Forgotten Opportunities: Early Stage Biotech and Medtech Investment

Due to the uncertainty in the development, clinical testing, and regulatory approval of both biotech and medical technologies, which increasingly have to be viewed with the same competitive lens, investors have over the past few years shied away from seed stage or Series A stage company investment in favor of those nearer to market introduction. However, with the advent of a great number of new technologies and advances in the underlying science, there is enormous opportunity to identify companies and emerging sectors arising from these advances. The problem in identifying realistically promising companies is that it must be done so without falling prey to the bad investment practices in the past that ensued from a poor understanding of the technologies and their remaining commercial hurdles. Without careful consideration of remaining scientific development needed, the product’s target market, its competitors, and the sum total of the company’s capabilities to commercialize these technologies, investment in these areas will fall short of investment objectives or fail them outright.

While any of these considerations have the capacity to preempt a successful market introduction, a failure to understand the science behind the product and its remaining development hurdles to commercialization is likely to be the biggest cause of failure.

“We’ve already had one glaring example of a company, and its investors, learning the hard way that health and science advisors are important: Theranos.” (link)

Venture Capital has backed away from early stage investment

Earlier stage investment, with its higher risk, has higher potential reward, so there is a big need for more effective evaluation of potential early stage investments in order to (1) seize these opportunities that will otherwise potentially be lost with the shift to later stage fundings, (2) sort out those companies/technologies with overwhelming commercialization hurdles from those that will profitably tap an opportunity, and (3) gain the value of these opportunities before the innovation appreciates in value, driving up the price of the investment.

The Biotech Bubble

Biotech in the 1980s was enamored with companies pursuing “magic bullets” — technologies that had the potential to cure cancer or heart disease or other conditions with large, untapped or under-treated populations. With few exceptions, these all-in-one-basket efforts were only able achieve a measure of humility in the VCs who had poured volumes of money into them.

Here was evidenced a fundamental problem with biotech at a time when true scientific milestones were being reached, including successes in mapping the human genome: Landmark scientific milestones do not equate with commercial success.

As a result, money fled from biotech as few products could make it to market due to persistent development and FDA hurdles. By the late 1980s, many biotechs saw three quarters of their value disappear.

A Renewed Bubble?

The status of biomedical science and technology, with multiple synergistic developments, will lead to wild speculation and investment, potentially leading to yet another investment bubble. However, there will be advances that can point to real timelines for market introduction that will support investment.

Recent advances, developments and trends supporting emerging therapeutics

  1. Stem cells. A double-edged sword in that these do represent some the biggest therapeutics that will emerge, yet caution is advised since the mechanisms to control stem cells are not always sufficient to prevent their nasty tendency to become carcinogenic.
  2. Drug discovery models, such as using human “organoids” and other cell-based models to test or screen new drugs.
  3. Systems to accelerate the rapid evaluation of hundreds, perhaps, thousands of potential drugs before moving to animal models or preclinicals.
    1. Machine-learning algorithms
    2. Cell/tissue/organ models
    3. Meta-analysis, the practice of analyzing multiple, independently produced clinical data to draw conclusions from the broader dataset.
  4. Cross-discipline science
    1. cell biologists, immunologists, molecular biologists and others have a better understanding of pathology and therapeutics as a result of information sharing; plus BIG DATA (e.g., as part of the “Cancer Moonshot”). Thought leaders have called for collection and harnessing of patient data on a large scale and centralized for use in evaluating treatments for specific patients and cancer types.
    2. Artificial intelligence applied to diagnosis and prescribed therapeutics (e.g., IBM Watson).
    3. Examples of resulting therapies, at a minimum, include multimodal treatment – e.g., radiotherapy and immunotherapy – but more often may be represented in considerably more backend research and testing to identify and develop products with greater specificity, greater efficacy, and lowered risk of complications.
  5. Materials science developments, selected examples:
    1. Scaffolds in tissue engineering
    2. Microgels
    3. Graphene
    4. Polyhedral boranes
    5. Nanometric imprinting on fiber
    6. Knitted muscles to provide power link
    7. 3-D printed skin and more complex organs to come
    8. Orthopedic scaffolds made from electrospun nanofibers
  6. CAR-T (chimeric antigen receptor T cell therapy)
  7. CRISPR/Cas-9. Gene editing
    1. Removal, insertion of individual genes responsible for disease
    2. Potential use for creating chimeras of human and other (e.g., pig) species in order to, for example, use pigs for growing human organs for transplant.
  8. Smart devices: smart biopsy needles, surgical probes to detect cancer margins, artificial pancreas. Devices using information

