Tag Archives: science

The Needle Issue #4

20 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

Lipid nanoparticles (LNPs), like those used in the FDA-approved siRNA drug Onpattro, remain the delivery vehicle of choice for mRNAs, gene-editing and base-editing therapies. One drawback of intravenously administered LNPs is adsorption of apolipoprotein E triggers rapid liver uptake via low-density lipoprotein (LDL) and other receptors on hepatocytes. This results in a relatively short half-life and limit application of LNPs in other organs. Peter Cullis, from the University of British Columbia, and his team report in Nature Communications a new LNP design that promises to enhance their lifetime in the blood.

In previous work, the team had established that LNPs consisting of an oil droplet of ionizable lipid like MC3, surrounded by a monolayer of bilayer-forming lipids like egg sphingomyelin and cholesterol, further surrounded by a proper lipid bilayer lasted longer in the circulation. In their new study, they systematically modified the ratio of bilayer lipid to ionizable lipid (RB/I) and found that LNPs with RB/I=4 showed liposomal morphology, high mRNA encapsulation efficiency, and excellent transfection properties in vitro and in vivo. Moreover, these LNPs with high proportions of bilayer forming lipids lasted longer in the circulation and showed higher transfection efficacy in lymph nodes and pancreas than Onpattro-like LNPs.

Cullis and his colleagues propose that the prolonged blood circulation lifetime is attributed to reduced plasma protein adsorption. The transfection competency of liposomal LNP systems is attributed to export of the solid core containing mRNA from the LNP as the endosomal pH is lowered. Their transfection potency, in turn, appears to depend on the cytoplasmic release of complexes that include mRNA and ionizable lipid, complexes that are generated as the endosome matures and its pH decreases. This work represents a promising strategy to increase the therapeutic index of drugs delivered by LNPs.

The new LNPs are being developed by Nanovation Therapeutics, a preclinical startup co-founded by Cullis in 2021. In September, Nanovation clinched a $600 million deal with Novo Nordisk to license worldwide rights to its long-circulating LNPs for extra hepatic delivery of two base-editing therapies for rare genetic diseases, and up to five additional targets in cardiometabolic and rare diseases. Cullis is a serial entrepreneur who has founded several companies around lipid-based delivery systems for nucleic acid-based drugs, including Inex Therapeutics/Protiva Biotherapeutics/Tekmira/Arbutus Pharma and subsequently Acuitas Therapeutics, which developed the MC3 LNP for Onpattro in collaboration with Alnylam Pharmaceuticals. The group also collaborated with Drew Weissman of the University of Pennsylvania on LNPs for mRNA vaccines, which lead to their use in mRNA COVID-19 vaccines.

To be a broad platform for the liver and beyond, LNPs must compete with several other delivery modalities, such as viral vectors and conjugates. In liver delivery, triantennary GalNAc-conjugated siRNAs, which target asialoglycoprotein receptors on hepatocytes, are now the delivery vehicle of choice for liver-targeted siRNAs. Apart from circulation lifetime, another issue that LNPs must contend with is organ accessibility due to fenestrations in blood vessels. In the case of the liver, pancreas, and bone marrow, pores are greater than 60 nm, allowing LNPs access to tissue. For mRNA vaccines, blood filtering lymph nodes also represent an excellent LNP target. However, tissues, such as brain (with its accompanying blood brain barrier), muscle and kidney have much tighter fenestrations (<15 nm), presenting an uphill delivery challenge for intravenous LNPs.

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The Needle Issue #3

13 May
Juan-Carlos-Lopez
Juan Carlos Lopez		 Andy-Marshall
Andy Marshall

A growing stable of biopharma companies are developing biparatopic antibodies, which hit the same target via two non-overlapping epitopes. Compared with monospecific mAbs, such antibodies display enhanced binding through increased avidity, slower target dissociation, improved internalization, and greater specificity against drug target families where members share significant structural similarity. Now in the Journal of Clinical Investigation, a group at the Broad led by William Sellers describes biparatopic mAbs that inhibit fibroblast growth factor receptor 2 fusions, which are found in a variety of cancers, including intrahepatic cholangiocarcinomas (ICCs).

