April 2014

10 April 2014

Forma Therapeutics’ expanded R&D collaboration with Celgene

By Allan Haberman, Ph.D|2019-05-02T21:10:56+00:00April 10, 2014|Cancer, Chemistry, Drug Development, Drug Discovery, Haberman Associates, Strategy and Consulting|

Ubiquitin pathway. Source: Rogerdodd, English language Wikipedia

On April 1, 2014, Forma Therapeutics (Watertown MA) announced that it had entered into an expanded strategic collaboration with Celgene (Summit, NJ).

Under the new agreement, Forma has received an upfront cash payment of $225 million. The initial collaboration between the two companies under the new agreement will be for 3 1⁄2 years. Celgene will also have the option to enter into up to two additional collaborations with terms of two years each for additional payments totaling approximately $375 million. Depending on the success of the collaborations and if Celgene elects to enter all three collaborations, the combined duration of the three collaborations may be at least 7 1⁄2 years.

Under the terms of the new agreement, Forma will control projects from the research stage through Phase 1 clinical trials. For programs selected for licensing, Celgene will take over clinical development from Phase 2 to commercialization. Forma will retain U.S. rights to these products, and Celgene will have the rights to the products outside of the U.S. For products not licensed to Celgene, FORMA will maintain worldwide rights.

During the term of the third collaboration, Celgene will have the exclusive option to acquire Forma, including the U.S. rights to all licensed programs, and worldwide rights to other wholly owned programs within Forma at that time.

The April 2013 agreement between Forma and Celgene

The new collaboration between Forma and Celgene builds on an earlier agreement between the two companies. On April 29, 2013, the two companies entered into a collaboration aimed at discovery, development, and commercialization of drug candidates to modulate targets involved in protein homeostasis.

Protein homeostasis, also known as proteostasis, involves a tightly regulated network of pathways controlling the biogenesis, folding, transport and degradation of proteins. The ubiquitin pathway (illustrated in the figure above) is one of these pathways. We recently discussed how the ubiquitin pathway is involved in the mechanism of action of thalidomide and lenalidomide (Celgene’s Thalomid and Revlimid).

Targeting protein homeostasis has application to discovery and development of drugs for oncology, neurodegenerative disease, and other disorders. However, the April 2013 Forma/Celgene agreement focused on cancer. Under that agreement, Forma received an undisclosed upfront payment. Upon licensing of preclinical drug candidates by Celgene, Forma was to be eligible to receive up to $200 million in research and early development payments. FORMA was also to be eligible to receive $315 million in potential payments based upon development, regulatory and sales objectives for the first ex-U.S. license, as well as up to a maximum of $430 million per program for further licensed products, in addition to post-sales royalties.

On October 8, 2013, Forma announced that it had successfully met the undisclosed first objective under its April 2013 strategic collaboration agreement with Celgene. This triggered an undisclosed payment to Forma. Progress in the April 2013 collaboration was an important basis for Celgene’s decision to enter into a new, broader collaboration with Forma a year later.

The scope of the new April 2014 Forma/Celgene collaboration

Unlike the April 2013 agreement, the April 2014 agreement between Forma and Celgene is not limited to protein homeostasis, or to oncology. The goal of the new collaboration is to “comprehensively evaluate emerging target families for which Forma’s platform has exceptional strength” over “broad areas of chemistry and biology”. The expanded collaboration will thus involve discovery and development of compounds to address a broad range of target families and of therapeutic areas.

According to Celgene’s Thomas Daniel, M.D. (President, Global Research and Early Development), Celgene’s motivation for signing the new agreement is based not only on the early success of the existing Forma/Celgene collaboration, but also on “emerging evidence of the power of Forma’s platform to generate unique chemical matter across important emerging target families”.

According to Forma’s President and CEO, Steven Tregay, Ph.D., the new collaboration with Cegene enables Forma to maintain its autonomy in defining its research strategy and conducting discovery through early clinical development. It also aligns Forma with Celgene’s key strengths in hematology and in inflammatory diseases.

