Immutep's Lag 3 Immunotherapy - IMP321 (Eftilagimod Alpha) in Metastatic breast cancer due to report in 2020

Immutep (ASX:IMM) is a biotechnology company working primarily in the field of cancer immunotherapy using the Lymphocyte Activation Gene 3 (LAG-3) immune control mechanism.

Frederic Triebel the Founder and Chief Scientist at Immutep discovered in the late 1990’s that a soluble protein called LAG-3 could activate dendritic cells in the vicinity of the tumour cells.  Dendritic cells are antigen presenting cells (APC’s) which stimulate T-cells to trigger an immune response to cancer.  The activation of T-cells are key to long remission is cancer.

Immutep (ASX:IMM) was previously known as Prima BioMed (ASX:PRR) with the company acquiring its now key LAG3 immunotherapy assets in late 2014.  The acquisition resulted in Immutep stopping the development of its autologous dendritic cell-based therapy (CVac) program in favour of LAG3 therapies.

Immutep is a French immunotherapy company developing a suite of products based on its LAG-3 technology with its flagship product being IMP321.  The market leader in the development of LAG-3 immunotherapy space is Bristol-Myers Squibb (BMS) with Immutep perhaps 2nd most advanced in this field.  BMS are expected to report a combination melanoma study of LAG3 in 2020.

The Immutep (IMM) capital structure includes ordinary shares, convertible notes, performance shares and options.  If one dilutes for everything today we have 526 million shares on issue, which equates to a $137 million market capitalisation AUD or $95 million USD.

The purpose of this article is to discuss the key Metastatic Breast Cancer (MBC) immuno-chemo program (IMP321) which is due to report next year.  Additionally Immutep is in 2a combination trial's with Keytruda in melanoma (IMP321), as well as trials with Pfizer (IMP321).  Programs are also progressing with GSK and Novartis albeit future royals are low single digit.  

Immutep's flagship clinical product is IMP321 (Eftilagimod Alpha) is being clinically trialed (AIPAC Trial) in Stage 4 HER2 negative, hormone receptive Metastatic Breast Cancer (MBC).  Around 66% of MBC patients globally are HER2 Negative.  Metastatic breast cancer cannot be cured with 5-year survival rates in the US only 22% (median survival 24-36 months). 

Immutep commenced the AIPAC trial in December 2015, announced full recruitment in June 2019 and is due to report its clinical trial results in the March 2020 quarter.  Chemotherapy is typically second/third line treatment with hormone therapies and hormone therapies in combination with CDK4/6 inhibitors the initial lines of treatment. 

The current Phase 2b AIPAC clinical trial is a substantial trial with circa 227 patients recuited, randomised 1:1 Chemotherapy (Paclitaxel) plus IMP321 (30mg dosage) vs Chemotherapy (Paclitaxel) plus sham.  Patients receive paclitaxel in combination with Immutep's LAG-3 immotherapy (IMP321) for six 4-week cycles followed by a monthly maintenance injection of IMP321. Excluding the run-in period of the clinical trial recruitment has taken 30 months which is probably ok.

Clinical Trial Time Line - AIPAC (Active Immunotherapy PAClitaxel)

• June 2019, 226 patients - Full recruitment
• Jan 2019, 179 patients reported
• Aug 2018, 126 patients
• June 2018, 113 patients
• Jan 2017, 1st patient enrolled in AIPAC randomised controlled study
• Dec 2015, AIPAC Clinical Trial Commences (15 patient safety component)

Immutep reported a small Phase 2a MBC clinical trial of thirty patients in 2010.  Of the 30 patients trialed 3 had progressive disease (10%), with 15 (50%) having an objective response or tumour shrinkage, after 6 months.  The standout clinical data was 90% of patients having stable disease followed by 50% having an objective response within the 6-month period.   The other positive insight was the highest dose studied (6.25 mg) demonstrated a 71% response rate over 6 months, with tumour shrinkage continuing once chemo stopped.  The company did not report on time-to-tumour progression which makes things harder.  More recently Immutep reported a 47% overall response rate in the safety run-in for AIPAC from 15 patients in June 2017, with the preferred 30 mg dosage getting a 44% overall response. Once again partial responses were seen late in the safety run component of the trial which is not inconsistent with other immunotherapy efficacy.

The write up of Immutep's 2010 study outlined the standard of care (chemo alone) delivered 5.6 months progression free survival with 25% of patients achieving tumour shrinkage and 50% of patients having progressed by 6 months.  There is however plenty of clinical research ambiguity around the time to progression in this setting.

Its difficult to get progression free survival data but Paclitaxel on its own showed 55% response rate and 7.5 months in progression free survival and medium survival time 20.1 months in 2nd/3rd line patients (study reported in 2013 prior to CDK4/6 inhibitor introduction).  The authors did however note their 2013 clinical data was amongst the strongest seen with 30% response rates being more typical. 

The Immutep 2010 clinical trail and the lead-in data from the AIPAC trial shows a combined 45 patients demonstrated 10 -13% median disease progression vs perhaps 30 - 50% (after 6 months) in the real world.
 
The current Immutep Phase 2 clinical trial in HER negative, hormone receptive, Metastatic Breast Cancer (MBC) is complicated by the standrad of care changing during the course of the 2015-2020 clinical trial period, with CDK4/6 inhibitors like Ibrance (chemical name: Plbociclib) in combination with hormone therapies Faslodex (Chemical fulvestrant) entering the standard of care as first line therapy.  

The introduction of  CDK4/6 inhibitors like Ibrancee means patients are receiving chemotherapy treatment latter noting median survival is 24-36 months.  The key clinical trail is PALOMA-3 which compared  palbociclib plus fulvestrant vs fulvestrant alone showed 11.2 months till disease progression vs 4.6 months for hormone therapy alone or a massive 6.6 month delay in progression.   

This standard of care delay means Immutep's AIPAC trial will be receiving second/third line patients circa 6.6 months latter in the second half of their AIPAC study, noting survival statistics in MBC are not great, so pretty safe to assume they are getting sicker patients whom are likely to progress quicker that the 7.5 months observed in chemo alone 2013 study above.   

The introduction of CDK4/6 inhibitors (for half the study) prior to chemotherapy should result in quicker disease progression (estimate 6 months).  This compares with our earlier Immutep data from 45 patients pre CDK4/6 inhibitors which showed circa 47%-50% response rates, 10-13% disease progressors with the caveat being these were healthier patients.  On the basis that Immutep's disease progression data is significantly slower than chemo (50% vs 30% response rates) there is logic to support a positive p value for progression free survival data analysis in March 2020, however clinical trials are notoriously fraught with difficulty.

A successful clinical trial in an indication as difficult as MBC could result in a drug approval in Europe sometime as early in 2021, albeit it would be safer to assume a pivotal clinical trial would be required.  It is likely Immutep will report before BMS in its MCC clinical study potentially opening up another important immunotherapy tool for oncologists. 

A clinical trial failure will result in investors focussing on Immutep's emerging relationships with Merck, Pfizer, GSK and Novartis.  With this company capitalised at less than $100 million USD there is some downside protection or potenial value in these clinical programs.