Sellers and his team showed that their mAbs inhibit signaling through FGFR2 fusions and inhibit ICC proliferation. They generated a panel of 15 biparatopic antibodies from 6 parental human antibodies and systematically tested them for their anti-proliferative activity on cells expressing FGFR2 fusions. Two showed greater potency than the parental antibodies, both in vitro and in vivo. Moreover, these biparatopic antibodies potentiated the action of FGFR2 inhibitors on cancer cells, and their inhibitory effect persisted, even against FGFR2 fusions with mutations that drive drug resistance. Mechanistically, the biparatopic antibodies promoted internalization and lysosomal degradation of FGFR2 fusions.

Sellers is also a scientific founder of Cambridge, Mass-based RedRidge Bio, which was funded in March via an undisclosed Series A venture round. Another recent startup, Attovia, took its first VHH biparatopic nanobody program against IL-31 into the clinic earlier this year and is collaborating with SciNeuro Pharmaceuticals on a neurology target.

The FGFR2 fusion work follows in the footsteps of studies by Regeneron demonstrating that biparatopic antibodies are effective inhibitors of oncogenic fusions of other receptor tyrosine kinases (RTKs). In that work, Regeneron researchers targeted fusions of another FGFR family member, FGFR3. In theory, the approach should be generalizable to any cancer arising from RTK fusions.

Biparatopic antibodies can work either in cis (binding the same target twice) or trans (binding two different molecules of the same target; e.g., to facilitate receptor clustering). Although they have been in clinical testing since 2011, it took until 2022 for the first biparatopic product to reach the market. Nanjing, China-based Legend Biotech (now J&J) got FDA approval for a T-cell therapy against refractory multiple myeloma featuring a chimeric antigen receptor (CAR) based on two single-domain antibodies targeting two different epitopes on B-cell maturation antigen (BCMA). Last November, FDA also gave the green light to Jazz Pharmaceuticals and Zymeworks’s zanidatamab, a biparatopic mAb that binds HER2 in trans and is indicated for patients with HER2-positive biliary tract cancer.

Similar to the antibody drug conjugate (ADC) space, a commercial stampede is currently underway in China to develop biparatopic mAbs against HER2, with at least 4 companies (Xuanzhu Biopharm, Alphamab Oncology, Chia Tai Tianqing Pharmaceutical and Beijing Mabworks) with products in clinical development. Given that big pharma has yet to make major announcements around biparatopic mAbs—notwithstanding AstraZeneca’s/Medimmune’s discontinued effort to develop MEDI4276, an anti HER2 ADC based on a biparatopic scaffold— the recent co-development partnership deal between Pierre Fabre Laboratorie and RedRidge Bio likely augurs more deal activity around this antibody modality in the near future.

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The Quest for the Perfect Investor Fit: How Much Does Life Science Expertise Matter?

2 Oct

By Danielle Silva, Business Development, LSN

Here at LSN, I speak with many life science entrepreneurs about investor fit. Typically, life science executives believe that fit is a one-way street, meaning that they need to do all they can to prove they are a fit for a prospective investor. While it is certainly true that an integral part of the fundraising process is proving that your company is a fit for the firm’s investment thesis, this is not a one-sided negotiation. It is just as important for life science companies to make sure a potential investor is a fit for what the firm is looking to attain, and therefore, finding a potential investor needs to be both a strategic and tactical play.

What many life science CEOs struggle with is whether they should favor investors that have expertise in a particular area versus investors that are experienced in a certain phase of development. The answer, by and large, depends on what the life science company is looking to achieve in the long run, but there is of course no easy answer to this dilemma. Many entrepreneurs consider the problem a simple one – why would you want an investor that doesn’t understand your technology, or one who does not have expertise in your particular indication area?

