANZE technology."

Phesgo is available in single-dose vials and can be administered in approximately eight minutes for the initial loading dose and approximately five minutes for each subsequent maintenance dose.(1) This is compared to approximately 150 minutes for a sequential infusion of a loading dose of Perjeta and Herceptin using the standard IV formulations, and between 60-150 minutes for subsequent maintenance infusions of the two medicines.(2,3) Phesgo can be administered by a healthcare professional in a treatment center or at a patient’s home.

The approval is based on results from the pivotal phase III FeDeriCa study, which met its primary endpoint, with Phesgo showing non-inferior levels of Perjeta in the blood during a given dosing interval (Ctrough), when compared to IV administration of Perjeta. The safety profile of Phesgo with chemotherapy was comparable to IV administration of Perjeta plus Herceptin and chemotherapy, and no new safety signals were identified, including no meaningful difference in cardiac toxicity. The most common adverse events in both arms were alopecia, nausea, diarrhea and anemia.(1,4)

The phase II PHranceSCa study showed that 85% (136/160) of people receiving treatment for HER2-positive breast cancer preferred treatment under the skin to IV administration due to less time in the clinic and more comfortable treatment administration.(1)

About ENHANZE Technology
Halozyme’s proprietary ENHANZE drug-delivery technology is based on its patented recombinant human hyaluronidase enzyme (rHuPH20). rHuPH20 has been shown to remove traditional limitations on the volume of biologics that can be delivered subcutaneously (just under the skin). By using rHuPH20, some biologics and compounds that are administered intravenously may instead be delivered subcutaneously. ENHANZE may also benefit subcutaneous biologics by reducing the need for multiple injections. This delivery has been shown in studies to reduce health care practitioner time required for administration and shorten time for drug administration.