Forma Therapeutics in Haberman Associates publications

We have been following Forma on the the Biopharmconsortium Blog since July 2011. At that time, I was a speaker at Hanson Wade’s World Drug Targets Summit (Cambridge, MA). At that meeting, Mark Tebbe, Ph.D. (then Vice President, Medicinal and Computational Chemistry at Forma) was also a speaker. At the conference, Dr. Tebbe discussed FORMA’s technology platforms, which are designed to be enabling technologies for discovery of small-molecule drugs to address challenging targets such as protein-protein interactions (PPIs).

In particular, Dr. Tebbe discussed Forma’s Computational Solvent Mapping (CS-Mapping) platform, which enables company researchers to interrogate PPIs in intracellular environments, to define hot spots on the protein surfaces that might constitute targets for small-molecule drugs. FORMA has been combining CS-Mapping technology with its chemistry technologies (e.g., structure guided drug discovery, diversity orientated synthesis) for use in drug discovery.

We also discussed Forma’s earlier fundraising successes as of January 2012, and cited Forma as a “built to last” research-stage platform company in an interview for Chemical & Engineering News (C&EN).

Finally, we discussed Forma and its technology platform in our book-length report, Advances in the Discovery of Protein-Protein Interaction Modulators, published by Informa’s Scrip Insights in 2012. (See also our April 25, 2012 blog article.)

In our report, we discussed Forma as a company that employs “second-generation technologies” for the discovery of small-molecule PPI modulators. This refers to a suite of technologies designed to overcome the hurdles that stand in the way of the accelerated and systematic discovery and development of PPI modulators. Such technologies are necessary to make targeting of PPIs a viable field.

Forma’s website now has a brief explanation of its drug discovery engine, as it is applied to targeting PPIs. This includes links to web pages describing:

CS-Map technology
Forma’s compound libraries, based in part on diversity-oriented synthesis
Cell-based high-throughput screening (HTS) technologies
Forma’s high speed solution phase parallel synthesis and purification platform. This platform provides Forma with the potential to perform medicinal chemistry at an extremely accelerated pace.

Our 2012 book-length report discusses technologies of these types, as applied to discovery of PPI modulators, in greater detail than the Forma website.

According to Dr. Daniel: “Progress in our existing [protein homeostasis] collaboration, coupled with emerging evidence of the power of FORMA’s platform to generate unique chemical matter across important emerging target families” led Celgene to enter into its new, expanded collaboration with Forma in April 2014. This suggests that Celgene is especially impressed by Forma’s chemistry and chemical biology platforms. it also suggests that chemistry technology platforms developed to address PPIs may be applicable to areas of drug discovery beyond PPIs as well.

Concluding remarks

Despite the enthusiasm for Forma and its drug discovery engine shown by Celgene, Forma’s other partners, and various industry experts, it must be remembered that Forma is still a research-stage company. The company has not one lone drug candidate in the clinic, let alone achieving proof-of-concept in humans. It is clinical proof-of-concept, followed by Phase 3 success and approval and marketing of the resulting drugs, that is the “proof of the pudding” of a company’s drug discovery and development efforts.

We await the achievement of such clinical milestones by Forma Therapeutics.

From a business strategy point of view, we have discussed Forma’s efforts to build a stand-alone, independent company for the long term in this blog and elsewhere. Now Forma has entered into an agreement with Celgene that might—in around 7-10 years—result in Forma’s acquisition. This would seem to contradict Forma’s “built to last” strategy.

However, in the business environment that has prevailed over the past several years, several established independent biotech companies, notably Genentech and Genzyme, have been acquired by larger companies. Even several Big Pharmas (e.g., Schering-Plough and Wyeth) have been acquired.

Nevertheless, we do not know what the business environment in the biotech/pharma industry will be like in 7-10 years, despite the efforts of strategists to predict it. And Celgene might forgo its option to acquire Forma, for any number of reasons. So the outlook for Forma’s status as an independent or an acquired company (which also depends on its success in developing drugs) is uncertain.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

1 April 2014

Neandertals, diabetes, and drug discovery

By Allan Haberman, Ph.D|2018-12-03T23:52:12+00:00April 1, 2014|Drug Development, Metabolic diseases|

Neanderthal Family

In our 2010 end-of-year blog article entitled “2010: Breakthroughs, Newsmakers, And Deals Of The Year”, we proposed an alternative nominee for the life science breakthrough of the year: the determination of the sequence of approximately two-thirds of the Neandertal genome by Svante Pääbo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.) and his colleagues. We stated that this momentous achievement was “of great cultural significance, since it indicates that Neandertals contributed some 1-4 percent of the genome sequences of non-African present-day humans.” (This figure is now thought to be 1.5 to 2.1 percent.)