 

We sum this up with these prerequisites for investment:

Prerequisites for Early Stage Med/Bio Investment

  1. A fully understood and managed gap between scientific advance and commercial reality.
    1. Investment must be tied to specific steps (prototyping, preclinicals, clinicals, physician training, etc.).
  2. A management team qualified in commercializing medtech or biotech products.
    1. CEOs (and/or Chief Medical Officers, Chief Scientific Officers) with medical science backgrounds (MD, PhD) favored over CPAs or even JDs.
  3. Reimbursement strategy pursued as something more than an afterthought
  4. Technology development in sync with end-user acceptance and training to leverage the benefits:
    1. Easier to use
    2. Fewer complications
    3. Attractive physician revenue streams
  5. Broad competitive advantage pursued:
    1. Product benefits must stand up against all competition, irrespective of technology type (devices competing with drugs, biotech).
    2. Benefits of reducing the cost of care for an existing patient population are paramount.
    3. Competitive advantage must consider the trend in technology development to avoid being disrupted by other products soon to reach the market.
  6. Predefined exit strategy; selected examples:
    1. Positioning to add innovation to a mid-cap or large-cap medtech or biotech as acquirers.
    2. Development of platform technologies for licensing or sale.
    3. IPO

 

Future investments are likely to track the historical focus on specific diseases and conditions:

Source: MedMarket Diligence, LLC and Emerging Therapeutic Company Investment and Deal Trends; Biotechnology Innovation Organization.


MedMarket Diligence, mediligence.com, tracks medical and biotechnology development to provide meaningful insights for manufacturers, investors, and other stakeholders.

Peripheral Stenting Procedures and Markets

First introduced about two decades ago as a bailout technique for suboptimal or failed iliac angioplasty, peripheral vascular stenting gradually emerged as a valuable and versatile tool for a variety of primary and adjuvant applications outside the domain of coronary and cerebral vasculature.  Today, peripheral vascular stenting techniques are commonly employed in the management of the most prevalent occlusive circulatory disorders and other pathologies affecting the abdominal and thoracic aortic tree and lower extremity arterial bed. Stents are also increasingly used in the management of the debilitating conditions like venous outflow obstruction associated with deep venous thrombosis and chronic venous insufficiency.

Notwithstanding a relative maturity of the core technology platforms and somewhat problematic opportunities for conversion to value-adding peripheral drug-eluting systems, peripheral vascular stenting appears to have a significant room for qualitative and quantitative growth both in established and emerging peripheral indications.

Source: MedMarket Diligence, LLC; “Global Market Opportunities in Peripheral Arterial and Venous Stents, Forecast to 2020.” Report #V201. Order online.

 

The best medtech investment opportunities

In reviewing patents, fundings, technology development trends, market development, and other hard data sources, we feel these are some of the strongest areas for investment in not only the medical device side of medtech, but also the broader biomedical technology arena:

  • Materials technologies
    • graphene
    • bioresorbables
    • biosensors
    • polymers
    • bioadhesives
  • Cell therapy and tissue engineering
    • cell-based treatments (diabetes, spinal cord injury, traumatic brain injury)
    • extracellular matrices in soft tissue repair and regeneration
  • Nanotechnology (subject of forthcoming report)
    • nano coatings
    • nano- and micromedical technologies for localized drug delivery
    • nanoparticles
  • 3D printing
    • prototype development
    • patient-specific implants
  • Minimally- and non-invasive technologies
    • transcatheter alternatives to surgery
    • NOTES (natural orifice transluminal endoscopic surgery)
  • Diabetes non-invasive glucose testing
  • Intraoperative surgical guidance
    • Cancer probes (e.g., fluorescent or optical coherence tomography, frozen section, cytologic imprint analysis, ultrasound, micro-computed tomography, near-infrared imaging, and spectroscopy)
  • neurostimulation and neuromodulation
  • point-of-care diagnostics
  • point-of-care imaging
  • AI-enhanced devices

In addition, there are many areas in healthcare in which there is much untapped demand with problems that, so far, seem to have eluded medtech solutions. These include infection control (Zika, MRSA, TB, nosocomial infections, etc.), chronic wound treatment (including decubitus/stasis/diabetic ulcers), type 2 diabetes and obesity.

