Biotech Values

[mcbio]

DNLI (TREM2) -

Of the targets you mention I know most about TDP43 - that's the major dysfunctional protein in ALS and also frontotemporal dementia. A misfolded form of TDP43 called pathologic TDP43 is the major observable brain pathology in ALS. But nobody really knows if the issue is loss of function of the protein (it is used in RNA processing) or whether it is a symptomatic response to something else.

Thanks. I was doing some digging and it looks like DNLI is actively targeting TREM2. See from S-1 on pg. 5: https://www.sec.gov/Archives/edgar/data/1714899/000119312517340997/d445892ds1.htm .

The description on the TREM2 program for AD from the S-1 is as follows:

"ATV: TREM2 is a therapeutic candidate designed to rescue microglial function in Alzheimer’s disease through modulating the activity of a genetically validated target. We have developed high affinity antibodies for TREM2 and are currently characterizing molecules in order to select a lead to couple with our proprietary ATV platform. We plan to file an IND or CTA for this program in 2020.

Therapeutic Rationale

A major component of Alzheimer’s disease pathology is the presence of neuro-immune dysfunction. Microglia, the resident immune cells of the brain, show signs of activation and release of toxic cytokines in patients with Alzheimer’s disease. Recent human genetic studies have identified single nucleotide polymorphism in a number of microglia specific genes that contribute to Alzheimer’s disease, which strongly implicates glial function as a contributor to disease risk. TREM2 is a cell surface receptor expressed exclusively by microglia in the brain which regulates multiple processes including survival, migration, phagocytosis, and cytokine release (Figure 27). In 2013, a rare variant of TREM2 was found to be associated with a three-fold higher risk of Alzheimer’s disease onset, which strongly implicates TREM2 as a functional contributor to disease progression.

The TREM2 mutations identified in patients with Alzheimer’s disease results in loss of normal TREM2 function. Mouse models of Alzheimer’s disease display more severe phenotypes in the absence of TREM2, including more diffuse amyloid plaques and increased synaptic loss. Conversely, data from our TREM2 expressing myeloid cell-based assays demonstrate that increasing TREM2 signaling can improve cellular survival and function, indicating that activating TREM2 has a beneficial effect on this cell type (Figure 29). Based on this combination of genetic and functional data, we hypothesize that positive modulation of TREM2 activity will improve microglia function and slow the progression of Alzheimer’s disease.

We believe that patients with a specific neuroinflammatory signature as a result of glial dysfunction may particularly benefit from therapeutics targeting positive modulation of TREM2. These patients could be identified through a combination of genetic, CSF and imaging biomarkers. This population could be expanded to encompass all prodromal to mild and moderate Alzheimer’s disease patients based on a demonstration of pathway modulation in the clinic.

Pharmacological Properties and Brain Exposure

We have generated multiple classes of anti-TREM2 antibodies with affinities less than 10nM. By using an array of functional assays, we have demonstrated that these antibodies have diverse functional effects, including several that show agonism, antagonism and positive allosteric modulation (Figure 28).

We have demonstrated that select antibodies with TREM2 agonist activity are able to improve the survival of cultured human macrophage (Figure 29). These data indicate that increasing TREM2 function can have a beneficial effect on myeloid linage cells. We are currently testing these and other anti-TREM2 antibodies in additional assays to determine which mechanism of action results in the desired effect on TREM2-mediated microglial function. We intend to then progress a lead antibody with a favorable affinity and activity profile to in vivo studies.

We will evaluate the lead TREM2 antibodies in vivo for target engagement and disease-relevant efficacy in animal models of Alzheimer’s disease. We will then progress the most promising of the lead TREM2 antibodies as a potential clinical candidate to be humanized and coupled with our ATV platform, ATV:TREM2, in order to improve brain uptake and enable target engagement in clinical studies.

Biomarker-Driven Development

The development of ATV:TREM2 is expected to be facilitated by a number of biomarkers to measure target engagement, pathway modulation and impact on disease progression. Upon cleavage of the extracellular domain of TREM2, a soluble form of TREM2, sTREM2, is released from the cell surface. sTREM2 is detectable in CSF. We have focused on anti-TREM2 antibodies that modulate the levels of sTREM2, enabling sTREM2 to be used as a biomarker of target engagement both in preclinical models and Phase 1 clinical trials. We intend to correlate TREM2 levels with downstream functional endpoints using preclinical models, allowing measurement of sTREM2 levels in a Phase 1 clinical trial to confirm target engagement and increase the probability of success.

The ability of ATV:TREM2 to modulate microglial function in preclinical models will be measured through histology and examination of microglial gene expression. These endpoints will be correlated to readouts that can be measured in clinical studies such TSPO-PET imaging and cytokine levels in CSF. As part of clinical trials, we plan to examine these endpoints both pre-dose and following treatment to assess microglia activation state.

Development Plan

The primary indication for ATV:TREM2 is Alzheimer’s disease. The development of ATV:TREM2 will be facilitated by a number of biomarkers to measure target engagement, pathway modulation and an impact on disease progression. Our focus on anti-TREM2 antibodies that modulate levels of sTREM2, a soluble form of TREM2, will enable sTREM2 to be used as a biomarker of target engagement both in preclinical models and Phase 1 clinical trials. sTREM2 is released from the cell surface upon cleavage of the extracellular domain of TREM2 and is detectable in CSF. In preclinical models dosed with ATV: TREM2, sTREM2 levels will be correlated with the ability of ATV:TREM2 to modulate microglial function as assessed through histology and examination of microglial gene expression. Understanding the relationship between changes in sTREM2 and microglial function, will enable assessment of both target engagement and a biologically relevant effect of ATV:TREM2 dosing in Phase 1 clinical trials. Early stage clinical studies will also assess candidate biomarkers to identify patients that are most likely to benefit from a TREM2 mediated approach. Examples of these candidate biomarkers include CSF sTREM2 and TSPO-PET, two biomarkers that are elevated in patients with Alzheimer’s disease. These examples may be used as both a patient selection biomarker to identify patients with pathologic neuro-immune function and as a measure of TREM2 pathway modulation.

These endpoints will be correlated to readouts that can be measured in clinical studies such TSPO-PET imaging and cytokine levels in CSF. As part of clinical trials, we plan to examine these endpoints both pre-dose and following treatment to assess microglia activation state. We plan to file an IND or CTA for this program in 2020."