However, we also said that we had not blogged on this work “simply because it [had] nothing to do with drug discovery and development.” We then further stated that “perhaps someday, for example, some of the products of genes that are found in present-day humans but not in Neandertals could emerge as potential drug targets…researchers [had] begun studying some of these gene products in cell culture systems.”

Now, as of early 2014, one of the genes identified via sequencing Neandertal genomes has been implicated in a novel pathway involved in type 2 diabetes in present-day humans. However, rather than being a modern human gene not present in Neandertals, it is a haplotype that introgressed into modern humans via admixture with Neandertals.

The study that identified this gene initially had no connection with Neandertal genome studies at all. I was published by the SIGMA (Slim Initiative in Genomic Medicine for the Americas) Type 2 Diabetes Consortium in the 6 February 2014 issue of Nature. SIGMA is a joint U.S.-Mexico project funded by the Carlos Slim Foundation. It focuses on several important diseases that have particular relevance to public health in Mexico and Latin America, including type 2 diabetes and cancer. Type 2 diabetes has approximately twice the prevalence in Mexican and other Latin American populations, as compared to U.S. non-Hispanic whites.

The researchers performed a genome-wide association study (GWAS), in which they analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans, including 3,848 with type 2 diabetes and 4,366 non-diabetic controls. As a result of that analysis, the researchers replicated the identification of haplotypes previously associated with type 2 diabetes. They also identified a novel locus associated with type 2 diabetes at genome-wide significance. This locus spans the genes that encode the solute carrier proteins SLC16A11 and SLC16A13. The risk haplotype carries four amino acid substitutions, all in SLC16A11. It is present at approximately 50% frequency in Native American individuals and around 10% in East Asians, but is rare in Europeans and Africans.

Each copy of the risk newly-identified haplotype is associated with an approximately 20% increased risk of type 2 diabetes. The haplotype would thus be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations. Mutations in SLC16A11 had never before been associated with type 2 diabetes. SLC16A11 thus represents a novel type 2 diabetes pathway.

The Neandertal connection

The researchers noted that the sequence of the risk haplotype is highly divergent, with an estimated time to the most recent common ancestor of both the novel haplotype and a European haplotype of 799,000 years. This is long before modern humans migrated from Africa into Eurasia. Moreover, the novel haplotype is not found in Africans and is rare in European populations. The researchers therefore hypothesized that the novel haplotype entered modern human populations via admixture with Neandertals.

At the time that this research was being conducted, the variant was not seen in published Neandertal (or Denisovan) genome sequences. However, with the help of Svante Pääbo, the researchers obtained access to a then-unpublished full-length Neandertal genome sequence from a Central Asian specimen. The Central Asian Neandertal genome sequence was homozygous across 5 killobases for the risk haplotype including all four missense SNPs in SLC16A11 . Over a span of 73 kb, the Neandertal sequence is nearly identical to that of individuals from the 1000 Genomes Project who are homozygous for the risk haplotype. The full-length Central Asian Neandertal genome has recently been published.

Moreover, the genetic length of the 73-kb risk haplotype is longer than would be expected if it had undergone recombination for the approximately 9,000 generations since the split with Neandertals. This is consistent with the hypothesis that the risk haplotype is not only similar to the Neandertal sequence, but was probably introduced into modern humans relatively recently through archaic admixture. Although this particular Neandertal-derived haplotype is common in the Americas, Native Americans and Latin Americans have the same proportion of Neandertal ancestry genome-wide as other Eurasian-derived populations. In general, although non-African populations have about the same percentage of Neandertal genes, different populations have different complements of genes derived from Neandertals.

Functional studies of SLC16A11

Although the risk haploype encodes four missense mutations in a single gene, the gene for SLC16A11, there is no formal genetic proof that SLC16A11 is responsible for increased risk of type 2 diabetes. Therefore, the researchers performed preliminary functional studies of SLC16A11.