 

Wound Hemostasis, Closure, and Sealing in the U.S. versus Asia/Pacific, 2015-2022

Sales of sealants, glues, and hemostats projected to 2022 for the U.S. and Asia/Pacific. While these products have had tremendous success in Japan, their sales in the rest of Asia/Pacific have not yet caught up to Japan, let alone to the U.S.

But that is expected to change as the most significant growth in these markets will indeed be coming from China, Korea, Australia, India, and elsewhere in these emerging markets.

Sales of Sealants, Glues, and Hemostats in the
U.S. and Asia/Pacific Markets, 2015-2022

Note: For direct comparative purposes, sales in these markets are shown on the same vertical scale.

Source: MedMarket Diligence, LLC; Report #S290. Available for purchase/download online.

Coronary revascularization options evolve

The number of options that are in use or development for coronary revascularization or other treatment for ischemic heart disease is extraordinary. Given the mortality associated with coronary artery disease, it is unsurprising that it has been the focus of so much development.

Below are the options that have evolved for treatment of ischemic heart disease, inclusive of surgical, interventional, and other medical approaches.

Coronary Revascularization and Other
Ischemic Heart Treatment Options

Source: MedMarket Diligence, LLC

See also “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022”, report #C500. Order online.

Peripheral Stenting Worldwide: Arterial, Venous, BMS, DES, AAA, TAA

First introduced about two decades ago as a bailout technique for suboptimal or failed iliac angioplasty, peripheral vascular stenting gradually emerged as a valuable and versatile tool for a variety of primary and adjuvant applications outside the domain of coronary and cerebral vasculature.  Today, peripheral vascular stenting techniques are commonly employed in the management of the most prevalent occlusive circulatory disorders and other pathologies affecting the abdominal and thoracic aortic tree and lower extremity arterial bed. Stents are also increasingly used in the management of the debilitating conditions like venous outflow obstruction associated with deep venous thrombosis and chronic venous insufficiency.

Notwithstanding a relative maturity of the core technology platforms and somewhat problematic opportunities for conversion to value-adding peripheral drug-eluting systems, peripheral vascular stenting appears to have a significant room for qualitative and quantitative growth both in established and emerging peripheral indications.

A panoply of stenting systems are available for the management of occlusive disorders and other pathologies affecting peripheral arterial and venous vasculature. Systems include lower extremity bare metal and drug-eluting stents for treatment of symptomatic PAD and critical limb ischemia resulting from iliac, femoropopliteal and infrapopliteal occlusive disease; stent-grafting devices used in endovascular repair of abdominal and thoracic aortic aneurysms; as well as a subset of indication-specific and multipurpose peripheral stents used in recanalization of iliofemoral and iliocaval occlusions resulting in CVI.

In 2015, these peripheral stenting systems were employed in approximately 1.565 million revascularization procedures worldwide, of which the lower extremity arterial stenting accounted for almost 1.252 million interventions (or 80.9%), followed by AAA and TAA endovascular repairs with 162.4 thousand interventions (or 10.5%) and peripheral venous stenting used in an estimated 132.6 thousand patients (or 8.6% of the total).

The U.S. clinical practices performed almost 528 thousand covered peripheral arterial and venous procedures (or 34.1% of the worldwide total), followed by the largest Western European states with over 511 thousand interventions (or 33.1%), major Asian-Pacific states with close to 377 thousand interventions (or 24.4%), and the rest-of-the-world with about 131 thousand peripheral stent-based interventions (or 8.4%).

Below is illustrated the global market for peripheral stenting by region in 2016 and by segment from 2014 to 2020.

Source: MedMarket Diligence, LLC; Report #V201. Available online.

 

Source: MedMarket Diligence, LLC; Report #V201. Available online.

