We are a precision oncology company focused on the discovery, development and commercialization of irreversible small molecules. We are creating an entirely new generation of molecular scaffolds, targeting genetically defined diseases. We believe that irreversible small molecules have the potential to address the key limitations of existing reversible therapeutics as well as to treat diseases where targeted therapies are not yet approved. The following table summarizes our product candidate pipeline. We own full worldwide development and commercialization rights to all of our programs.
MENIN Program: A Novel Approach
MLL-rearranged ALL & AML
Chromosomal Abnormalities and the Onset of Cancer
Recurrent Chromosomal Anomalies in ALL and AML
Menin is a 67kDa protein important to transcriptional regulation, impacting major processes such as cell cycle control, apoptosis and DNA damage repair. It plays an essential role in oncogenic signaling in subgroups of genetically defined leukemias, such as mixed lineage leukemia – rearranged (MLL-r) and other cancers dependent on menin. MLL-r leukemias are characterized by MLL gene (also known as KMT2A) translocation abnormalities. These abnormalities result in the formation of fusion genes encoding fusion proteins comprised of MLL1 and a corresponding fusion partner domain. The interaction of these fusion proteins with menin drives the expression of downstream target genes HOXA9 and MEIS1, triggering leukemic cell proliferation.Caslini C, Yang Z, El-Osta M, et al. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res. 2007;67(15):7275-7283.Kühn MW, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181.Winters AC, Bernt KM. MLL-rearranged leukemias—an update on science and clinical approaches. Front. Pediatr. 2017;5:4.
Menin binds directly to the conserved N-terminus of MLL proteins, making it an ideal target that can be exploited consistently by a menin inhibitor therapeutic.Caslini C, Yang Z, El-Osta M, et al. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res. 2007;67(15):7275-7283.Kühn MW, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181.in vitro and in vivo.Caslini C, Yang Z, El-Osta M, et al. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res. 2007;67(15):7275-7283.Winters AC, Bernt KM. MLL-rearranged leukemias—an update on science and clinical approaches. Front. Pediatr. 2017;5:4.
Inhibiting oncogenic signaling in subgroups of genetically defined leukemias by specifically blocking the essential menin-MLL interaction can lead to cell death.Modified after Uckelmann, ASH 2018, Abstract # 546
Given the clear involvement of MLL and NPM1 in acute leukemias and the poor clinical outcomes provided by available treatments, we believe a new treatment that can inhibit the function of both targets by disrupting or even preventing interactions with menin could address this unmet need.
The role of menin-MLL interactions in oncogenic signaling has been extensively studied in liquid tumors, predominantly AML and ALL as discussed above. As reflected in the figure below, elevated menin and MLL levels and association with disease has also been observed in other liquid tumors (including multiple myeloma and DLBCL) and multiple solid tumors (including tumors of the breast, liver, lung, pancreas, bone and colon).
Menin is implicated across a range of liquid and solid tumors through its interactions with various forms of MLL.Cierpicki & Grambacka, Future Med. Chem. (2014)
Our lead product candidate, BMF-219, is a potent, selective, orally-bioavailable, irreversible inhibitor of menin that disrupts the protein-protein interaction between menin and MLL. We are developing BMF-219 for the treatment of cancers that are highly dependent on menin including leukemias containing the MLL fusion protein. In preclinical studies, BMF-219 demonstrated robust anti-tumor effects across a range of liquid and solid tumor models, including MLL-r AML, NPM1 mutant AML, and KRAS mutant colorectal, lung and pancreatic tumors. BMF-219 has also been shown to have a favorable tolerability profile and PK properties as a once-daily oral therapy. Based on our preclinical findings, our irreversible approach may have significant advantages over reversible inhibitors, including selectivity, potency, durability and safety. We are currently completing IND enabling studies and expect to file an IND with the FDA in the second half of 2021.
The figure below reflects the role of BMF-219 in the inhibition of menin, which acts as a transcription-regulating scaffold and provides a target to modulate normal and rearranged MLL effects on transcriptional upregulation.
Schematic of key proteins and their interactions in the regulation of gene transcription.Adapted from Rao & Dou (2015). Nat.Rev.Cancer. 15: 334-346. Our lead product candidate, BMF-219, is intended to irreversibly inhibit the interaction between menin and wild type MLL and MLL fusions
[back to top]
The National Cancer Institute estimates over 20,000 new cases of AML and over 6,000 new cases of ALL in the United States in 2020. MLL-r leukemia has limited therapeutic options and affects between 5% and 10% of adults and approximately 35% of pediatric patients with AML as well as between 10% and 15% of adults and between 60% and 70% of pediatric patients with ALL.Hess, JL, Ann. Rev. of Pathol. 2012, 7:283-301. Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu. Rev. Pathol.: Mechanisms of Disease. 2012;28(7):283-301.Kühn MW, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6(10):1166-1181.