While it is certainly important for investors to have a basic understanding of your disease area, this is only truly important if you are seeking scientific advisors for your firm. If this is the case, then finding a partner that has expertise in your disease area may be favorable to finding an investor that has knowledge of your stage of development. But what if, conversely, the executive is seeking a quick exit or a recapitalization? In this case, it may be more attractive to find an investor with a laser focus on your particular area. These investors already have a great knowledge of the space and thus probably already have a solid network that will be willing to acquire the company once the firm hits certain milestones.

Most life science executives I speak with, however, are not seeking scientific advisors, and instead are seeking investors with the business acumen to help take their product from discovery to distribution. These companies would benefit from a relationship with an investor that has knowledge of their particular phase of development, and who can thereby help to scale their business. It is also very beneficial for companies to be partnered with investors who have a deep knowledge of their phase of the clinical development cycle. These investors will have the expertise to help life science firms partner with appropriate firms in the R&D services space (such as CROs and other service providers).

Again, there is no clear solution to this problem. If your company is seeking an investor with a deep network in the space, then choosing an investor with sector expertise may be the answer. These investors, however, may not be able to help you scale your business to the point where your firm is an attractive investment or acquisition target for a larger investor within their network. Simply put, the answer is convoluted, no investor is the same, and everyone brings something different to the table. Life science executives should clearly define their goals in terms of growth and exit before deciding on an investor based on sector fit versus development phase fit.

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Creating a Dialogue with Life Science Investors

2 Oct

By Dennis Ford, CEO, LSN

I write about this subject often – I guess the main reason is that if I can get the message right, I can help educate life science fund-raisers that a current and accurate map does exist for raising capital. If you are in fundraising mode, please have an updated map. There, I said it!

The most interesting component of the fundraising dynamic is the concept of “introduction”. Scientist meets investor, buyer meets seller. One of the initial goals of any fundraising campaign is to get in front of potential investors, and this can be done in two general ways: the first being referral, and the second, fit. I will agree that a referral is often a good way to get a meeting, but many believe that it is the only way to get to a decent investor target.

Being a street-savy salesperson, I always get a bit riled when someone announces that referrals are the only way in. I mean, what if you get referred to an investor and he just simply doesn’t have a current mandate to invest, and if he did, it would be a medical device and you happen to be a therapeutic? My point here is that even though a referral may get you some preferential treatment in the form of a first meeting, there always needs to be a good fit. After all, it’s the final meeting that really counts. I am a big fan of the referral, but I am an even bigger fan of fit.

In my “sales guy mind,” the highest form of a qualified investor lead is a declared fit. A declared fit boils down to this: an investor actively declares a targeted and specific intent on investing in a certain part of the market. I think that is the highest form of investor target – self-declared mandate from the mouth of an potential investor. I mean, what else would a fundraiser want? OK, maybe I shouldn’t have asked that question… because I know the answer: a referred introduction, right?  No, wrong!

Of course, if you know someone who can provide an intro, that’s great. Sans that magical referral/intro, if you are a fit for the declared mandate, all you have to do is tell him via email or phone that you know what they are seeking and you are a fit. Honestly, that’s how it works. Spamming gets you a 1-2% hit rate, but reaching out based on fit gets you a 20-30% hit rate. Why? Because you match what the investor is looking for. Being armed with the knowledge of an investor’s current interest gives you the power to refer yourself.

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Phase I of the JOBS Act: Are you ready for the general solicitation revolution?

2 Oct

By Lucy Parkinson, Research Analyst, LSN

Back in April 2012, the JOBS act was passed with the aim of (the clue is in the name) Jumping Our Business Startups. The SEC has moved slowly on implementing the JOBS Act and is saving the most innovative provisions for a second phase of changes, but as of Monday, September 23rd, the long-standing ban on making general solicitations to accredited investors has been rescinded. This will have a huge effect on the institutional landscape of investing, as companies can now use mass public advertising to look for investors, rather than being restricted to using funds from family, friends, and private networks of accredited investors.