Technologies at Medtech Startups, December 2016

Below is a list of technologies under development at startups identified thus far in December 2016 and included in the Medtech Startups Database:

  • Nanoparticle-based imaging for the treatment of epilepsy.
  • Implantable device for continuous relief of congestive heart failure.
  • Nanofiber technology for soft tissue repair.
  • Technology to facilitate intubation.
  • Medical device to manage skin complications suffered by ileostomy patients.
  • An implant for arthritis sufferers that mimics the natural motions of the joint.
  • Embolic protection device used during TAVR procedures.
  • Glucose monitor for diabetes using low-power RF/Microwave detection in fingertips.
  • Novel disinfection and sterilization solutions.
  • Drug delivery.
  • Dental and orthopedic applications of nanomaterials.
  • Catheter and guidewire technologies.

For a comprehensive list of the technologies at medtech startups identified by month, see link.

Cardiovascular Surgical and Interventional Procedures Worldwide, 2015-2022

In 2016, the cumulative worldwide volume of the the following CVD procedures is projected to approach 15.05 million surgical and transcatheter interventions:

  • roughly 4.73 million coronary revascularization procedures via CABG and PCI (or about 31.4% of the total),
  • close to 4 million percutaneous and surgical peripheral artery revascularization procedures (or 26.5% of the total);
  • about 2.12 million cardiac rhythm management procedures via implantable pulse generator placement and arrhythmia ablation (or 14.1% of the total);
  • over 1.65 million CVI, DVT, and PE targeting venous interventions (representing 11.0% of the total);
  • more than 992 thousand surgical and transcatheter heart defect repairs and valvular interventions (or 6.6% of the total);
  • close to 931 thousand acute stroke prophylaxis and treatment procedures (contributing 6.2% of the total);
  • over 374 thousand abdominal and thoracic aortic aneurysm endovascular and surgical repairs (or 2.5% of the total); and
  • almost 254 thousand placements of temporary and permanent mechanical cardiac support devices in bridge to recovery, bridge to transplant, and destination therapy indications (accounting for about 1.7% of total procedure volume).

screen-shot-2016-11-07-at-7-26-38-am

CABG: Coronary artery bypass graft; PCI: Percutaneous coronary intervention; AAA: Abdominal aortic aneurysm; TAA: Thoracic abdominal aneurysm; CVI: Chronic venous insufficiency; DVT: Deep vein thrombosis; PE: Pulmonary embolectomy.

Source: MedMarket Diligence, LLC; Report #C500, “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022.” (To request report excerpts, click here.)

The Evolution of Coronary Revascularization Markets

Coronary artery bypass grafting (CABG) is the most common type of cardiovascular surgical intervention, which “bypasses” acute or chronic coronary artery obstructions via a newly created vascular conduit and thus reinstate normal or sufficient blood flow to the ischemic but still viable areas of the myocardium.

The majority of CABG surgeries (up to 75%) are still performed on the fully arrested heart which is accessed via a foot-long incision over the sternum and completely separated patient’s rib cage. Following a full sternotomy, the CABG patient is typically placed on extracorporeal cardiopulmonary bypass (CPB) with a heart-lung machine, which allows the surgeon to operate on a still and bloodless field. Simultaneously, the patient’s greater saphenous vein or internal mammary artery, or both are harvested (mobilized) for use as a bypass conduit in the ongoing procedure. Depending on the location, character and number of the coronary artery occlusions, the surgery might involve between one and seven coronary bypasses.

Once the bypasses are completed, the heart is restarted and, if it functions normally, the patient is removed from the heart-lung machine and the chest is closed up, the sternum is stabilized with stainless steel wire, and the chest and leg wounds are closed with sutures or clips. Patient’s recovery from a routine uncomplicated CABG usually involves seven to ten days of hospital stay, including two to three days spent in the cardiac intensive care unit.

Less Invasive CABG

Over the past decade, several less-invasive versions of the CABG were developed with the view of reducing morbidity and potentially serious complications associated with extensive surgical trauma and the use of aortic clamping and CPB. The current arsenal of less-invasive coronary artery bypass techniques includes minimally-invasive direct CABG (MIDCAB), full-sternotomy “off-pump” CABG (OPCAB), port-access CABG (P-CAB) with peripheral cannulation and endoclamping of aorta, and endoscopic computer (robotics)-assisted CABG (C-CAB).