Patients with MLL rearrangements often suffer from failure of induction therapy or disease relapse, resulting in poor clinical outcomes. In pediatric AML, the five-year event-free survival ranges between 31% and 50% depending on the MLL-translocation subtypes.Winters AC, Bernt KM. MLL-rearranged leukemias—an update on science and clinical approaches. Front. Pediatr. 2017;5:4.https://www.cancer.net/cancer-types/leukemia-acute-lymphocytic-all/statisticsBalgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood … Continue reading
A perhaps more dire area of unmet need is relapsed/refractory (r/r) AML. Despite evolving insights into the pathogenesis of AML, over 11,000 patients with AML die each year from the disease in the United States.NCI SEEROthus M, Appelbaum FR, Petersdorf SH, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transplant. 2015;21(3):559-564.Weisdorf D. The role of second transplants for leukemia. Best Pract Res Clin Haematol. 2016;29(4):359-364.Tallman MS, Wang ES, Altman JK, et al; OCN. Acute myeloid leukemia, version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17(6):721-749.DEWOLF and TALLMAN. How I treat relapsed or refractory AML. Blood 27 AUGUST 2020. | VOLUME 136, NUMBER 9 1023
The development of precision medicine against fusion-driven tumors, as in the case of MLL-r Leukemias, represents Breakthrough-Therapy potential. Due to the high importance of the pathway involved and subsequent impact as a targeted agent, there is also the potential for an expedited drug development, thereby shortening the FDA approval time. Due to the potential for such precision medicine to treat or prevent a rare disease or condition that affects less than 200,000 persons in the US, such programs typically achieve an Orphan Drug designation. Orphan drug designation awardees are granted the following benefits from the FDA: Tax credits of 50% of the clinical drug testing cost awarded upon approval; Eligibility for market exclusivity for 7 years post approval; Waiver of new drug application (NDA)/ biologics license application (BLA) application fee.
It has been known for quite some time, that certain cancers contain specific chromosomal defects that are believed to be causally related to the onset and/or progression of the disease. An early example of such a chromosomal anomaly is the so-called Philadelphia (Ph’) chromosome, which was first identified in 1959 by Drs. Hungerford and Nowell (both working in Philadelphia at the time, hence the name). This was the result of a balanced chromosomal translocation where the tips of chromosomes 9 and 22 break off, and swap places, as is illustrated in the scheme below:
Fig. 1. Schematic of the Philadelphia chromosome formationhttps://en.wikipedia.org/wiki/Philadelphia_chromosome
As was first discovered by Janet Rowley’s group in Chicago (in 1973), by juxtaposing the ABL1 gene on chromosome 9 to the BCR (breakpoint cluster region) gene on chromosome 22, a fusion gene residing on the aberrant chromosome 22 (or: Ph’ chromosome) is formed, which encodes an abnormal Bcr-abl protein that is responsible for causing the disease (in this particular case mainly a form of blood cancer called Chronic Myeloid Leukemia).
The normal Bcr protein functions as a growth “switch” (a so-called tyrosine kinase) that can be switched on or off, depending on the normal physiological needs of the cell, but the abnormal Bcr-abl protein, which in principle has retained this same function, lacks the off-switch, and is therefore constitutively “on”, thereby spurring cancer growth.
When detailed knowledge regarding the above biological mechanism and, consequently, a novel obvious drug target became available, several companies initiated programs aiming at disrupting the aberrant growth signal triggered by the Bcr-abl protein. In the late 1990s, Novartis developed a drug (imatinib mesylate, marketed in the USA as Gleevec), that was able to rather specifically bind to the active site within the Bcr and Bcr-abl protein and, by doing so, shut off the protein, and took away the main growth stimulus for the cancer cells. Therefore the development of Gleevec has greatly improved overall survival rates in Ph’-positive CML.
Interestingly, about 15% (estimates vary between 5% and 20%) of ALL and AML cases are found to contain a similar, but distinctly different chromosomal anomaly. In this case it frequently involves the KMTA2 (or: MLL1, which is an old synonym for KMT2A) gene which resides on the long arm of chromosome 11 and encodes Lysine [K]-specific Methyl Transferase 2A, an enzyme with a role in the epi-genetic regulation of DNA activation and one of many (over 80 have been described) fusion genes (discussed below). It should also be noted that leukemias with MLL1 involvement seem to be most resistant to existing therapy and have a relatively grim prognosis. Interestingly, in infant leukemias, MLL1 rearrangements occur at an incidence as high as 70-80%
The scenario involved here is strikingly similar: chromosomal changes typically trigger the break of MLL1 (here referred to as KMT2A) within the breakpoint cluster region (indicated with “BCR” in Figure 2 below).
Fig. 2. Functional domains within the normal KMT2A protein
Two reciprocal fusion genes are formed, one of which contains the MLL1 protein domains that reside upstream (or: N-terminal) of the breakpoint cluster region, followed by none or more functional domains encoded by the C-terminus of one of the fusion genes, (in the below graph, AF4 is listed as an example) as shown in Figure 3 below.
Fig. 3. Schematic representation of typical, oncogenic KMT2A (= MLL1) fusion proteins
Fig. 4. Proteins involved in repressive functions of MLL are grouped above, whereas proteins involved in activation of MLL-dependent transcription are grouped below the schematic KMT2A bar
The expected reciprocal fusion product (composed of the N-terminal of one of the fusion genes fused to the C-terminus of KMT2A) appears be formed in only a minority of KMT2A-rearranged patients (less than 15%), and is therefore considered to only play a minor role (if one at all) in the tumorigenic process. In addition, experiments with these reciprocal fusion genes / proteins have shown that these are typically not able to trigger tumor formation like the fusion gene that contains the MBD, AT, SNL and RD domains of KMT2A / MLL1 (like the one shown in figure 4 above) is able to do.
Hence, the fusion protein schematically shown in figure 4 is generally believed to drive tumor initiation and/or progression, and should therefore be considered a rational target for drug development efforts, comparable to the Bcr-abl protein described above.