So does your start-up’s fundraising campaign have to change? Not necessarily, but you may reap great benefits by using the new regulations to your advantage and seeking for investors with a wider net than was previously possible. However, obeying the restrictions surrounding general solicitation is not as straightforward as you might think. As such, any company looking to raise capital would be advised to spend some time with their lawyer before sending out a mass solicitation; similar to the domain of intellectual property, we could see an influx of law firms seeking to partner with emerging biotech companies to guide them through the regulatory quagmire and maximize their visibility with investors.

While many life science companies could benefit from following the new path laid out for general solicitations, some may wish to eschew the added regulatory burdens and stick with the old model that, in addition to accredited investors, allows them to ask up to 35 unaccredited friends and family to contribute to each funding round. This doesn’t mean foregoing all the benefits of the law; the investment groups themselves will have more room to advertise for contributions under the new law, and that may lead to investors having more dry powder to invest – particularly to under-the-radar angel firms, who have previously found it hard to advertise to prospective investors. Building partnerships with these lesser-known investors will remain as important than ever.

Will general solicitation be worth the added costs? It could be, and this is especially true for life science companies. One thing LSN has observed frequently about emerging types of investors in the life science space is that more so than investors in other industries, they often have personal motives. Essentially, what we’re seeing is funding provided by angels, family offices and venture philanthropy funds looking for more than just ROI – the founders of these investment vehicles often want to make an impact on the world by targeting a particular disease that has affected their life or runs in their family. So, when we start to see general solicitations blaring from every billboard, TV set or web search, life science pitches will have a unique draw that other startup prospects lack because in this industry, general and personal come together.

This distinction will only become more valuable when phase two of the JOBS Act rolls out equity crowdfunding. For that, we’ll have to wait until next year.

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Hot Life Science Investor Mandate 1: Venture Philanthropy Seeks Early-Stage Companies for Several Allocations

2 Oct

A venture philanthropy group established in 2008 and based in the Eastern US makes equity and convertible note investments of approximately $1 million into companies seeking up to $5 million that are targeting cardiovascular and neurovascular diseases. The firm invests in privately held companies at both the seed and venture stage, and is planning on making 3-4 allocations over the next 12 months. The firm operates under an evergreen structure and is constantly seeking new investment opportunities.

The group is currently looking for companies in both the Biotech Therapeutic & Diagnostics and Medtech sectors. Within these sectors, the firm is opportunistic in terms of subsector, although they do have special interest in companies developing regenerative technologies. The firm’s main focus is on companies developing technologies for cardiovascular and neurovascular diseases – however, they will also consider investing in companies targeting diabetes and metabolic disorders. The firm looks to invest in companies with a product in preclinical or phase 1 of clinical trials for Biotech Therapeutics and Diagnostics, and companies with a product in development or prototype stages for Medtech.

As a venture philanthropy organization, the group is only willing to allocate to companies who have a clear impact on patient therapy and/or standard of care, an adequate level of IP protection, well-defined use of proceeds with quantifiable and achievable milestones, and a clear understanding of the next round of fundraising needs including how much and likely sources.

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Hot Life Science Investor Mandate 2: PE/VC Hybrid has High AUM, Wide Range of Interests

2 Oct

A private equity / venture capital firm which was founded in 1994 and is based in the Western US manages a total of 7 funds with a combined AUM of $2 billion. The typical investment size is anywhere from $5 – $10 million initially, and up to $20 million over the lifetime of the investment. The firm provides both equity investments and convertible notes to companies located all over the globe. They plan to make 2-3 investments over the next 6-9 months.

The firm is interested in companies in biotech therapeutics & diagnostics, medtech, and biotech R&D services. They are also interested in other organizations in the biotech space, such as agricultural biotechnology or industrial biotechnology. In terms of subsector and indication, the firm is entirely opportunistic; however, they are not interested in companies that do not have a viable proof-of-concept for their technology, and strongly prefer to invest in companies that have entered into clinical trials.

The group prefers to invest in experienced management teams, and generally provides a professional to serve on company’s board of directors, in addition to assisting with operational activities. The firm will consider all management teams on a case-by-case basis, and may consider rearranging the management team if necessary.

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