Designed to limit surgical trauma of conventional CABG, the MIDCAB procedure is best suited for patients with occluding lesions either in the left anterior descending (LAD) artery, or the right coronary artery (RCA). In contrast to conventional CABG, it is performed on a beating heart without the use of CPB. In MIDCAB surgery, access to targeted arteries is achieved through a limited left anterior thoracotomy in the case of occluded LAD, and right thoracotomy or limited lateral thoracotomy in cases involving diseased proximal RCA or circumflex artery. Because of the smaller surgical trauma and off-pump performance (without aorta clamping), the MIDCAB procedure typically results in fewer complications, lower morbidity and shorter hospital stays compared to conventional CABG. However, its utility is limited to a subset of patients with one or two coronary vascular targets, which constitute a small fraction (<3%) of the total caseloads referred for CABG.

The OPCAB procedure is performed on a beating heart after reduction of cardiac motion with a variety of pharmacological and mechanical devices. These include slowing the heart rate with ß-blockers and calcium channel blockers and the use of special mechanical devices intended to stabilize the myocardium and mobilize target vessels. The use of various retraction techniques allows to gain access to vessels on the lateral and inferior surfaces of the heart. Because the OPCAB technique also involves surgical access via median sternotomy, its primary benefit is the avoidance of complications resulting from the use of cardiopulmonary bypass, not surgical trauma.

Over the past decade, the OPCAB surgery emerged as the most popular form of less-invasive coronary artery bypass procedures in the U.S, and Western Europe. By the beginning of this decade, an estimated 25% of all CABGs performed in these geographies were done without the use of CPB. However, in recent years, the relative usage of OPCAB techniques remained largely unchanged. In the view of many cardiac surgeons, the latter was predicated by the increasing morphological complexity of cases referred for CABG (rather than PCI) and generally superior immediate and longer-term bypass graft patency and patient outcomes obtainable with technically less-demanding on-pump CABG surgery.

In contrast to that, the relative usage of “neurological complications sparing” OPCAB techniques is significantly higher in major Asia-Pacific states reaching over 60% of all CABG procedures in China, India, and Japan.

The rarely used P-CAB procedure involves the use of cardiopulmonary bypass and cardioplegia of a globally arrested heart. Vascular access for CPB is achieved via the femoral artery and vein. Compared to the MIDCAB technique, the use of multiple ports allow access to different areas of the heart, thus facilitating more complete revascularization, and the motionless heart may allow a more accurate and reliable anastomosis. In distinction from conventional CABG, median sternotomy is avoided, which reduces trauma and complications. However, potential morbidity of the port-access operation includes multiple wounds at port sites, the limited thoracotomy, and the groin dissection for femoral-femoral bypass. The procedure is also technically difficult and time consuming and therefore has not achieved widespread popularity.

The Hybrid CABG-PCI procedure combines the use of surgical bypass (typically MIDCAB) and percutaneous coronary interventional techniques (angioplasty and stenting) for optimal management of multi-vessel coronary occlusions in high risk patients. The main rationale behind the utilization of hybrid procedure is to achieve maximally possible myocardial revascularization with minimally possible trauma and reduced probability of post-procedural complications. The most common variation of the hybrid revascularization involves MIDCAB-based radial anastomosis between the left anterior descending artery and left internal thoracic artery accompanied by the PTCA/stenting-based recanalization of less critical coronary artery occlusions.

CABG Utilization Trends and Procedure Volumes

Since the advent of coronary angioplasty in the late 1970s, the relative role and share of CABG procedures in myocardial revascularization have been steadily declining due to a continuing penetration of treated patient caseloads by a less invasive PTCA. This general trend was further expedited by the advent of coronary stents. At the very end of the past decade, the rate of transition towards percutaneous coronary interventions in myocardial revascularization started tapering off, primarily due to growing maturity of PTCA/stenting technology and nearly full coverage of patient caseloads with one- or uncomplicated two-vessel disease amendable through angioplasty and stenting. At the same time, a growing popularity of the less-invasive CABG regimens resulted in some additional influx into CABG caseloads from a no-option patient cohort. A less-invasive surgical coronary bypass also emerged as a preferred treatment option for some gray-area patients that were previously referred for sub-optimal PTCA and stenting to avoid potential complications of conventional CABG.