Via immunofluorescence studies, the researchers found that SLC16A11 was expressed in the liver, the salivary glands and the thyroid. When the gene for SLC16A11 was introduced into HeLa cells, SLC16A1 was found to localize in the endoplasmic reticulum, but not in the plasma membrane, Golgi apparatus, or mitochondria. Other SLC16 family members show distinct intracellular localization pattern within the membranous structures of the cell.

SLC16A11, and other SLC16 family members, are solute carrier transporters (SLCs). We discussed SLCs and their role in transporting small-molecule nutrients and drugs across the blood-brain barrier in our 2009 book-length report, Blood-Brain Barrier: Bridging Options for Drug Discovery and Development, published by Cambridge Healthtech Institute. We also discussed SLCs in a 2009 article entitled “Strategies to Overcome Blood-Brain Barrier” in Genetic Engineering and Biotechnology News.

SLC16 family proteins are monocaboxylate transporters, which transport such compounds as lactate, pyruvate and ketone bodies, as well as thyroid hormone and aromatic amino acids, across biological membranes. As of 2008, of the 14 known members of this family, eight (including SLC16A11) had unknown functions.

The SIGMA researchers expressed SLC16A11 (or control proteins) in HeLa cells, and looked for changes in intracellular concentrations of approximately 300 polar and lipid metabolites. Expression of SLC16A11 resulted in substantial increases in intracellular triacylglycerol (triglyceride) levels, with smaller increases in intracellular diacylglycerols, and decreases in lysophosphatidylcholine, cholesteryl esters, and sphingomyelin. Since triglyceride synthesis occurs in the endoplasmic reticulum of hepatocytes, the researchers hypothesized that SLC16A11 may have a role in hepatic lipid metabolism.

Moreover, serum levels of triglycerides and accumulation of intracellular lipids are associated with insulin resistance, the metabolic syndrome, and the risk of developing type 2 diabetes. Thus, although further functional studies of SLC16A11 are needed, the researchers hypothesize that the novel risk allele for type 2 diabetes that they identified may exert its pro-diabetic effect by altering lipid metabolism in the liver.

Conclusions

This study, a GWAS in Mexican and other Latin American samples, is an illustration of how genetic mapping studies in understudied populations may identify previously undiscovered aspects of disease pathogenesis.

The risk gene identified in this study, SLC16A11, has not previously been associated with type 2 diabetes. It thus potentially represents a novel diabetes pathway, which might yield new targets for drug discovery. This new pathway might be important in type 2 diabetes not only in Native Americans and Latin Americans, but in other populations as well, even in those that lack mutations in SLC16A11.

The study initially had nothing to do with Neandertal genetics. However, the researchers noted unusual population genetics features of the risk haplotype that they identified, which led them to identify this haplotype as having entered modern human populations via introgression from Neandertals. Via the initial introgression, natural selection and/or genetic drift, the haplotype became fixed in Native Americans and some East Asians, but not in other Eurasian-derived populations such as Europeans and Euro-Americans.

It is extremely unlikely that either Neandertals, or Native Americans and Latin Americans in pre-modern times, had type 2 diabetes. However, modern diets, perhaps in concert with other risk genes, produced type 2 diabetes in carriers of the mutant SLC16A11 gene. The well-know case of the Pima Indians indicates that change from native diets and high levels of physical activity to processed foods and a more “Western” lifestyle is the major cause of the high levels of type 2 diabetes and obesity in this genetically-predisposed population. (It is not known, however, whether SLC16A11 is a factor in Pima Indians.)

As for studies of the Neandertal genome, John Hawks, Ph.D. (University of Wisconsin), an anthropologist who has been active in studies of the genetics of Neandertals and of Upper Paleolithic modern humans, believes that studies of the genomes of these ancient peoples may have relevance for the biology of present-day humans. [I took a Massive Open Online Course (MOOC) led by Dr. Hawks, entitled “Human Evolution: Past and Future” between late January and early March, 2014.]

Other researchers who study ancient genomes generally agree. As indicated by the SIGMA diabetes study, both genes for modern humans that were not present in Neandertals, and genes introgressed from Neandertals into modern humans may be relevant to modern human biology—and perhaps eventually to drug discovery.