In 2006 – for the first time in about two decades – the U.S. and European volumes of CABG procedures experienced a visible increase, which was repeated in 2007 and reproduced on a smaller and diminishing scale in the following two years.

The cited unexpected reversal of a long established downward procedural trend reflected an acute (and, probably, somewhat overblown) end-users’ concern about long-term safety (AMI-prone late thrombosis) of drug-eluting stents (DES), which prompted a steep decline in utilization of DES in 2006, 2007, followed by a smaller and tapering decreases in 2008 and 2009 with corresponding migration of advanced CHD patients referred for radical intervention to bare metal stenting and CABG surgery.

In 2010 – 2015 the volume of CABG surgeries remained relatively unchanged, notwithstanding a visible decline in percutaneous coronary interventions and overall myocardial revascularization procedures.

In the forthcoming years, the cumulative global volume of CABG procedures is unlikely to experience any significant changes, while their relative share in coronary revascularization can be expected to decline from about 15.4% in 2015 to roughly 12.3% by the end of the forecast period (2022). The cited assertion is based on the expectation of eventual stabilization and renewal of nominal growth in utilization of PCI in the U.S. and Europe coupled with continuation of robust expansion in the usage of percutaneous revascularization techniques in Asia-Pacific (especially India and China, where PCI volumes were growing by 20% and 10% annually over the past half decade, according to local healthcare authorities).

In 2016, the worldwide volume of CABG surgeries leveled at approximately 702.5 thousand procedures, of which roughly 35.2% involved the use of less-invasive OPCAB techniques. During the forecast period, the global number of CABG procedures is projected to experience a nominal 0.1% average annual increase to about 705.9 corresponding surgical interventions in the year 2022. Within the same time frame, the relative share of less-invasive bypass surgeries is expected to register modest gains expanding to approximately 36.7% of the total in 2022.

Coronary Revascularization Procedures, 2015-2022 
(Figures in thousands)

screen-shot-2016-11-02-at-11-17-58-am
CABG and Primary PCI in Coronary Revascularization to 2022.

In, “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022”, Report #C500, we forecast cardiovascular procedure utilization, caseload, technology trends, and device market impacts, for the U.S., Western Europe, Asia/Pacific, and Rest of World.

Medical, Surgical Sealants — Fibrin and Others

screen-shot-2016-10-26-at-2-23-29-pmFibrin is the result of the combination of solutions of thrombin and fibrinogen. This forms a clot just as in the body during the coagulation cascade. The thrombin then breaks the fibrinogen molecules into smaller bits of another blood protein, called fibrin. Fibrin molecules arrange themselves into a lattice with strands cross-linked by the blood component, Factor XIII. This resulting cross-linked net helps to stabilize the clot.

Numerous variants of fibrin sealant exist, including autologous products. Other, non-fibrin sealant types are thrombin, collagen & gelatin-based sealants.

Fibrin sealants are used in the US in a wide array of applications; they are used the most in orthopedic surgeries, where the penetration rate is thought to be 25-30%. Fibrin sealants can, however, be ineffective under wet surgical conditions. The penetration rate in other surgeries is estimated to be about 10-15%.

Fibrin-based sealants were originally made with bovine components. These components were judged to increase the risk of developing bovine spongiform encephalopathy (BSE), so second-generation commercial fibrin sealants (CSF) avoided bovine-derived materials. The antifibrinolytic tranexamic acid (TXA) was used instead of bovine aprotinin. Later, the TXA was removed, again due to safety issues. Today, Ethicon’s (JNJ) Evicel is an example of this product, which Ethicon says is the only all human, aprotinin free, fibrin sealant indicated for general hemostasis. Market growth in the sealants sector is driven by the need for improved biocompatibility and stronger sealing ability—in other words, meeting the still-unsatisfied needs of physician end-users.

The current market penetration of sealant products in the US stands at about 25% of eligible surgeries, with their largest volume of use in orthopedics.

Selected Fibrin and Other Sealant Types*

screen-shot-2016-10-26-at-2-10-21-pm

*Market status on each detailed in report S290.

Source: MedMarket Diligence, LLC; Sealants, Glues, Hemostats to 2022.